Mannuronates, guluronates, and guluronate topical gels or creams and methods of making same

Abstract

The present invention relates to a gel or cream formulation for topical use, the formulation 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, where, based on 100 g of the gel or cream formulation, the content of the beta-D-mannuronic acid or alpha-L-guluronic acid or the mixture of beta-D-mannuronic acid and alpha-L-guluronic acid or alpha-L-guluronic acid or alpha-L-guluronic acid or alpha-L-guluronic acid or alpha- the total amount of 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 is from 0.5 g to 40 g, said formulation further comprising caffeic acid. Furthermore, the present invention relates to a gel or cream formulation for topical use in a method of treating inflammation and / or any inflammatory response and / or pain, as well as a method of preparing the gel or cream formulation.

Description

Technical Field

[0001] The present invention relates to a gel or cream preparation for topical use, comprising β-D-mannuronic acid, α-L-guluronic acid, or a mixture of β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof, wherein the total amount of β-D-mannuronic acid, α-L-guluronic acid, or a mixture of β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof is 0.5 g to 40 g per 100 g of the gel or cream preparation, and further comprising caffeic acid. Furthermore, the present invention relates to a gel or cream preparation for topical use in a method for treating inflammation and / or any inflammatory reaction and / or pain, and a method for preparing the gel or cream preparation. 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.

[0007] Topical formulations in the form of gels or creams are known for a variety of pharmaceutical agents, and their therapeutic efficacy has been demonstrated. However, many patients do not respond adequately to conventional therapies using existing topical gels or creams (e.g., analgesic or anti-inflammatory formulations based on diclofenac or piroxicam as active ingredients). Therefore, there is a pressing need to provide alternative or improved topical formulations with analgesic and / or anti-inflammatory properties. Summary of 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 the form of a gel or cream formulation, for example as an anti-inflammatory gel or cream formulation for topical use, or as an analgesic gel or cream formulation for topical use.

[0009] Thus, in a first aspect, the present invention relates to a gel or cream formulation for topical use, comprising:

[0010] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0011] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0012] (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,

[0013] wherein, based on 100 g of the gel or cream 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 0.5 g to 40 g;

[0014] The gel or cream 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 gel or cream 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 %, more preferably 0.05 wt % to 0.3 wt %, such as 0.1 wt % to 0.3 wt %.

[0015] In various embodiments,

[0016] (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 or ammonium β-D-mannuronate and combinations thereof, more preferably sodium β-D-mannuronate; and / or

[0017] (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 or ammonium α-L-guluronate and combinations thereof, more preferably sodium α-L-guluronate.

[0018] 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;

[0019] Preferably, β-D-mannuronate and α-L-guluronate, their oligomers or their pharmaceutically acceptable salts 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 / or 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

[0020] 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).

[0021] In various embodiments, the total amount of the following components in the gel or cream formulation is 0.5 g to 35 g / 100 g of gel or cream, preferably 1 g to 30 g / 100 g of gel or cream, more preferably 5 g to 20 g / 100 g of gel or cream, and most preferably 5 g to 10 g / 100 g of gel or cream:

[0022] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0023] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0024] (iii) a mixture of β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof or pharmaceutically acceptable salts thereof.

[0025] In various embodiments, the gel or cream formulation may further comprise at least one other pharmaceutical agent described herein and / or at least one other ingredient described herein.

[0026] Preferably, the gel or cream formulation is for topical use as described herein for anti-inflammatory purposes. In another embodiment, the gel or cream formulation is an analgesic topical gel or cream formulation as described herein.

[0027] In a second aspect, the gel or cream formulations of the invention are for topical use in a method of treating (or preventing) the following conditions:

[0028] (i) inflammation and / or any inflammatory reaction, preferably joint and / or muscle inflammation and / or any inflammatory reaction; and / or

[0029] (ii) pain, preferably joint and / or muscle pain.

[0030] In a third aspect, the present invention relates to a method for preparing the gel or cream formulation described herein. Preferably, the gel or cream formulation can be the gel or cream formulation for topical anti-inflammatory use described herein, or the gel or cream formulation for topical analgesia described herein.

[0031] In various embodiments, the method is a method for preparing a gel formulation, comprising the steps of:

[0032] (i) providing a (first) solution comprising at least one gel-forming substance and optionally at least one preservative;

[0033] (ii) providing a (second) solution, said (second) solution:

[0034] (a) containing β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof, preferably β-D-mannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, based on 100 g of the gel preparation; or

[0035] (b) containing 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, based on 100 g of the gel preparation; or

[0036] (c) a mixture comprising β-D-mannuronic acid and α-L-guluronic acid, their oligomers or pharmaceutically acceptable salts thereof, preferably guluromannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, based on 100 g of the gel preparation;

[0037] (iii) optionally providing at least one other solution;

[0038] (iv) optionally adjusting the pH of the second solution to a pH of 1 to 5, preferably 2 to 4, more preferably 3;

[0039] (v) mixing the solutions of step i) and step ii) and optionally step iii); and

[0040] (vi) optionally adjusting the pH to 4 to 8, more preferably 5 to 7, most preferably 5.5 to 6.5;

[0041] The caffeic acid or its salt is contained in at least one of the first solution of step i), the second solution of step ii), and the optional at least one other solution of step iii), for example, in the form of a powder, preferably such that: based on the total weight of the gel preparation, the total amount of caffeic acid in the gel preparation 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 %.

[0042] 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

[0043] 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.

[0044] 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.

[0045] Numerical values ​​without decimal places herein refer to the full value with one decimal place, for example, 99% means 99.0%, unless otherwise defined.

[0046] The term "about" in connection with numerical values ​​refers to a deviation of ±10%, preferably ±5%, relative to the given numerical value.

[0047] 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%.

[0048] 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.

[0049] Hereinafter, the term "gel or cream formulation" is used to describe a gel or cream formulation for topical use, preferably a topical anti-inflammatory and / or topical analgesic gel formulation. The terms "gel" and "gel formulation" as well as "cream" and "cream formulation" are intended to encompass all types of viscous formulations commonly used in the art, including pastes, ointments, and lotions.

