A rutin composition for treating arthritis and a method for preparing the same

Abstract

The present application belongs to the technical field of medicine, and particularly relates to a rutin composition for treating arthritis and a preparation method thereof. The rutin composition for treating arthritis comprises the following active ingredients in parts by weight: rutin 20-25 parts, typhaneoside 10-18 parts, and alisol B 11-acetate 8-15 parts. The rutin in the composition has significant anti-inflammatory and antioxidant effects, and can reduce the inflammatory response of arthritis. The typhaneoside has analgesic and anti-inflammatory properties, and the alisol B 11-acetate has anti-inflammatory and cartilage protection effects. The two components produce a synergistic effect with the rutin, and enhance the therapeutic effect of the composition. The three active ingredients are used in combination, and provide a new scheme for treating arthritis.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a rutin composition for treating arthritis and a preparation method thereof. BACKGROUND

[0002] Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation of the joints, which is characterized by chronic inflammatory joint lesions and accompanied by multiple systemic involvement. Without systematic treatment, it can be repeated for many years, eventually leading to joint deformity, loss of function, and causing great pain to patients.

[0003] At present, the commonly used arthritis treatment drugs in clinical practice mainly include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids and disease-modifying antirheumatic drugs (DMARDs), etc. NSAIDs are the first choice for the treatment of RA, including salicylic acid, traditional non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 (COX-2) inhibitors. However, long-term use of these drugs is often accompanied by serious side effects, such as gastrointestinal damage, liver and kidney function damage, and increased cardiovascular risk. Therefore, researchers are looking for treatment opportunities from various angles, and Chinese herbal medicines are increasingly valued for their low toxicity, multi-target treatment and low cost, becoming a new hotspot for the development of RA treatment drugs.

[0004] Rutin is a natural flavonoid compound, widely exists in sophora, buckwheat, citrus and other plants, and has significant anti-inflammatory, antioxidant and immunomodulatory effects. Studies have shown that rutin can inhibit the production of inflammatory factors such as TNF-α, IL-1β and IL-6, reduce synovial inflammation, and protect chondrocytes. Patent CN118217221A discloses a preparation method of rutin-loaded black phosphorus nanosheet composite hydrogel and its anti-arthritic application. However, single rutin preparation has limitations such as low bioavailability and single target, which affects its clinical efficacy. Typhaneoside is an effective component extracted from traditional Chinese medicine Typha angustata. Modern pharmacological studies have confirmed that it has analgesic, anti-inflammatory and immunomodulatory effects. Resveratrol is a natural polyphenolic compound, widely exists in grapes, giant knotweed and other plants, and has been confirmed to have anti-inflammatory, antioxidant, immunomodulatory and cartilage protection effects. It can inhibit the release of TNF-α, IL-1β and IL-6 and other pro-inflammatory factors through the inhibition of NF-κB and MAPK inflammatory signaling pathways, but has defects such as low bioavailability and poor stability.

[0005] Although there are reports on the use of rutin for the treatment of arthritis in the prior art, the combination of rutin, typhaneoside and resveratrol derivatives has not been disclosed. SUMMARY

[0006] In order to overcome the deficiencies of the prior art, the primary object of the present application is to provide a rutin composition for treating arthritis, wherein the rutin has significant anti-inflammatory and antioxidant effects, can reduce the inflammatory response of arthritis, the typhaneoside has analgesic and anti-inflammatory properties, the grifolic acid derivative has anti-inflammatory and cartilage protection effects, and the two have a synergistic effect with the rutin, thereby enhancing the therapeutic effect of the composition, and the combination of the three active ingredients provides a new scheme for treating arthritis.

[0007] Another object of the present application is to provide a preparation method of the rutin composition for treating arthritis.

[0008] The object of the present application is achieved by the following technical solutions.

[0009] A rutin composition for treating arthritis, comprising the following active ingredients in parts by weight: 20-25 parts of rutin, 10-18 parts of typhaneoside, and 8-15 parts of grifolic acid derivative; the grifolic acid derivative has the following structural formula:

[0010] .

