WO2006063506A1

WO2006063506A1 - Utilization for carbon nanosphere in anti-cancer medicine

Info

Publication number: WO2006063506A1
Application number: PCT/CN2005/002112
Authority: WO
Inventors: Weijia Yang; Yiping Sun; Hanxiang Sun
Original assignee: Weijia Yang; Yiping Sun; Hanxiang Sun
Priority date: 2004-12-13
Filing date: 2005-12-07
Publication date: 2006-06-22
Also published as: CN1634588A; CN1274366C

Abstract

Carbon nanosphere and its utilization in manufacture of anti-cancer medicine are disclosed in this invention. The carbon nanosphere of the invention can be used as carrier for the target anti-cancer medicine, it can enhance the therapeutic effect significantly, reduce the side effect of the chems and radiotherapy, and can reduce the damage to the normal cells and immune system of the organism utmostly.

Description

TECHNICAL FIELD The present invention relates to medicinal nanocarbon spheres and their use in the preparation of medicaments for treating cancer. More specifically, the present invention relates to a medicinal nano carbon sphere having bio-oriented properties, used as an anti-tumor drug, a bio-oriented anti-tumor drug using medicinal nano-carbon spheres as a carrier, and a preparation method thereof The invention also relates to the application of the medicinal nano carbon sphere in preparing a medicament for treating cancer, treating a cardiovascular and cerebrovascular disease, and treating a rheumatoid rheumatoid disease medicine. BACKGROUND OF THE INVENTION Seven million people die each year from malignant tumors in the world, and about 2 million new cases occur each year in China. Tumors have become one of the leading causes of human death, and the prevention and treatment of cancer is very arduous. At present, the main means of treating cancer is early detection and surgical resection, but surgical resection does not solve the problem of metastatic lesions. Because metastasis often causes postoperative recurrence, chemotherapy or radiotherapy is usually added after surgery to prevent metastasis. However, the effects of chemotherapy and radiotherapy are not satisfactory, because the difference between the therapeutic dose and the poisoning dose is small, especially the hematopoietic cells are extremely sensitive to radiotherapy and radiotherapy, and inevitably cause serious systemic side effects during treatment. Can not be used for a long time or in large doses.

The ideal drug is to direct the drug to the lesion area to the maximum extent, so that the concentration of the drug in the lesion area and the normal cell area is greatly different, thereby effectively protecting the normal cells and tissues from harm, which is the guiding drug. In this regard, there have recently been formulations of lymphatic targeting drugs, such as the use of activated carbon-based targeting agents, but no reports on targeted preparations using medicinal nanocarbon spheres have been reported in domestic and foreign literature. The inventors have long-term research and a large number of experiments, and the results show that the medicinal nano-carbon spheres have biological guiding properties, have obvious inhibitory effects on tumors, and have a good drug-loading effect, and the present invention has been completed on the basis of the above. SUMMARY OF THE INVENTION A first object of the present invention is to provide a medicinal nanocarbon sphere having bio-oriented properties and useful as an antitumor drug or carrier.

A second object of the present invention is to provide an antitumor drug having bio-oriented properties using a medicinal nanocarbon sphere as a carrier and a preparation method thereof.

A third object of the present invention is to provide a use of a medicinal nanocarbon sphere for the preparation of a medicament for treating cancer.

A fourth object of the present invention is to provide a medicament for the use of a medicinal nanocarbon sphere for the preparation of a medicament for treating cardiovascular and cerebrovascular diseases.

Still another object of the present invention is to provide a medicinal nanocarbon sphere for the preparation of a medicament for treating rheumatism and rheumatoid diseases. The present invention provides a medicinal nano-carbon sphere which can be used as an anti-tumor drug or carrier with bio-oriented properties, and is characterized in that the medicinal nano-alignment is active. The carbon spheres have a particle size of 2 nm to 1000 nm, 90% of which have a particle diameter of 300 nm, a specific surface area of 100-3000 M ² /g, an ash content of less than 8%, and a loss on drying of less than 5%, lead, cadmium, and arsenic. , the mercury content is less than 20ppm, the abnormal toxicity test should be non-toxic; the microbial limit test should check the total number of bacteria per gram should be less than 100. The raw material for preparing the medicinal nano carbon spheres may be selected from nano carbon materials, such as the commercially available VXC72 nano carbon spheres produced by Carbot Corporation of the United States, and the characteristics thereof are shown in Table 1: Table 1