[0050] In the context of the present invention, a "cream formulation" may be a two-phase (semi-solid) dosage form comprising an aqueous phase in addition to a lipid phase (emulsion). In various embodiments, the cream dosage form may be a hydrophilic cream or a lipophilic cream.

[0051] In the present invention, a "gel formulation" may be a (semi-solid) finely dispersed system having at least two liquid phases or at least one liquid phase and at least one solid phase, wherein the continuous phase preferably comprises a gel-forming substance. Suitable gel formulations include, but are not limited to, aqueous gels and alcohol-based gels. Aqueous gel formulations are particularly preferred in the present invention.

[0052] Viscosity is an important physical property of topical preparations and also affects the release rate of the drug. Viscosity can be measured in a variety of ways, including vibration viscometers, capillary viscometers, rotational rheometers, microfluidic rheometers, and non-contact rheometers. Unless otherwise defined, all viscosities mentioned herein are measured by rotational rheometers. Preferably, the viscosity of the preparation 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 preparation can be subjected to a steady-state flow method (0.1 to 100s -1 ) to characterize the flow characteristics, and obtain a low (2.0s -1 ), medium (20.0s -1 ) and high (75.0s -1 ) viscosity value under shear rate. In a preferred embodiment, the shear rate (shear viscosity value) of the gel is 75.0 to 85.0s -1 , the shear rate of the cream is 60.0 to 70.0s -1 In particular, the viscosity of the formulation according to the present invention is from 0.85 Pa·s to 35 Pa·s, preferably from 1 Pa·s to 10 Pa·s, more preferably from 2.5 Pa·s to 4 Pa·s, more preferably from 3 Pa·s to 3.7 Pa·s, and most preferably from 3.1 Pa·s to 3.35 Pa·s, measured at 25°C using a laboratory digital Brookfield viscometer and a gel shear rate of 75.0s -1 to 85.0s -1, the shear rate of the cream is 60.0s -1 to 70.0s -1 .

[0053] β-D-mannuronic acid has the following formula (I):

[0054]

[0055] α-L-guluronic acid has the following formula (II):

[0056]

[0057] Because mannuronic acid and guluronic acid are diastereomers, they share many physicochemical properties as well as biological and pharmaceutical characteristics, such as anti-inflammatory agents with immunosuppressive and immunomodulatory activities. 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, their pharmaceutically acceptable salts, or mixtures thereof, and vice versa.

[0058] According to the present invention, β-D-mannuronic acid or α-L-guluronic acid or a mixture thereof can be included in the gel or cream 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.

[0059] Thus, in various embodiments, a gel or cream formulation for topical use may be:

[0060] (i) a mannuronate gel or cream preparation; or

[0061] (ii) a guluronate gel or cream preparation; or

[0062] (iii) Guluomannuronate gel or cream preparation.

[0063] In various embodiments, the gel or cream formulation comprising β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof is a mannuronate gel or cream 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.

[0064] In various embodiments, β-D-mannuronate, preferably β-D-mannuronate, can also be added to the gel or cream 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.

[0065] 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.

[0066] In various embodiments, the gel or cream formulation comprising α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof is a guluronate gel or cream formulation. Specifically, in various embodiments, the α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof may be an 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.

[0067] In various embodiments, α-L-guluronic acid, preferably α-L-guluronate, can also be added to the gel or cream formulation 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.

[0068] 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.

[0069] In various embodiments, the gel or cream formulation comprising a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts is a gulomannuronate gel or cream formulation. 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, ammonium β-D-mannuronate and combinations thereof, and sodium α-L-guluronate, potassium α-L-guluronate, magnesium α-L-guluronate, calcium α-L-guluronate, ammonium α-L-guluronate and combinations thereof, and particularly preferably a mixture of sodium β-D-mannuronate and sodium α-L-guluronate.

[0070] In various embodiments, a mixture of β-D-mannuronic acid and α-L-guluronic acid, preferably guluromannuronate, can also be added to the gel or cream formulation 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 α-L-guluronate. - (homo)oligomers of 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.

[0071] In various embodiments, β-D-mannuronic acid and / or α-L-guluronic acid, oligomers thereof or pharmaceutically acceptable salts thereof (preferably guluronic acid salts) 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, 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.

[0072] 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.

[0073] 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 a gel or cream formulation 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. Thus, in various embodiments, the gel or cream formulation comprises alginate hydrolysate (gulomannuronate) at the concentrations described herein, preferably 0.5 g to 40 g / 100 g gel or cream, more preferably 0.5 g to 35 g / 100 g gel or cream, more preferably 1 g to 30 g / 100 g gel or cream, more preferably 5 g to 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 gel or cream.

[0074] Preferably, the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers or their pharmaceutically acceptable salts (preferably guluromannuronate) can be:

[0075] (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

[0076] (2) Alginate hydrolyzate (powder).

[0077] In various embodiments, the total amount of the following components in the gel or cream formulation is 0.5 g to 35 g / 100 g of gel or cream, 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 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, more preferably 5 g to 15 g / 100 g of gel or cream, and most preferably 5 g to 10 g / 100 g of gel or cream:

[0078] (i) β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof, or

[0079] (ii) α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts thereof, or

[0080] (iii) a mixture of β-D-mannuronic acid or α-L-guluronic acid, oligomers thereof or pharmaceutically acceptable salts thereof.

[0081] In one embodiment, the total amount of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof in the gel or cream formulation, preferably in the 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 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, more preferably 5 g to 15 g / 100 g of gel or cream, and most preferably 5 g to 10 g / 100 g of gel or cream.

[0082] 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 in the guluronate 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 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, more preferably 5 g to 15 g / 100 g of gel or cream, and most preferably 5 g to 10 g / 100 g of gel or cream.