[0011] Further, the grifolic acid derivative is prepared by the following preparation process:

[0012] (1) 2-indolone and furfural are added to a solvent, and a catalyst is added, and reflux reaction is carried out; after the reaction is completed, filtration, washing, and purification are carried out to obtain intermediate 1;

[0013] (2) Grifolic acid is added to water, and sodium hydroxide, 1,2-dichloroethane, and tetrabutylammonium bromide are added, and stirring reaction is carried out; after the reaction solution is extracted, the organic phases are combined, and the organic phases are washed with water, dried, filtered, concentrated, and purified to obtain intermediate 2;

[0014] (3) Intermediate 2 is added to a solvent, and intermediate 1 and K2CO3 are added, and stirring reaction is carried out; after the reaction solution is extracted, the organic phases are combined, and the organic phases are washed with water, dried, filtered, concentrated, and purified to obtain the grifolic acid derivative.

[0015] Further, in step (1), the amount ratio of 2-indolone, furfural, catalyst, and solvent is 10 mmol: 11-12 mmol: 0.1-0.5 mmol: 15-20 mL, the catalyst is piperidine, and the solvent is ethanol.

[0016] Further, in step (1), the reflux reaction time is 4-5 h.

[0017] Further, in step (2), the white hulupinol, sodium hydroxide, 1,2-dichloroethane, tetrabutylammonium bromide and water are used in a ratio of 20 mmol: 75-80 mmol: 180-200 mmol: 2-2.2 mmol: 15-20 mL.

[0018] Further, in step (2), the reaction temperature is 75-85℃, and the reaction time is 12-14 h.

[0019] Further, in step (3), the intermediate 2, intermediate 1, K2CO3 and solvent are used in a ratio of 10 mmol: 50-60 mmol: 20-25 mmol: 80-100 mL; and the solvent is DMF.

[0020] Further, in step (3), the stirring reaction temperature is 50-60℃, and the stirring reaction time is 24-30 h.

[0021] The present application also provides a preparation method of the rutin composition for treating arthritis as described above, which comprises the following steps: mixing the raw materials according to the weight ratio to obtain the rutin composition.

[0022] The present application has the following effects compared with the prior art:

[0023] 1. The rutin in the composition of the present application has significant anti-inflammatory and antioxidant effects, can reduce the inflammatory response of arthritis, the typhaneoside has analgesic and anti-inflammatory properties, the hulupinol derivative has anti-inflammatory and cartilage protection effects, and the two have a synergistic effect with the rutin, thereby enhancing the therapeutic effect of the composition, improving the swelling of the foot and the inflammation of the joints caused by arthritis, and reducing the serum collagen-specific antibody level of the arthritis mouse, and the three active ingredients are used in combination, and have a good therapeutic effect on collagen-induced rheumatoid arthritis in mice, and the composition provides a new scheme for treating arthritis.

[0024] 2. The rigid indole ketone-furan heterocyclic structure is introduced at the phenolic hydroxyl group of the hulupinol, the stability of the whole molecule is enhanced, the extension of the conjugated system can effectively disperse the unpaired electrons of the free radicals, and the damage of oxidative stress to the molecule is reduced. Compared with hulupinol, the derivative after structural modification has stronger anti-inflammatory effect and performs better in anti-arthritis. DETAILED DESCRIPTION

[0025] The technical solutions of the present application are further described below in combination with the specific embodiments. However, those skilled in the art should understand that the following examples are only used to illustrate the present application, and should not be regarded as limiting the present application. The specific conditions not mentioned in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used, such as those not specifically mentioned, are conventional products obtained through market channels.

[0026] Example 1

[0027] A rutin composition for treating arthritis, comprising the following active ingredients by weight: rutin (CAS No.: 153-18-4) 22 parts, typhaneoside (CAS No.: 104472-68-6) 15 parts, and a calamus alcohol derivative 12 parts.

