Mannuronate, guluronic acid, and glumannuronic acid topical gel or cream and method for producing same

Abstract

The present invention relates to a topical gel or cream formulation containing β-D-mannuronic acid, α-L-guluronic acid, 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, α-L-guluronic acid, or the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts is 0.5 g to 40 g per 100 g of the gel or cream formulation, and further containing caffeic acid. The present invention also relates to a topical gel or cream formulation for use in a method for treating inflammation and / or any inflammatory response and / or pain, and to a method for producing the gel or cream formulation.

Description

[Technical Field]

[0001] The present invention relates to a topical gel or cream formulation containing β-D-mannuronic acid, α-L-guluronic acid, 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, α-L-guluronic acid, or the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts is 0.5 g to 40 g per 100 g of the gel or cream formulation, and further containing caffeic acid. The present invention also relates to a topical gel or cream formulation for use in a method for treating inflammation and / or any inflammatory response and / or pain, and to a method for producing the gel or cream formulation. [Background technology]

[0002] Mannuronic acid and guluronic acid are naturally occurring uronic acids isolated and purified from various forms of alginates (polymers used as thickeners, binders, gelling agents, or lubricants). Alginates may originate from brown algae (e.g., brown algae and kelp) and / or bacteria belonging to the genera Pseudomonas and Azotobacter. The properties of alginates vary depending on their species of origin. Alginates exist 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.

[0007] Topical formulations in the form of gels or creams are known to be used for a variety of medications, and their therapeutic efficacy has been demonstrated. However, many patients have responded poorly to conventional treatments with existing topical gels or creams (e.g., painkillers and anti-inflammatory drugs containing diclofenac or piroxicam as active ingredients). Therefore, there is a need to provide alternative or improved topical formulations with painkilling and / or anti-inflammatory properties. Summary of the Invention [Problem to be solved by the invention]

[0008] Surprisingly, we have found that β-D-mannuronic acid or α-L-guluronic acid, their oligomers or 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 topically in a gel or cream formulation, for example as a topical anti-inflammatory gel or cream formulation or as a topical analgesic gel or cream formulation. [Means for solving the problem]

[0009] 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. A topical gel or cream formulation 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 0.5 g to 40 g per 100 g of the gel or cream formulation; The gel or cream preparation further comprises caffeic acid or a salt thereof, for example, powdered caffeic acid or a salt thereof, and the content of caffeic acid or a salt thereof relative to the total weight of the gel or cream preparation 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, for example, 0.1% by weight to 0.3% by weight.

[0010] In various embodiments, (i) the β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is a β-D-mannuronate, 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, 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.

[0011] 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 their pharmaceutically acceptable salts are mixed and are 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 / or 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).

[0012] In various embodiments, the total amount of the following ingredients in the gel or cream formulation is 0.5g to 35g / 100g of gel or cream, preferably 1g to 30g / 100g of gel or cream, more preferably 5g to 20g / 100g of gel or cream, and most preferably 5g to 10g / 100g of gel or cream. (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.

[0013] In various embodiments, the gel or cream formulation may further comprise at least one additional agent described herein and / or at least one additional ingredient described herein.

[0014] Preferably, the gel or cream formulation is an anti-inflammatory topical formulation as described herein. In another embodiment, the gel or cream formulation is an analgesic topical gel or cream formulation as described herein.

[0015] In a second aspect, the gel or cream formulation of the invention is for topical use in a method for treating (or preventing) the following conditions: (i) inflammation and / or any inflammatory response, preferably inflammation of the joints and / or muscles and / or any inflammatory response; and / or (ii) Pain, preferably joint and / or muscle pain.

[0016] In a third aspect, the present invention relates to a method of making a gel or cream formulation as described herein. Preferably, the gel or cream formulation may be an anti-inflammatory topical gel or cream formulation as described herein, or an analgesic topical gel or cream formulation as described herein.

[0017] In various embodiments, the method comprises producing a gel formulation, the method comprising: (i) providing a (first) solution comprising at least one gel-forming substance and optionally at least one preservative; (ii) providing a (second) solution, said (second) solution comprising: (a) containing β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably β-D-mannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, per 100 g of the gel formulation; or (b) a total amount of α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably α-L-guluronic acid salt, in a range of 0.5 g to 40 g, preferably 5 g to 10 g, per 100 g of the gel formulation; or (c) containing a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, per 100 g of the gel formulation; (iii) optionally providing at least one additional solution; (iv) optionally adjusting the pH of the second solution to pH 1-5, preferably 2-4, more preferably 3; (v) mixing the solutions of step i) and step ii) and optional step iii); and (vi) optionally adjusting the pH to 4 to 8, more preferably 5 to 7, most preferably 5.5 to 6.5; Preferably, the method is such that caffeic acid or a salt thereof, for example powdered caffeic acid or a salt thereof, is contained in at least one of the first solution in step i), the second solution in step ii), and the at least one additional solution in optional step iii), so that the total amount of caffeic acid in the gel formulation is 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 %, relative to the total weight of the gel formulation.

[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. Thus, for example, "at least one preservative" means that there can be one type of preservative or two or more different types of preservatives. For dosage, the term refers to the total amount of such species. For example, in the case of preservatives, this means that the given dosage is the total amount of all preservatives in the composition / formulation. As used herein, the singular forms "a," "an," and "the" include the plural reference unless otherwise specified. Thus, 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.

[0020] 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%.

[0021] The term "about" in reference to a numerical value refers to a variation of ±10%, preferably ±5%, from the stated numerical value.

[0022] 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.

[0023] 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.

[0024] Hereinafter, the term "gel or cream formulation" is used to describe a topical gel or cream formulation, preferably a topical anti-inflammatory and / or topical analgesic gel formulation. The terms "gel" and "gel formulation" and "cream" and "cream formulation" are intended to encompass all viscous formulation types commonly used in the art, including pastes, ointments, and lotions.

[0025] In the context of the present invention, a "cream formulation" may be a two-phase (semi-solid) dosage form (emulsion) that contains an aqueous phase in addition to a lipid phase. In various embodiments, the cream may be a hydrophilic cream or a lipophilic cream.

[0026] In the context of the present invention, a "gel formulation" may be a (semi-solid) microdispersion system having at least two liquid phases, or at least one liquid phase and at least one solid phase, the continuous phase of which preferably contains a gel-forming substance. Suitable gel formulations include, but are not limited to, aqueous gels and alcoholic gels. In the present invention, aqueous gel formulations are particularly preferred.