[0083] In another embodiment, the total amount of the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers or pharmaceutically acceptable salts thereof in the gel or cream formulation, preferably in the gulomomannuronate 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 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, more preferably 5 g to 15 g / 100 g of gel or cream, and most preferably 5 g to 10 g / 100 g of gel or cream.

[0084] According to the present invention, the gel or cream formulation for topical use further comprises 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, 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.

[0085] 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 food sources, such as apples, pears, artichokes, and berries. In various embodiments, caffeic acid may play a variety of roles in the body, including anti-inflammatory effects. Caffeic acid is commercially available, for example, from Sigma Aldrich, or can be isolated from coffee or other food sources.

[0086] Preferably, the formulation of the present invention is used as an anti-inflammatory topical gel or cream formulation.

[0087] In various embodiments, the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers or their pharmaceutically acceptable salts, preferably guluromannuronate gel or cream formulation, comprises or consists of:

[0088] 0.1 g to 39.9 g of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof, and

[0089] 0.1g to 39.9g of α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts thereof, provided that, based on 100g of the gel or cream 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 is at least 0.5g and at most 40g; preferably, based on 100g of the gel or cream preparation, the total amount of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof is 0.1g to 39.9g. The 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 20 g, more preferably 5 g to 15 g, and most preferably 5 g to 10 g. Based on 100 g of the gel or cream preparation, 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 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 can be: 5.01 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. In one embodiment, based on 100 g of the gel or cream formulation, the mixture comprises or consists of 5 g of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof and 5 g of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof. 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.

[0090] The above concentration ranges for different gel or cream formulations mean that, in addition to the caffeic acid defined herein, the gel or cream formulation of the present invention further comprises, based on the total weight of the gel or cream formulation, 0.5 to 40 wt%, preferably 0.5 to 35 wt%, more preferably 1 to 30 wt%, more preferably 2 to 20 wt%, more preferably 5 to 20 wt%, for example 5 wt%, 10 wt%, 15 wt% or 20 wt%, more preferably 5 to 15 wt%, most preferably 5 to 10 wt% of the following components:

[0091] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0092] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0093] (iii) a mixture of β-D-mannuronic acid, an oligomer thereof, or a pharmaceutically acceptable salt thereof and α-L-guluronic acid, an oligomer thereof, or a pharmaceutically acceptable salt thereof.

[0094] In various embodiments, the gel or cream formulation of the present invention may comprise 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) agents, drugs and / or herbs.

[0095] In various embodiments, the gel or cream formulation comprises at least one additional pharmaceutical agent.

[0096] In various embodiments, the at least one additional agent is selected from, but not limited to, analgesics, anti-inflammatory agents, and agents with anti-allergic properties, or combinations thereof.

[0097] In the context of the present invention, analgesics are defined as drugs that eliminate, relieve or reduce pain. Examples include, but are not limited to, menthol, lidocaine, camphor, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids.

[0098] 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 diclofenac, naproxen or ibuprofen, and / or corticosteroids, such as cortisol, cortisone, betamethasone, but are not limited to these.

[0099] The agents with anti-allergic properties that can be added to the gel or cream formulation for topical use according to the present invention are all anti-allergic or anti-allergic (desensitizing) agents that are safe for human use. Examples include, but are not limited to, antihistamines and diphenhydramine hydrochloride.

[0100] 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, or an anti-allergic or anti-sensitivity (desensitizing) agent such as an antihistamine and diphenhydramine hydrochloride.

[0101] Thus, in various embodiments, the gel or cream formulation for topical use according to the present invention is an analgesic topical gel or cream formulation, and / or an anti-inflammatory topical gel or cream formulation, and / or a gel or cream formulation having anti-allergic properties.

[0102] In various embodiments, the gel or cream formulations may contain other ingredients known to those skilled in the art and conventionally used in such formulations, such as (one or more) adjuvants (carriers, skin protectants, disinfectants, preservatives, gel-forming substances, emulsifiers, etc.).

[0103] For example, the following adjuvants may be used in the formulations of the present invention, but are not limited to: particulate carriers (e.g., talc, zinc oxide, starch, starch derivatives, diatomaceous earth); gel-forming substances (e.g., gelatin, tragacanth gum, cellulose, cellulose derivatives, alginates, polyacrylic acid); cream-forming substances (e.g., lanolin, beeswax, olive oil, peanut oil, liquid paraffin); humectants (e.g., urea, glycerol, propylene glycol); pressure-sensitive polymers (e.g., polyacrylates and adhesive resins); ointment bases (e.g., petroleum jelly, fats, cellulose derivatives, polyacrylic acid, alginates); emulsifiers (e.g., sodium lauryl sulfate "SLS", stearic acid, lanolin, lecithin, sorbitan esters); esters), monoglycerides); preservatives (e.g., alcohols, glycols, benzoates and their derivatives, such as benzalkonium chloride); antioxidants (e.g., butylated hydroxyanisole, vitamin E, ascorbic acid and its derivatives); thickeners (e.g., hydroxypropyl methylcellulose); pH adjusters; binders (e.g., polyvinyl pyrrolidone, starch, hydroxypropyl methylcellulose, polyethylene glycol); fillers (e.g., microcrystalline cellulose, sorbitol); colorants; flavorings; sweeteners (e.g., sorbitol, aspartame); solvents (e.g., such as water, ethanol, ethanol-water mixtures); solubilizers (such as glycerol, propylene glycol); skin penetration enhancers (such as alcohols, terpenes, propylene glycol); plasticizers (such as sorbitol, glycerol, phthalates); wetting agents (such as sodium lauryl sulfate, polysorbates); synthetic and natural oils (such as medium-chain triglycerides, paraffin, synthetic and / or natural waxes, sweet almond oil); propellants for aerosols or foam sprays (such as norflurane, creflurane, dichlorofluoromethane, trichlorofluoromethane, propane, butane, isobutane, nitrogen).

