CN117205188A - Application of vitamin K4 in the preparation of drugs for the treatment of melanoma - Google Patents

Abstract

The application relates to application of vitamin K4 in preparation of a medicine for treating melanoma. According to the application, experiments show that vitamin K4 can promote death of melanoma cells and reduce tumor volume, so that vitamin K4 is developed as a medicament for treating melanoma, and has the advantages of low price, small side effect and the like, vitamin K4 and other medicaments for treating melanoma such as immune checkpoint inhibitors are further developed to treat melanoma, and the vitamin K4 can enhance the treatment effect of the immune checkpoint inhibitors.

Description

Application of vitamin K4 in the preparation of drugs for the treatment of melanoma

Technical field

This application relates to the field of biomedicine, specifically the application of vitamin K4 in the preparation of drugs for the treatment of melanoma.

Background technique

Melanoma is a highly aggressive malignant tumor derived from melanocytes with increasing incidence worldwide and poor prognosis. Current treatments for melanoma include surgery, chemotherapy, immunotherapy and targeted therapy, but melanoma is insensitive to traditional chemotherapy and radiotherapy. Currently, with the widespread use of immune checkpoint inhibitors, the use of PD-1 inhibitors and PD-L1 inhibitors can significantly reduce tumor burden and improve the overall survival of patients with advanced melanoma, and can be used in stage II-III high-risk patients. Postoperative adjuvant treatment for risk of recurrence. However, even in sensitive tumor types including melanoma, the response rate of immunotherapy is less than 30%, and some patients develop toxic side effects after immunotherapy, and some patients are resistant to immune checkpoint inhibitor treatment. medicine.

Therefore, there is an urgent need to develop new combination therapies or new drugs to treat or improve the therapeutic efficacy of melanoma patients.

Contents of the invention

Based on this, it is necessary to provide a new drug for treating melanoma-vitamin K4 and its application.

The specific technical solutions are as follows:

A first aspect of the present application provides the use of vitamin K4 in the preparation of medicaments for treating melanoma.

In one embodiment, the vitamin K4 is combined with other drugs for treating melanoma.

In one embodiment, the other drugs for treating melanoma include immunotherapy drugs.

In one embodiment, the immunotherapy drug includes an immune checkpoint inhibitor. Alternatively, the immune checkpoint inhibitor includes one or more of a PD-1 inhibitor and a PD-L1 inhibitor.

The second aspect of the present application provides the use of vitamin K4 in the preparation of drugs that promote melanoma cell apoptosis or inhibit tumor growth.

The third aspect of the present application provides the use of vitamin K4 in the preparation of products that enhance the effect of immune checkpoint inhibitors in treating melanoma or increase the sensitivity of melanoma to immune checkpoint inhibitors.

A fourth aspect of the present application provides a medicament for melanoma treatment, the medicament comprising vitamin K4.

Optionally, the other drugs for treating melanoma include immunotherapy drugs.

The immunotherapy drugs include immune checkpoint inhibitors.

Optionally, the immune checkpoint inhibitor includes one or more of PD-1 inhibitor and PD-L1 inhibitor.

Optionally, the drug also includes a PD-1 inhibitor.

In one embodiment, the medicine further includes pharmaceutically acceptable excipients.

In one embodiment, the excipients include at least one of a diluent, a filler, an excipient, a binder, a wetting agent, a disintegrating agent, a surfactant, a lubricant and a flavoring agent.

In one embodiment, the drug is an oral agent or an injection.

Compared with traditional technology, this application has the following beneficial effects:

This application found through experiments that vitamin K4 can promote the death of melanoma cells and reduce the size of tumors. Therefore, vitamin K4 is developed as a drug for treating melanoma. This drug has the advantages of low price and small side effects.

Furthermore, this application also uses the combination of vitamin K4 and immune checkpoint inhibitors to treat melanoma. It is found that the combination of vitamin K4 and immune checkpoint inhibitors has a synergistic effect on reducing tumor volume and inhibiting tumor growth; the drug Combination use can enhance the effect of immune checkpoint inhibitors, and has broader application prospects than using them alone.

Description of the drawings

Figure 1 shows the results of detecting apoptosis of different melanoma cells;

Figure 2 is a physical diagram of tumor volume recording of different drug groups in Example 2.

