Antitumor composition and application thereof

Abstract

The present invention relates to the field of medical technology, and more particularly to anti-tumor compositions and their applications. The present invention provides a combination of a mitochondrial autophagy agonist and a chemotherapy drug that can produce a more effective tumor inhibitory effect. Experimental studies have shown that the combination of the two drugs can produce a significant synergistic effect. In particular, the combination of the two drugs has a significant therapeutic effect on liver cancer, resolving the clinical problem of low chemotherapy sensitivity in liver cancer and the lack of clinically available chemotherapy sensitizers.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to an anti-tumor composition and application thereof. Background Art

[0002] Tumors are neoplasms formed by the abnormal proliferation and differentiation of cells in the body. They include both benign and malignant tumors (cancer). Benign tumors typically grow slowly, have clear boundaries, do not invade surrounding tissues, and have no metastatic potential. Malignant tumors, on the other hand, grow rapidly, can invade surrounding tissues and organs, and metastasize to distant sites. Malignant tumors are one of the major threats to human health, and their occurrence is related to multiple factors, including genetics, environment, and lifestyle.

[0003] Treatment options for cancer primarily include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. With the continuous advancement of medical technology, new treatments and approaches continue to emerge, bringing more hope and options to cancer patients.

[0004] Mitophagy is a pathway of intracellular autophagy. Under normal physiological conditions, it helps cells eliminate aging and diseased mitochondria by selectively degrading damaged mitochondria. It is a conserved biological self-defense mechanism for maintaining intracellular homeostasis. When mitochondria become damaged or diseased due to various factors, mitochondrial membrane permeability and potential change, inducing PTEN-induced putative kinase 1 (PINK1) and Parkin E3 ubiquitin ligase, which activate downstream biochemical responses. Under normal physiological conditions, PINK1 is rapidly degraded after targeting mitochondria. However, when mitochondria are damaged or undergo pathological changes, PINK1 cannot enter mitochondria due to changes in mitochondrial membrane permeability and electrical potential. Instead, PINK1 is anchored to the outer mitochondrial membrane. Through its phosphorylase activity, PINK1 phosphorylates and activates ubiquitin and the ubiquitin-like domain of Parkin, leading to their accumulation around mitochondria. This further recruits autophagy-related receptors such as NDP52 and optineurin (OPTN), which activate microtubule-associated protein 1 light chain 3 (LC3), particularly the conversion of LC3B-I to lipidated LC3B-II. Simultaneously, autophagy-related receptors promote the formation of numerous mitophagosomes, the primary sites for contact and fusion between mitochondria and organelles such as the endoplasmic reticulum and lysosomes, influencing the final fate of mitophagosomes.

[0005] Appropriate levels of mitophagy are a survival strategy for tumors. In extreme situations where tumors attempt to resist chemotherapeutic drug killing, anti-tumor immunity, apoptosis caused by elevated levels of oxygen free radicals (ROS), nutrient deficiency, and hypoxia, appropriate mitophagy is a self-protective mechanism by which tumor cells utilize limited energy to eliminate harmful or damaged mitochondria, thereby mitigating apoptotic cell death caused by excessive mitochondrial damage. However, excessive mitophagy depletes mitochondria and is detrimental to tumor cell survival. Furthermore, abnormal mitophagy signaling pathways in tumor cells are closely linked to events such as mitochondrial-induced apoptosis. When metabolic stress caused by drug killing, DNA damage, inflammation, hypoxia, and nutrient deficiency exceeds a certain threshold or triggers an abnormal mitophagy switch, mitophagy can be exacerbated, potentially leading to cell death. For example, the effects of chemotherapeutic drugs and targeted molecular therapies can lead to irreversible mitophagy, ultimately causing cell death. Therefore, proper mitochondrial autophagy is an important pathway for tumor cell survival and drug resistance, while excessive mitochondrial autophagy causes excessive mitochondrial damage, which can lead to cell apoptosis or even death.