[0028] The calamus alcohol derivative is prepared by the following process:

[0029]

[0030] (1) 2-indolone, furfural, and a catalyst of piperidine were added into ethanol, and the amount ratio of 2-indolone, furfural, catalyst of piperidine, and ethanol was 10 mmol: 11.5 mmol: 0.3 mmol: 18 mL, and reflux reaction was performed for 4.5 h; after the reaction was completed, the product was collected after filtration and washing with ethanol, and then purified by silica gel column chromatography (chloroform / methanol = 9:1) to obtain intermediate 1 (yield 86.4%); 1 H NMR(C 13 H9NO2, 400 MHz, d6-DMSO) δ 10.89 (s, 1H, -NH), 8.75-8.73(d, 1H, Ar-H), 8.15-8.13(d, 1H, Ar-H), 7.67-7.65 (d, 1H, Ar-H), 7.55 (s, 1H,-CH), 7.41-7.39 (t, 1H, Ar-H), 7.10-7.08 (t, 1H, Ar-H), 7.01-6.99 (d, 1H, Ar-H), 6.84-6.82 (t, 1H, Ar-H); HRMS (ESI + ): [M+H] + Calculated 212.06, found 216.07.

[0031] (2) Resveratrol was added into water, and then sodium hydroxide, 1,2-dichloroethane, and tetrabutylammonium bromide were added, and the amount ratio of resveratrol, sodium hydroxide, 1,2-dichloroethane, tetrabutylammonium bromide, and water was 20 mmol: 78 mmol: 190 mmol: 2.1 mmol: 18 mL; stirring was performed at 80°C for 13 h; after the reaction solution was cooled to room temperature, it was diluted with water and extracted with ethyl acetate (3x30 mL), and the combined organic phase was washed with water, dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain intermediate 2 (yield 80.5%); 1H NMR (C 20 H 21 Cl3O3, 400 MHz, d6-DMSO) δ7.82-7.79 (d, 2H, Ar-H), 7.08-7.05(d, 2H, Ar-H), 6.92-6.89 (d, 1H, CH), 6.84(s, 2H, Ar-H), 6.83-6.82 (d, 1H, CH), 6.25 (s, 1H, Ar-H), 4.25-4.22 (t, 6H, -OCH2), 4.10-4.08 (t, 6H, -CH2); HRMS (ESI + ): [M+H] + Calcd 415.06, found 415.07.

[0032] (3) Intermediate 2 was added into N,N-dimethylformamide (DMF), then intermediate 1 and K2CO3 were added, the amount of intermediate 2, intermediate 1, K2CO3 and DMF was 10 mmol: 55 mmol: 23 mmol: 90 mL; the reaction was stirred at 55°C for 28 h; the reaction solution was cooled to room temperature, diluted with water, then extracted with ethyl acetate (3 x 30 mL), the organic phase was combined, washed with water, dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain the white hedyarol derivative (yield 78.5%); 1 H NMR (C 59 H 45 N3O9, 400 MHz, d6-DMSO) δ 8.75-8.73 (d, 3H, Ar-H), 8.15-8.13(d, 3H, Ar-H), 7.82-7.79 (d, 2H, Ar-H), 7.67-7.65 (d, 6H, Ar-H), 7.52-7.50(t, 3H, Ar-H), 7.28 (s, 3H, -CH), 7.10-7.06 (m, 5H, Ar-H), 6.92-6.89 (d, 1H,CH), 6.86-6.83 (m, 5H, Ar-H), 6.83-6.82 (d, 1H, CH), 6.25 (s, 1H, Ar-H),4.45-4.42 (t, 6H, -OCH2), 3.90-3.87 (t, 6H, -CH2); HRMS (ESI + ): [M+H] + Calcd 940.32, found 940.34.

[0033] The present application also provides a preparation method of the rutin composition for treating arthritis, and the specific steps are as follows: mixing the raw materials according to the weight parts to obtain the rutin composition.

[0034] Example 2

[0035] A rutin composition for treating arthritis, which comprises the following active ingredients in parts by weight: rutin 20 parts, typhaneoside 10 parts, and oridonin derivative 8 parts.