[0104] In various embodiments, the at least one additional ingredient is selected from the group consisting of preservatives, alkaline agents, colorants, flavors, gel-forming substances, cream-forming substances, emulsifiers, thickeners, and combinations thereof.

[0105] In various embodiments, the gel or cream formulation comprises at least one preservative, preferably selected from 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.

[0106] The gel or cream formulation may be free or substantially free of parabens.

[0107] In various embodiments, the gel or cream formulation is free or substantially free of antibacterial and / or antifungal agents.

[0108] In various embodiments, the gel or cream formulation is free or substantially free of parabens, antibacterial agents, and antifungal agents.

[0109] Preferably, the gel or cream formulation is a gel formulation.

[0110] Preferably, the gel formulation according to the invention comprises at least one gel-forming substance and / or at least one thickening agent.

[0111] Preferably, suitable gel-forming materials are selected from pharmaceutical-grade components. Suitable polymers include, but are not limited to, highly absorbent polymers, such as those disclosed in WO 92 / 16245, which comprise hydrophilic cellulose derivatives partially cross-linked to form a three-dimensional structure. Such polymers are highly absorbent because they can absorb at least ten times their own weight in water. The cross-linked structure of the polymer renders it insoluble in water, but water is readily absorbed and retained within the polymer's three-dimensional structure to form a gel. The rate of water loss from such a gel is lower than that from a solution.

[0112] In various embodiments, sodium carboxymethylcellulose, hydroxyethylcellulose, carbomer (polyacrylate / polyacrylic acid; eg, in powder form), and xanthan gum may be advantageously used as gel-forming substances.

[0113] In particular, the at least one gel-forming substance is selected from carbomers ((homo)polymers of acrylic acid and its salts), celluloses, alginates or derivatives thereof or combinations thereof, typically of pharmaceutical grade quality.

[0114] In particular, carbomer (acrylic acid polymer) is used as a suitable base for many commercial gels, which readily absorb water and form a gel on contact.

[0115] For example, carbomer is commercially available under the trade names Carbomer 104, Carbomer 934, Carbomer 934P, Carbomer 940, Carbomer 941, Carbomer 974P, Carbomer 980, Carbomer 1342, Carbomer sodium salt, etc., where the numbers refer to molecular size and adhesion.

[0116] In a preferred embodiment, the gel formulation of the present invention comprises Carbomer 934 (P).

[0117] The gel-forming material (preferably carbomer) is preferably present in an amount of from about 0.8 wt % to about 6.0 wt %, more preferably from about 1.5 wt % to about 4 wt %, more preferably from about 2.0 wt % to about 3.0 wt %, for example 2.5 wt %, based on the total weight of the gel formulation.

[0118] 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.

[0119] In various embodiments, the cream-forming material may be selected from lanolin, beeswax, olive oil, coconut oil, avocado oil, peanut oil, argan oil and / or petrolatum (petroleum jelly), essential oils, mineral oils and / or synthetic oils (e.g., liquid paraffin, glycerin, zinc oxide, butyl stearate and diethylene glycol laurate), or combinations thereof.

[0120] Suitable emulsifiers can be anionic, cationic, neutral, amphoteric or composite emulsifiers or combinations thereof, and / or synthetic or natural emulsifiers or combinations thereof. In a preferred embodiment, at least one emulsifier is a synthetic and / or natural emulsifier, preferably selected from lecithin, lanolin, sorbitan esters, cetyl alcohol, cetearyl alcohol, stearic acid, (mono) stearin, mono / diglycerides, sodium lauryl sulfate (SLS), benzalkonium chloride, polyoxyethylene castor oil, carnauba wax, candelilla wax, beeswax or combinations thereof.

[0121] Preferred natural emulsifiers are, for example, lanolin, lecithin, carnauba wax, candelilla wax, beeswax, or a combination thereof.

[0122] In various embodiments, the gel or cream formulation may include at least one alkaline agent, for example in solution, typically used to adjust the pH of the gel or cream formulation.

[0123] According to the present invention, the gel or cream formulation is preferably administered topically, preferably to a subject in need thereof.

[0124] In a preferred embodiment, the subject is a mammal, particularly a human.

[0125] In a preferred embodiment, the gel or cream formulations of the present invention are for topical use in a method of treating (or preventing) the following conditions:

[0126] i) inflammation and / or any inflammatory reaction, preferably joint and / or muscle inflammation and / or any inflammatory reaction; and / or

[0127] ii) pain, preferably joint and / or muscle pain.

[0128] In other preferred embodiments, the gel or cream formulations of the present invention are topically administered to a subject in need thereof in a method for treating (or preventing) the following conditions:

[0129] i) inflammation and / or any inflammatory reaction, preferably joint and / or muscle inflammation and / or any inflammatory reaction; and / or

[0130] ii) pain, preferably joint and / or muscle pain.

[0131] In such embodiments, it is particularly preferred that the gel or cream formulation comprises at least one additional agent, preferably at least one analgesic, anti-inflammatory, or agent with anti-allergic properties, or a combination thereof, wherein the additional agent is as described herein.

[0132] In various embodiments, the gel or cream formulation comprises at least one additional agent, preferably selected from menthol, lidocaine, camphor, nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, naproxen or ibuprofen, corticosteroids such as Cortisol, cortisone or betamethasone, opioids, or anti-allergic or anti-sensitivity (desensitization) agents such as antihistamines and diphenhydramine hydrochloride.

[0133] Preferably, the at least one additional agent is, but is not limited to, a nonsteroidal anti-inflammatory drug (NSAID) and / or a corticosteroid.

[0134] In another aspect, the present invention relates to a method for preparing the gel or cream formulation of the present invention. The gel or cream formulation is a gel or cream formulation for topical use as described herein.