The preparation method of the medicinal nano carbon sphere of the invention is as follows:

The commercially available medicinal nano carbon spheres 0. lg, added 0. 1N hydrochloric acid 5mL, soaked for 8 hours, added water 50mL, after 'filtering, repeated washing to PH of 6, force B 0. 1N sodium hydroxide 5mL, treatment 8 Hour, filter, wash to pH 8-9, add 0. 1N hydrochloric acid 5mL, filter, and dry until medicinal nano carbon spheres meet the quality requirements. The invention provides a bio-oriented anti-tumor drug (referred to as A preparation agent) which uses medicinal nano carbon sphere as a carrier, and is characterized in that its composition and composition are as follows: rice carbon sphere 5 - lOOmg

0- 10mg

0-30 mg

Sex agent 0-15mg

0-500mg of the above antitumor drug, characterized in that the raw material for preparing the medicinal nano carbon sphere is selected from the group consisting of nano carbon materials, such as VXC-72; the guiding agent is selected from the group consisting of folic acid and salts thereof, such as calcium leucovorin; From polyvinylpyrrolidone, acacia, tragacanth, polyvinyl carboxymethylcellulose, hydroxypropylmethylcellulose, etc., preferably polyvinylpyrrolidone; surfactant selected from Tween, poly Oxyethylene castor oil, poloxamer, etc., preferably poloxamer; the excipient is selected from serum albumin or gamma globulin. The preparation method of the above antitumor drug comprises the following steps:

Preparation of anti-help water guide

(1) A medicinal nano-carbon sphere that meets the quality requirements of a swollen hanging surface;

(2) adding a suspending agent and/or a surfactant according to the ratio of the naphtha agent;

(3) Add the guiding agent according to the ratio, ultrasonically oscillate for 30~60 minutes, autoclave for 30~60 minutes, dispense, potting, autoclave for 45 minutes, and obtain the finished liquid preparation;

(4) The excipients are added according to the ratio, and freeze-dried under aseptic conditions to obtain a lyophilized powder type finished product. The invention also provides another anti-tumor drug (abbreviated as B preparation) having biological guiding properties using medicinal nano carbon sphere as a carrier, characterized in that its composition and composition are as follows: rice carbon sphere 5 - l OOmg

0-20 mg

Active ingredient 1 - lOOmg

0-30 mg

Sex agent 0-15mg

0—500mg

Moderate amount. The antitumor drug is characterized in that the raw material of the medicinal nano carbon sphere is selected from the group consisting of nano carbon materials, such as VXC72; the directing agent is selected from the group consisting of folic acid and salts thereof, such as calcium leucovorin; and the antitumor active ingredient is selected from the group consisting of antitumor agents. chemotherapeutic agents, anti-cancer radiotherapy _drugs: tumor angiogenesis inhibiting substances, anti-tumor antibodies or semi antibodies, interferon or other anti-cancer peptide, preferably anti-tumor chemotherapy and radiotherapy agents; suspending agent is selected from polyethylene Pyrrolidone, acacia, tragacanth, polyvinyl carboxymethylcellulose, hydroxypropylmethylcellulose, etc., preferably polyvinylpyrrolidone; surfactant selected from Tween, polyoxyethylene castor oil, Bo Losham et al, preferably poloxamer; the excipient is selected from serum albumin or gamma globulin. A method for preparing the above antitumor drug, characterized in that the method comprises the following steps:

(1) Preparation of medicinal nano carbon spheres meeting quality requirements -

(2) adding a suspending agent and/or a surfactant and an antitumor active ingredient according to a ratio, and mixing uniformly;

(3) Add the guiding agent according to the ratio, ultrasonically oscillate for 30~60 minutes, autoclave for 30~60 minutes, potting, autoclaving for 45 minutes, and obtain the finished liquid preparation;

(4) The excipient is added according to the ratio, and the product is obtained by freeze-drying under aseptic conditions. The invention also provides the use of the medicinal nano carbon sphere in preparing a medicament for treating cancer.

The invention also provides the application of the medicinal nano carbon sphere in preparing medicine for treating cardiovascular and cerebrovascular diseases.

