Viscous formulation containing tetrahydropyrimidines

Abstract

The present invention relates to a viscous formulation having an adjustable viscosity, comprising a composition containing at least one tetrahydropyrimidine-4-carboxylic acid and / or a derivative thereof and at least one or more compounds selected from the group of cellulose ethers and glycosaminoglycans. In the formulation, the new use of the tetrahydropyrimidine-4-carboxylic acid or one of the derivatives thereof as a viscosity-increasing agent is particularly advantageous. The viscous formulation according to the invention is suitable for cosmetics and medical products and in particular for topical application to the skin and mucous membrane. The invention also relates to a composition for producing the viscous formulation.

Description

[0001] BIP00380WO bitop AG 30.12.2025 Viscous formulation containing tetrahydropyrimidines

[0002] The present invention relates to a viscous formulation with adjustable viscosity, comprising a composition of at least one tetrahydropyrimidine-4-carboxylic acid and / or a derivative thereof, and at least one or more compounds selected from the group consisting of cellulose ethers and glycosaminoglycans. The novel use of tetrahydropyrimidine-4-carboxylic acid or one of its derivatives as a viscosity-enhancing agent proves particularly advantageous in this formulation. The viscous formulation according to the invention is suitable for cosmetics and medical devices, and especially for topical application to the skin and mucous membranes. A composition for preparing the viscous formulation is also provided.

[0003] Ectoin, a member of the tetrahydropyrimidine group, is a well-known active ingredient used in various medical devices and cosmetics. Due to its cell membrane stabilizing, protein stabilizing, and protective effects, ectoin is a very popular compatible solution, also known as an extremolyte. Medical devices and cosmetics are usually applied topically to the skin and mucous membranes and self-administered by the consumer / patient. These are primarily topical formulations applied to the skin and mucous membranes by the consumer / patient using various application methods (spray, inhalant, drops, gel, solution, etc.). The challenge with these products is their short shelf life or residence time at the site of action, such as the oral mucosa, nasal mucosa, upper respiratory tract, eye area (eyelid, open eye), and genital area.Due to the regular secretion of bodily fluids / secretions and the everyday habits of consumers / patients (saliva, tears, nasal mucus, genital and vaginal discharge, washing, showering), topically applied products are quickly washed off / worn away. Polymers are frequently used to influence the viscosity of such formulations, and thus the final products, in order to extend their shelf life or duration of action. Depending on the site of action and especially after application, the previously set viscosity of the product to be applied can be affected by contact with the environment at the site of action during application. Additionally, the excipients used to adjust the viscosity can cause side effects and undesirable reactions in the user. Generally, it is desirable to keep the proportion of excipients as low as possible and to minimize the proportion of therapeutically relevant or effective ingredients.The ratio of cosmetically active ingredients to excipients should be as high as possible. This is particularly true for pharmaceutical compositions used for the prevention or treatment of various medical conditions affecting the eye, nose, mouth, upper respiratory tract, and intimate area. It is therefore desirable to have access to formulations that allow for finely adjustable viscosity and can be adapted to the specific product requirements. These product requirements depend on the type of application, the desired site of action, and the desired ease of use by the user. Thus, one object of the present invention is to provide a new viscosity-enhancing agent suitable for producing viscous formulations for use in cosmetics and medical devices.Consequently, a composition and various combinations of viscosity-enhancing compounds are to be provided, enabling flexible viscosity adjustment to meet product requirements. A viscous formulation suitable for topical application by spraying, dripping, and massaging is to be developed. A further objective is to provide a viscous formulation that allows for viscosity adjustment to suit product requirements. Additionally, a formulation with adjustable viscosity is to be developed, allowing the stability and residence time of the formulation and its active ingredients at the desired site of action to be controlled via the viscosity setting.

[0004] It has now been discovered that ectoine, a member of the tetrahydropyrimidine group, increases the viscosity of aqueous solutions based on a polymer component with polar functional groups. This has not been previously described and is surprising. It is particularly surprising that ectoine increases the viscosity of aqueous solutions containing cellulose ethers. The effect is concentration-dependent as well as dependent on the degree of substitution of the cellulose ethers. With increasing degree of substitution of the cellulose ethers, the interaction between ectoine and the cellulose ethers increases. This has the advantage that by combining ectoine or hydroxyectoine with various cellulose ethers, the required concentration of cellulose ethers can be reduced while maintaining the same viscosity.The viscous formulation containing the composition according to the invention is suitable as artificial tear products, medical devices for use on skin and mucous membranes and cosmetics, but can also serve as a vehicle for the administration of various active ingredients, e.g. ophthalmics.

[0005] A first aspect of the present invention is a viscous formulation with adjustable viscosity, in particular a viscosity-variable formulation or a viscous formulation with adjustable viscosity, preferably adjustable kinematic viscosity, particularly in relation to / compared to pure water / aqueous solution and preferably measured as kinematic viscosity using an Ubbelohde glass capillary viscometer of type Mikro-BIP00380WO bitop AG 30.12.2025 Ubbelohde viscometer, wherein the viscous formulation comprises a composition containing one or more compounds:

[0006] a) at least one tetrahydropyrimidine-4-carboxylic acid, preferably 2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid or hydroxyectoin, and / or a derivative thereof, and b) at least one or more compounds selected from the group consisting of cellulose ethers of formula aa, cellulose ethers of Ib and cellulose ethers of Ic and glycosaminoglycans of formula II:

[0007]

[0008] lower degree of substitution

[0009] medium degree of substitution

[0010]

[0011]

[0012] where n is an integer and R is a substitution which is independently selected from H, alkyl, hydroxy, alkyl-hydroxy, ether and carboxymethyl groups, n is any integer from 1, 2, 3, 4, 5, 6, 8, 9, 10 to 10,000.

[0013] Cellulose ethers are cellulose derivatives produced by partial or complete substitution of the hydrogen atoms of the hydroxyl groups of cellulose with alkyl and / or aryl groups. The alkyl / aryl groups can be functional non-ionic, anionic, or cationic. Cellulose ethers are characterized by their average degree of substitution (DS) and their molar degree of substitution (MS). Compounds of formula 1a have a lower degree of substitution, those of formula 1b have a medium degree, and those of formula 1c have a high degree. BIP00380WO bitop AG 30.12.2025 The production of cellulose ethers results in mixtures of differently substituted substances. Therefore, a precise classification can only be made on a product-specific basis. For example, hydroxyethylcellulose with a low degree of substitution can be produced.However, by changing the reaction conditions, a highly substituted hydroxyethylcellulose can also be produced.

[0014] Ectoine exists as a zwitterion in aqueous solutions. The more polar the functional groups of the organic residue (R) are—for example, a very high proportion of the OH group—the higher the polarity. Conversely, carbon atoms containing substitution groups reduce the polarity. This impairs the interaction with ectoine. The more polar the organic residue, the greater the interaction between ectoine and the cellulose ether, as ectoine acts on the surrounding water and the cellulose ether through the polarized regions in its molecule. Hydroxyectoine exhibits higher cosmotropic and polar properties due to its additional hydroxyl group. Therefore, hydroxyectoine is expected to be significantly more effective and increase the viscosity of cellulose ethers more than ectoine.

[0015] The viscous formulation according to the invention comprises a composition with (b) at least one or more cellulose ethers having a low, medium, or high degree of substitution. In one embodiment, the viscous formulation according to the invention has a composition which (b) contains at least one or more cellulose ethers having a medium to high degree of substitution. In one embodiment of the viscous formulation, at least one or more cellulose ethers with a high degree of substitution are used.

[0016] Cellulose ethers according to the invention are characterized by their average degree of substitution (DS) and their molar degree of substitution (MS) and exhibit a degree of substitution of ≥ 0.85 to ≥ 3, ≥ 1.0 to ≥ 3, ≥ 1.35 to ≥ 3, ≥ 1.5 to ≥ 3, ≥ 1.85 to ≥ 3, ≥ 2.00 to ≥ 3, ≥ 2.15 to ≥ 3, ≥ 2.35 to ≥ 3, ≥ 2.5 to ≥ 3, and ≥ 2.85 to ≥ 3. Thus, the theoretical maximum is a DS of 3.0.

[0017] Commercially available hydroxyethylcelluloses (HEC) have substitution degrees of 0.85 to 1.35 (DS) and 1.5 to 3 (MS), respectively. One product is available under the brand name Natrosol™. For methylcellulose (MC), the DS ranges from 1.3 to 2.6. For hydroxyethylmethylcellulose (HEMC), DS(Me) values ​​of 1.46–1.66 and DS(HE) values ​​of 0.14–0.17 have been reported (Anal Chem.BIP00380WO bitop AG 30.12.2025 2006 Feb 15;78(4):1146–57. doi: 10.1021 / ac051484q.). HEC is described not only with a variable DS, but also with a high MS of HEC 1: 1.89, HEC 2: 1.94, HEC 3: 3.03 (Macromol Biosci. 2006 Jun 16;6(6):435-44. doi:10.1002 / mabi.200600028.)