[0135] According to the present invention, the gel or cream preparation obtained by the method of the present invention comprises:

[0136] Based on 100g of the gel or cream preparation, the total amount is 0.5g to 40g, preferably the total amount is 0.5g to 35g, more preferably the total amount is 1g to 30g / 100g gel or cream, more preferably 2g to 20g / 100g gel or cream, most preferably 5g to 20g / 100g 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, especially 5g to 10g / 100g gel or cream of the following components:

[0137] (i) β-D-mannuronate, its oligomers, or pharmaceutically acceptable salts thereof, preferably β-D-mannuronate; or

[0138] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably α-L-guluronic acid salt; or

[0139] (iii) a mixture of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof (preferably β-D-mannuronate) and α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof (preferably α-L-guluronate);

[0140] And further caffeic acid or a salt thereof (e.g. in powder form), preferably in an amount of 0.001 to 1 wt %, more preferably 0.01 to 0.5 wt %, more preferably 0.05 to 0.3 wt %, for example 0.1 to 0.3 wt %, based on the total weight of the gel or cream formulation.

[0141] This means that the gel or cream formulation of the present invention comprises:

[0142] Based on the total weight of the gel or cream preparation, preferably 100 g of the gel or cream preparation (final preparation), 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, most preferably 5 to 10% by weight of the following components:

[0143] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0144] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0145] (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;

[0146] And further caffeic acid or a salt thereof (e.g. in powder form), the content is preferably 0.001 to 1 wt %, more preferably 0.01 to 0.5 wt %, more preferably 0.05 to 0.3 wt %, for example 0.1 to 0.3 wt %, based on the total weight of the gel or cream formulation (final formulation).

[0147] In various embodiments, in the method according to the present invention, β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof (preferably β-D-mannuronate) and / or α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts thereof (preferably α-L-guluronate) are added in powder form.

[0148] In an embodiment where the resulting gel or cream preparation is a guluromannuronate gel or cream preparation comprising a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers or pharmaceutically acceptable salts thereof (preferably β-D-mannuronate and α-L-guluronate), the gel or cream preparation preferably comprises or consists of:

[0149] Caffeic acid, preferably in an amount of 0.001 to 1 wt%, more preferably 0.01 to 0.5 wt%, more preferably 0.05 to 0.3 wt%, for example 0.1 to 0.3 wt%, based on the total weight of the gel or cream formulation, and

[0150] 0.1 g to 39.9 g of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, and

[0151] 0.1 g to 39.9 g of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof,

[0152] Provided that, based on 100 g of the gel or cream 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 is at least 0.5 g and at most 40 g; preferably, based on 100 g of the gel or cream preparation, the total amount of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof 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, most preferably 5 g to 10 g; and

[0153] Based on 100 g of the gel or cream formulation, the 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 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 can 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.

[0154] 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 guluronic acid gel or cream formulation. Preferably, the total amount of alginate hydrolysate (powder) used is 0.5g to 40g / 100g of gel or cream formulation, more preferably 5g to 20g / 100g of gel or cream formulation, and most preferably 5g to 10g / 100g of gel or cream formulation.

[0155] In various embodiments, β-D-mannuronate, its oligomers or pharmaceutically acceptable salts thereof (preferably β-D-mannuronate) is 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, 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 mannuronate gel or cream formulations.

[0156] In various embodiments, α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts thereof (preferably α-L-guluronate) is 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, 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 gel or cream preparations.

[0157] 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 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 their and / or their oligomers, preferably their homo-oligomers, consisting of sodium oligomannuronate or potassium oligomannuronate or magnesium oligomannuronate or calcium oligomannuronate or ammonium oligomannuronate and sodium oligoguluronate or potassium oligoguluronate or magnesium oligoguluronate or calcium oligoguluronate or ammonium oligoguluronate and combinations thereof, wherein sodium β-D-mannuronate, sodium α-L-guluronate, sodium oligomannuronate and sodium oligoguluronate and combinations thereof are preferred in the guluromannuronate gel or cream preparation.

[0158] In particular, the oligomannuronate or oligoguluronate comprises 2 to 16 β-D-mannuronic acid monomers or α-L-guluronic acid monomers, preferably 3 to 6 β-D-mannuronic acid monomers or α-L-guluronic acid monomers, such as 3 or 4 or 5 or 6 β-D-mannuronic acid monomers or α-L-guluronic acid monomers.

[0159] In a preferred embodiment, the gel or cream formulation obtained by the process of the present invention may comprise at least one further pharmaceutical agent, preferably selected from analgesics, anti-inflammatory agents and / or agents with anti-allergic properties as described above.

[0160] Thus, in various embodiments, the method of the present invention is a method for preparing an analgesic gel or cream formulation, an anti-inflammatory gel or cream formulation, and / or a gel or cream formulation having anti-allergic properties.

[0161] The gel or cream preparation obtained by the method of the present invention may further comprise at least one other ingredient, for example, one or more adjuvants described herein.

[0162] Preferably, the method is used to prepare the gel preparation of the present invention, wherein the method comprises the following steps:

[0163] (i) providing a (first) solution comprising at least one gel-forming substance and optionally at least one preservative;

[0164] (ii) providing a (second) solution, said (second) solution:

[0165] (a) containing β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof, preferably β-D-mannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, based on 100 g of the gel preparation; or

[0166] (b) containing 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, based on 100 g of the gel preparation; or

[0167] (c) a mixture comprising β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof, preferably guluromannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, based on 100 g of the gel preparation;

[0168] (iii) optionally providing at least one other solution;

[0169] (iv) optionally adjusting the pH of the second solution to a pH of 1 to 5, preferably 2 to 4, more preferably 3;

[0170] (v) mixing the solutions of step i) and step ii) and optionally step iii); and

[0171] (vi) optionally adjusting the pH to 4 to 8, more preferably 5 to 7, most preferably 5.5 to 6.5;

[0172] The caffeic acid or its salt is contained in at least one of the first solution of step i), the second solution of step ii), and the optional at least one other solution of step iii), for example, in the form of a powder, preferably such that: based on the total weight of the gel preparation, the total amount of caffeic acid in the gel preparation 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 %.