[0027] Viscosity can be measured by various means, including a kinematic viscometer, a capillary viscometer, a rotational rheometer, a microfluidic rheometer, and a non-contact rheometer. Unless otherwise specified, all viscosities referred to herein are measured by a rotational rheometer. Preferably, the viscosity of the formulations of the present invention is 0.85 Pa·s to 35 Pa·s, preferably 1 Pa·s to 10 Pa·s, more preferably 2.5 Pa·s to 4 Pa·s, more preferably 3 Pa·s to 3.7 Pa·s, and most preferably 3.1 Pa·s to 3.35 Pa·s, measured at 25°C using a laboratory digital Brookfield viscometer (rotational viscometer). In various embodiments, the viscosity is measured by the steady flow method (0.1 to 100 s -1 The flow characteristics of the formulation were determined by the following method: -1 ), Medium (20.0s -1 ) and high (75.0s -1 In a preferred embodiment, the shear rate (shear viscosity value) of the gel is 75.0 to 85.0 s -1 The shear rate of the cream is 60.0 to 70.0 s -1 In particular, the viscosity of the formulation of the present invention is 0.85 Pa·s to 35 Pa·s, preferably 1 Pa·s to 10 Pa·s, more preferably 2.5 Pa·s to 4 Pa·s, more preferably 3 Pa·s to 3.7 Pa·s, and most preferably 3.1 Pa·s to 3.35 Pa·s, and is measured at 25°C and a gel shear rate of 75.0 s using a laboratory digital Brookfield viscometer. -1 ~85.0s -1 , the shear rate of the cream is 60.0 s -1 ~70.0s -1 It is measured in

[0028] β-D-mannuronic acid has the following formula (I):

[0029] [ka] β-D-mannuronic acid ( 4 C1) (I)

[0030] α-L-guluronic acid has the following formula (II):

[0031] [ka] α-L-guluronic acid ( 1 C4) (II)

[0032] Because mannuronic acid and guluronic acid are epimers, they share many physicochemical and biological / pharmaceutical properties, e.g., as anti-inflammatory agents with immunosuppressive and immunomodulatory activity. 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.

[0033] According to the present invention, β-D-mannuronic acid or α-L-guluronic acid or a mixture thereof may be included in a gel or cream formulation 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 the group consisting of sodium, potassium, magnesium, calcium, ammonium, and other pharmaceutically acceptable countercations.

[0034] Thus, in various embodiments, the topical gel or cream formulation comprises: (i) a mannuronate gel or cream formulation; or (ii) a guluronic acid salt gel or cream formulation; or (iii) Glumannuronate gel or cream preparation may be.

[0035] In various embodiments, the gel or cream formulation containing β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is a mannuronate gel or cream formulation. 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.

[0036] In various embodiments, β-D-mannuronic acid, preferably β-D-mannuronate, can also be added to the gel or cream formulation 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.

[0037] 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.

[0038] In various embodiments, the gel or cream formulation containing α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is a guluronic acid salt gel or cream formulation. 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.

[0039] In various embodiments, α-L-guluronic acid, preferably α-L-guluronic acid salt, can also be added to the gel or cream formulation as a precursor, said precursor being 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.

[0040] 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.

[0041] In various embodiments, the gel or cream formulation containing a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof is a glumannuronate gel or cream formulation. 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, 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, 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, and combinations thereof, and particularly preferably a mixture of sodium β-D-mannuronate and sodium α-L-guluronic acid.

[0042] In various embodiments, a mixture of β-D-mannuronic acid and α-L-guluronic acid, preferably glumannuronate, can also be added to the gel or cream formulation as a precursor, said precursor being 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.

[0043] 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.

[0044] 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.

[0045] 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 gel or cream formulations as an alginate hydrolysate (preferably alginate hydrolysate powder, also referred to as glumannuronate). In particular, alginate hydrolysate (glumannuronate) is a separated precipitate of sodium alginate containing mannuronic acid / mannuronate and guluronic acid / guluronic acid. Thus, in various embodiments, the gel or cream formulation comprises alginate hydrolysate (glucanuronate) at a concentration described herein, preferably between 0.5g and 40g / 100g of gel or cream, more preferably between 0.5g and 35g / 100g of gel or cream, more preferably between 1g and 30g / 100g of gel or cream, more preferably between 5g and 20g / 100g of gel or cream, more preferably between 5g and 15g / 100g of gel or cream, and most preferably between 5g and 10g / 100g of gel or cream.

[0046] 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 oligomers, or pharmaceutically acceptable salts thereof (especially β-D-mannuronate) (powder) with α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof (especially α-L-guluronic acid) (powder); or (2) Alginate hydrolysate (powder).

[0047] In various embodiments, the total amount of the following ingredients in the gel or cream formulation is 0.5g to 35g / 100g of gel or cream, preferably 1g to 30g / 100g of gel or cream, more preferably 2g to 20g / 100g of gel or cream, more preferably 5g to 20g / 100g of gel or cream, for example 5g / 100g of gel or cream, 10g / 100g of gel or cream, 15g / 100g of gel or cream or 20g / 100g of gel or cream, more preferably 5g to 15g / 100g of gel or cream, and most preferably 5g to 10g / 100g of gel or cream. (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 or α-L-guluronic acid, their oligomers or pharmaceutically acceptable salts thereof.

[0048] In one embodiment, the total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof in a gel or cream formulation, preferably a mannuronate gel or cream formulation, is 0.5 g to 40 g / 100 g of gel or cream, preferably 0.5 g to 35 g / 100 g of gel or cream, more preferably 1 g to 30 g / 100 g of gel or cream, more preferably 2 g to 20 g / 100 g of gel or cream, more preferably 5 g to 20 g / 100 g of gel or cream, for example, 5 g / 100 g gel or cream, 10 g / 100 g gel or cream, 15 g / 100 g gel or cream, or 20 g / 100 g gel or cream, more preferably 5 g to 15 g / 100 g gel or cream, and most preferably 5 g to 10 g / 100 g of gel or cream.

[0049] In another embodiment, the total amount of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof in the gel or cream formulation, preferably the guluronic acid salt gel or cream formulation, is 0.5g to 40g / 100g of gel or cream, preferably 0.5g to 35g / 100g of gel or cream, more preferably 1g to 30g / 100g of gel or cream, more preferably 2g to 20g / 100g of gel or cream, more preferably 5g to 20g / 100g of gel or cream, for example 5g / 100g gel or cream, 10g / 100g gel or cream, 15g / 100g gel or cream, or 20g / 100g gel or cream, more preferably 5g to 15g / 100g gel or cream, and most preferably 5g to 10g / 100g of gel or cream.