[0036] The oridonin derivative is prepared by the following preparation process:

[0037] (1) 2-indolone, furfural and a catalyst piperidine are added into ethanol, and the amount ratio of the 2-indolone, furfural, catalyst piperidine and ethanol is 10 mmol: 11 mmol: 0.1 mmol: 15 mL, and reflux reaction is carried out for 4 h; after the reaction is completed, the product is collected by filtration and washed with ethanol, and then purified by silica gel column chromatography (chloroform / methanol = 9:1) to obtain intermediate 1 (yield 85.0%); 1 H NMR and HRMS (ESI + ) results are the same as those of Example 1.

[0038] (2) Oridonin is added into water, and then sodium hydroxide, 1,2-dichloroethane and tetrabutylammonium bromide are added, and the amount ratio of oridonin, sodium hydroxide, 1,2-dichloroethane, tetrabutylammonium bromide and water is 20 mmol: 75 mmol: 180 mmol: 2 mmol: 15 mL; stirring is carried out at 75°C for 14 h; the reaction solution is cooled to room temperature, diluted with water, and then extracted with ethyl acetate (3×30 mL), and the organic phase is combined, washed with water, dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain intermediate 2 (yield 79.8%); 1 H NMR and HRMS (ESI + ) results are the same as those of Example 1.

[0039] (3) Intermediate 2 is added into DMF, and then intermediate 1 and K2CO3 are added, and the amount ratio of intermediate 2, intermediate 1, K2CO3 and DMF is 10 mmol: 50 mmol: 20 mmol: 80 mL; stirring is carried out at 50°C for 30 h; the reaction solution is cooled to room temperature, diluted with water, and then extracted with ethyl acetate (3×30 mL), and the organic phase is combined, washed with water, dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain oridonin derivative (yield 77.5%); 1 H NMR and HRMS (ESI + ) results are the same as those of Example 1.

[0040] The present application also provides a preparation method of the rutin composition for treating arthritis, and the specific steps are as follows: mixing the raw materials according to the weight parts to obtain the rutin composition.

[0041] Example 3

[0042] A rutin composition for treating arthritis, which comprises the following weight parts of active ingredients: rutin 25 parts, typhaneoside 18 parts, and oridonin derivative 15 parts.

[0043] The oridonin derivative is prepared by the following preparation process:

[0044] (1) 2-indolone, furfural and a catalyst piperidine are added into ethanol, and the amount ratio of the 2-indolone, furfural, catalyst piperidine and ethanol is 10 mmol: 12 mmol: 0.5 mmol: 20 mL, and reflux reaction is carried out for 5 h; after the reaction is completed, the product is collected by filtration and washed with ethanol, and then purified by silica gel column chromatography (chloroform / methanol = 9:1) to obtain intermediate 1 (yield 85.8%); 1 H NMR and HRMS (ESI + ) results are the same as those of Example 1.

[0045] (2) Oridonin is added into water, and then sodium hydroxide, 1,2-dichloroethane and tetrabutylammonium bromide are added, and the amount ratio of oridonin, sodium hydroxide, 1,2-dichloroethane, tetrabutylammonium bromide and water is 20 mmol: 80 mmol: 200 mmol: 2.2 mmol: 20 mL; stirring is carried out at 85°C for 12 h; the reaction solution is cooled to room temperature, diluted with water, and then extracted with ethyl acetate (3×30 mL), and the organic phase is combined, washed with water, dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain intermediate 2 (yield 80.2%); 1 H NMR and HRMS (ESI + ) results are the same as those of Example 1.

[0046] (3) Intermediate 2 is added into DMF, and then intermediate 1 and K2CO3 are added, and the amount ratio of intermediate 2, intermediate 1, K2CO3 and DMF is 10 mmol: 60 mmol: 25 mmol: 100 mL; stirring is carried out at 60°C for 24 h; the reaction solution is cooled to room temperature, diluted with water, and then extracted with ethyl acetate (3×30 mL), and the organic phase is combined, washed with water, dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain oridonin derivative (yield 79.3%); 1 H NMR and HRMS (ESI+ )Results are the same as Example 1.

[0047] The present application also provides a method for preparing the rutin composition for treating arthritis as described above, and the specific steps are as follows: mixing the raw materials according to the weight parts to obtain the rutin composition.

[0048] Comparative Example 1

[0049] This comparative example 1 is basically the same as Example 1, except that the whiteveil alcohol derivative is replaced by whiteveil alcohol, and the rest is the same as Example 1.