[0173] If caffeic acid is absent in both the first solution and the second solution, step iii) is not optional and caffeic acid is present in at least one of the other solutions.

[0174] 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 in / mixed with water (preferably deionized water) to obtain the (first) solution.

[0175] Preferably, the gel-forming substance is polyacrylic acid (carbomer), cellulose, alginate or a derivative or combination thereof, preferably a (homo)polymer of acrylic acid (eg carbomer).

[0176] Further preferably, the final concentration of at least one gel-forming substance, preferably polyacrylic acid (carbomer), in the gel preparation is from about 0.8 wt % to about 6.0 wt %, preferably from about 1.5 wt % to about 4 wt %, more preferably from about 2.0 wt % to about 3.0 wt %, for example about 2.5 wt %, based on the total weight of the gel preparation, preferably based on 100 g of the gel preparation.

[0177] In various preferred embodiments, the (second) solution of step ii) is an aqueous solution. Further preferably, the following is dissolved in water, preferably deionized water, to obtain the (second) solution: β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof (preferably β-D-mannuronic acid for mannuronic acid gel formulations), or α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof (preferably α-L-guluronic acid for guluronic acid gel formulations), or a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof (preferably β-D-mannuronic acid and α-L-guluronic acid, particularly guluronic acid, for guluronic acid salt gel formulations). The concentration is preferably as described above for the general method for preparing gel or cream formulations, so that the concentration in the final formulation is as described herein. In various embodiments, alginate hydrolyzate (powder) can be used as guluromannuronate (as a mixture of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof and α-L-guluronan, its oligomers, or pharmaceutically acceptable salts thereof) in a guluromannuronate gel formulation and dissolved in water (preferably deionized water) to obtain a (second) solution. Preferably, the alginate hydrolyzate (powder) is added in an amount such that a concentration of 0.5 g to 40 g / 100 g of the gel formulation is obtained, more preferably 5 g to 20 g / 100 g of the gel formulation, and most preferably 5 g to 10 g / 100 g of the gel formulation is obtained.

[0178] After the solutions of step i) and step ii) are prepared, the solution of step ii) is mixed with the solution of step i).

[0179] In various embodiments, before and / or after mixing, a solution of an alkaline agent is added to at least one of the solutions, preferably to the (second) solution of step ii), or to the gel formulation after mixing, to adjust the pH. If the gel is a water-based gel, the alkaline agent solution is preferably a NaOH solution.

[0180] In a preferred embodiment, an alkaline agent solution (preferably NaOH solution) is added to the dissolved mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or a mixture of mannuronic acid and guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof in step ii) to adjust the pH, preferably, to a pH of 1 to 5, more preferably 2 to 4, for example a pH of 3.

[0181] 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.

[0182] 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, as measured at 25°C using a laboratory digital Brookfield viscometer (rotational viscometer). In various embodiments, the formulation is subjected to a steady-state flow method (0.1 to 100 s -1 ) to characterize the flow characteristics, and the low (2.0s at 25 ° C -1 ), medium (20.0s -1 ) and high (75.0s -1 ) viscosity value under shear rate. In a preferred embodiment, the shear rate (shear viscosity value) of the gel is 75.0 to 85.0s -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, most preferably 3.1 Pa·s to 3.35 Pa·s, at 25°C and a shear rate of 75.0s -1 -85.0s -1 The viscosity was measured using a laboratory digital Brookfield viscometer under the conditions of .

[0183] In a preferred embodiment, the solution of step i) and / or the solution of step ii) may comprise at least one further pharmaceutical agent, preferably selected from analgesics, anti-inflammatory agents and / or agents with anti-allergic properties as described above.

[0184] Thus, in various embodiments, the method of the present invention is a method of preparing an analgesic gel formulation, an anti-inflammatory gel formulation, and / or a gel formulation having anti-allergic properties.

[0185] The (first) solution of step i) and / or the (second) solution of step ii) may further comprise at least one further ingredient, for example one or more adjuvants as described herein.

[0186] Other pharmaceutical agents and / or other ingredients (auxiliaries) may also be contained in other solutions, for example, in a third solution or a fourth solution that can be added in a subsequent step (optional step iii).

[0187] Preferably, if further solutions are present, they are also aqueous solutions as described above. In various embodiments, the pH may be adjusted, preferably as described above, prior to mixing with the solutions of steps i) and / or ii).

[0188] In various embodiments, if other solutions are present, they are mixed with the solution of step i) and / or the solution of step ii) or a mixture of both. Subsequently, preferably, the pH is adjusted to 4 to 8, more preferably 5 to 7, most preferably 5.5 to 6.5.

[0189] Additional water may be added to the resulting solution to obtain the gel formulation of the present invention. This step is optional, for example, to adjust the final concentration of the components of the gel formulation and / or to adjust the consistency and / or viscosity of the gel formulation.

[0190] In various embodiments, the method comprises the steps of:

[0191] (i) providing a (first) solution comprising at least one gel-forming substance and optionally at least one other pharmaceutical agent and / or at least one other ingredient (e.g. at least one preservative);

[0192] (ii) providing a (second) solution, said (second) solution comprising:

[0193] (a) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts 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, most preferably 5 g to 10 g, based on 100 g of the gel preparation; or

[0194] (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 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, most preferably 5 g to 10 g, based on 100 g of the gel preparation; or

[0195] (c) a mixture of β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof (preferably guluromannuronate), 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, most preferably 5 g to 10 g, based on 100 g of the gel preparation; and

[0196] optionally at least one other agent and / or at least one other ingredient;

[0197] (iii) optionally providing at least one further solution comprising caffeic acid and / or at least one further agent and / or at least one further ingredient;

[0198] (iv) optionally adjusting the pH of the second solution to a pH of 1 to 5, preferably 2 to 4, more preferably 3;

[0199] (v) mixing the solutions of step i) and step ii) and optionally step iii);

[0200] (vi) optionally adjusting the pH of the resulting solution to 4 to 8, more preferably 5 to 7, most preferably 5.5 to 6.5;

[0201] (vii) optionally adjusting 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, most preferably 3.1 Pa·s to 3.35 Pa·s, in a laboratory digital Brookfield viscometer (rotational viscometer) at 25°C and preferably a shear rate of 75.0 s -1 -85.0s -1 Measured under the conditions of

[0202] (viii) optionally adding water to the resulting solution to obtain a gel formulation, preferably a gel formulation as described herein;

[0203] The caffeic acid or its salt is contained in at least one of the first solution of step i), the second solution of step ii), and the optional at least one other solution of step iii), for example, in the form of a powder, preferably such that: based on the total weight of the gel preparation, the total amount of caffeic acid in the gel preparation 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 %.