The invention also provides the application of the medicinal nano carbon sphere in preparing medicine for treating rheumatism and rheumatoid diseases. For the latter two applications, the formulation used is a medicinal nanocarbon sphere that does not adsorb anti-tumor active ingredients, the dosage and principle of which is the same as the anticancer preparation, which is directed to the arteriosclerotic region and the rheumatoid rheumatoid lesion through the reticuloendothelial system. Gather, then detach by phagocytosis and eliminate the lesion.

The administration route of the preparation of the invention is as follows: The preparation of the invention needs to pass through the blood flow and the reticuloendothelial system to function, and any administration route which can directly or indirectly enter the bloodstream or lymphatic system is suitable, preferably intravenous administration and abdominal cavity. Administration, in addition, can be administered intramuscularly and mucosally; since the M cells in the intestinal wall have the ability to drink less than 100 nm of microparticles, the preparation of the present invention can also be administered orally. The dosage depends on the type of drug and the mode of administration, and the recommended dose for intravenous or intramuscular administration: adult dose (referred to as medicinal nanocarbon content) 10-80 mg, once every other day or twice a week, The dosage of the intraperitoneal administration can be increased to 5,000 mg; the oral dose can be used according to the condition of 0.1 to 5 g / time. All of the above are doses of medicinal nano-carbon spheres, and the doses contained in the case of loading anti-tumor active ingredients are lower than the conventional doses used in clinical practice, and are flexibly controlled according to the condition, generally 1/10~2/ 10. The following beneficial effects on medicinal nanocarbon spheres and their applications are as follows:

Animal experiments showed that the medicinal nano-carbon spheres with a particle size of 2 - 300 nm have good bio-directing properties, and their guiding effect is achieved by the movement, aggregation and fixation of phagocytic cells in the reticuloendothelial system to the inflammatory zone. This tropism can be greatly enhanced by loading cancer cells to proliferate substances. Therefore, the medicinal nanocarbon spheres are automatically enriched in the tumor area of the tumor through the blood vessel wall under the action of the immune system. Because cancer cells are less differentiated than normal cells, they have strong phagocytic ability. After the medicinal nano-carbon spheres are phagocytized by cancer cells, the metabolism of cancer cells is disturbed and leads to death. Therefore, the medicinal nano-carbon sphere itself has tumor suppression. The role of growing and killing tumor cells. If the medicinal nano-carbon spheres are used as carriers to adsorb and carry anti-tumor active ingredients, the effect of killing cancer cells is enhanced, thereby preparing various anti-tumor targeted drugs, so that tumor microvasculature and tumor cell interstitial The concentration of the drug reaches tens or even hundreds of times of the conventional treatment method, which greatly enhances the anti-tumor effect and reduces the side effects of chemotherapy and radiotherapy drugs. Therefore, on the basis of the use of medicinal nano-carbon spheres, the dose of clinical routine chemotherapy and radiotherapy can be reduced to 10-20% of the original dose, but instead it achieves a better therapeutic effect than the conventional dose, and can minimize the commonly seen It is difficult to avoid the side effects of normal cells and immune system in radiotherapy and chemotherapy. In addition, the research results also show that the medicinal nano carbon sphere of the invention has the effects of preventing and treating vascular atherosclerosis, coronary heart disease and cerebral thrombosis, and has obvious therapeutic effects on infectious diseases such as rheumatoid rheumatism, and the mechanism is due to all lesions. There is inflammation in the area, and the medicinal nano-carbon spheres have a tendency to move toward these lesions. In the phagocytic cells of the lesion, the medicinal nano-carbon spheres are foreign bodies, which stimulate the phagocytic properties, and gradually peel off the lesions during the process of phagocytosis. . The beneficial effects of the present invention are illustrated below by animal testing:

(1) Acute toxicity test of medicinal nano carbon spheres:

1. Anti-tumor agent: The medicinal nano-carbon ball is prepared by using VXC72 produced by Carbot Company of the United States as a raw material, and the anti-tumor active ingredient is not added to obtain a medicinal nano-carbon ball preparation. 2. Test animals: CD-1 mice were provided by the Animal Center of Peking University Hospital.