[0050] In another embodiment, in a gel or cream formulation, preferably in a glumannuronate gel or cream formulation, the total amount of the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers or their pharmaceutically acceptable salts is 0.5g to 40g / 100g of gel or cream, preferably 0.5g to 35g / 100g of gel or cream, more preferably 1g to 30g / 100g of gel or cream, more preferably 2g to 20g / 100g of gel or cream, more preferably 5g to 20g / 100g of gel or cream, for example 5g / 100g gel or cream, 10g / 100g gel or cream, 15g / 100g gel or cream or 20g / 100g gel or cream, more preferably 5g to 15g / 100g gel or cream, and most preferably 5g to 10g / 100g of gel or cream.

[0051] According to the present invention, the topical gel or cream formulation further comprises caffeic acid or a salt thereof (e.g., in powder form), the content of which 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 gel or cream formulation.

[0052] 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 exert various effects in the body, including anti-inflammatory effects. Caffeic acid can be purchased, for example, from Sigma-Aldrich, or isolated from coffee and other food sources.

[0053] Preferably, the formulations of the present invention may be used as anti-inflammatory topical gel or cream formulations.

[0054] In various embodiments, the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts (preferably a glumannuronate gel or cream formulation) comprises or consists of the following ingredients:

[0055] 0.1 g to 39.9 g of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, and 0.1 g to 39.9 g 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 per 100 g of gel or cream preparation is 0.5 g to 40 g; preferably, the total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof per 100 g of gel or cream preparation is 0.5 g to 35 g, preferably 1 g to 30 g, more preferably 2 g to 35 g. The total amount of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof per 100 g of gel or cream formulation is 0.5 g to 35 g, preferably 1 g to 30 g, more preferably 2 g to 20 g, more preferably 5 g to 20 g, more preferably 5 g to 15 g, and most preferably 5 g to 10 g. In various embodiments, the total amount of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof may be 5.01 g / 100 g of gel or cream, 10 g / 100 g of gel or cream, 15 g / 100 g of gel or cream, or 20 g / 100 g of gel or cream. In one specific embodiment, for 100 g of the gel or cream formulation, the mixture comprises or consists of 5 g of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof and 5 g of α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof. 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.

[0056] The concentration ranges mentioned above for the different gel or cream formulations mean that the gel or cream formulation of the present invention comprises, in addition to caffeic acid as defined herein, further comprising 0.5 to 40% by weight, preferably 0.5 to 35% by weight, more preferably 1 to 30% by weight, more preferably 2 to 20% by weight, more preferably 5 to 20% by weight, for example 5% by weight, 10% by weight, 15% by weight or 20% by weight, more preferably 5 to 15% by weight and most preferably 5 to 10% by weight of the following ingredients, relative to the total weight of the gel or cream formulation: (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.

[0057] In various embodiments, the gel or cream formulations of the present invention may include 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-guluronic acid or mixtures thereof) and caffeic acid, as well as other (preferably chemically pure) drugs, pharmaceuticals and / or herbs.

[0058] In various embodiments, the gel or cream formulation comprises at least one additional pharmaceutical agent.

[0059] In various embodiments, the at least one additional agent is selected from the group consisting of, but not limited to, analgesics, anti-inflammatory agents, and anti-sensitivity agents, or combinations thereof.

[0060] In the context of this invention, an analgesic is defined as a medication that relieves, alleviates, or reduces pain. Examples include, but are not limited to, menthol, lidocaine, camphor, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioid medications.

[0061] 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, nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, naproxen, or ibuprofen, and / or corticosteroids such as cortisol, cortisone, or betamethasone.

[0062] Anti-sensitizing agents that can be added to the topical gel or cream formulations of the present invention are any anti-allergy or anti-sensitizing (desensitizing) agents that are safe for human use, including, but not limited to, antihistamines and diphenhydramine hydrochloride.

[0063] In various embodiments, the gel or cream formulation comprises at least one additional agent selected from the group consisting of menthol; lidocaine; camphor; a nonsteroidal anti-inflammatory drug (NSAID) such as diclofenac, naproxen, or ibuprofen; a corticosteroid such as cortisol, cortisone, or betamethasone; an opioid medication; or an anti-allergy or anti-sensitivity (desensitizing) agent such as an antihistamine and diphenhydramine hydrochloride.

[0064] Thus, in various embodiments, the topical gel or cream formulations of the present invention are analgesic topical gel or cream formulations, and / or anti-inflammatory topical gel or cream formulations, and / or anti-sensitivity gel or cream formulations.

[0065] In various embodiments, the gel or cream formulations may contain additional ingredients known to those skilled in the art and commonly used in such formulations, such as one or more adjuvants (carriers, skin protectants, disinfectants, preservatives, gel-forming substances, emulsifiers, etc.).

[0066] For example, the formulations of the present invention may contain particulate carriers (e.g., talc powder, zinc oxide, starch, starch derivatives, diatomaceous earth); gel-forming substances (e.g., gelatin, tragacanth, cellulose, cellulose derivatives, alginates, polyacrylic acid); cream-forming substances (e.g., lanolin, beeswax, olive oil, peanut oil, liquid paraffin); humectants (e.g., urea, glycerin, propylene glycol); pressure-sensitive polymers (e.g., polyacrylates and binder resins); ointment bases (e.g., petrolatum, fats, cellulose derivatives, polyacrylic acid, alginates); emulsifiers (e.g., sodium lauryl sulfate "SLS", stearic acid, lanolin, lecithin, sorbitan esters, etc.) esters, monoglycerides); preservatives (e.g., alcohols, glycols, benzoates and their derivatives, e.g., benzalkonium chloride); antioxidants (e.g., butylated hydroxyanisole, vitamin E, ascorbic acid and its derivatives); thickeners (e.g., hydroxypropyl methylcellulose); pH adjusters; binders (e.g., polyvinylpyrrolidone, starch, hydroxypropyl methylcellulose, polyethylene glycol); fillers (e.g., microcrystalline cellulose, sorbitol); colorants; flavor enhancers; sweeteners (e.g., sorbitol, aspartame); solvents (e.g., water, ethanol, ethanol-water mixtures); solubilizers (e.g., gluten Adjuvants such as, but not limited to, glycerin, propylene glycol; skin penetration enhancers (e.g., alcohols, terpenes, propylene glycol); plasticizers (e.g., sorbitol, glycerin, phthalates); humectants (e.g., sodium lauryl sulfate, polysorbates); synthetic and natural oils (e.g., medium chain triglycerides, paraffin, synthetic and / or natural waxes, sweet almond oil); aerosol or foam spray propellants (e.g., norflurane, cryflurane, dichlorofluoromethane, trichlorofluoromethane, propane, butane, isobutane, nitrogen gas) may be used.

[0067] In various embodiments, the at least one additional ingredient is selected from the group consisting of a preservative, an alkaline agent, a colorant, a fragrance, a gel-forming substance, a cream-forming substance, an emulsifier, a thickener, and combinations thereof.