[0018] According to formula Ib, carboxymethylcellulose (R = CH2COOH) has, for example, a medium degree of substitution (DS) of 2.0. Formula aa corresponds to a low degree of substitution (DS) of 1.0 and formula Ic to a degree of substitution (DS) of 3.0.

[0019] In a further embodiment of the viscous formulation according to the invention, composition b) contains at least one or more cellulose ethers selected from the group comprising, according to formula Ic, hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose (HEMC), or methylethylcellulose (MEC), and according to formula Ib, carboxymethylcellulose (CMC), methylcellulose (MC), and / or ethylhydroxyethylcellulose, or a combination of at least two of the aforementioned cellulose ethers. Characterization of the cellulose ethers:

[0020] 1. Hydroxyethylcellulose (HEC): Water-soluble. HEC is a nonionic polymer that is soluble in both cold and warm water.

[0021] 2. Hydroxypropylmethylcellulose (HPMC) (synonym Hypromellose): Water-soluble.

[0022] HPMC is a nonionic polymer that is soluble in both cold and warm water.

[0023] 3. Hydroxyethylmethylcellulose (HEMC): Water-soluble. HEMC is also a nonionic polymer and dissolves well in water.

[0024] 4. Methylethylcellulose (MEC): Water-soluble. MEC is a nonionic polymer that is soluble in water.

[0025] 5. Carboxymethylcellulose (CMC): Water-soluble. CMC is an anionic polymer and dissolves well in water.

[0026] 6. Methylcellulose (MC): Water-soluble. Methylcellulose is a nonionic polymer that is soluble in cold water but gels upon heating.

[0027] 7. Ethylhydroxyethylcellulose (EHEC): Water-soluble. EHEC is a nonionic polymer and dissolves well in water.

[0028] In a further embodiment of the viscous formulation according to the invention, the composition b) comprises a hydroxyethylcellulose (HEC) or a carboxymethylcellulose (CMC) or a combination of a hydroxyethylcellulose (HEC) and a carboxymethylcellulose (CMC).

[0029] In a further embodiment of the viscous formulation according to the invention, the composition b) contains at least one or more cellulose ethers which have a medium to high degree of substitution (DS), preferably a degree of substitution greater than or equal to 1.35, greater than or equal to 1.5, greater than or equal to 1.85, greater than or equal to 2.00, greater than or equal to 2.15, greater than or equal to 2.35, greater than or equal to 2.5 or greater than or equal to 2.85.

[0030] In a further embodiment of the viscous formulation according to the invention, this comprises a) at least one 2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid and / or a derivative thereof, preferably ectoine and / or hydroxyectoine.

[0031] In a further embodiment of the viscous formulation according to the invention, the at least one tetrahydropyrimidine-4-carboxylic acid or a derivative thereof is a 2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid (ectoine), S-ectoine, R-ectoine, a mixture of S- and R-ectoine, a hydroxyectoine, a salt, an ester, or an amide of one of the aforementioned compounds, or a mixture of at least two of the aforementioned compounds. Preferred salts include sodium salts and potassium salts of the aforementioned compounds. Na-ectoine and Ka-ectoine are particularly preferred, which are preferably obtained in solution in a sodium- or potassium-containing buffer.

[0032] In a further embodiment of the viscous formulation according to the invention, the composition contains at least 0.05% of at least one tetrahydropyrimidine-4-carboxylic acid or a derivative thereof, in amounts greater than or equal to 0.1%, greater than or equal to 0.2%, greater than or equal to 0.3%, greater than or equal to 0.4%, greater than or equal to 0.5%, and in each case less than or equal to 10%, preferably 2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid and / or hydroxyectoin. In a further embodiment, the composition contains at least one tetrahydropyrimidine-4-carboxylic acid or a derivative thereof in the range of greater than or equal to 0.5% to less than or equal to 9%, greater than or equal to 0.5% to less than or equal to 8%, greater than or equal to 0.5% to less than or equal to 7%, and greater than or equal to 0.5% to less than or equal to 5%. All percentages are given as weight percent.

[0033] The aforementioned concentration ranges of the at least one tetrahydropyrimidine-4-carboxylic acid or a derivative thereof, preferably S-ectoin and / or hydroxyectoin, can be combined with any concentration of the at least one cellulose ether of the embodiments described herein.

[0034] In a further embodiment of the viscous formulation according to the invention, the composition contains greater than or equal to 0.05% of at least one cellulose ether, or the composition contains a concentration of at least one cellulose ether in the range of greater than or equal to 0.05% to less than or equal to 10.0%. All percentages are given as weight percent.

[0035] In another embodiment, the at least one cellulose ether is present at a concentration of 0.2% or greater, 0.3% or greater, 0.4% or greater, 0.5% or greater, 1.0% or greater, 1.5% or greater, 2.0% or greater, 2.5% or greater, and 5.0% or greater. The required concentration of the cellulose ether depends on the molar mass and degree of substitution of the respective cellulose ether, as well as on its combination with the selected concentration of the tetrahydropyrimidine-4-carboxylic acid.

[0036] In one embodiment of the viscous formulation, the composition contains greater than or equal to 0.05% to less than or equal to 5.0%, greater than or equal to 0.05% to less than or equal to 2.5%, greater than or equal to 0.3% to less than or equal to 2.5% moderately substituted and / or highly substituted cellulose ethers comprising hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, or methylethylcellulose, according to formula Ib the carboxymethylcellulose (CMC), methylcellulose, and / or ethylhydroxyethylcellulose or a combination thereof.

[0037] In a further embodiment of the viscous formulation according to the invention, the composition contains ≥ 0.1% ectoin, ≥ 0.2%, ≥ 0.3%, ≥ 0.4%, ≥ 0.5% ectoin up to ≥ 10.00% ectoin, in the presence of ≥ 0.05% at least one cellulose ether, ≥ 0.1%, ≥ 0.2%, ≥ 0.3%, ≥ 0.4%, ≥ 2.5% at least one cellulose ether, each dissolved in water, and has a viscosity of ≥ 0.1 mm 2 / s on, greater than or equal to 0.2 mm 2 / s, greater than or equal to 0.233 mm 2 / s, greater than or equal to 0.3 mm 2 / s, greater than or equal to 0.4 mm 2 / s, greater than or equal to 0.5 mm 2 / s, greater than or equal to 0.6 mm 2 / s, greater than or equal to 0.7 mm 2 / s, equal to 0.716 mm 2 / s, greater than or equal to 0.8 mm 2 / s, greater than or equal to 0.9 mm 2 / s, greater than or equal to 0.94 mm 2 / s, greater than or equal to 4.0 mm2 / s to less than or equal to 1000 mm 2 / s, each measured as kinematic viscosity using an Ubbelohde glass capillary viscometer.

[0038] In a further embodiment of the viscous formulation according to the invention, the composition contains / comprises ≥ 0.1% to ≥ 10.00% ectoin, in the presence of ≥ 0.05% of at least one cellulose ether, ≥ 0.1%, ≥ 0.2%, ≥ 0.3%, ≥ 0.4%, ≥ 2.5% of at least one cellulose ether, each dissolved in water, with a viscosity of ≥ 0.1 mm. 2 / s, greater than or equal to 0.2 mm 2 / s, greater than or equal to 0.233 mm 2 / s, greater than or equal to 0.3 mm 2 / s, greater than or equal to 0.4 mm 2 / s, greater than or equal to 0.5 mm 2 / s, greater than or equal to 0.6 mm 2 / s, greater than or equal to 0.7 mm 2 / s,BIP00380WO bitop AG 30.12.2025 equals 0.716 mm 2 / s, greater than or equal to 0.8 mm2 / s, greater than or equal to 0.9 mm 2 / s, greater than or equal to 0.94 mm 2 / s, greater than or equal to 4.0 mm 2 / s, greater than or equal to 7.5 mm 2 / s, greater than or equal to 10.0 mm 2 / s each up to less than or equal to 10,000 mm 2 / s, in particular measured as kinematic viscosity using an Ubbelohde glass capillary viscometer.