Trial acceptance

3, the dosage and mode of administration: Take clean male CD-1 mice, 18-22 grams, a total of 60, divided into 6 groups, try the sample test

10 rats in each group were administered with tail vein injection according to the dose of each group under the aseptic conditions on a daily basis, twice a week, 0.1 ml / time / time, and the cumulative dose was calculated. Date of receipt

The source is said to:

The test results are shown in Table 2. Table 2

The regression equation is: Y = - 12. 6303 + 7. 3487Χ , ( r=0. 9586 )

When a=0. 01, r is 0. 9170, (where Y is the probability unit plus 5, X is the logarithm of the dose log x) Calculated LD50 is 250. 6801mg/kg

The confidence interval for the confidence coefficient a=0. 05 is: 201. 4321 ^LD50^311. 9688, 0. 0950 The results show that the acute toxicity LD50 of the medicinal nanocarbon sphere of the present invention to mice is 250. 68 mg / Kg, which It is shown that the formulation of the present invention is less toxic and very safe.

(II) Antitumor test of medicinal nano carbon sphere (A preparation): The purpose of this experiment is to evaluate the antitumor effect of the drug on S180 tumor-bearing mice. Materials and Method

S2

Velgene

Status: Ampoule package

October 26, 2004

Experimental animals from October 26, 2004 to November 8, 2004: Experimental animals were CD mice, SPF-VAF grade, 70 in total, male, 18g-22 g, provided by the Ministry, certificate number: SCXK (Beijing) 2002-0001. Feeding environment: Raised in SPF animal laboratory, the temperature is 25 ° C soil 2 ° C, the relative humidity is 55% ± 15%. Certificate No.: SYXK (Beijing) 2002-0002. Feed: Special feed for mouse growth, provided by Beijing Keao Xieli Feed Co., Ltd.

Certificate No.: Jingdong (2000) No. 015. Animal grouping and grouping method

According to the time of tumor inoculation and the weight of the inoculation, randomization was divided into 5 groups, 14 in each group.

Negative control: Sterilized saline group (Datong Huida Pharmaceutical Co., Ltd., production batch number: 0311081., specification: 10ml: 90mg)

Positive control: cyclophosphamide group (Jiangsu Hengrui Pharmaceutical Co., Ltd., batch number 04070821, specification: 0. 2g / branch)

Low dose group: lmg/kg body reorganization

Medium dose group: 2mg/kg body reorganization

High dose group: 4mg/kg body recombination Experimental method:

1. Preparation of inoculated tumor solution: The tumor-bearing mice were aseptically manipulated, and the cells were counted under a microscope to prepare a concentration of 2 X 10, 7 cells/ml, and 20 ml for inoculation.

2, tumor inoculation: aseptic operation, subcutaneous inoculation of tumor fluid 0. 2ml / only, that is, 4 X 106 cells / mouse. :

3. Administration method: In addition to the positive control group, each group was administered with tail vein injection on the first day, the third day, the sixth day, the eighth day, and the tenth day of the inoculation; the positive control group was intraperitoneally injected with cyclophosphamide, The drug was administered on the first day, the third day, the sixth day, the eighth day, and the tenth day of the inoculation at a dose of 30 mg/kg. Detection Indicator-

1. Observe the animal's health status and death daily.

2. Animal weight and tumor weight were weighed at the end of the experiment.

3, necropsy animals, observe the pathological changes of the main organs. Data statistics:

The efficacy of solid tumors is expressed as a percentage of tumor weight inhibition.

Tumor weight inhibition rate (1-T/C) χ100%

When the tumor inhibition rate is greater than 40%, and there is a significant difference in statistical processing, it is considered that there is a sign.

Statistical processing was performed using SPSS for windows. If the death rate of the rats in the administration group exceeds 20%, or the average weight loss exceeds 15%, it means that the drug is toxic.

Result

1. The effect of drugs on animal body weight and survival status, see Table 3 Effect of drugs on animal weight and living conditions

Group Animal initial weight Animal mortality rate at the end of the experiment

(g) heavy (g)

Negative control group 21.8±1.01 27.2±3.74 14.3

Positive control group 21.3±0.98 29.7±1.45

Low dose group 21.0±1.23 28.5±2.88 5.1

Medium dose group 21.6±1.1 1 29.3±1.83 6.4

High dose group 21.2±1.17 27.9±5.08 7.4

2. Antitumor effect of drugs on tumor-bearing mice See Table 4 Table 4 Antitumor effect of drugs on tumor-bearing mice

Group tumor weight

(g) %

Negative control group 1.23 ± 0.28

Positive control group 0.60±0.23** 51.3

Low dose group 0.31 ±0.22** 75.1

Medium dose group 0.69±0.32** 44.2

High dose group 0.65 +0.55** 47.3

**p<0. 01, compared with the negative control group, there was a significant difference.

3. Gross pathological observation of major organs

The results of the high, medium and low dose groups showed that the organ shape, texture and color of the liver were normal. in conclusion