Detailed ways

In order to make the above objects, features and advantages of the present application more obvious and easy to understand, the specific implementation modes of the present application will be described in detail below with reference to the accompanying drawings. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application. However, the present application can be implemented in many other ways different from those described here. Those skilled in the art can make similar improvements without violating the connotation of the present application. Therefore, the present application is not limited by the specific embodiments disclosed below.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this application belongs. The terminology used herein in the description of the application is for the purpose of describing specific embodiments only and is not intended to limit the application.

As used in this article, the term "and/or" includes any one of two or more related listed items, and also includes any and all combinations of the related listed items. Any and All combinations include any two of the related listed items, any more of the related listed items, or a combination of all of the related listed items. For example, "A and/or B" includes three parallel solutions: A, B and A+B. For another example, the technical solution of "A, B, C, and/or D" includes any one of A, B, C, and D, as well as any and all combinations of A, B, C, and D. That is, it includes the combination of any two or any three of A, B, C, and D, and also includes the four-item combination of A, B, C, and D.

As used herein, the terms "plurality", "multiple types", "multiple times", "multiple groups", etc., unless otherwise specified, refer to a quantity greater than 2 or equal to 2. For example, "one or more" means one or more than two.

As used in this article, the terms "optionally", "optional" and "optional" mean optional, that is, any one selected from the two juxtapositions of "yes" or "no". kind. If there are multiple "optionals" in a technical solution, each "optional" will be independent unless otherwise specified and there is no contradiction or mutual restriction.

As used herein, the terms "further" and the like are used for descriptive purposes and indicate differences in content, but should not be understood as limiting the scope of the present application.

In the open technical features or technical solutions described by words such as "including" and "including" used in this article, if there is no other explanation, additional members other than the listed members are not excluded and can be regarded as both provided by Closed features or solutions are provided with the listed members, and open features or solutions are provided with additional members in addition to the listed members.

As used herein, in the “first aspect”, “second aspect”, “third aspect” and “fourth aspect”, the terms “first”, “second”, “third” and “third” "Four" is for descriptive purposes only and cannot be understood as indicating or implying relative importance or quantity, nor as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third" and "fourth" only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

Currently, for the treatment of melanoma patients who lack surgical indications and postoperative patients with a high risk of recurrence, the main treatments are immune checkpoint inhibitors and PD-1 inhibitors, but the response rate is less than 30%. Toxic side effects occur, and some patients are completely drug-resistant, so the treatment effect is poor.

Vitamin K4 is mainly suitable for coagulation disorders caused by vitamin K deficiency. For example, vitamin K deficiency caused by intestinal malabsorption; obstructive jaundice, chronic ulcerative colitis, chronic pancreatitis and reduced intestinal absorption function after extensive small bowel resection caused by various reasons; long-term use of antibiotics can lead to vitamin K deficiency in the body , Broad-spectrum antibiotics or intestinal sterilizing drugs can kill or inhibit the bacterial community in the normal intestine, resulting in less vitamin synthesis by the bacteria in the intestine. As a coenzyme of carboxylase, vitamin K4 participates in the synthesis of coagulation factors II, VII, IX, and X. The glutamic acid residues on these factors must form 9-12 γ- Carboxyglutamic acid can enable these factors to have the ability to bind to Ca ²⁺ and connect the phospholipid surface and regulatory proteins, so that these factors have coagulation activity, thereby producing coagulation. If vitamin K4 is lacking or the epoxide reduction reaction is blocked (such as antagonized by coumarins), the synthesis of factors II, VII, IX, and X will remain in the precursor state, prolonging the prothrombin time and causing bleeding. There are currently no studies using vitamin K4 to treat melanoma.

This application screened dozens of vitamin drugs (including but not limited to K3, K2 and K4) and found that only vitamin K4 has a certain killing effect on melanoma cell lines. Through a series of creative experiments, it was proved that vitamin K4 It has certain killing ability against melanoma. At the same time, the combination of vitamin K4 and immune checkpoint inhibitors can achieve a synergistic effect in the treatment of melanoma, indicating that vitamin K4 can increase the body's sensitivity to immunotherapy drugs and improve the therapeutic effect of immune checkpoint inhibitors.

Based on this, one embodiment of the present application provides the use of vitamin K4 in preparing drugs for treating melanoma.