[0068] In various embodiments, the gel or cream formulation comprises at least one preservative, preferably selected from the group consisting of antibacterial agents, antifungal agents, alcohols, glycols, benzoates and / or their derivatives, essential oils, or combinations thereof. Preferred preservatives include, but are not limited to, antibacterial agents, antifungal agents, propylene glycol, butylene glycol, pentylene glycol, ethoxydiglycol, phenoxyethanol, benzyl benzoate, methylisothiazolinone, zinc pyrithione, benzalkonium chloride, sodium benzoate, alcohols, essential oils or their derivatives, or combinations thereof.

[0069] The gel or cream formulation may be free or substantially free of parabens.

[0070] In various embodiments, the gel or cream formulation is free or substantially free of antibacterial and / or antifungal agents.

[0071] In various embodiments, the gel or cream formulation is free or substantially free of parabens, antibacterial agents, and antifungal agents.

[0072] Preferably, the gel or cream formulation is a gel formulation.

[0073] Preferably, the gel formulation according to the invention comprises at least one gel-forming substance and / or at least one thickening agent.

[0074] Preferably, suitable gel-forming materials are selected from pharmaceutical-grade ingredients. Suitable polymers include, but are not limited to, highly water-absorbent polymers, including hydrophilic cellulose derivatives partially crosslinked to form a three-dimensional structure, as disclosed in WO 92 / 16245. Such polymers are highly water-absorbent because they can absorb at least 10 times their own weight in water. Due to their crosslinked structure, such polymers are insoluble in water, but readily absorb and retain water in the three-dimensional structure of the polymer, forming a gel. The rate of water loss from such gels is slower than that from solutions.

[0075] In various embodiments, sodium carboxymethylcellulose, hydroxyethylcellulose, carbomale (polyacrylate / polyacrylic acid; e.g., powdered), and xanthan gum may be suitably used as gel-forming materials.

[0076] In particular, the at least one gel-forming substance is generally selected from pharmaceutical-grade quality carbomales ((homo)polymers of acrylic acid and its salts), celluloses, alginates or derivatives thereof or combinations thereof.

[0077] In particular, carbomale (an acrylic acid polymer) is used as a suitable base for many commercial gels and readily absorbs water on contact to form a gel.

[0078] For example, carbomals can be purchased under the trade names Carbomal 104, Carbomal 934, Carbomal 934P, Carbomal 940, Carbomal 941, Carbomal 974P, Carbomal 980, Carbomal 1342, Carbomal sodium salt, etc. (where the numbers refer to molecular size and adhesiveness).

[0079] In a preferred embodiment, the gel formulation of the present invention comprises Carbomal 934(P).

[0080] The amount of the gel-forming substance (preferably carbomale) present relative to the total weight of the gel preparation is preferably about 0.8% by weight to about 6.0% by weight, more preferably about 1.5% by weight to about 4% by weight, more preferably about 2.0% by weight to about 3.0% by weight, for example, 2.5% by weight.

[0081] If the gel or cream formulation is a cream formulation, it preferably comprises at least one cream-forming substance and / or at least one emulsifier.

[0082] In various embodiments, the cream-forming substance may be selected from the group consisting of lanolin, beeswax, olive oil, coconut oil, avocado oil, peanut oil, argan oil and / or petrolatum (petrolatum), essential oils, mineral oil and / or synthetic oils (e.g., liquid paraffin, glycerin, zinc oxide, butyl stearate and diglycol laurate), or combinations thereof.

[0083] Suitable emulsifiers may be anionic, cationic, neutral, amphoteric or complex emulsifiers or combinations thereof, and / or synthetic or natural emulsifiers or combinations thereof. In a preferred embodiment, the at least one emulsifier is a synthetic and / or natural emulsifier, preferably selected from the group consisting of lecithin, lanolin, sorbitan esters, cetyl alcohol, cetearyl alcohol, stearic acid, glyceryl (mono)stearate, mono / diglycerides, sodium lauryl sulfate (SLS), benzalkonium chloride, polyoxyethylene castor oil, carnauba wax, candelilla wax, beeswax or combinations thereof.

[0084] Preferred natural emulsifiers are, for example, lanolin, lecithin, carnauba wax, candelilla wax, beeswax, or combinations thereof.

[0085] In various embodiments, the gel or cream formulation may include at least one alkaline agent, for example in solution, generally to adjust the pH of the gel or cream formulation.

[0086] In accordance with the present invention, the gel or cream formulation is preferably administered topically to a subject in need thereof.

[0087] In a preferred embodiment, the subject is a mammal, particularly a human.

[0088] In a preferred embodiment, a gel or cream formulation according to the invention is administered topically in a method for treating (or preventing) the following conditions: i) inflammation and / or any inflammatory response, preferably inflammation of the joints and / or muscles and / or any inflammatory response; and / or ii) Pain, preferably joint and / or muscle pain.

[0089] In other preferred embodiments, a gel or cream formulation according to the present invention is administered topically to a subject in need thereof in a method for treating (or preventing) the following diseases: i) inflammation and / or any inflammatory response, preferably inflammation of the joints and / or muscles and / or any inflammatory response; and / or ii) Pain, preferably joint and / or muscle pain.

[0090] In such embodiments, it is particularly preferred that the gel or cream formulation comprises at least one additional agent as described herein, preferably at least one analgesic, anti-inflammatory or anti-sensitivity agent, or a combination thereof.

[0091] In various embodiments, the gel or cream formulation preferably comprises at least one additional agent selected from the group consisting of menthol; lidocaine; camphor; a nonsteroidal anti-inflammatory drug (NSAID) such as diclofenac, naproxen, or ibuprofen; a corticosteroid such as cortisol, cortisone, or betamethasone; an opioid medication; or an anti-allergy or anti-sensitivity (desensitizing) agent such as an antihistamine and diphenhydramine hydrochloride.

[0092] Preferably, the at least one additional agent is, but is not limited to, a nonsteroidal anti-inflammatory drug (NSAID) and / or a corticosteroid.

[0093] In a further aspect, the present invention relates to a method of producing a gel or cream formulation according to the present invention, wherein said gel or cream formulation is a topical gel or cream formulation as described herein.

[0094] According to the present invention, the gel or cream formulation obtained by the method of the present invention comprises: The following ingredients, in a total amount of 0.5 g to 40 g, preferably 0.5 g to 35 g / 100 g, more preferably 1 g to 30 g / 100 g of gel or cream, more preferably 2 g to 20 g / 100 g of gel or cream, and most preferably 5 g to 20 g / 100 g of gel or cream, for example, 5 g / 100 g, 10 g / 100 g, 15 g / 100 g, or 20 g / 100 g of gel or cream, and particularly 5 g to 10 g / 100 g of gel or cream: (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably β-D-mannuronate; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably α-L-guluronic acid salts; or (iii) a mixture of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably β-D-mannuronate) and α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably α-L-guluronic acid). Including, Furthermore, the gel or cream formulation contains 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, more preferably 0.05% by weight to 0.3% by weight, for example, 0.1% by weight to 0.3% by weight, based on the total weight of the gel or cream formulation.