[0050] Comparative Example 2

[0051] This comparative example 2 is basically the same as Example 1, except that the typhonioside is omitted, and the rest is the same as Example 1.

[0052] Comparative Example 3

[0053] This comparative example 3 is basically the same as Example 1, except that the typhonioside and whiteveil alcohol derivative are omitted, and the rest is the same as Example 1.

[0054] Test Example

[0055] 1 Experimental Animals

[0056] DBA / 1 mice were selected as experimental animals, male, body weight 18-22 g, a total of 90, adaptively fed in a SPF laboratory for 1 week, and the environmental temperature was controlled at 23-25°C and the relative humidity was 55%.

[0057] 2. Animal grouping

[0058] The above DBA / 1 mice were randomly divided into a blank control group, a model group, a positive control group, an Example 1 group, an Example 2 group, an Example 3 group, a comparative example 1 group, a comparative example 2 group, and a comparative example 3 group, 10 mice in each group.

[0059] 3. Construction of collagen-induced rheumatoid arthritis (CIA) mouse model

[0060] The bovine type II collagen (CII) was dissolved in 0.01M glacial acetic acid to prepare 4mg / mL bovine type II collagen, then emulsified with an equal volume of Freund's complete adjuvant as antigen, after the mice were anesthetized by intraperitoneal injection of Cetirizine (50mg / kg), the fur on the tail root was removed, and after disinfection, 100µL of the antigen was injected into the tail root for sensitization. On the 21st day, the same dose of antigen (4mg / mL bovine type II collagen emulsified with an equal volume of Freund's incomplete adjuvant) was injected for immune attack. The blank control group was injected with normal saline.

[0061] 4. Administration method

[0062] From the 21st day, the example 1 group, the example 2 group, the example 3 group, the comparative example 1 group, the comparative example 2 group, the comparative example 3 group are respectively given 30mg / kg corresponding rutin composition by gavage, the blank control group and the model group are given the same amount of normal saline; the positive control group is given 1mg / kg methotrexate by gavage, once a day, for 28d.

[0063] 5. Index detection

[0064] (1) Mouse arthritis score: On the 14th day, the 21st day and the 28th day after administration, the severity of arthritis in mice of each group was observed and scored, and the scoring standard is shown in Table 1; the total score of 4 feet of each mouse was scored, and the highest score of each mouse was 16, the higher the arthritis index score, the more serious the arthritis symptoms of the mouse. The scoring results are shown in Table 2.

[0065] Table 1 Mouse arthritis scoring standard

[0066]

[0067] Table 2 Mouse arthritis index score after administration

[0068]

[0069] As can be seen from Table 2, compared with the blank control group, the mouse arthritis index score of the model group increased significantly, joint lesions appeared, and the model was successfully constructed. After 28 days of treatment, the arthritis index score of examples 1-3 decreased, and decreased significantly compared with the model group; the treatment effect was similar to that of the positive control group. Compared with example 1, comparative example 1 replaced the arodistomol derivative with arodistomol, comparative example 2 omitted the typhaneoside; comparative example 3 omitted the typhaneoside and arodistomol derivative; the treatment effect decreased to varying degrees. Among them, the effect of comparative example 3 is the worst. It shows that typhaneoside and arodistomol derivative can synergize with rutin to enhance the treatment effect of arthritis inflammation.

[0070] (2) Mouse hind foot thickness: At the same time of scoring the mouse arthritis, the thickness of the mouse bilateral hind foot was measured by vernier caliper, and the final result was recorded in Table 3.

[0071] Table 3 Mouse foot thickness (mm)

[0072]

[0073] As shown in Table 3, compared with the blank control group, the foot thickness of the model group mice was obviously increased, indicating that the swelling degree of the mouse foot was obviously increased. After treatment for 28 days, the foot thickness of the mice of Examples 1-3 was obviously decreased, and was lower than that of the model group; the treatment effect was similar to that of the positive control group. Compared with Example 1, the effects of Comparative Examples 1-3 were poor. The above results show that the new calamus glycoside and the ephedra alkyd derivative can synergize with rutin to improve the foot inflammation level of the CIA model mice and enhance the treatment effect of arthritis inflammation.