[0204] In various embodiments, the method according to the present invention is a method for preparing a cream formulation according to the present invention.

[0205] 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.

[0206] Water-in-oil (W / O) or oil-in-water (O / W) emulsions are known to those skilled in the art and can be prepared conventionally. Preferably, the (topical) cream formulation contains a higher content of oily / lipophilic substances than the gel. In one embodiment, the cream formulation of the present invention comprises about 60 to 75% by weight of an aqueous base and about 20 to 30% by weight of an oily base, based on the total weight of the cream formulation.

[0207] According to the present invention, the cream formulation may comprise:

[0208] (a) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably β-D-mannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, based on 100 g of the cream preparation; or

[0209] (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, based on 100 g of the cream preparation; or

[0210] (c) a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably guluromannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, based on 100 g of the cream formulation. In various embodiments, alginate hydrolysate (powder) can be added as guluromannuronate (as a mixture of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof and α-L-guluromannuronate, its oligomers, or pharmaceutically acceptable salts thereof) for use in the guluromannuronate cream formulation. Preferably, an alginate hydrolyzate (powder) is added in an amount of 0.5 g to 40 g / 100 g of the cream formulation, more preferably 5 g to 20 g / 100 g of the cream formulation, and most preferably 5 g to 10 g / 100 g of the cream formulation, and additionally caffeic acid or a salt thereof (e.g., in powder form), the content of which 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 %, based on the total weight of the cream formulation.

[0211] Further ingredients include, for example, at least one cream-forming substance, at least one emulsifier, at least one plasticizer, such as cetyl stearoyl 2-ethylhexanoate, and / or at least one preservative as described above.

[0212] Preferably, the method is used to prepare the cream preparation according to the present invention, wherein the method comprises the following steps:

[0213] (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;

[0214] (ii) providing a (second) composition, said (second) composition:

[0215] (a) containing β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably β-D-mannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g, based on 100 g of the cream preparation; or

[0216] (b) containing 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, based on 100 g of the cream preparation; or

[0217] (c) a mixture comprising β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably guluromannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g, based on 100 g of the cream preparation;

[0218] (iii) optionally, adding at least one other agent and / or at least one other ingredient in the first step, the second step, or other steps;

[0219] (iv) optionally adjusting the pH of the second solution to a pH of 1 to 5, preferably 2 to 4, more preferably 3;

[0220] (v) mixing the solutions of i) and ii);

[0221] (vi) optionally adjusting the pH to 4 to 8, more preferably 5 to 7, most preferably 5.5 to 6.5;

[0222] In the first step and / or the second step and / or other optional steps, caffeic acid or a salt thereof (for example, in powder form) is added, preferably so that the total amount of caffeic acid in the cream preparation is 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 cream preparation.

[0223] Preferably, in step i), a semi-solid composition or emulsion is prepared, 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.

[0224] Further suitable ingredients include, for example, at least one thickener as described herein and / or at least one (organic) solvent, such as propylene glycol.

[0225] The other pharmaceutical agents are preferably those described above.In various embodiments, the method of the present invention is a method for preparing an analgesic cream formulation, an anti-inflammatory cream formulation and / or a cream formulation with anti-allergic properties.

[0226] 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 production.

[0227] The gel or cream formulations of the present invention can be filled or packaged in any suitable packaging, such as tubes, films or other packaging. These packaging can be made of any suitable material, such as aluminum-based tubes or low melting point polyolefin packaging, such as polyethylene packaging.

[0228] All embodiments and examples described herein for the topical gel or cream formulations of the present invention also apply to topical gel or cream formulations for use in a method for treating inflammation and / or any inflammatory reaction and / or pain, and methods for preparing the same, and vice versa.

[0229] Other embodiments are described in the following non-limiting examples.

[0230] Example

[0231] 1. A method for preparing mannuronic acid, guluronic acid and guluronic acid salt powders from sodium alginate.

[0232] Mannuronic acid, guluronic acid and guluronic acid salt were synthesized according to the WHO GMP standards for material production.

[0233] To synthesize "β-D-mannuronic acid," "α-L-guluronic acid," and "guluronic acid salt," sodium alginate (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 light cream to light brown. The hydrolyzate was cooled to room temperature and the precipitate was separated by centrifugation (3700 g). The precipitate was used as guluronic acid salt (alginate hydrolyzate). The precipitate was re-dissolved by neutralizing it with a 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) was spread on a petri dish and dried to obtain α-L-guluronic acid in powder form. The powder can be used in guluronate gel or cream preparations, and / or in a mixture of β-D-mannuronic acid and α-L-guluronate gel or cream preparations. The remaining supernatant of the α-L-guluronate precipitation 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 on a petri dish and dried to obtain β-D-mannuronic acid in powder form. It can be used in mannuronic acid gel or cream preparations, and / or in a mixture of β-D-mannuronic acid and α-L-guluronate gel or cream preparations. The precipitate was determined by Fourier transform infrared spectroscopy (FT-IR) and carbon-13 nuclear magnetic resonance (C-NMR). 13 C-NMR) spectroscopy confirmed the identity and purity of α-L-guluronic acid and β-D-mannuronic acid.

[0234] The supplied powders (mannuronic acid) and (guluronic acid) are stored dry and sterile at room temperature (22 to 26°C) to prepare topical gels or creams.