Under the experimental conditions, the low-dose group, the middle-dose group and the high-dose group all had anti-tumor effect, and the low-dose group had the highest tumor inhibition rate, and the drug was found to have a sign; while the high, medium and low-dose groups showed experimental results. The drug is less toxic.

(3) Trial of medicinal nanocarbon spheres to kill cancer cells in vitro:

Using kidney cancer cell R11, cultured in 1640 culture medium, the A preparation was added to the cell culture flask under the condition of 2 mg/50 ml of the culture solution under sterile conditions to observe the change of R11 cells, and the observation result showed that the cancer cells stopped on the day. Growing, the next day the cancer cells devour a large number of particles and then begin to swell and rupture. The particles uniformly distributed in the culture flask are enriched Inside the cell (the particles are almost invisible in the background of the culture flask), indicating that the particles are actively phagocytized by the cancer cells, the number of cells begins to decrease, and the cells completely dissolve into empty shells after one week, which proves that after the cells actively phagocytose the cells, the cell metabolism is Disturbed and caused cell death. The following examples are merely illustrative of the invention and are not intended to limit the scope of the invention. Example 1 Preparation of medicinal nano carbon spheres:

Select US CARB0T company VXC72 medicinal nano carbon sphere 0. lg, add 0. 1N hydrochloric acid 5mL, soak for 8 hours, add water 50mL, filter, wash repeatedly to PH6, add 0. 1N sodium hydroxide 5mL, treatment for 8 hours, filter Washed to PH8- 9, added 0. 1N hydrochloric acid (about) 5mL, washed to pH = 6-7, filtered, dried to obtain the finished medicinal nano carbon spheres.

The dry weight was 0.08 g, and the yield was 80%. It has been tested to meet the requirements of the medicinal nanocarbon spheres of the present invention. EXAMPLE 2 Example 1 was acceptable carbon nanocapsules embodiment 40mg, 35mL water was added, with stirring, was added a surfactant Tween - 80 to about 0. 5g, uniformly stirring, was added polyvinylpyrrolidone K30 suspending agents embankment 2-one _{G ;} were stirred hook, add water to 50mL, ultrasonic oscillation 30 minutes, stopped for 5 minutes, shaken for 4 minutes to be sufficiently dispersed pharmaceutical carbon nanocapsules a uniform nanosuspension, dispensing, potting, autoclaving After lyophilization for 45 minutes, the lyophilized powder was obtained. Example 3 The medicinal nano carbon spheres prepared in Example 1 were 40 mg, added with water 35 mL, stirred, and added with a surfactant Tween-80 of about 0.5 g, stirred and ticked, and added with polyvinylpyrrolidone K30 suspension 2 g and added. 5-Fu 3mg, stir well, add water to 50mL, ultrasonically shake for 15 minutes, stop for 5 minutes, shake for another 15 minutes, fully disperse the medicinal nano carbon sphere into a uniform nano-suspension, dispense and potting The mixture was autoclaved for 45 minutes to obtain a finished product of the liquid type preparation. Example 4 40 mg of the medicinal nano carbon sphere prepared in Example 1 was added, 35 mL of water was added, and the mixture was stirred, and the surfactant Tween-80 was added. About 0. 5g, Stir well, add 2 g of polyvinylpyrrolidone K30 suspension _; add 2 mg of excipient serum albumin, stir well, add water to 50 mL, shake for 15 minutes, stop for 5 minutes, then oscillate After 15 minutes, the medicinal nano carbon spheres are fully dispersed into a uniform nano-suspension, and the freeze-dried powder is obtained by freeze-drying. Example 5 40 mg of the medicinal nanocarbon sphere prepared in Example 1 was placed in a filter flask, and after evacuation, 2 ml of a 1% aqueous solution of calcium leucovorin was injected. The shaker was shaken well, and 35 mL of water was added to the solution, stirred, and the surfactant Tween-80 was added to about 0.5 g. Stir well, 2 g of polyvinylpyrrolidone K30 suspension was added; 2 mg of excipient serum albumin was added. Stir well, add water to 50mL, ultrasonically shake for 5 minutes, stop for 5 minutes, shake for another 4 minutes, fully disperse the medicinal nano carbon sphere into a uniform nano-suspension, dispense, potting, autoclave for 45 minutes. , freeze-dried to get the finished product of lyophilized powder.