[0074] (3) ELISA detection of the anti-CII antibody level in the serum of the mice: 3 h after the last administration, the mice were anesthetized by intraperitoneal injection of Xuetai (50 mg / kg), the eyeball was removed to take blood, centrifugation was performed at 10,000 rpm for 10 min, the supernatant was taken, and the absorbance value of the sample at 450 nm / 650 nm was measured according to the instruction of the total immunoglobulin G (IgG) ELISA kit. The experimental results are shown in Table 4.

[0075] Table 4

[0076]

[0077] As shown in Table 4, compared with the blank control group, the absorbance value of the total immunoglobulin G of the model group mice was obviously increased. Compared with the model group, after treatment, the total immunoglobulin G level of the mice of Examples 1-3 was obviously decreased, and was lower than that of the model group, indicating that the rutin composition obtained by the application can reduce the collagen-specific antibody level in the serum of the arthritis model mice. And compared with Example 1, the effects of Comparative Examples 1-3 were relatively poor. The above results show that the rutin composition of Examples 1-3 of the application can antagonize the increase of the antibody level in the serum of the arthritis model mice.

[0078] Finally, it should be pointed out that the above examples are only used to illustrate the technical solutions of the application, but not to limit it. The basic principles and main features of the application have been described above with specific embodiments, and some modifications or replacements can be made on the basis of the application, but these modifications or replacements do not make the essence of the corresponding technical solution deviate from the scope of the application claimed.

Claims

1. A rutin composition for treating arthritis, characterized in that, The rutin composition comprises the following active ingredients in parts by weight: 20-25 parts rutin, 10-18 parts typhain, and 8-15 parts resveratrol derivative; the structural formula of the resveratrol derivative is as follows: 。 2. The rutin composition for treating arthritis according to claim 1, characterized in that, The resveratrol derivative was prepared by the following process: (1) Add 2-indolone and furfural to a solvent, then add a catalyst and reflux the reaction. After the reaction is complete, filter, wash and purify to obtain intermediate 1. (2) Add resveratrol to water, then add sodium hydroxide, 1,2-dichloroethane and tetrabutylammonium bromide, and stir to react; after extraction, combine the organic phases of the reaction solution, and wash, dry, filter, concentrate and purify the organic phases to obtain intermediate 2; (3) Add intermediate 2 to the solvent, then add intermediate 1 and K2CO3, and stir to react; after extraction, combine the organic phases of the reaction solution, and wash, dry, filter, concentrate and purify the organic phases to obtain the resveratrol derivative.

3. The rutin composition for treating arthritis according to claim 2, characterized in that, In step (1), the ratio of 2-indolone, furfural, catalyst, and solvent is 10 mmol: 11-12 mmol: 0.1-0.5 mmol: 15-20 mL, the catalyst is piperidine, and the solvent is ethanol.

4. The rutin composition for treating arthritis according to claim 2, characterized in that, In step (1), the reflux reaction time is 4-5 hours.

5. The rutin composition for treating arthritis according to claim 2, characterized in that, In step (2), the ratio of resveratrol, sodium hydroxide, 1,2-dichloroethane, tetrabutylammonium bromide and water is 20 mmol: 75-80 mmol: 180-200 mmol: 2-2.2 mmol: 15-20 mL.

6. The rutin composition for treating arthritis according to claim 2, characterized in that, In step (2), the reaction temperature is 75-85℃ and the time is 12-14 h.

7. The rutin composition for treating arthritis according to claim 2, characterized in that, In step (3), the ratio of intermediate 2, intermediate 1, K2CO3 and solvent is 10 mmol: 50-60 mmol: 20-25 mmol: 80-100 mL; the solvent is DMF.

8. The rutin composition for treating arthritis according to claim 2, characterized in that, In step (3), the temperature of the stirring reaction is 50-60℃ and the time is 24-30 h.

9. A method for preparing a rutin composition for treating arthritis according to any one of claims 1-8, characterized in that, The process includes the following steps: Mix the ingredients according to their weight proportions.

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