[0095] This is because the gel or cream formulation of the present invention: A gel or cream formulation, preferably 100 g of the gel or cream formulation (final formulation), contains 0.5 to 40% by weight, preferably 0.5 to 35% by weight, more preferably 1 to 30% by weight, more preferably 2 to 20% by weight, more preferably 5 to 20% by weight, for example 5% by weight, 10% by weight, 15% by weight or 20% by weight, more preferably 5 to 15% by weight, and most preferably 5 to 10% by weight of the following component: (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 Including, Furthermore, it means that the content of caffeic acid or a salt thereof (e.g., powdered) is 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 %, relative to the total weight of the gel or cream formulation (final formulation).

[0096] In various embodiments, in the methods of the present invention, β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably β-D-mannuronate) and / or α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably α-L-guluronic acid) are added in powder form. In embodiments where the resulting gel or cream formulation is a glumannuronate gel or cream formulation comprising 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-guluronic acid), said gel or cream formulation preferably comprises the following ingredients: caffeic acid, 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, more preferably 0.05% by weight to 0.3% by weight, for example 0.1% by weight to 0.3% by weight, relative to the total weight of the gel or cream formulation; 0.1 g to 39.9 g of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, and 0.1 g to 39.9 g of α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof Contains or consists of these components, 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 per 100 g of the gel or cream formulation is 0.5 g or more and 40 g or less; preferably, the total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof per 100 g of the gel or cream formulation is 0.5 g to 35 g, more preferably 1 g to 30 g, more preferably 2 g to 20 g, more preferably 5 g to 20 g, more preferably 5 g to 15 g, and most preferably 5 g to 10 g; and The amount of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof per 100 g of gel or cream formulation is 0.5 g to 35 g, preferably 1 g to 30 g, more preferably 2 g to 20 g, more preferably 5 g to 20 g, more preferably 5 g to 15 g, and most preferably 5 g to 10 g. In various embodiments, the total amount of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof may be 5.01 g / 100 g of gel or cream, 10 g / 100 g of gel or cream, 15 g / 100 g of gel or cream, or 20 g / 100 g of gel or cream.

[0097] 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 a glumannuronate gel or cream formulation. Preferably, the alginate hydrolysate (powder) is used in a total amount of 0.5 g to 40 g per 100 g of the gel or cream formulation, more preferably 5 g to 20 g per 100 g of the gel or cream formulation, and most preferably 5 g to 10 g per 100 g of the gel or cream formulation.

[0098] In various embodiments, the β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably a 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 gel or cream formulations.

[0099] In various embodiments, the α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably 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, 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 for guluronic acid gel or cream formulations.

[0100] In various embodiments, the 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-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, potassium oligomannuronate, magnesium oligomannuronate, calcium oligomannuronate, or ammonium oligomannuronate, sodium oligoguluronic acid, potassium oligomannuronate, magnesium oligomannuronate, calcium oligomannuronate, or ammonium oligomannuronate, and combinations thereof, and among these, preferred are sodium β-D-mannuronate, sodium α-L-guluronic acid, sodium oligomannuronate, sodium oligoguluronic acid, and combinations thereof in glumannuronate gel or cream formulations.

[0101] 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. In a preferred embodiment, the gel or cream formulation obtained by the method of the present invention may comprise at least one additional agent, preferably selected from the analgesic, anti-inflammatory and / or anti-sensitivity agents described above.

[0102] Thus, in various embodiments, the methods of the present invention are methods of making analgesic gel or cream formulations, anti-inflammatory gel or cream formulations, and / or anti-sensitivity gel or cream formulations.

[0103] The gel or cream formulation obtained by the method of the present invention may comprise at least one additional ingredient, such as one or more of the adjuvants described herein.

[0104] Preferably, the method is a method for producing a gel formulation of the present invention, comprising the steps of: (i) providing a (first) solution comprising at least one gel-forming substance and optionally at least one preservative; (ii) providing a (second) solution, said (second) solution comprising: (a) containing β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably β-D-mannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, per 100 g of the gel formulation; or (b) a total amount of α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably α-L-guluronic acid salt, in a range of 0.5 g to 40 g, preferably 5 g to 10 g, per 100 g of the gel formulation; or (c) containing a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, per 100 g of the gel formulation; (iii) optionally providing at least one additional solution; (iv) optionally adjusting the pH of the second solution to pH 1-5, preferably 2-4, more preferably 3; (v) mixing the solutions of step i) and step ii) and optionally step iii); and (vi) optionally adjusting the pH to 4 to 8, more preferably 5 to 7, most preferably 5.5 to 6.5; Preferably, the caffeic acid or a salt thereof, e.g., powdered caffeic acid or a salt thereof, is contained in at least one of the first solution in step i), the second solution in step ii) and the at least one additional solution in optional step iii) so that the total amount of caffeic acid in the gel formulation is 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 %, relative to the total weight of the gel formulation.

[0105] If neither the first nor the second solution contains caffeic acid, step iii) is not optional and caffeic acid is present in at least one additional solution.

[0106] In various preferred embodiments, the (first) solution of step i) is an aqueous solution. Preferably, at least one gel-forming substance and optionally at least one preservative are dissolved / mixed in water (preferably deionized water) to obtain the (first) solution.

[0107] Preferably, the gel-forming substance is polyacrylic acid (carbomal), cellulose, alginate or derivatives or combinations thereof, preferably a (homo)polymer of acrylic acid (eg carbomal).

[0108] More preferably, the final concentration of the at least one gel-forming substance (preferably polyacrylic acid (carbomale)) in the gel formulation is about 0.8% by weight to about 6.0% by weight, preferably about 1.5% by weight to about 4% by weight, more preferably about 2.0% by weight to about 3.0% by weight, for example about 2.5% by weight, based on the total weight of the gel formulation, preferably per 100 g of the gel formulation.

[0109] In various preferred embodiments, the (second) solution in step ii) is an aqueous solution. More preferably, β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably β-D-mannuronic acid used in mannuronic acid gel formulations), or α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably α-L-guluronic acid used in guluronic acid gel formulations), or a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomer, or a pharmaceutically acceptable salt thereof (preferably β-D-mannuronic acid and α-L-guluronic acid, particularly glumannuronate, used in glumannuronate gel formulations) is dissolved in water (preferably deionized water) to obtain the (second) solution. The concentrations are preferably those commonly used for preparing gel or cream formulations, as described above, such that the concentrations in the final formulation are as described herein. In various embodiments, the alginate hydrolysate (powder) can be used in a glumannuronate gel formulation 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, which is dissolved in water (preferably deionized water) to obtain a (second) solution. Preferably, the alginate hydrolysate (powder) is added in an amount to obtain a gel formulation having a concentration of 0.5 g to 40 g / 100 g, more preferably 5 g to 20 g / 100 g, and most preferably 5 g to 10 g / 100 g.