[0006] Targeting mitophagy is an emerging area of ​​drug development for chemotherapy sensitization, but it is currently limited to basic research. Therefore, identifying clinical drugs that regulate mitophagy as combination therapies for chemotherapy sensitization is expected to rapidly translate basic research ideas into clinical applications. Summary of the Invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide an anti-tumor composition and application thereof.

[0008] The composition provided by the present invention is composed of a mitochondrial autophagy agonist and a chemotherapy drug.

[0009] The chemotherapy drug is selected from at least one of epirubicin, platinum chemotherapy drugs or pentafluorouracil;

[0010] The mitochondrial autophagy agonist is selected from at least one of CCCP, olaparib or ketoconazole.

[0011] The platinum-based chemotherapy drugs include cisplatin and other platinum-derived chemotherapy drugs; and their salts or derivatives of the same name. For example, cisplatin, carboplatin or oxaliplatin. The present invention has found that the combined use of mitochondrial autophagy agonists and chemotherapy drugs (epirubicin, cisplatin and 5-fluorouracil) has an inhibitory effect on liver cancer ( Figure 1), and proved that the combination of the two drugs can produce significant synergistic effects. In the present invention, the two drugs in the composition can be mixed or exist independently of each other, and the present invention is not limited to this.

[0012] In the present invention, the mass ratio of the mitophagy agonist to the chemotherapy drug is 1:(0.0005-1000). Preferably, the mass ratio of the mitophagy agonist to the chemotherapy drug is 1:(0.0025-500). For example, the mass ratio of the mitophagy agonist to the chemotherapy drug is (0.62-26):(0.1-1.6).

[0013] In some embodiments, the composition is composed of epirubicin and CCCP, wherein the mass ratio of epirubicin to CCCP is (0.1-1.6):(0.62-10) or (0.4-1.6):(0.62-10) or (0.8-1.6):(0.62-10) or 1.6:(0.62-10) or 1.6:(2.5-10) or 1.6:(5-10); in some specific embodiments, the mass ratio of epirubicin to CCCP is 0.1:0.62, 0.1:1 0.25, 0.1:2.5, 0.1:5, 0.1:10, 0.2:0.62, 0.2:1.25, 0.2:2.5, 0.2:5, 0.2:10, 0.4:0.62, 0.4:1.25, 0.4:2.5, 0.4:5, 0.4:10, 0.8:0.62, 0.8:1.25, 0.8:2.5, 0.8:5, 0.8:10, 1.6:0.62, 1.6:1.25, 1.6:2.5, 1.6:5, or 1.6:10.

[0014] In other embodiments, the composition is composed of epirubicin and olaparib, wherein the mass ratio of epirubicin to olaparib is (0.1-1.6):(1.25-20) or (0.1-1.6):(5-20) or 1.6:(1.25-2.5) or (0.4-1.6):(5-20) or (0.1-1.6):20 or 0.4:(5-20) or 0.4:(5-10); in some specific embodiments, the mass ratio of epirubicin to olaparib is 0.1:1 0.25, 0.1:2.5, 0.1:5, 0.1:10, 0.1:20, 0.2:1.25, 0.2:2.5, 0.2:5, 0.2:10, 0.2:20, 0.4:1.25, 0.4:2.5, 0.4:5, 0.4:10, 0.4:20, 0.8:1.25, 0.8:2.5, 0.8:5, 0.8:10, 0.8:20, 1.6:1.25, 1.6:2.5, 1.6:5, 1.6:10, or 1.6:20.

[0015] In other embodiments, the composition is composed of epirubicin and ketoconazole, wherein the mass ratio of epirubicin to ketoconazole is (0.1-1.6):(1.62-26) or (0.4-1.6):(1.62-26) or (0.4-1.6):(6.5-26) or (0.8-1.6):(6.5-26) or 1.6:(6.5-26) or 1.6:(13-26). In some specific embodiments, the mass ratio of epirubicin to ketoconazole is 0.1:1.62, 0.1:3.25, 0.1:6.5, 0.1:13, 0.1:26, 0.2:1.62, 0.2:3.25, 0.2:6.5, 0.2:13, 0.2:26, ​​0.4:1.62, 0.4:3.25, 0.4:6.5, 0.4:13, 0.4:26, 0.8:1.62, 0.8:3.25, 0.8:6.5, 0.8:13, 0.8:26, 1.6:1.62, 1.6:3.25, 1.6:6.5, 1.6:13 or 1.6:26.