As used herein, the term "treatment" is used to refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms, and/or therapeutic in terms of partial or complete cure of the disease and/or adverse effects caused by the disease. As used herein, "treatment" encompasses diseases in animals, including: (a) preventing the occurrence of a disease or condition in an individual susceptible to the disease but not yet diagnosed with the disease; (b) inhibiting the disease, such as arresting the progression of the disease; or (c) To alleviate disease, such as reducing symptoms associated with a disease. "Treatment" as used herein encompasses any administration of a drug to an individual to treat, cure, alleviate, ameliorate, alleviate or inhibit a disease in the individual, including but not limited to administering a drug containing a drug described herein to an individual in need.

In one specific example, vitamin K4 is combined with other drugs to treat melanoma.

In one specific example, other drugs to treat melanoma include immunotherapy drugs.

In a specific example, immunotherapy drugs include immune checkpoint inhibitors, therapeutic antibodies, cancer vaccines, cell therapy drugs, small molecule inhibitors, etc.

In one specific example, the immunotherapy drug is an immune checkpoint inhibitor. Alternatively, the immune checkpoint inhibitor includes one or more of PD-1 inhibitor and PD-L1 inhibitor.

In this application, cell experiments found that vitamin K4 has a certain killing effect on melanoma cells; animal experiments found that vitamin K4 can shrink tumors, and it was found that after the combination of vitamin K4 and PD-1, the tumor size was significantly reduced, and even completely reduced. In the tumor-free state, the two have a synergistic effect, proving that vitamin K4, as an adjuvant drug for PD-1 monoclonal antibodies, can enhance the effect of immune checkpoint inhibitors.

One embodiment of the present application also provides the use of vitamin K4 in preparing drugs that promote melanoma cell apoptosis or inhibit tumor growth or reduce tumor volume.

In a specific example, melanoma cells include one or more of SK-MEL-28 cells, A375 cells, B16-F10 cells, and YUMM1.7 cells. Through drug screening, it was found that vitamin K4 has a certain killing effect on melanoma cells SK-MEL-28, A375, B16-F10, and YUMM1.7.

In one specific example, vitamin K4 is combined with other drugs to treat melanoma.

In one specific example, other drugs to treat melanoma include immunotherapy drugs.

In a specific example, immunotherapy drugs include immune checkpoint inhibitors, therapeutic antibodies, cancer vaccines, cell therapy drugs, small molecule inhibitors, etc.

In one specific example, the immunotherapy drug is an immune checkpoint inhibitor. Alternatively, the immune checkpoint inhibitor includes one or more of PD-1 inhibitor and PD-L1 inhibitor.

One embodiment of the present application also provides the application of vitamin K4 in the preparation of products that enhance the effect of immune checkpoint inhibitors in treating melanoma or increase the sensitivity of melanoma to immune checkpoint inhibitors.

In one specific example, vitamin K4 is combined with other drugs to treat melanoma.

In one specific example, other drugs to treat melanoma include immunotherapy drugs.

In a specific example, immunotherapy drugs include immune checkpoint inhibitors, therapeutic antibodies, cancer vaccines, cell therapy drugs, small molecule inhibitors, etc.

In one specific example, the immunotherapy drug is an immune checkpoint inhibitor. Alternatively, the immune checkpoint inhibitor includes one or more of PD-1 inhibitor and PD-L1 inhibitor.

One embodiment of the present application also provides a drug for treating melanoma, which drug includes vitamin K4; optionally, the drug also includes a PD-1 inhibitor.

The combination of vitamin K4 and PD-1 inhibitors shows a synergistic effect in inhibiting tumor growth and reducing tumor size.

In embodiments involving pharmaceutical uses and drugs in this technical solution, an effective amount of the drug may be involved. In this technical solution, a therapeutically effective amount refers to an amount that can treat, improve or slow down any disease/symptom to be treated or produce a positive effect therein. In this technical solution, the therapeutic effect is observed by adjusting the ingredients contained in the drug and their mass ratios, and is ultimately determined into three levels: preferred, more preferred, and particularly preferred. In addition, the effective and precise dose in this technical solution can be determined by the attending physician, taking into account factors such as the specific situation of the subject receiving treatment, the duration of treatment, the severity of the disease, and reasonable medical judgment, and can be determined by mathematical methods based on the results of animal experiments. To determine the therapeutically effective amount of a pharmaceutical composition for administration to humans. The therapeutically effective amount of a drug to be administered for treatment or prophylaxis can be readily determined by one skilled in the art, and the optimal dose will vary with the particular compound used, mode of administration, formulation strength, and progression of disease symptoms. In addition, dosages will need to be adjusted to appropriate therapeutic levels due to factors associated with the specific subject being treated, including subject age, weight, diet, and time of administration.