[0039] The kinematic viscosity of further embodiments of the formulation according to the invention is in a range of greater than or equal to 0.1 mm. 2 / s to less than or equal to 10,000 mm 2 / s, of greater than or equal to 1.0 mm 2 / s, of greater than or equal to 2.0 mm 2 / s, of greater than or equal to 3.0 mm 2 / s, of greater than or equal to 4.0 mm 2 / s, of greater than or equal to 5.0 mm 2 / s, of greater than or equal to 6.0 mm 2 / s, of greater than or equal to 7.0 mm 2 / s, of greater than or equal to 8.0 mm 2 / s, of greater than or equal to 9.0 mm 2 / s, of greater than or equal to 10.0 mm 2 / s up to and including 6,000 mm 2 / s, up to and including 4,000 mm 2 / s, up to and including 2,000 mm 2 / s, up to and including 1,000 mm 2 / s, up to and including 800 mm 2 / s, up to and including 600 mm 2 / s, up to and including 400 mm 2 / s, up to and including 300 mm 2 / s, up to and including 250 mm 2 / s, up to and including 200 mm 2 / s. Other viscosity ranges within the meaning of the invention include: 7.5 - 22.5 mm 2 / s, 10 - 40 mm 2 / s, 7.5 - 22.5 mm 2 / s, 7.5 - 22.5 mm 2 / s, 4.5 - 25 mm 2 / s, 4.5 - 25 mm 2 / s, 100 - 200 m 2 / s, 4 - 20 mm 2 / s and 2500 - 8000 mPa ■ s

[0040] ■=> Viscosity (0.31 HEC M + 0.5 Ectoin) greater than or equal to 0.233 mm2 / s, measured as kinematic viscosity using an Ubbelohde glass capillary viscometer

[0041] ■=> Viscosity (2.0 HEC M + 0.5 Ectoin) greater than or equal to 0.716 mm2 / s, measured as kinematic viscosity using an Ubbelohde glass capillary viscometer

[0042] ■=> Viscosity (0.31 HEC M + 0.1 Ectoin) greater than or equal to 0.94 mm2 / s, measured as kinematic viscosity using an Ubbelohde glass capillary viscometer

[0043] In a further embodiment of the viscous formulation according to the invention, the at least one cellulose ether in composition b) comprises at least one hydroxyethylcellulose with an average molar mass of ≥ 90,000, ≥ 100,000, ≥ 200,000, ≥ 300,000, ≥ 400,000, ≥ 500,000, ≥ 600,000, ≥ 700,000, ≥ 800,000, ≥ 900,000, ≥ 1,000,000, and ≥ 1,300,000.

[0044] In one embodiment of the viscous formulation, the composition comprises at least one hydroxyethylcellulose with an average molar mass of ≥ 200,000 to ≤ 900,000, and of ≥ 300,000 to ≤ 750,000. In another embodiment, the at least one cellulose ether HEC M has an average molar mass of 720,000. In yet another embodiment, the hydroxyethylcellulose is present in combination with ectoine in the composition and, in dissolved form, constitutes the viscous formulation.

[0045] In a further embodiment of the viscous formulation according to the invention, composition b) contains / comprises at least one glycosaminoglycan, preferably a hyaluronic acid (HA). In one embodiment, the HA has a molar mass in the range of 200 kDa to less than or equal to 2000 kDa, in the range of 200 kDa to 1800 kDa, in the range of 200–400 kDa, or in the range of 1600–1800 kDa. Each of the embodiments of the HA can be combined with each embodiment of the tetrahydropyrimidine-4-carboxylic acid, preferably the 2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid and / or hydroxyectoin.

[0046] For example, a 0.2% HA solution with a molar mass of 1600 to 1800 kDa has a viscosity of 10–40 mm² / s. With increasing molar mass of the hyaluronic acid, the effect described herein becomes stronger in combination with at least one tetrahydropyrimidine-4-carboxylic acid.

[0047] Glycosaminoglycans consist of linearly repetitive disaccharide units, in which the disaccharide units are linked to an amino sugar (e.g., N-acetylglucosamine) via a 1,3-glycosidic bond. The chain of the resulting polysaccharide is formed via a 1,4-glycosidic bond. The disaccharide units consist of esters of a uronic acid, predominantly glucuronic acid, and in rare cases, iduronic acid. Possible side groups of the glycosaminoglycans are hydroxyl, carboxy, or sulfate groups, thus resulting in a negatively charged polysaccharide. Glycosaminoglycans can be classified as sulfated or non-sulfated. Hyaluronic acid is the only non-sulfated glycosaminoglycan.

[0048] In a further embodiment of the viscous formulation according to the invention, compounds a) and b) of the composition are present in dissolved form, preferably in an aqueous and / or buffered solution. An “aqueous formulation” means and includes pure water, ultrapure water, distilled water, sodium chloride (NaCl), physiological solutions, buffered systems based on citrate, phosphate, TRIS, glycine, borate, and / or acetate. These buffer systems can be prepared from substances such as citric acid, monosodium phosphate, disodium phosphate, glycine, boric acid, sodium tetraborate, acetic acid, or sodium acetate. In one embodiment, the buffer is a trisodium citrate dihydrate buffer. BIP00380WO bitop AG 30.12.2025 In a further embodiment of the viscous formulation according to the invention, the composition contains / comprises:

[0049] a) at least one tetrahydropyrimidine-4-carboxylic acid or a derivative thereof, preferably ectoine and / or hydroxyectoine, wherein ectoine represents S-ectoine, R-ectoine or a mixture of R-ectoine and S-ectoine,

[0050] b1) at least one hydroxyethylcellulose (HEC) or one carboxymethylcellulose (CMC) or a combination of one hydroxyethylcellulose (HEC) and one carboxymethylcellulose (CMC), and

[0051] b2) at least one hyaluronic acid, preferably an HA, preferably an HA with a molar mass of 200 kDa to less than or equal to 2000 kDa, of 200 kDa to 1800 kDa, of 200 - 400 kDa or 1600 to 1800 kDa.

[0052] In a further embodiment of the viscous formulation according to the invention, the formulation is a cosmetic or pharmaceutical formulation. In particular, the pharmaceutical formulation is suitable and intended for medical devices, and the cosmetic formulation is suitable and intended for care products and cosmetics.

[0053] In one embodiment, the viscous formulation is suitable and intended for application to the epidermis and / or mucous membranes. In another embodiment, the viscous formulation can be applied and spread topically to the epidermis and / or mucous membranes. This applies equally to cosmetic and pharmaceutical formulations, and in particular to medical devices, personal care products, and cosmetics.

[0054] The viscous formulation can be applied to the site of action in controlled and defined quantities. The advantage of this formulation is that the amount of cellulose ether can be varied by adjusting the concentration of ectoin. This also allows for control of the viscosity of the final product. By controlling the viscosity of the viscous formulation, the spreading and flow of the product at the site of action can be controlled, thus ensuring the residence time and stability of the viscous formulation and any active ingredients it may contain.

[0055] For example, a dropper, due to the device's technical features, dispenses a defined quantity of eye drop solution or eye gel from the primary packaging. This defined drop can be applied precisely to a specific site of action. A single-dose ampoule, e.g., for mouthwash solutions, dispenses a single 5 ml dose. A spray device releases a defined quantity of the formulation with each spray. This controlled administration, combined with the longer residence time at the site of action, is particularly advantageous for medical devices that interact with the body (human or animal) through physical interaction.

[0056] For skincare and cosmetic products, the longer dwell time of a higher viscosity formulation is also advantageous. For example, a vaginal gel is more viscous, making it easier to massage in and preventing it from running.

[0057] Care products include: contact lens solution, cleaning products, lip care products such as Labello, nasal balm, hair tonic, cleansing ear spray, cleansing nasal douche.

[0058] In a further embodiment of the viscous formulation according to the invention, in particular in the form of a cosmetic or pharmaceutical formulation, it is a topically applicable formulation and can be applied to the epidermis, in particular the epidermis of the body, lips, inner ear, hands, face, especially the closed eyes, or it is a viscous formulation suitable for topical application.

[0059] In a further embodiment of the viscous formulation according to the invention, particularly in the form of a cosmetic or pharmaceutical formulation, it is a topically applicable formulation and can be applied to a mucous membrane (mucosa) comprising the mucous membrane of the nose, mouth, pharynx, and genital area (vagina, glans). Preferably, these formulations are available as cosmetic or pharmaceutical formulations, depending on the intended use. Particularly preferred are formulations available as medical devices.

[0060] In a further embodiment of the viscous formulation according to the invention, it is a topically applicable formulation and can be applied to the eyelid surface, to the open eye (eyeball surface), in particular to the meibomian layer of the open eye. Preferably, these formulations are available as cosmetic or pharmaceutical formulations, depending on the intended use. Particularly preferred are formulations available as medical devices.

[0061] In a further embodiment of the viscous formulation according to the invention, particularly in the form of a cosmetic or pharmaceutical formulation, it can be applied topically to the respective site of action by dripping, spraying, massaging, or creaming. BIP00380WO bitop AG 30.12.2025 In a further embodiment of the viscous formulation according to the invention, particularly in the form of a cosmetic or pharmaceutical formulation, the formulation exhibits a longer residence time of the composition contained in the formulation at the respective site of action after application, particularly compared to a formulation that does not contain tetrahydropyrimidine-4-carboxylic acid and / or a derivative thereof, at least one or more cellulose ethers, and / or glycosaminoglycans.