[0110] After the solutions of step i) and step ii) are prepared, the solution of step ii) and the solution of step i) are mixed together.

[0111] In various embodiments, before and / or after mixing, an alkaline agent solution is added to at least one of the solutions, preferably the (second) solution of step ii) or the mixed gel formulation to adjust the pH. If the gel is a water-based gel, the alkaline agent solution is preferably a NaOH solution.

[0112] In a preferred embodiment, an alkaline solution (preferably NaOH solution) is added to the dissolved mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, or guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, or a mixture of mannuronic acid and guluronic acid, their oligomer, or a pharmaceutically acceptable salt thereof, in step ii) to adjust the pH, preferably to 1 to 5, more preferably to 2 to 4, e.g., 3.

[0113] Preferably, after mixing the solutions of step i) and step ii), the pH is adjusted to 4 to 8, more preferably 5 to 7, most preferably 5.5 to 6.5.

[0114] In various embodiments, the viscosity of the resulting solution (or final gel formulation) is adjusted to 0.85 Pa·s to 35 Pa·s, preferably 1 Pa·s to 10 Pa·s, more preferably 2.5 Pa·s to 4 Pa·s, more preferably 3 Pa·s to 3.7 Pa·s, and most preferably 3.1 Pa·s to 3.35 Pa·s, and measured at 25°C using a laboratory digital Brookfield viscometer (rotational viscometer). In various embodiments, the viscosity is measured using a steady flow method (0.1 to 100 s -1 The flow characteristics of the formulation were determined by the following method: -1 ), Medium (20.0s -1 ) and high (75.0s -1 ) viscosity value at shear rate. In a preferred embodiment, the shear rate (shear viscosity value) of the gel is 75.0 to 85.0 s -1 Specifically, the viscosity of the resulting solution is adjusted to 0.85 Pa·s to 35 Pa·s, preferably 1 Pa·s to 10 Pa·s, more preferably 2.5 Pa·s to 4 Pa·s, more preferably 3 Pa·s to 3.7 Pa·s, and most preferably 3.1 Pa·s to 3.35 Pa·s, and the solution is heated at 25°C and a shear rate of 75.0 s -1 ~85.0s -1 The viscosity is measured using a laboratory digital Brookfield viscometer under the following conditions.

[0115] In a preferred embodiment, the solution of step i) and / or the solution of step ii) may contain at least one additional agent, preferably selected from the group consisting of analgesics, anti-inflammatory agents and / or anti-sensitivity agents as described above.

[0116] Thus, in various embodiments, the methods of the present invention are methods for producing analgesic gel formulations, anti-inflammatory gel formulations, and / or anti-sensitivity gel formulations.

[0117] The (first) solution of step i) and / or the (second) solution of step ii) may comprise at least one additional component, such as one or more of the adjuvants described herein.

[0118] Additional agents and / or additional ingredients (auxiliaries) may be contained in additional solutions, such as a third or fourth solution, which may be added in a later step (optional step iii).

[0119] Preferably, when an additional solution is present, the additional solution is also an aqueous solution as described above. In various embodiments, the pH may be adjusted as described above, preferably before mixing with the solution of steps i) and / or ii).

[0120] In various embodiments, if an additional solution is present, the additional solution is mixed with the solution of step i) and / or the solution of step ii) or a mixture thereof, followed by adjusting the pH to preferably between 4 and 8, more preferably between 5 and 7, and most preferably between 5.5 and 6.5.

[0121] Water may be added to the resulting solution to obtain the gel formulation of the present invention, which is an optional step, for example, to adjust the final concentrations of the components of the gel formulation and / or to adjust the consistency and / or viscosity of the gel formulation.

[0122] In various embodiments, the method comprises: (i) providing a (first) solution comprising at least one gel-forming substance and optionally at least one additional agent and / or at least one additional ingredient (e.g., at least one preservative); (ii) providing a (second) solution, said (second) solution comprising: (a) β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably β-D-mannuronate) in a total amount of 0.5 g to 40 g, preferably 0.5 g to 35 g, more preferably 1 g to 30 g, more preferably 2 g to 20 g, more preferably 5 g to 20 g, more preferably 5 g to 15 g, and most preferably 5 g to 10 g, per 100 g of the gel preparation; or (b) α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably α-L-guluronic acid salt) in a total amount of 0.5 g to 40 g, preferably 0.5 g to 35 g, more preferably 1 g to 30 g, more preferably 2 g to 20 g, more preferably 5 g to 20 g, more preferably 5 g to 15 g, and most preferably 5 g to 10 g, per 100 g of the gel preparation; or (c) a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof (preferably glumannuronate), in a total amount of 0.5 g to 40 g, preferably 0.5 g to 35 g, more preferably 1 g to 30 g, more preferably 2 g to 20 g, more preferably 5 g to 20 g, more preferably 5 g to 15 g, and most preferably 5 g to 10 g, per 100 g of the gel formulation; and optionally including at least one additional agent and / or at least one additional ingredient; (iii) optionally providing at least one additional solution comprising caffeic acid and / or at least one additional agent and / or at least one additional ingredient; (iv) optionally adjusting the pH of the second solution to pH 1-5, preferably 2-4, more preferably 3; (v) mixing the solutions of step i) and step ii) and optional step iii); (vi) optionally adjusting the pH of the resulting solution to 4 to 8, more preferably 5 to 7, and most preferably 5.5 to 6.5; (vii) Optionally, adjust the viscosity of the resulting solution to 0.85 Pa·s to 35 Pa·s, preferably 2.5 Pa·s to 4 Pa·s, more preferably 3 Pa·s to 3.7 Pa·s, and most preferably 3.1 Pa·s to 3.35 Pa·s, and measure the viscosity of the resulting solution using a laboratory digital Brookfield viscometer (rotational viscometer) at 25°C, preferably at a shear rate of 75.0 s -1 ~85.0s -1 measuring under the condition of (viii) optionally adding water to the resulting solution to obtain a gel formulation, preferably a gel formulation as described herein; Preferably, caffeic acid or a salt thereof, for example in powder form, is contained in at least one of the first solution in step i), the second solution in step ii) and the at least one additional solution in optional step iii) so that the total amount of caffeic acid in the gel formulation is 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 gel formulation.