In a specific example, the in vivo dosage of vitamin K4 is 10 mg/kg to 50 mg/kg; the in vivo dosage of the PD-1 inhibitor is 10 μg/kg to 500 μg/kg.

In a specific example, the drug also includes pharmaceutically acceptable excipients.

As used herein, the term "pharmaceutically acceptable" means that a substance must be chemically and/or toxicologically compatible with the other ingredients containing the drug and/or the mammal being treated therewith. Preferably, "pharmaceutically acceptable" as used herein refers to those approved by federal regulatory agencies or national governments or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals.

As used herein, the term "pharmaceutically acceptable excipients" refers to excipients that are pharmacologically and/or physiologically compatible with the subject and the active ingredient, which are well known in the art and include, but are not limited to: Surface Active agents, diluents, preservatives, stabilizers, fillers, excipients, binders, disintegrants and flavoring agents.

For example, surfactants include, but are not limited to, cationic, anionic or nonionic surfactants such as Tween-80. Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols and polyols (such as glycerol), and the like. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, etc. Stabilizers have the meaning commonly understood by those skilled in the art, which can stabilize the desired activity of active ingredients in medicines, including but not limited to sodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose) , lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dry whey, albumin or casein) or their degradation products (such as lactalbumin hydrolyzate), etc. Fillers include, but are not limited to, microcrystalline cellulose, lactose, starch, precrossified starch, mannitol and sorbitol, etc. Excipients include, but are not limited to, mannitol, dextran, lactose, trehalose, sucrose, maltose, sorbitol, glucose, cyclodextrin and glycine, etc. Binders include, but are not limited to, hydroxypropylcellulose, methylcellulose, ethylcellulose, povidone, crospovidone, etc. Disintegrating agents include, but are not limited to, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, etc. Lubricants include but are not limited to magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycols and sodium lauryl sulfate. Flavoring agents include but are not limited to ⑴ sweeteners, ① natural: sucrose, simple syrup, fruit juice syrup, glycerin, sorbitol, mannitol, stevioside; ② synthetic: saccharin sodium, aspartame/protein sugar/aspartame Sweetener. ⑵Fragrance ①Natural: lemon, mint volatile oil; ②Artificial: apple flavor, banana flavor.

The drug of the present application can be administered in various ways, such as oral administration and injection administration.

In one specific example, dosage forms for oral administration include solid dosage forms and liquid dosage forms. Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient, such as sodium citrate or dicalcium phosphate, or with: (a) fillers or compatibilizers, such as starch, lactose, Sucrose, glucose, mannitol and silicic acid; (b) Binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, such as glycerol; (d) disintegrating agents, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarding agents, such as paraffin; (f) absorption accelerators, For example, quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents. Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active ingredient can be in microencapsulated form with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredients, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, specifically, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. Besides these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. For example, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances.

In a specific example, dosage forms for injection administration include, but are not limited to, intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, and intracavitary injection. Can be used with conventional catheterization techniques or infusion. Injectable preparations may be presented in unit dosage form, for example, in ampoules or multi-dose containers, with an added preservative. The pharmaceuticals may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. As an alternative, the active ingredient may be in the form of a powder for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

The embodiments of the present application will be described in detail below with reference to examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. For experimental methods that do not indicate specific conditions in the following examples, priority is given to the guidelines given in this application. You can also follow the experimental manuals or conventional conditions in this field. You can also follow the conditions recommended by the manufacturer, or refer to the experimental methods in this field. Known experimental methods.

In the following specific examples, the measurement parameters of raw material components are involved. Unless otherwise specified, there may be slight deviations within the range of weighing accuracy. Temperature and time parameters are involved, allowing for acceptable deviations due to instrument testing accuracy or operating accuracy.

Example 1

This example proves through cell testing that vitamin K4 has a certain adjuvant therapeutic effect on melanoma.