[0062] In a further embodiment of the viscous formulation according to the invention, it contains a composition with an anti-inflammatory effect, a composition with an anti-allergic effect, a composition with an epithelial barrier stabilizing effect, a composition with a lipid layer stabilizing effect, a composition with a wound healing promoting effect and / or a composition with a mucosa decongestant effect.

[0063] Such formulations are preferably used in or for medical devices. This is particularly advantageous because the viscosity of medical devices can be precisely controlled using the inventive formulation, thus allowing their effect to be adapted to the desired site of action.

[0064] In a further embodiment of the viscous formulation according to the invention, the composition additionally contains an antiviral, an antifungal, an antibacterial and / or anti-inflammatory active ingredient.

[0065] Such active substances include: other compatible solutes, di-myo-inositol phosphate (DIP), cyclic 2,3-diphosphoglycerate (cDPG), 1,1-diglycerol phosphate (DGP), β-mannosylglycerate (Firoin), β-mannosylglyceramide (Firoin A), di-mannosyl-di-inositol phosphate (DMIP), glucosylglycerol, taurine, betaine, citrulline, 4,5-dihydro-2-methyl-imidazole-4-carboxylic acid (DHMICA) and 4,5,6,7-tetrahydro-2-methyl-1H-[1,3]-diazepine-4-S-carboxylic acid (Homoectoin) as well as corresponding derivatives, in particular salts, esters or amides. Other suitable active substances include local anti-inflammatories, e.g. steroids, cyclosporine A, beta-blockers, antibiotics, gentamicin, kanamycin, neomycone, tobramycin, ciprofloxacin, ofloxacin, chlortetracycline, erythromycin, fusidic acid, lomefloxacin, levofloxacin and oxytetracycline.

[0066] In a further embodiment of the viscous formulation according to the invention, the formulation, in particular the cosmetic or pharmaceutical formulation, is in the form of a solution, gel, ointment, lotion, emulsion, or aerosol. Thus, the present formulation according to the invention is suitable for providing cosmetics, care products, and medical devices in the dosage form of solution, gel, ointment, lotion, emulsion, or aerosol.

[0067] In a further embodiment of the viscous formulation according to the invention, it is suitable or intended for application to a site of action by means of a spray device, a dropper bottle or a suitable metering device for dispensing defined quantities.

[0068] In another embodiment of the viscous formulation according to the invention, it is available in the form of a mouth spray, nasal spray, ear spray, throat spray, mouth / throat spray, inhalation spray, mouthwash, inhalation solution, contact lens solution, cleaning solution (e.g., for dentures), care products (lip balm, lip balm), nasal balm, or hair tonic. In one embodiment, the formulation according to the invention is a pharmaceutical formulation available in the form of a nasal spray, ear spray, throat spray, mouth / throat spray, inhalation spray, mouthwash, or inhalation solution, and is preferably provided as a medical device. In another embodiment, the formulation according to the invention is a cosmetic formulation available in the form of a contact lens solution, cleaning solution (e.g., for dentures), care products (lip balm, lip balm), nasal balm, or hair tonic.

[0069] Another aspect of the present invention is a composition comprising at least one cellulose ether, preferably one with an average molar mass of greater than or equal to 200,000 to less than or equal to 900,000, or of greater than or equal to 300,000 to less than or equal to 750,000, and at least one tetrahydropyrimidine-4-carboxylic acid and / or a derivative thereof, preferably ectoine, wherein the cellulose ether is present in a concentration of greater than or equal to 0.05% of at least one cellulose ether, greater than or equal to 0.1%, greater than or equal to 0.2%, greater than or equal to 0.3%, greater than or equal to 0.4%, or greater than or equal to 0.5% of at least one cellulose ether, and the tetrahydropyrimidine-4-carboxylic acid and / or a derivative thereof, preferably (R / S)-2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid and / or hydroxyectoine, in a concentration of greater than or equal to 0.05%. 0.1%, greater than or equal to 0.2%, greater than or equal to 0.3%, greater than or equal to 0.4%, greater than or equal to 0.5%.in particular, up to a concentration of less than or equal to 10%. The composition can be in dry form, in particular as a powder, granules, or any other form suitable for producing the desired mixture or combination according to the invention. BIP00380WO bitop AG 30.12.2025 Another aspect of the present invention is the use of the composition described above for producing a viscous formulation according to the invention.

[0070] Another aspect of the present invention is a tetrahydropyrimidine-4-carboxylic acid or a derivative thereof for use as a viscosity-increasing agent, particularly for increasing the viscosity, especially the kinematic viscosity, of a cellulose ether-containing, and in particular an aqueous, cellulose ether-containing, formulation. In one embodiment, the cellulose ether-containing formulation according to the invention comprises at least one or more cellulose ethers selected from the group consisting of hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, methylethylcellulose, carboxymethylcellulose, methylcellulose, and / or ethylhydroxyethylcellulose, or a combination of at least two of the aforementioned cellulose ethers. Preferably, the cellulose ether-containing formulation is an aqueous formulation, and preferably the cellulose ether is a hydroxyethylcellulose.

[0071] In a further embodiment of the use according to the invention, the tetrahydropyrimidine-4-carboxylic acid or a derivative thereof is a derivative of: 2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid, (S)-2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid, (R)-2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid and / or (4S,5S)-5-hydroxy-2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid.

[0072] Brief description of the characters

[0073] Fig. 1 Structure of an Ubbelohde glass capillary viscometer. The individual components, represented by numbers, are described in the text. 1 - Vent tube, 2 - Capillary tube, 3 - Filling line, 4 - Reservoir, 6 - Liquid barrier, 7 - Capillary, 8 - Measuring vessel (globe), 9 - Pre-charge sphere, 10 - Fill limit markings

[0074] Fig. 2 Calibration curve for ectoine.

[0075] Fig. 3 Calibration curve for HEC M.

[0076] Fig. 4 Calibration curve for HEC G.

[0077] Fig. 5 Calibration curve for CMC.

[0078] Fig. 6 Calibration curve for HA.

[0079] Fig. 7 Overview of the calibration curve

[0080] Fig. 8 Measurement of 0.5% ectoine with different concentrations of HEC M

[0081] Fig. 9 Measurement of 1.0% ectoine with different concentrations of HEC M

[0082] Fig. 10 Measurement of 2.0% ectoine with different concentrations of HEC M

[0083] Fig. 11 All measurements of Ectoine + HEC MBIP00380WO bitop AG 30.12.2025 Fig. 12 Measurement of Ectoine + HEC G

[0084] Fig. 13 Measurement of Ectoin + CMC

[0085] Fig. 14 Measurement of Ectoin + HA

[0086] Fig. 15 Measurement of HEC M + HA

[0087] Fig. 16 Measurement of ectoine with HEC M + 0.05% HA + 2.0% ectoine

[0088] Fig. 17 Measurement of ectoine with HEC M + 0.1% HA + 2.0% ectoine

[0089] Fig. 18 Measurement of ectoine with HEC M + 0.2% HA + 2.0% ectoine

[0090] Detailed description of the figures

[0091] Fig. 1 shows the setup of the Ubbelohde glass capillary viscometer of type micro-Ubbelohde viscometer, type 536 20 / II, used in the experiments described herein.

[0092] Figures 2 to 7 graphically represent the calibration of the individual components in dissolved form in a citrate buffer.

[0093] Figure 2 shows the calibration curve for ectoine. Solutions with concentrations of 0.0%, 0.5%, 1.0%, 1.5%, 2.0%, and 2.5% ectoine were prepared and measured. The calibration curve can be continued if necessary (3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, and 10% ectoine-containing solution (water or buffer)). A linear fit was used because the viscosity increase between each concentration step is very small.

[0094] Figure 3 shows the calibration curve for HEC M. Solutions with concentrations of 0.00%, 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, and 0.40% HEC M were prepared and measured. The calibration curve can be continued as needed and adjusted according to the required or planned amount of HEC M in the product. The calibration curve shows that HEC M can be classified as significantly increasing viscosity compared to ectoine (Figure 2).

[0095] Figure 4 shows the calibration curve for HEC G. Solutions with concentrations of 0.00%, 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, and 0.40% HEC G were prepared and measured. The calibration curve can be continued as needed and adjusted according to the required or planned amount of HEC M in the product. At the same mass concentration, HEC G does not increase viscosity as much as HEC M, but can be considered to significantly increase viscosity compared to ectoine.

[0096] Figure 5 shows the calibration curve for CMC. Solutions with concentrations of 0.00%, 0.05%, 0.10%, 0.15%, 0.20%, and 0.25% CMC were prepared and measured. The calibration curve can be continued as needed and adjusted according to the required or planned amount of CMC in the product. At the same mass concentration, CMC increases the viscosity more than all other substances used.