[0016] The present invention also provides use of the composition as described in any of the preceding items in the preparation of anti-tumor drugs.

[0017] In some embodiments, the tumor is liver cancer, gallbladder cancer, pancreatic cancer, small intestine tumor, colorectal cancer, esophageal cancer, gastric cancer, digestive system tumor, bladder cancer, blood system tumor, bone tumor, cartilage tumor, lung cancer, tracheal tumor, glottic cancer, brain cancer, central nervous system tumor, peripheral nervous system tumor, head and neck tumor, kidney cancer, laryngeal cancer, nasopharyngeal cancer, lung cancer, muscle tissue cancer, oral or nasal mucosa cancer, ovarian cancer, breast cancer, prostate cancer, cervical cancer, endometrial cancer, external genitalia tumor, genitourinary tract tumor, adrenal tumor, skin cancer, spleen tumor, testicular cancer and / or thyroid cancer. In a specific embodiment, the tumor is liver cancer. More specifically, the tumor is primary liver cancer. More specifically, the tumor is hepatocellular carcinoma.

[0018] In some embodiments, the anti-tumor effect includes inhibiting tumor cell activity and / or promoting tumor cell apoptosis.

[0019] In some specific embodiments, in the anti-tumor agent, the tumor cells are liver cancer cells, more specifically, the liver cancer cells are MHCC97H and / or Bel-7402.

[0020] Furthermore, the present invention also provides an anti-tumor drug, which comprises the above-mentioned composition and pharmaceutically acceptable excipients.

[0021] The pharmaceutically acceptable excipients include one or a mixture of two or more of flavoring agents, fillers, lubricants, preservatives, suspending agents, food colorings, diluents, emulsifiers, disintegrants or plasticizers.

[0022] The dosage form of the drug of the present invention is a gastrointestinal administration dosage form and / or a parenteral administration dosage form.

[0023] The dosage form for administration through the gastrointestinal tract is powder, tablet, granule, capsule, solution, emulsion or suspension.

[0024] The non-gastrointestinal administration dosage form is an injection dosage form, a respiratory tract administration dosage form, a skin administration dosage form, a mucosal administration dosage form or a cavity administration dosage form.

[0025] The present invention does not limit the content of the composition in the medicine, nor does it limit the dosage per administration. Preferably, the dosage administered is not less than the effective dose. In the medicine, the dosage of the composition is also not less than the effective amount.

[0026] The drugs of the present invention also include other therapeutic agents with anti-tumor activity, which are selected from mitomycin, gemcitabine, capecitabine, irinotecan, oxaliplatin, cyclophosphamide, methotrexate, adriamycin, vincristine, sorafenib, sunitinib, bevacizumab, erlotinib, lenvatinib mesylate capsules, regorafenib, lenvatinib, entecavir, extended-release polyethylene glycol (PEG) Alfa-2a), interferon, lamivudine, icariin, Huachansu capsules, Kanglaite injection, Cidan capsules, sodium cantharidate and vitamin B6 injection, Jinlong capsules, Biejia decoction pills, Huaier granules, elemene injection, Kangai injection, Aidi injection, Ganfule capsules, Brucea javanica oil soft capsules, compound cantharidin capsules, transfer factor, various immune checkpoint drugs (PD-1 antibody, PD-L1 antibody, TIGIT antibody, CTLA4 antibody, etc.), gamma globulin; various Chinese herbal combinations, including but not limited to modified Chaihu Shugan San from Jingyue Complete Works, modified Gexia Zhuyu Decoction from Yilin Gaicuo, modified Xiaoyao San from Taiping Huimin Heji Jufang, modified Yinchenhao Decoction combined with Wuling San from Treatise on Febrile Diseases, and modified Yiguanjian from Liuzhou Medical Talks.