The steps of the cell experiment are as follows: melanoma cells SK-MEL-28, A375, B16-F10, and YUMM1.7 were seeded in a ^6- well plate at 5x10 cells/well in an incubator at 37°C and 5% _CO2 . For culture, the SK-MEL-28 cell line and A375 cell line used DMEM medium with 10% FBS, the B16-F10 cell line used 1640 medium with 10% FBS, and the YUMM1.7 cell line used DMEM/10% FBS. F-12 medium. The vitamin K4 powder purchased from Taosu Biochemical Company (Cat. No. T2570) was dissolved in DMSO and prepared into a 100 μM vitamin K4 solution. The vitamin K4 solution was added to each well of the culture medium in the experimental group to prepare a concentration of 25 μM, and it was used for 16 hours. The control group It is a complete culture medium without adding vitamin K4. The cell morphology is directly observed under a microscope to detect the apoptosis of melanoma cells. With the action of the drug, the cells swell and die.

The results are shown in Figure 1. When vitamin K4 acted on 4 different melanoma cells, cell enlargement and death occurred.

Example 2

After YUMM1.7 cells were subcutaneously grown into tumors in c57 mice, administration was started when the tumor volume reached 50-100 mm ³ . The experiment was divided into 5 groups, with 10 mice in each group: untreated control group (Ctrl), IgG control group, PD-1 monoclonal antibody group, oral vitamin K4 group, and PD-1 monoclonal antibody and oral vitamin K4 combined group.

Among them, the IgG control group: the concentration of IgG (BioXell Company, product number BE0089) is 100 μg/kg, intraperitoneally injected once every three days; the PD-1 monoclonal antibody group: the concentration of PD-1 monoclonal antibody (BioXell Company, product number BE0146) is 100 μg/kg, intraperitoneal injection once every three days; oral vitamin K4 group: oral vitamin concentration is 30 mg/kg (dissolve vitamin K4 powder in corn oil), intragastric administration once a day; combined use of PD-1 monoclonal antibody and oral vitamin K4 Group: The concentration of PD-1 monoclonal antibody is 100 μg/kg, which is intraperitoneally injected once every three days, and the oral vitamin concentration is 30 mg/kg (vitamin K4 powder is dissolved in corn oil), which is administered by gavage once a day.

After the PD-1 monoclonal antibody was used four times, mice in each group were killed and materials were collected for analysis.

The results are shown in Figure 2. The comparison of tumor size in the 5 groups is as follows. After the combination of vitamin K4 and PD-1 monoclonal antibody, the tumor size was significantly reduced, and 3 mice were even completely tumor-free, proving that vitamin K4 acts as a PD-1 antibody. 1. The adjuvant use of monoclonal antibodies has certain effects and has certain therapeutic potential.

The technical features of the above-described embodiments can be combined in any way. To simplify the description, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, All should be considered to be within the scope of this manual.

The above-described embodiments only express several implementation modes of the present application, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the invention patent. It should be noted that, for those of ordinary skill in the art, several modifications and improvements can be made without departing from the concept of the present application, and these all fall within the protection scope of the present application. Therefore, the protection scope of the patent of this application should be determined by the appended claims, and the description and drawings can be used to interpret the content of the claims.

Claims (10)

1. Application of vitamin K4 in the preparation of drugs for the treatment of melanoma. 2. The application according to claim 1, characterized in that the vitamin K4 is used in combination with other drugs for treating melanoma. 3. The application according to claim 2, wherein the other drugs for treating melanoma include immunotherapy drugs. 4. The application according to claim 3, wherein the immunotherapy drug includes an immune checkpoint inhibitor; Optionally, the immune checkpoint inhibitor includes one or more of PD-1 inhibitor and PD-L1 inhibitor. 5. Application of vitamin K4 in the preparation of drugs that promote melanoma cell apoptosis or inhibit tumor growth. 6. Application of vitamin K4 in the preparation of products that enhance the effect of immune checkpoint inhibitors in treating melanoma or increase the sensitivity of melanoma to immune checkpoint inhibitors. 7. A drug for the treatment of melanoma, characterized in that the drug includes vitamin K4; Optionally, the other drugs for treating melanoma include immunotherapy drugs; The immunotherapy drugs include immune checkpoint inhibitors; Optionally, the immune checkpoint inhibitor includes one or more of PD-1 inhibitor and PD-L1 inhibitor; Optionally, the drug also includes a PD-1 inhibitor. 8. The medicine according to claim 7, characterized in that the medicine further includes pharmaceutically acceptable excipients. 9. The medicine according to claim 8, characterized in that the auxiliary materials include diluents, fillers, excipients, adhesives, wetting agents, disintegrating agents, surfactants, lubricants and flavoring agents. of at least one. 10. The drug according to any one of claims 7 to 9, characterized in that the drug is an oral dosage form or an injection form.