[0097] Figure 6 shows the calibration curve for HA. Solutions with HA concentrations of 0.00%, 0.05%, 0.10%, 0.15%, 0.20%, and 0.25% were prepared and measured. At the same mass concentration, HA increases viscosity to a similar extent as HEC G, but can be classified as significantly viscosity-increasing compared to ectoine. Figure 7 summarizes all calibration curves.

[0098] Fig. 8 shows the actual measured values ​​of the solutions prepared from the combination of HEC M and ectoine: 0.1% HEC M + 0.5% ectoine; 0.2% HEC M + 0.5% ectoine; 0.31% HEC M + 0.5% ectoine. The calculated values ​​[calc] from the calibration curve for 0.5% ectoine are plotted for comparison. Ectoine leads to an increase in the viscosity of an HEC M solution. Fig. 9 shows the actual measured values ​​of the solutions prepared from the combination of HEC M and ectoine: 0.1% HEC M + 1.0% ectoine; 0.2% HEC M + 1.0% ectoine; 0.31% HEC M + 1.0% ectoine. A further increase in viscosity is observed at higher concentrations of ectoine. Fig. 10 shows the actual measured values ​​of the solutions prepared from the combination of HEC M and ectoine: 0.1% HEC M + 2.0% ectoine; 0.2% HEC M + 2.0% ectoine; 0.31% HEC M + 2.0% ectoine. A further increase in viscosity is observed at higher concentrations of ectoine. Fig. 11 compares the measurements.

[0099] Fig. 12 shows all measurements for solutions with a combination of HEC G and different concentrations of ectoine: 2.0% ectoine and 0.5% ectoine respectively; The values ​​calculated from the calibration curves ([should] synonymous with [calc]) are plotted for comparison.

[0100] Fig. 13 shows all measurements for solutions with a combination of CMC and different concentrations of ectoine: 2.0% ectoine and 0.5% ectoine respectively; The values ​​calculated from the calibration curves ([should] synonymous with [calc]) are plotted for comparison.

[0101] Fig. 14 shows all measurements for solutions with a combination of HA and different concentrations of ectoine: 2.0% ectoine and 0.5% ectoine respectively; The values ​​calculated from the calibration curves ([should] synonymous with [calc]) are plotted for comparison.

[0102] Fig. 15 shows all measurements for solutions with a combination of HA and different concentrations of HEC M: 2.0 % HEC M, 1.0 % HEC M or 0.5 Ectoin.

[0103] Fig. 16 shows all measurements for solutions with a combination of 0.05% HA + 2.0% ectoine and different concentrations of HEC M: 0.1% HEC M, 0.2% HEC M and 0.31% HEC M.

[0104] Fig. 17 shows all measurements for solutions with a combination of 0.1% HA + 2.0% ectoine and various concentrations of HEC M: 0.1% HEC M, 0.2% HEC M, and 0.31% HEC M. BIP00380WO bitop AG 30.12.2025. Fig. 18 shows all measurements for solutions with a combination of 0.2% HA + 2.0% ectoine and various concentrations of HEC M: 0.1% HEC M, 0.2% HEC M, and 0.31% HEC M.

[0105] Examples

[0106] 1. Materials and methods

[0107] The principles of the methodology used are known to those skilled in the art from EN ISO 13485:2016, chapters 7.4 and 7.5, as well as from the European pharmacopeia, where the method is described in section 2.2.9 “capillary viscosity method”.

[0108] Other chemicals used: Acetone, Aqua care, Carboxymethylcellulose (CAS 9004-32-4, Carl Roth GmbH + Co. KG), Ectoin (bitop AG), HEC G (Ashland, natrosol™, 300,000 Da), HEC M (Ashland, natrosol™; 720,000 Da), Hyaluronic acid (ExperChem, Raya Hyaluron EP2, 200-400 kDa), Ultrapure water > 18.0 MQ*cm

[0109] 1.1 Background

[0110] Viscosity is a measure of a fluid's resistance to flow. The reciprocal of viscosity is fluidity, a measure of a fluid's ability to flow. The higher the viscosity, the thicker (less fluid) the fluid; the lower the viscosity, the thinner (more fluid) it is, meaning it can flow faster under the same conditions. Particles in viscous fluids are more strongly bound to each other and therefore less mobile.

[0111] To investigate the movement of molecules in liquids, a whole range of experimental approaches are available. For example, relaxation times can be measured in NMR or ESR experiments to draw conclusions about the mobility of particles. Another important method is inelastic neutron scattering, in which the energy that neutrons give off or absorb as they pass through a sample is measured and then correlated with the motion of the particles. A somewhat more common approach is viscosity measurement.

[0112] Unlike in gases, a molecule in a liquid must escape the attraction of its neighboring molecules if it wants to move through the medium. To do this, it must expend a small amount of energy. The probability that a molecule will gain an energy E A possesses is proportional to & E A / RTTherefore, the mobility of the molecules in the liquid will also depend on the temperature in this way. Since viscosity is inversely proportional to the mobility of the particles, we expect viscosity to have a dependence of the form r] oc & E A / RT The temperature should therefore decrease exponentially with increasing temperature. This behavior is also observed experimentally, at least for relatively small temperature ranges (BIP00380WO bitop AG 30.12.2025). The activation energy associated with viscosity is comparable to the average potential energy of intermolecular interactions.

[0113] One of the difficulties in interpreting viscosity measurements of liquids is that the temperature dependence of the densities has a pronounced influence on the measured viscosity. The temperature at constant volume, i.e., at constant density, is therefore much lower than at constant pressure. The activation energy E A is determined by the interactions between the molecules in the liquid, but their calculation is an extraordinarily difficult, as yet unsolved problem.

[0114] To describe the relationship between momentum flux and viscosity, we consider the Newtonian flow of a fluid in the a-direction. We can imagine this flow as consisting of many thin, parallel layers sliding past each other. The layer directly against the container wall remains stationary, and the velocity of the other layers is proportional to their distance b from the container wall. The molecules constantly move back and forth between the layers, transferring their momentum in the a-direction from one layer to the next. When molecules from a slower layer arrive in a layer, they slow it down slightly because they have a smaller momentum in the a-direction than the rest of the layer. Conversely, molecules from faster layers accelerate a layer. We interpret this braking effect as the viscosity of the fluid.Since the braking effect depends on the transfer of the a-component of momentum between the layers, the flux of this quantity in the b-direction also determines the viscosity. The flux of the a-component of momentum is proportional, as no flux occurs when all layers are moving at the same speed. Consequently,

[0115]

[0116] J(a — component of momentum) =

[0117]

[0118] The constant is the viscosity coefficient (often simply referred to as "the viscosity") of the medium, expressed in kg rrr 1 s -1 .

[0119] For now, it suffices to know that solutions with high viscosity flow slowly and strongly impede the movement of objects within them. The presence of dissolved macromolecules increases the viscosity of a solution. This effect is very pronounced even at low concentrations, as large molecules significantly hinder the flow of the liquid. At low concentrations, the viscosity of the solution depends on [BIP00380WO bitop AG 30.12.2025] o (1 + [n]c + [n]'c 2 + . . . )

[0120] with the viscosity λ of the pure solvent. The intrinsic viscosity [λ?] is analogous to a virial coefficient; it has the dimension (concentration)-I. Several methods are available for measuring viscosities. In our case, we use an Ubbelohde glass capillary viscometer type 53620 / 11.

[0121] The dynamic viscosity, or viscosity coefficient q, is the tangential force per unit area, denoted as shear stress T and expressed in Pascals, required to move a 1-square-meter layer of fluid parallel to the slip plane at a speed (v) of 1 meter per second relative to a parallel layer at a distance (x) of 1 meter. The unit of dynamic viscosity is the Pascal-second (Pa-s). The most commonly used divisor is the millipascal-second (mPa-s).

[0122] The kinematic viscosity v, expressed in square meters per second, is obtained by dividing the dynamic viscosity q by the density p, expressed in kilograms per cubic meter, of the fluid measured at the same temperature, i.e.

[0123]

[0124] Kinematic viscosity is usually expressed in square millimeters per second. A capillary viscometer can be used to determine the viscosity of liquids. BIP00380WO bitop AG 30.12.2025 1.2 Method

[0125] 1.2.1 Calibrated.

[0126] 1.2.2 Measurement of the combinations

[0127] This work instruction describes the determination of the kinematic viscosity of Newtonian fluids using an Ubbelohde glass capillary viscometer (Fig. 1).

[0128] Initially, ultrapure water is weighed into a sterilized Schott bottle. Then, the trisodium citrate dihydrate is weighed in and dissolved for 5 minutes using a magnetic stirrer at approximately 500 rpm until the solution is clear. All measurements were performed in a citrate buffer.