[0027] The present invention also provides an anti-tumor method, which comprises administering the aforementioned drug or the aforementioned composition.

[0028] In the anti-tumor method of the present invention, two or more active ingredients are administered simultaneously or sequentially, which is not limited by the present invention. The dosing interval of the pre- and post-administration is any time interval within 30 days, preferably any time interval within 3 days, preferably not longer than 24 hours, preferably not longer than 12 hours, preferably not longer than 6 hours, preferably not longer than 5 hours, more preferably not longer than 4 hours, even more preferably not longer than 3 hours, more preferably not longer than 2 hours and most preferably not longer than 1 hour and / or not longer than 6 hours, preferably not longer than 5 hours, more preferably not longer than 4 hours, even more preferably not longer than 3 hours, more preferably not longer than 2 hours and most preferably not longer than 1 hour after the administration of other therapeutic agents.

[0029] In the anti-tumor method of the present invention, the administration of the drug includes but is not limited to sublingual administration, oral administration, subcutaneous injection, intradermal injection, intramuscular injection, intravenous injection, intravenous drip, intraperitoneal administration, anal administration, airway administration, transdermal or other mucosal administration, etc.

[0030] In the anti-tumor method of the present invention, the administration frequency of two or more drugs may be the same or different, and the present invention is not limited thereto. For example, the administration frequency of two or more drugs is independently selected from the group consisting of once a month, once every 15 days, once every 7 days, once every other day, once a day, twice a day, three times a day, or four times a day.

[0031] The present invention provides a combination of a mitochondrial autophagy activator and a chemotherapy drug that can produce a more effective tumor inhibitory effect. Experimental studies have shown that the combination of the two drugs can produce a significant synergistic effect. In particular, the combination of the two drugs has a good therapeutic effect on liver cancer, solving the clinical problem of liver cancer's low chemotherapy sensitivity and the lack of clinically available chemotherapy sensitizers. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 Schematic diagram of the treatment of liver cancer with mitochondrial autophagy agonists (CCCP, Olaparib, Ketoconazole) combined with chemotherapy drugs (epirubicin, cisplatin, and 5-Fu).

[0033] Figure 2 Scanning electron microscopy (TEM) validation of three mitophagy activators inducing mitophagy in liver cancer cells: (A) TEM validation of three mitophagy activators (CCCP, ketoconazole, and olaparib) inducing mitophagy in HCC cancer cell line (Bel-7402); (B) TEM-based statistical analysis of mitophagosomes in liver cancer cells (Bel-7402) (n=50 for each of the two groups, 10 in each); (C) TEM-based validation of three mitophagy activators (CCCP, ketoconazole, and olaparib) inducing mitophagy in HCC cancer cell line (MHCC97H); (D) TEM-based statistical analysis of mitophagosomes in liver cancer cells (MHCC97H) (n=50 for each of the two groups, 10 in each);

[0034] Figure 3Syngerfinder platform analysis was performed to investigate the effect of mitochondrial autophagy activators on enhancing the effect of the chemotherapy drug epirubicin in liver cancer. (A) Synergy analysis of epirubicin with CCCP was performed, which yielded a dose-response matrix and 2D and 3D drug synergy models (ZIP synergy score 7.109±2.73). (B) Synergy analysis of epirubicin with olaparib was performed, which yielded a dose-response matrix and 2D and 3D drug synergy models (ZIP synergy score 5.884±3.32). (C) Synergy analysis of epirubicin with ketoconazole was performed, which yielded a dose-response matrix and 2D and 3D drug synergy models (ZIP synergy score 3.423±1.24).

[0035] Figure 4 Analysis by the Syngerfinder platform showed that the Bliss synergy score of epirubicin and CCCP was 6.995±2.73; the Bliss synergy score of epirubicin and olaparib was 5.884±3.32; and the Bliss synergy score of epirubicin and ketoconazole was 3.342±1.24.