[0123] In various embodiments, the method of the present invention is a method of making a cream formulation of the present invention.

[0124] In various embodiments, in a (topical) cream formulation, the ingredients are dissolved or dispersed in a water-in-oil (W / O) emulsion or an oil-in-water (O / W) emulsion.

[0125] Water-in-oil (W / O) or oil-in-water (O / W) emulsions are known to those skilled in the art and can be prepared according to conventional methods. Preferably, a (topical) cream formulation has a higher oily / lipophilic substance content than a gel. In one embodiment, the cream formulation of the present invention comprises approximately 60-75% by weight of an aqueous base and approximately 20-30% by weight of an oily base, based on the total weight of the cream formulation.

[0126] According to the present invention, the cream formulation comprises: (a) β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably β-D-mannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, per 100 g of the cream formulation; or (b) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably α-L-guluronic acid salts, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, per 100 g of the cream formulation; or (c) A 100 g cream formulation may contain a total of 0.5 g to 40 g, preferably 5 g to 10 g, of a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronate. In various embodiments, alginate hydrolysate (powder) may be added as glumannuronate (as a mixture of β-D-mannuronic acid, its oligomers, or their pharmaceutically acceptable salts and α-L-guluronic acid, its oligomers, or their pharmaceutically acceptable salts) and used in a glumannuronate cream formulation. Preferably, the alginate hydrolysate (powder) is added in an amount of 0.5 g to 40 g per 100 g of cream formulation, more preferably 5 g to 20 g per 100 g of cream formulation, and most preferably 5 g to 10 g per 100 g of cream formulation, relative to the total weight of the cream formulation, and caffeic acid or a salt thereof (e.g., powdered) is added 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 %.

[0127] Additional ingredients include, for example, at least one cream-forming substance, as described above, at least one emulsifier, at least one plasticizer (such as cetyl stearoyl 2-ethylhexanoate), and / or at least one preservative.

[0128] Preferably, the method is a method for producing a cream formulation according to the present invention, comprising the steps of: (i) providing a (first) composition comprising at least one cream-forming substance and optionally at least one emulsifier, at least one plasticizer and / or at least one preservative; (ii) providing a (second) composition, said (second) composition comprising: (a) a cream formulation containing β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably β-D-mannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g, per 100 g of the cream formulation; or (b) a cream formulation containing α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably α-L-guluronic acid salt, in a total amount of 0.5 g to 40 g, preferably 5 g, per 100 g of the cream formulation; or (c) a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g, per 100 g of the cream formulation; (iii) optionally adding at least one additional agent and / or at least one additional ingredient in the first step or the second step or an additional step; (iv) optionally adjusting the pH of the second solution to pH 1-5, preferably 2-4, more preferably 3; (v) mixing the solutions of i) and ii); (vi) optionally adjusting the pH to 4 to 8, more preferably 5 to 7, most preferably 5.5 to 6.5; Preferably, in this method, caffeic acid or a salt thereof (e.g., powdered) is added in the first step and / or the second step and / or an optional additional step so that the total amount of caffeic acid in the cream formulation is 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 %, relative to the total weight of the cream formulation.

[0129] Preferably, step i) produces a semi-solid composition or emulsion, preferably a water-in-oil (W / O) emulsion or an oil-in-water (O / W) emulsion. In various embodiments, at least one cream-forming substance and optionally at least one emulsifier, at least one plasticizer and / or at least one preservative and further optionally caffeic acid are dissolved / mixed in water, preferably deionized water. Additional suitable ingredients include, for example, at least one thickener as described herein and / or at least one (organic) solvent, such as propylene glycol.

[0130] The additional agents are preferably as described above. In various embodiments, the method of the present invention is a method of making an analgesic cream formulation, an anti-inflammatory cream formulation, and / or an anti-sensitivity cream formulation.

[0131] In various embodiments, the resulting gel or cream formulation can be sterilized. Suitable methods for sterilizing the formulation include, for example, heat / steam treatment, radiation, and aseptic manufacturing.

[0132] The gel or cream formulations of the present invention may be filled or packaged in any suitable packaging, such as tubes, films or other packaging, which may be made from any suitable material, for example, aluminum tubes or low melting point polyolefin packaging, such as polyethylene packaging.

[0133] All embodiments and examples of the topical gel or cream formulations according to the invention described herein also apply to the topical gel or cream formulations in methods for treating inflammation and / or any inflammatory response and / or pain, and to methods for making said gel or cream formulations, and vice versa. Other embodiments are found in the non-limiting examples below. [Example]

[0134] 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. Sodium alginate (sodium alginate) was used to synthesize β-D-mannuronic acid, α-L-guluronic acid, and glumannuronate. In the first step, sodium alginate (100 g) was gently 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 pale cream to light brown. The hydrolyzate was cooled to room temperature and the precipitate was separated by centrifugation (3700 g). This precipitate was used as glumannuronate (alginate hydrolyzate). The precipitate was redissolved by neutralization 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 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 in guluronic acid gel or cream formulations, and / or in a mixture of β-D-mannuronic acid and α-L-guluronic acid for glumannuronate gel or cream formulations. 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 can be used in mannuronic acid gel or cream formulations, and / or in a mixture of β-D-mannuronic acid and α-L-guluronic acid for glumannuronate gel or cream formulations. Fourier transform infrared (FT-IR) spectroscopy and carbon-13 nuclear magnetic resonance (C-NMR) spectroscopy (C-NMR) were analyzed. 13 The properties and purity of α-L-guluronic acid and β-D-mannuronic acid were verified by C-NMR spectroscopy.

[0135] To prepare topical gels or creams, the provided powders (mannuronic acid) and (guluronic acid) were stored under sterile conditions in a dry place at room temperature (22-26°C).

[0136] 2. Methods for producing mannuronate, guluronic acid, and glumannuronate topical gels I): In the first step, the appropriate preservative was dissolved in 70 mL of boiling deionized water, and then 2.5 g of Carbomal 934P was added to obtain a clear solution, which was then cooled (Solution 1). II): In another glass beaker, IIa): For mannuronic acid gel formulation, 10 g of mannuronic acid powder was added to 20 mL of deionized water, and then 30% NaOH was added to adjust the pH to 3 to completely dissolve the mannuronic acid (Solution 2a). IIb): For the guluronic acid gel formulation, 10 g of guluronic acid powder was added to 20 mL of deionized water, and then 30% NaOH was added to adjust the pH to 3 to completely dissolve the guluronic acid (Solution 2b). IIc): For the glumanuronate gel formulation, 5 g of mannuronic acid powder and 5 g of guluronic acid powder were added to 20 mL of deionized water, and 30% NaOH was added to adjust the pH to 3, dissolving the powders (Solution 2c). Another method for preparing glumanuronate gel is to use the first precipitate from the sodium alginate hydrolysis step. Therefore, 10 g of glumanuronate (sodium alginate hydrolysate) powder was added to 20 mL of deionized water, and 30% NaOH was added to dissolve the powder until the pH reached 3 (Solution 2c).