[0129] The buffer solution described above was used for the various solutions. Ectoin was then weighed in. To prepare a combination of ectoin and hyaluronic acid, the hyaluronic acid was added after a short dissolving time of < 5 min, and the stirrer speed was increased to 1000 rpm. This was stirred for 1 hour until the hyaluronic acid was completely dissolved. To prepare a combination of ectoin, hyaluronic acid, and a cellulose ether, the cellulose ether was then added. The sample was stirred for at least 2 hours, or until completely dissolved. If the sample was not dissolved after 2 hours, stirring continued until the entire sample was dissolved.

[0130] Sterile conditions are maintained throughout the entire process, as some solutions, depending on their concentration, require stirring for more than 24 hours until they are completely dissolved.

[0131] The water bath is set to 25.0°C ± 1.0°C and pre-tempered for approximately 15 minutes. All prepared combinations were tempered and maintained at 25.0°C. The temperature is monitored with a calibrated thermometer. To prevent water contamination, a water bath protectant is added regularly.

[0132] The selection of the correct capillaries for viscosity measurement depends on the expected or existing viscosity of the sample. Since the viscosity of all existing medical devices currently ranges between 0 and 30 mm, 2 If the value is / s, the Type II viscometer is used as the standard instrument. With this type, the Hagenbach correction is quite small and can therefore be disregarded.

[0133] Before each measurement, the viscometer is cleaned with water or, if necessary, ethanol, and then dried with acetone, the acetone being removed with compressed air. The BIP00380WO bitop AG 30.12.2025 viscometer is checked before all work is carried out. It must be completely dry and free of dust or other residues.

[0134] Approximately 5 ml of sample are poured into the reservoir (4) via the filling port (3). The fill line (10) is marked on the reservoir (see Fig. 1).

[0135] The filled viscometer is suspended in the water bath and secured. Care is taken to ensure that no water drips into the viscometer's tubes and that the viscometer is perfectly vertical. The sample is allowed to come to room temperature for approximately 15 minutes before the analysis begins.

[0136] The opening of the vent tube (1) is closed with a finger. The measuring vessel and the pre-filling ball (9) are filled with a Peleus ball by pulling on the capillary tube (2). No air bubbles should form in the capillary tube (2). The pulling is stopped by removing the Peleus ball from the vent tube (1). The retention time between the upper (M1) and lower (M2) float marks is measured. The lower edge of the meniscus is crucial for the beginning and end of the retention. The first measurement is recorded but not used for the calculation; therefore, the capillary tube must first be rinsed with sample solution. Three measurements are performed to average the results. After use, the viscometer must be cleaned.

[0137] Calculation of the kinematic viscosity v [mm 2 / s] follows the formula below and is obtained by multiplying the mean retention time t [sec.] with the corresponding device constant K (see certificate of the viscometer).

[0138] v = K * tBIP00380WO bitop AG 30.12.2025 1.3 Abbreviations and Definitions

[0139] HEC Hydroxyethylcellulose

[0140] CMC Carboxymethylcellulose

[0141] HA Hyaluronic Acid

[0142] Kin. Kinematic

[0143] Calculated / calculated based on the calibration curve

[0144] Calculation curve

[0145] Other chemicals used: Acetone, Aqua care, Carboxymethylcellulose, Ectoin, HEC G, HEC M, Hyaluronic acid, Ultrapure water > 18.0 MQ*cm

[0146]

[0147] 2.1 Calibration

[0148] 2.1.1 Calibration of Ectoin

[0149] For the measurement of ectoine solutions, a mass concentration range of 0 g / 100 g to 2.5 g / 100 g was defined. The viscosity of ectoine-containing solutions is close to that of ultrapure water (Table 1).

[0150] Table 1

[0151] Sample No. w (Ectoin) Viscosity

[0152] [g / 100g] [mm] 2 / s ]

[0153] Ö 0.0 0.971

[0154] 1.1 0.5 1.004

[0155] 1.2 1.0 1.018

[0156] 1.3 1.5 1.039

[0157] 1.4 2.0 1.044

[0158] 1.5 2.5 1.056

[0159] The calibration curve (Fig. 2) for ectoine-containing solutions clearly shows that ectoine is not a viscosity increaser in the classical sense. The viscosity increases only minimally, even with an increase in mass concentration to 2.5%. This results in an increase to 1.056 mm. 2 / s recorded. This means a net increase of 0.085 mm. 2 / s, which is just a 9% increase. Since the increase in viscosity is so negligible compared to the increase in concentration, a linear increase can be assumed in this range. BIP00380WO bitop AG 30.12.2025 2.1.2 Calibration HEC M

[0160] For the measurement of HEC M, a mass concentration range of 0 g / 100 g to 0.4 g / 100 g was established. The viscosities of solutions containing HEC M are exorbitantly higher with increasing concentration than those of water or solutions containing only ectoine (Table 2).

[0161] Table 2

[0162] Sample No. w (HEC M) Viscosity

[0163] [g / 100g] [mm] 2 / s ]

[0164] Ö Öj)Ö 0.971

[0165] 2.11 0.05 1.475

[0166] 2.12 0.10 2.209

[0167] 2.13 0.15 3.199

[0168] 2.14 0.20 4.572

[0169] 2.15 0.25 6.710

[0170] 2.16 0.30 9,800

[0171] 2.17 0.35 14.308

[0172] 2.18 0.40 20.405

[0173] The calibration curve for solutions containing HEC M (Fig. 3) clearly shows that HEC M is a viscosity increaser in the classical sense. The comparatively large cellulose molecules exhibit strong inhibition of momentum transfer. This is clearly evident from the significant increase in viscosity. A linear increase cannot be assumed here, as the influence on viscosity increases considerably with increasing mass concentration. Therefore, a biquadratic fit is used to describe the viscosity-increasing behavior. The viscosity increases from 0.40% to 20.405 mm² when the mass concentration is increased. 2 / s, which is an increase of 2001%. This means a net increase of 19,434 mm. 2 / s.

[0174] 2.1.3 Calibration HEC G

[0175] For the measurement of HEC G-containing solutions, a mass concentration range of 0 g / 100 g to 0.4 g / 100 g was established. The viscosities of solutions containing HEC G are exorbitantly higher with increasing concentration than those of water or solutions containing only ectoine, but lower than those of HEC M (Tables 2 and 3). This is because the cellulose molecules of HEC G have a molar mass of 300,000 Da, while HEC M has a molar mass of 720,000 Da. The larger a long-chain molecule is, the greater its viscosity increases. Molecules consisting of multiple repeating units are called polymers. The polymers considered here are so-called macromolecules. BIP00380WO bitop AG 30.12.2025 Table 3

[0176] Sample No. w (HEC G) Viscosity

[0177] [g / 100g] [mm] 2 / s ]

[0178] 0 0.00 0.971

[0179] 2.21 0.05 1.197

[0180] 2.22 0.10 1.413

[0181] 2.23 0.15 1.723

[0182] 2.24 0.20 2.053

[0183] 2.25 0.25 2.447

[0184] 2.26 0.30 2.917

[0185] 2.27 0.35 3.433

[0186] 2.28 0.40 4.061

[0187] The calibration curve for solutions containing HEC G (Fig. 4) clearly shows that HEC G is a viscosity increaser in the classical sense. The cellulose molecules exhibit an inhibition of momentum transfer. This is clearly evident from the increase in viscosity. A linear increase cannot be assumed here, as the influence on viscosity increases significantly with increasing mass concentration. Therefore, a biquadratic fit is used to describe the viscosity-increasing behavior. The viscosity increases from 0.40% to 4.061 mm² when the mass concentration is increased. 2 / s, which is an increase of 318%. This means a net increase of 3.09 mm. 2 / s. Depending on the desired viscosity range for a product, different molecular sizes of the same molecular base are used. This allows the viscosity, a physical property, to be influenced while maintaining the same chemical properties.

[0188] 2.1.4 Calibration CMC

[0189] For the calibration of CMC, a mass concentration range of 0 g / 100 g to 0.25 g / 100 g was established. The viscosities of solutions containing CMC are exorbitantly higher with increasing concentration than those of water (Table 4) or solutions containing only ectoine, and also higher than those of HEC M at the same mass concentration. This is because the cellulose molecules of CMC have different functional groups and a different number of repeating units than HEC M. Thus, a difference among the cellulose ethers is detectable. BIP00380WO bitop AG 30.12.2025 Table 4

[0190] Samples w (CMC) viscosity

[0191] No. [g / 100g] [mm 2 / s ]

[0192] 3.1 0.05 1.944

[0193] 3.2 0.10 3.515

[0194] 3.3 0.15 5.686

[0195] 3.4 0.20 8.815

[0196] 3.5 0.25 13.264

[0197] The calibration curve for solutions containing CMC (Fig. 5) clearly shows that CMC is the strongest viscosity increaser used. The cellulose molecules exhibit the strongest inhibition of momentum transfer. This is clearly evident from the increase in viscosity. A linear increase cannot be assumed here, as the influence on viscosity increases significantly with increasing mass concentration. Therefore, a biquadratic fit is used to describe the viscosity-increasing behavior. The viscosity increases from 0.25% to 13.264 mm² when the mass concentration is increased. 2 / s, which is an increase of 1266%. This means a net increase of 12,293 mm. 2 / s.