[0036] Figure 5 Analysis using the DrugComb platform showed that the LOEWE synergy scores of epirubicin and CCCP were (9.61, 18.68, 8.84); the LOEWE synergy scores of epirubicin and olaparib were (5.60, 9.25, 8.85); and the LOEWE synergy scores of epirubicin and ketoconazole were (6.72, 7.68, 6.13).

[0037] Figure 6 Analysis by the DrugComb platform showed that the HSA synergy scores of epirubicin and CCCP were (13.39, 12.74, 11.65); the HSA synergy scores of epirubicin and olaparib were (11.97, 9.35, 14.17); and the HSA synergy scores of epirubicin and ketoconazole were (9.60, 10.90, 9.95). DETAILED DESCRIPTION

[0038] The present invention provides anti-tumor compositions and their uses. Those skilled in the art can refer to the present disclosure and appropriately modify the process parameters to achieve the desired results. It should be noted that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention. The methods and uses of the present invention have been described using preferred embodiments. It is apparent that those skilled in the art can modify, adapt, and combine the methods and uses herein to implement and apply the present invention without departing from the content, spirit, and scope of the present invention.

[0039] Unless otherwise defined herein, scientific and technical terms related to the present invention shall have the meanings that are understood by those of ordinary skill in the art.

[0040] Furthermore, unless otherwise indicated herein, singular terms shall include pluralities and plural terms shall include the singular. More specifically, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless expressly indicated otherwise.

[0041] The terms "include," "comprising," and "having" are used interchangeably herein and are intended to indicate the inclusiveness of a solution, meaning that other elements may be present in addition to the listed elements. It should also be understood that the use of "include," "comprising," and "having" in this document also provides a "consisting of" solution.

[0042] The term "and / or" as used herein encompasses "and," "or," and "all or any other combination of elements linked by the term." In this application, the term "and / or" describes an association between associated objects, indicating that three possible relationships exist. For example, "A and / or B" can mean: A exists alone, A and B exist simultaneously, or B exists alone. A and B can be singular or plural.

[0043] In this application, "at least one" means one or more, and "more than one" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single or plural items.

[0044] Throughout this application, the numerical ranges and parameters involved are presented as precisely as possible in the specific examples. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. Therefore, unless otherwise expressly stated, it should be understood that all numerical ranges or specific data used in this disclosure are subject to reasonable deviation within a certain range, for example, within ±10%, ±5%, ±1%, or ±0.5%.

[0045] In the examples of the present invention, propofol combined with epirubicin is used as an example to demonstrate that propofol combined with chemotherapy drugs can effectively inhibit liver cancer. In fact, propofol combined with various chemotherapy drugs can achieve therapeutic effects on liver cancer, including combinations such as propofol combined with epirubicin, propofol combined with cisplatin, and propofol combined with 5-Fu. The modes of administration are also not limited to simultaneous administration, asynchronous administration, sequential administration, or administration of various combinations.

[0046] In the present application, the subject of the liver cancer inhibition is a human or a mammal, and the mammal includes bovines, equines, ovines, porcines, canines, felines, rodents, and primates.

[0047] The test materials used in the present invention are all common commercial products and can be purchased in the market.

[0048] Among them, CCCP / Carbonyl Cyanide m-Chlorophenylhydrazone, or: Carbonylcyanide 3-chlorophenylhydrazone; Carbonyl Cyanide m-Chlorophenylhydrazone

[0049] Olaparib, whose English name is Olaparib.

[0050] Ketoconazole, whose English name is Ketoconazole.

[0051] Epirubicin / epirubicin is also known as epirubicin and its English name is Epidoxorubicin.

[0052] Cisplatin also includes other platinum-derived chemotherapy drugs; and their salts or derivatives of the same name.

[0053] Pentafluorouracil / 5-Fu is also known as 5-fluorouridine nucleoside, and its English name is 5-Fluorouracil. The non-fluorouracil also includes its salts or derivatives with the same name.