[0137] III): (Solution 2) was added to (Solution 1) to obtain a clear solution, and then the pH was gradually adjusted to 5.5-6 (Solution 3). IV): Deionized water was added to (Solution 3) until the total (final) weight was 100 g. V): The synthesized mannuronic acid topical gel (using solution 2a) and guluronic acid topical gel (using solution 2b) and glucuronic acid topical gel (using solution 2c) may be packaged and stored under sterile conditions.

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) 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. A topical gel or cream formulation 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 0.5 g to 40 g per 100 g of the gel or cream formulation; The gel or cream formulation further comprises caffeic acid or a salt thereof, for example, powdered caffeic acid or a salt thereof, and the content of 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, for example 0.1% by weight to 0.3% by weight, based on the total weight of the gel or cream formulation.

2. The viscosity of the formulation is 0.85 Pa s to 35 Pa s, preferably 2.5 Pa s to 4 Pa ​​s, more preferably 3 Pa s to 3.7 Pa s, and most preferably 3.1 Pa s to 3.35 Pa s, and the viscosity is measured using a laboratory digital Brookfield viscometer (rotational viscometer) at 25°C, preferably at a gel shear rate of 75.0 s －１ ~85.0s －１ Or the shear rate of the cream is 60.0 s －１ ~70.0s －１ 2. The gel or cream formulation according to claim 1, wherein the viscosity is measured under the following conditions:

3. (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 their pharmaceutically acceptable salts, preferably glumannuronate, 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, preferably sodium β-D-mannuronate and / or sodium α-L-guluronic acid; or (iv) A gel or cream formulation according to claim 1 or 2, 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).

4. 4. The gel or cream formulation 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.

5. 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 or potassium oligomannuronate or magnesium oligomannuronate or calcium oligomannuronate or ammonium oligomannuronate and sodium oligoguluronic acid or potassium oligoguluronic acid or magnesium oligoguluronic acid or calcium oligoguluronic acid or ammonium oligoguluronic acid, and combinations thereof, preferably sodium oligomannuronate and / or sodium oligoguluronic acid; and / or (iii) A gel or cream formulation according to claim 4, 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.

6. 6. The gel or cream formulation according to claim 1, wherein the total amount of the following ingredients in the gel or cream formulation is 1 g to 30 g per 100 g of gel or cream, more preferably 5 g to 20 g per 100 g of gel or cream, and most preferably 5 g to 10 g per 100 g of gel or cream: (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, oligomers thereof, or pharmaceutically acceptable salts thereof.

7. The mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably the glumannuronate formulation, comprises or consists of 0.1 g to 39.9 g of β-D-mannuronic acid, its oligomers, or their pharmaceutically acceptable salts, and 0.1 g to 39.9 g 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 is 0.5 g to 40 g per 100 g of gel or cream formulation; preferably the total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is 0.5 g to 35 g, preferably 1 g to 30 g, more preferably 2 g to 20 g, more preferably 5 g to 15 g, and most preferably 5 g to 10 g, per 100 g of the gel or cream formulation; and 7. The gel or cream formulation according to claim 6, wherein the total amount of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof is 0.5 g to 35 g, preferably 1 g to 30 g, more preferably 2 g to 20 g, more preferably 5 g to 15 g, and most preferably 5 g to 10 g, per 100 g of the gel or cream formulation.

8. 8. A gel or cream formulation according to any one of claims 1 to 7, further comprising at least one additional agent, preferably selected from the group consisting of analgesics, anti-inflammatory agents and anti-sensitivity agents or combinations thereof.

9. 9. The gel or cream formulation of claim 1, further comprising at least one additional ingredient, wherein the additional ingredient is selected from the group consisting of a preservative, an alkaline agent, a colorant, a fragrance, a gel-forming substance, an emulsifier, and combinations thereof.

10. 10. The gel or cream formulation of claim 9, wherein the at least one preservative is selected from the group consisting of antibacterial agents, antifungal agents, alcohols, glycols, benzoates and / or their derivatives, essential oils or combinations thereof.

11. 11. A gel or cream formulation according to any one of claims 1 to 10, characterized in that the gel or cream formulation is free or substantially free of parabens and / or antibacterial and / or antifungal agents.

12. 12. A gel formulation according to any one of claims 9 to 11, characterized in that the at least one gel-forming substance is a poly(acrylic acid) (carbomal), cellulose, alginate or a derivative thereof, or a combination thereof, preferably a (homo)polymer of acrylic acid (carbomal).

13. 12. The cream formulation according to any one of claims 9 to 11, wherein the at least one emulsifier is a synthetic or natural emulsifier, preferably selected from the group consisting of lecithin, lanolin, sorbitan esters, cetyl alcohol, cetearyl alcohol, stearic acid, glyceryl (mono)stearate, mono / diglycerides, sodium lauryl sulfate (SLS), benzalkonium chloride, polyoxyethylene castor oil, carnauba wax, candelilla wax, beeswax, and combinations thereof.

14. 14. A gel or cream formulation according to any one of claims 1 to 13, characterized in that it is used topically in a method for treating (or preventing) the following diseases: (i) inflammation and / or any inflammatory response, preferably inflammation of the joints and / or muscles and / or any inflammatory response; and / or (ii) pain, preferably joint and / or muscle pain;

15. A method for producing a gel or cream formulation, preferably a gel formulation, according to any one of claims 1 to 13, comprising the steps of: (i) providing a (first) solution comprising at least one gel-forming substance and optionally at least one preservative; (ii) providing a (second) solution, said (second) solution comprising: (a) β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably β-D-mannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, per 100 g of the gel formulation; or (b) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably α-L-guluronic acid salt, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, per 100 g of the gel formulation; or (c) including a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, per 100 g of the gel formulation; (iii) optionally providing at least one additional solution; (iv) optionally adjusting the pH of the second solution to pH 1-5, preferably 2-4, more preferably 3; (v) mixing the solutions of step i), step ii) and optional step iii); and (vi) optionally adjusting the pH to between 4 and 8, more preferably between 5 and 7, and most preferably between 5.5 and 6.5; 1. A method for producing a gel or cream formulation, characterized in that caffeic acid or a salt thereof, e.g., powdered caffeic acid or a salt thereof, is contained in at least one of the first solution of step i), the second solution of step ii) and the at least one additional solution of optional step iii), such that the total amount of caffeic acid in the gel formulation is 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 gel formulation.

Images