Claims

Claim

A medicinal nanocarbon sphere having bio-oriented properties and useful as an antitumor drug or carrier, characterized in that the medicinal nanocarbon sphere has a particle diameter of 2 nm to 100 nm, wherein 90% of the particles have a particle diameter of 300 nm, Specific surface area

100-3000M7g, ash content less than 8%, loss on drying should be less than 5%, lead, cadmium, arsenic, mercury content less than 20ppra, abnormal toxicity test should be non-toxic; microbial limit test to check total bacteria The number should be less than 100 per gram.

2. An antitumor drug comprising the medicinal nanocarbon sphere of claim 1 as a carrier, characterized in that its composition and composition are as follows:

Medicinal nano carbon sphere 5 - lOOmg

Directing agent 0-10 mg

Suspension 0-30mg

Surfactant 0-15mg

Excipient Q—500mg

Water amount.

The antitumor drug according to claim 2, wherein: the raw material for preparing the medicinal nano carbon sphere is selected from the group consisting of nano carbon materials; the directing agent is selected from the group consisting of folic acid and salts thereof; and the suspending agent is selected from the group consisting of polyvinylpyrrolidone and Arabian. Gum, tragacanth, polyvinyl carboxymethyl cellulose, hydroxypropyl methylcellulose; surfactant selected from Tween, polyoxyethylene castor oil, poloxamer; excipient selected from serum white Protein or gamma globulin.

4. An antitumor drug according to claim 1, wherein the composition and composition thereof are as follows:

Medicinal nano carbon sphere 5 - lOOmg

Directing agent 0-20 mg

Antitumor active ingredient 1 - lOOmg

Suspension 0-30mg

Surfactant 0-15mg

Excipient 0—500mg

Water amount.

The antitumor drug according to claim 4, wherein the raw material for preparing the medicinal nano carbon sphere is selected from the group consisting of nanometers Carbon material; the guiding agent is selected from the group consisting of folic acid and its salts; the antitumor active ingredient is selected from the group consisting of an antitumor chemotherapeutic drug, an antitumor radiotherapy drug, a substance that inhibits tumor angiogenesis, an antitumor antibody or a semi-antibody, an interferon or an anticancer. Peptides; suspending agent is selected from the group consisting of polyvinylpyrrolidone, acacia, tragacanth, polyvinyl alcohol carboxymethyl cellulose, hydroxypropyl methylcellulose; surfactant selected from Tween, polyoxyethylene castor oil , Bolosum; the excipient is selected from serum albumin or gamma globulin.

The antitumor drug according to claim 2, wherein the raw material for preparing the medicinal nano carbon sphere is VXC72; the guiding agent is calcium leucovorin; the antitumor active ingredient is antitumor chemotherapy and radiotherapy; The agent is polyvinylpyrrolidone; the surfactant is poloxamer; the excipient is serum albumin.

The method for preparing an antitumor drug according to any one of claims 2 to 5, wherein the method comprises the following steps:

(1) preparing a medicinal nano carbon sphere that meets quality requirements;

(2) Adding suspending agents and/or surfactants and anti-tumor active ingredients according to the ratio, and mixing them evenly,

(3) Add the guiding agent according to the ratio, ultrasonically oscillate for 30~60 minutes, autoclave for 30~60 minutes; subpackage, potting, autoclave for 45 minutes to obtain the finished product of the liquid type preparation;

(4) The excipients are added according to the ratio under aseptic conditions, and freeze-dried to obtain a lyophilized powder type finished product.

8. The use of the medicinal nanocarbon sphere of claim 1 for the preparation of a medicament for treating cancer.

9. The use of the medicinal nanocarbon sphere of claim 1 for the preparation of a medicament for treating cardiovascular and cerebrovascular diseases.

10. The use of the medicinal nanocarbon sphere of claim 1 for the preparation of a medicament for treating rheumatic diseases.