[0198] 2.1.5 Calibration HA

[0199] For the calibration of HA, a mass concentration range of 0 g / 100 g to 0.4 g / 100 g was established. The viscosities of solutions containing HA are higher with increasing concentration than those of water (Table 5) or solutions containing only ectoine, but lower than those of HEC M. Unlike HEC and CMC, HA is not a cellulose-based molecule but rather based on D-glucuronic acid and N-acetyl-D-glucosamine.

[0200] The calibration curve for HA-containing solutions (Fig. 6) clearly shows that HA is a viscosity increaser in the classical sense.

[0201] Table 5

[0202] Sample No. w (HA) Viscosity

[0203] [g / 100g] [mm] 2 / s ]

[0204] 4.1 0.05 1.271

[0205] 4.2 0.10 1.586

[0206] 4.3 0.15 1.963

[0207] 4.4 0.20 2.398

[0208] 4.5 0.25 2.857

[0209] The HA molecules exhibit inhibition of momentum transfer. This is clearly evident from the increase in viscosity. A linear increase cannot be assumed here, as the influence on viscosity increases significantly with increasing mass concentration. Therefore, a biquadratic fit is used to describe the viscosity-increasing behavior. The viscosity increases from a mass concentration of 0.25% to a viscosity of 2.857 mm. 2 / s, which is an increase of 194%. This means a net increase of 1.89 mm. 2 / s. Thus, despite different chemical properties, the same physical properties can be achieved at the same mass concentration.

[0210] 2.1.6 Calibration Summary

[0211] When viscosity is plotted as a function of mass concentration, it is clearly evident that the viscosity-increasing effect rises as follows: HEC G < HA < HEC M CMC (Fig. 7).

[0212] The stronger the viscosity-increasing effect, the less linear the substance's behavior can be represented. To determine individual values ​​that were not measured, the values ​​are interpolated as needed. For this purpose, the basic structure of a biquadratic equation is used:

[0213]

[0214] used. a, b, c and d are specific constants which must be determined individually for each substance.

[0215] 2.2 Real measurements of the combinations

[0216] 2.2.1 Measurements of the combination HEC M + Ectoin

[0217] When a solution containing HEC M is mixed with ectoine, the viscosity increases unexpectedly sharply in a range between 0.0% and 0.31% by mass. A concentration range of 0–0.31 g / 100 g was investigated for this purpose.

[0218] Table 6

[0219] Samples w (Ectoin) w (HEC M) viscosity

[0220] No. [ g / 100 g ] [ g / 100 g ] [ mm 2 / s ]

[0221] 7.01 0.5 0.10 2.15

[0222] 7.02 0.5 0.20 4.64

[0223] 7.03 0.5 0.31 10.87

[0224] 7.04 1.0 0.10 2.22

[0225] 7.05 1.0 0.20 5.00

[0226] 7.06 1.0 0.31 11.57

[0227] 7.07 2.0 0.10 2.23

[0228] 7.08 2.0 0.20 5.05

[0229] 7.09 2.0 0.31 11.37BIP00380WO bitop AG December 30, 2025

[0230] The addition of 0.5% by mass of ectoine increases the viscosity of 0.31% HEC M above the additive effect, which amounts to 0.033 mm. 2 / s would have, on 0.233 mm 2 / s. Thus, a synergistic effect has been detected.

[0231] The addition of 0.1% by mass of ectoine increases the viscosity of 0.31% HEC M above the additive effect, which amounts to 0.033 mm. 2 / s would have, on 0.94 mm 2 / s. Thus, a synergistic effect has been detected.

[0232] The addition of 0.5% by mass of ectoine increases the viscosity of 2% HEC M above the additive effect, which amounts to 0.033 mm. 2 / s would have, on 0.716 mm 2 / s. Thus, a synergistic effect has been detected.

[0233] Table 6a

[0234]

[0235] Table 6b

[0236]

[0237] Table 6c:

[0238]

[0239] Ectoine thus significantly increases the viscosity of HEC-M-containing solutions. This has not been demonstrated in any previous model. BIP00380WO bitop AG 30.12.2025 2.2.2 Measurements of the combination of ectoine with HEC G

[0240] Since HEC G does not increase viscosity as much as HEC M, this example clearly shows how the increase in viscosity depends on the ectoine concentration.

[0241] The left pair of values ​​describes the HEC G solution with a 2.0% ectoine content. It is clearly evident that the unexpected increase is significantly higher than for 0.5% ectoine additions. The two additional beams clearly show that the influence of the ectoine increases with viscosity in a range of 0.21 to 0.31%, or within a viscosity range of 2.21 mm. 2 / s up to 3.1 mm 2 / s

[0242] 2.2.3 Measurements of the combination of ectoine with CMC

[0243] The influence of ectoine on the viscosity of CMC is present, but not as significant as on HEC and is therefore not described further.

[0244] 2.2.4 Measurements of the combination of ectoine with HA

[0245] When a solution containing hyaluronic acid (HA) is mixed with ectoine, the viscosity increases by a factor between 0.0% and 0.31 by mass. However, a particularly large increase is not to be expected, as HA is not a good viscosity increaser.

[0246] 2.2.5 Measurements of the combination of ectoine + cellulose ether + hyaluronic acid

[0247] The cellulose ethers were combined with hyaluronic acid and ectoin and analyzed. A significant synergistic effect is clearly evident. Ectoin greatly increases viscosity, thus requiring a considerably smaller amount of cellulose ether or hyaluronic acid to achieve the same viscosity. This effect is independent of the order in which the substances are added.

[0248] The experiment is based on the measurement of cellulose ethers and hyaluronic acid to rule out the known viscosity increase effect that occurs when two different polymers dissolve. BIP00380WO bitop AG 30.12.2025

[0249] Table 7

[0250] Sample No. w (HEC M) w (HA) Viscosity

[0251] [ g / 100 g ] [ g / 100 g ] [ mm 2 / s ]

[0252] 6.01 0.10 0.05 5.35

[0253] 6.02 0.20 0.05 11.42

[0254] 6.03 0.31 0.05 24.49

[0255] 6.04 0.10 0.10 10.86

[0256] 6.05 0.20 0.10 24.02

[0257] 6.06 0.31 0.10 51.10

[0258] 6.07 0.10 0.20 37.90

[0259] 6.08 0.20 0.20 66.19

[0260] 6.09 0.31 0.20 167.06

[0261] Figure 15 clearly shows that an increase in polymer concentration results in a more than additive effect. This effect is particularly evident when considering points (0.311, 24.49) and (3.11, 167.06). A quadrupling of the HA value from 0.5% by mass to 2.0% by mass results in a factor of 6.8. This cannot be explained by an additive effect, but the phenomenon is known.

[0262] The following analysis assumes a mass fraction of ectoine of 2% and examines its effect on a dipolymer mixture. Ectoine significantly increases the viscosity of the mixture, and the synergistic effect increases with rising polymer concentration. This effect is currently unexplained, as other low-molecular-weight substances have not yet produced the same effect. The synergistic effect observed here must be explicitly distinguished from the effects with pure polymer mixtures. Ectoine is not a polymer, but rather a tetrapyrimidine with a strong water-binding capacity. Ectoine does not form any oligomers or polymers in aqueous solutions. Instead, it forms a hydrocomplex, meaning the ectoine molecule is completely surrounded by water. Therefore, ectoine cannot be considered a polymer in any way.It is clearly evident that ectoine has an additional effect on the viscosity of a polymer mixture that has polar functional groups.

[0263] Thus, although the viscosity of the mixture of HEC M and HA increases at a constant ectoine content, the gradient of the viscosity is significantly higher due to the addition of ectoine.

[0264] The figures clearly show that the addition of 2% by mass of ectoine results in a significant increase in viscosity, especially at higher viscosities. The calculated increases are 0.077 mm. 2 The values ​​that would occur with the additive addition of 2% by mass of ectoine were significantly exceeded. BIP00380WO bitop AG 30.12.2025 For CMC, the effect is considerably smaller, as the different functional groups play a role here; therefore, the effect is not described further.

[0265] For HEC G, the effect is smaller at the same concentration because the molecular chains are smaller and therefore the viscosity is lower for the same mass used.

[0266] 3. Summary

[0267] Ectoin, in combination with cellulose ethers such as hydroxyethylcellulose and polysaccharides such as hyaluronic acid, increases viscosity in a way that cannot be described by an additive effect.