[0235] 2. Preparation of Mannouronate, Guluronate, and Guluromannuronate Topical Gels

[0236] I): In the first step, the preferred preservative is dissolved in 70 mL of boiling deionized water, and then 2.5 g of Carbomer 934P is added to obtain a clear and transparent solution. After cooling, the solution is cooled (Solution 1).

[0237] II): In another glass beaker:

[0238] IIa): For the mannuronic acid gel preparation, 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).

[0239] IIb): For the guluronate gel preparation, 10 g of guluronate 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 guluronate (solution 2b).

[0240] IIc): For the preparation of a gulaumannuronate gel, 5 g of mannuronic acid powder and 5 g of guluronic acid powder were added to 20 mL of deionized water, and the pH was adjusted to 3 by adding 30% NaOH to dissolve the powder (Solution 2c). Another method for preparing a gulaumannuronate gel utilizes the first precipitate produced during the hydrolysis of sodium alginate. To this end, 10 g of gulaumannuronate (sodium alginate hydrolyzate) powder was added to 20 mL of deionized water, and 30% NaOH was added until the pH reached 3 to dissolve the powder (Solution 2c).

[0241] III): After adding (Solution 2) to (Solution 1) to obtain a clear solution, slowly adjust the pH to 5.5-6 (Solution 3).

[0242] IV): Deionized water was added (solution 3) until the total (final) weight reached 100 g.

[0243] V): Synthetic mannuronate topical gel (using solution 2a) and guluronate topical gel (using solution 2b) and guluromannuronate topical gel (using solution 2c) can be packaged under sterile conditions and then stored.

Claims

1. A gel or cream formulation for topical use, 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, Based on 100 g of the gel or cream 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 0.5 g to 40 g; The gel or cream 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 gel or cream 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 %, more preferably 0.05 wt % to 0.3 wt %, such as 0.1 wt % to 0.3 wt %.

2. The gel or cream preparation according to claim 1, wherein 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, as measured using a laboratory digital Brookfield viscometer (rotational viscometer) at 25°C and a shear rate of 75.0s for the gel. -1 to 85.0s -1 Or the shear rate of the cream is 60.0s -1 to 70.0s -1 Measured under the conditions of .

3. The gel or cream preparation according to claim 1 or 2, 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, 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).

4. The gel or cream preparation according to any one of claims 1 to 3, 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.

5. The gel or cream preparation according to claim 4, 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, ammonium oligomannuronate, and sodium oligoguluronate, potassium oligoguluronate, magnesium oligoguluronate, calcium oligoguluronate, 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.

6. The gel or cream preparation according to any one of claims 1 to 5, wherein The total amount of the following components in the gel or cream preparation is 1 g to 30 g / 100 g of gel or cream, more preferably 5 g to 20 g / 100 g of gel or cream, and most preferably 5 g to 10 g / 100 g 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, oligomers thereof or pharmaceutically acceptable salts thereof.

7. The gel or cream preparation according to claim 6, wherein The mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts, preferably the guluromannuronate preparation, 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, based on 100 g of the gel or cream 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 is at least 0.5 g and at most 40 g; preferably, Based on 100 g of the gel or cream preparation, the total amount of β-D-mannuronic 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, most preferably 5 g to 10 g; and Based on 100 g of the gel or cream preparation, 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.

8. The gel or cream preparation according to any one of claims 1 to 7, wherein The gel or cream formulation comprises at least one further medicament, preferably selected from analgesics, anti-inflammatory agents and agents with anti-allergic properties or combinations thereof.

9. The gel or cream preparation according to any one of claims 1 to 8, wherein The gel or cream formulation further comprises at least one other ingredient selected from the group consisting of preservatives, alkaline agents, colorants, fragrances, gel-forming substances, emulsifiers, and combinations thereof.

10. The gel or cream preparation according to claim 9, wherein The at least one preservative is selected from antibacterial agents, antifungal agents, alcohols, glycols, benzoates and / or their derivatives, essential oils, or combinations thereof.

11. The gel or cream preparation according to any one of claims 1 to 10, wherein The gel or cream formulation is free or substantially free of parabens and / or antibacterial and / or antifungal agents.

12. The gel preparation according to any one of claims 9 to 11, wherein The at least one gel-forming substance is polyacrylic acid (carbomer), cellulose, alginate or a derivative thereof or a combination thereof, preferably a (homo)polymer of acrylic acid (carbomer).

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

14. The gel or cream preparation according to any one of claims 1 to 13, wherein The gel or cream formulation is for topical use in a method of treating (or preventing) the following conditions: (i) inflammation and / or any inflammatory reaction, preferably joint and / or muscle inflammation and / or any inflammatory reaction; and / or (ii) pain, preferably joint and / or muscle pain.

15. A method for preparing the gel or cream preparation according to any one of claims 1 to 13, wherein: The method is preferably used to prepare a gel formulation, and the method comprises the following steps: (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: (a) containing β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof, preferably β-D-mannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, based on 100 g of the gel preparation; or (b) containing 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, based on 100 g of the gel preparation; or (c) a mixture comprising β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof, preferably guluromannuronate, in a total amount of 0.5 g to 40 g, preferably 5 g to 10 g, based on 100 g of the gel preparation; (iii) optionally providing at least one other solution; (iv) optionally adjusting the pH of the second solution to a pH of 1 to 5, preferably 2 to 4, more preferably 3; (v) mixing the solutions of step i) and step ii) and optionally step iii); as well as (vi) optionally adjusting the pH to 4 to 8, more preferably 5 to 7, most preferably 5.5 to 6.5; Wherein, caffeic acid or a salt thereof, for example, caffeic acid or a salt thereof in powder form is contained in at least one of the first solution of step i), the second solution of step ii), and optionally at least one other solution of step iii), preferably such that: based on the total weight of the gel preparation, the total amount of caffeic acid in the gel preparation 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 %.

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