[0268] Ectoin increases the viscosity of a mixture of at least two polymers that have polar functional groups to an extent that cannot be described additively.

[0269] 4. Overview of medical devices / care products

[0270]

Claims

BIP00380WO bitop AG 30.12.2025 Patent claims 1. Viscous formulation with adjustable viscosity, comprising a composition containing one or more compounds: a) at least one tetrahydropyrimidine-4-carboxylic acid and / or a derivative thereof, and b) at least one or more compounds selected from the group consisting of cellulose ethers of formula aa, cellulose ethers of Ib and cellulose ethers of Ic and glycosaminoglycans of formula II: la. Ib. where n is an integer and R is a substitution which is independently selected from H, alkyl, hydroxy, alkyl-hydroxy, ether and carboxymethyl groups.

2. Viscous formulation according to claim 1, wherein the composition b) contains at least one or more cellulose ethers selected from the group consisting of hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, methylethylcellulose, carboxymethylcellulose, methylcellulose, and / or ethylhydroxyethylcellulose, or a combination of at least two of the aforementioned cellulose ethers. BIP00380WO bitop AG 30.12.2025 3. Viscous formulation according to claim 1 or 2, wherein the composition b) contains at least one or more cellulose ethers exhibiting a medium to high degree of substitution.

4. Viscous formulation according to any one of claims 1 to 3, wherein the at least one tetrahydropyrimidine-4-carboxylic acid or a derivative thereof is a 2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid (ectoine), S-ectoine, R-ectoine, a mixture of S- and R-ectoine, a hydroxyectoine, a salt, an ester or an amide of any of the aforementioned compounds, or a mixture of at least two of the aforementioned compounds.

5. Viscous formulation according to any one of claims 1 to 4, wherein the composition contains greater than or equal to 0.05% of at least one tetrahydropyrimidine-4-carboxylic acid or a derivative thereof, greater than or equal to 0.1%, greater than or equal to 0.2%, greater than or equal to 0.3%, greater than or equal to 0.4% or greater than or equal to 0.5% to less than or equal to 10%.

6. Viscous formulation according to any one of claims 1 to 5, wherein the composition contains greater than or equal to 0.05% of at least one cellulose ether or the composition contains a concentration of at least one cellulose ether in a range of greater than or equal to 0.05% to less than or equal to 10.0%.

7. Viscous formulation according to any one of claims 1 to 6, wherein the composition comprises ≥ 0.1% to ≥ 10.00% ectoin, in the presence of ≥ 0.05% at least one cellulose ether, ≥ 0.1%, ≥ 0.2%, ≥ 0.3%, ≥ 0.4%, ≥ 2.5% at least one cellulose ether, each dissolved in water, having a viscosity of ≥ 0.1 mm 2 / s, greater than or equal to 0.2 mm 2 / s, greater than or equal to 0.233 mm 2 / s, greater than or equal to 0.3 mm 2 / s, greater than or equal to 0.4 mm 2 / s, greater than or equal to 0.5 mm 2 / s, greater than or equal to 0.6 mm 2 / s, greater than or equal to 0.7 mm 2 / s, equal to 0.716 mm 2 / s, greater than or equal to 0.8 mm 2 / s, greater than or equal to 0.9 mm 2 / s, greater than or equal to 0.94 mm 2 / s, greater than or equal to 4.0 mm 2 / s, greater than or equal to 7.5 mm 2 / s, greater than or equal to 10.0 mm 2 / s each up to less than or equal to 10,000 mm 2 / s, in particular measured as kinematic viscosity using an Ubbelohde glass capillary viscometer.

8. Viscous formulation according to any one of claims 1 to 7, wherein the at least one cellulose ether in composition b) comprises at least one hydroxyethylcellulose with an average molar mass of greater than or equal to 90,000, greater than or equal to 100,000, greater than or equal to 200,000, greater than or equal to 300,000, greater than or equal to 400,000, greater than or equal to 500,000, greater than or equal to 600,000, greater than or equal to 700,000, greater than or equal to 800,000, greater than or equal to 900,000, greater than or equal to 1,000,000, and less than or equal to 1,300,000.

9. Viscous formulation according to any one of claims 1 to 8, wherein the composition further comprises b) at least one glycosaminoglycan.

10. Viscous formulation according to any one of claims 1 to 9, wherein the compounds of the composition are present in dissolved form, preferably in an aqueous and / or buffered solution.

11. Viscous formulation according to any one of claims 1 to 10, wherein the composition comprises: a) at least one tetrahydropyrimidine-4-carboxylic acid or a derivative thereof, preferably ectoine and / or hydroxyectoine, b1) at least one hydroxyethylcellulose (HEC) or one carboxymethylcellulose (CMC) or a combination of one hydroxyethylcellulose (HEC) and one carboxymethylcellulose (CMC), and b2) at least one hyaluronic acid.

12. Viscous formulation according to any one of claims 1 to 11, wherein this is a cosmetic or pharmaceutical formulation.

13. Viscous formulation according to any one of claims 1 to 12, wherein it is a topically applicable formulation and is applicable to the epidermis, in particular the epidermis of the body, lips, inner ear, hands, face, especially the closed eyes.

14. Viscous formulation according to any one of claims 1 to 13, wherein it is a topically applicable formulation and is applicable to a mucous membrane (mucosa) comprising the mucous membrane of the nose, mouth, pharynx and genital area.

15. Viscous formulation according to any one of claims 1 to 14, wherein it is a topically applicable formulation and can be applied to the eyelid surface of the open eye. BIP00380WO bitop AG 30.12.2025 16. Viscous formulation according to any one of claims 1 to 15, wherein it can be applied topically to the respective site of action by dripping, spraying, massaging or creaming.

17. Viscous formulation according to any one of claims 1 to 16, wherein this formulation, after application to the respective site of action, exhibits a longer residence time of the composition contained in the formulation at the respective site of action.

18. Viscous formulation according to any one of claims 1 to 17, wherein it contains a composition with an anti-inflammatory effect, a composition with an anti-allergic effect, a composition with an epithelial barrier stabilizing effect, a composition with a lipid layer stabilizing effect, a composition with a wound healing effect and / or a composition with a mucosa decongestant effect.

19. Viscous formulation according to any one of claims 1 to 18, wherein the composition additionally contains an antiviral, an antifungal, an antibacterial and / or anti-inflammatory agent.

20. Viscous formulation according to one or more of claims 1 to 19, wherein the formulation is in the form of a solution, a gel, an ointment, a lotion, an emulsion or an aerosol.

21. Viscous formulation according to any one of the preceding claims 1 to 20, which is in the form of a mouth spray, a nasal spray, an ear spray, a throat spray, a mouth / throat spray or an inhalation spray, mouthwash, inhalation solution, contact lens solution, cleaning solution (e.g. dentures), care products (lips, lip balm), nasal balm or hair tonic.

22. Composition comprising at least one cellulose ether, preferably one with a mean molar mass of greater than or equal to 200,000 to less than or equal to 900,000, or of greater than or equal to 300,000 to less than or equal to 750,000, and at least one tetrahydropyrimidine-4-carboxylic acid and / or a derivative thereof, preferably ectoine, wherein the cellulose ether is present in a concentration of greater than or equal to 0.05% of at least one cellulose ether, BIP00380WO bitop AG 30.12.2025, greater than or equal to 0.1%, greater than or equal to 0.2%, greater than or equal to 0.3%, greater than or equal to 0.4%, greater than or equal to 0.5% of at least one cellulose ether, and the tetrahydropyrimidine-4-carboxylic acid and / or a derivative thereof in a concentration of greater than or equal to 0.05%, greater than or equal to 0.1%, greater than or equal to 0.2%, greater than or equal to 0.3%, greater than or equal to 0.4%. %, greater than or equal to 0.5%.

23. A tetrahydropyrimidine-4-carboxylic acid or a derivative thereof for use as a viscosity-increasing agent or as a viscosity-enhancing agent, in particular for increasing the viscosity of a cellulose ether-containing, especially an aqueous cellulose ether-containing, formulation.

24. A tetrahydropyrimidine-4-carboxylic acid or a derivative for use according to claim 24, wherein the cellulose ether-containing formulation contains at least one or more cellulose ethers selected from the group comprising hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, methylethylcellulose, carboxymethylcellulose, methylcellulose, and / or ethylhydroxyethylcellulose or a combination of at least two of the aforementioned cellulose ethers.

25. The tetrahydropyrimidine-4-carboxylic acid or a derivative thereof for use according to claim 23 or 23, wherein derivatives comprise: 2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid, (S)-2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid, (R)-2-methyl-3,4,5,6-tetrahydropyrimidine-4-carboxylic acid and / or (4S,5S)-5-hydroxy-2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid.

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