[0054] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution. Some or all of the steps can be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0055] The examples of the present invention describe some cases. These examples illustrate certain implementations of the present invention. However, this does not mean that the effects of the present invention can only be achieved in these cases. In fact, any concentration of each component between the two endpoints shown in the examples can achieve a good anti-tumor effect. In addition, many attempts were made during the research and development process, such as using different chemotherapy drugs or propofol analogs, using different ratios, etc. to conduct tumor cell inhibition experiments, but the results of these attempts were not as good as those described in the examples, and will not be repeated here.

[0056] The present invention will be further described below in conjunction with the embodiments:

[0057] Example

[0058] In the preliminary experiment, a preliminary safety experiment (IC50) was conducted on the drug concentrations shown in the following examples, and the combination regimen for treating in vivo and in vitro liver cancer models was determined through combined drug experiments and IC50 concentration detection again. The selected combination drug concentration was lower than the IC50 of the above-mentioned single drug, and in the regimen described in this case, the drug dose was much lower than the median lethal concentration (IC50, 0.1ug / ml or 0.17uM) for non-tumor cells HEK293T cells recorded in the existing literature (see J Nat Prod. 2016 Sep 23; 79 (9): 2397-402. doi: 10.1021 / acs.jnatprod.6b00639.) or the highest clinical dose.

[0059] Combination therapy with the aforementioned mitochondrial autophagy activator and epirubicin was tested in HepG2 cells. Synergistic effects of drug combinations were analyzed using the online combination drug analysis platforms Syngerfinder (https: / / synergyfinder.fimm.fi) and DrugComb (https: / / drugcomb.fimm.fi).

[0060] Dosage:

[0061] Epirubicin: 0.1 μg / ml, 0.2 μg / ml, 0.4 μg / ml, 0.8 μg / ml, 1.6 μg / ml;

[0062] CCCP: 0.62μg / ml, 1.25μg / ml, 2.5μg / ml, 5μg / ml, 10μg / ml;

[0063] Ketoconazole: 1.62μg / ml, 3.25μg / ml, 6.5μg / ml, 13μg / ml, 26μg / ml;

[0064] Olaparib: 1.25μg / ml, 2.5μg / ml, 5μg / ml, 10μg / ml, 20μg / ml.

[0065] The results are as follows Figures 2 to 6 As shown:

[0066] 1. Three mitophagy activators (CCCP, ketoconazole, and olaparib) can induce mitophagy in liver cancer cells;

[0067] 2. Analysis by the Syngerfinder platform showed that the ZIP synergy score of epirubicin and CCCP was 7.109±2.73; the ZIP synergy score of epirubicin and olaparib was 5.912±3.32; and the ZIP synergy score of epirubicin and ketoconazole was 3.423±1.24. This indicates that epirubicin can produce a synergistic effect with the three mitophagy activators ( Figure 3 ).

[0068] 3. Analysis by the Syngerfinder platform showed that the Bliss synergy score of epirubicin and CCCP was 6.995±2.73; the Bliss synergy score of epirubicin and olaparib was 5.884±3.32; and the Bliss synergy score of epirubicin and ketoconazole was 3.342±1.24. This indicates that epirubicin can produce a synergistic effect with the three mitophagy activators ( Figure 4 ).

[0069] 4. Analysis by DrugComb platform showed that the LOEWE synergy scores of epirubicin and CCCP were (9.61, 18.68, 8.84); the LOEWE synergy scores of epirubicin and olaparib were (5.60, 9.25, 8.85); and the LOEWE synergy scores of epirubicin and ketoconazole were (6.72, 7.68, 6.13). This indicates that epirubicin can produce a synergistic effect with the three mitophagy activators ( Figure 5 ).

[0070] 5. Analysis by DrugComb platform showed that the HSA synergy scores of epirubicin and CCCP were (13.39, 12.74, 11.65); the HSA synergy scores of epirubicin and olaparib were (11.97, 9.35, 14.17); and the HSA synergy scores of epirubicin and ketoconazole were (9.60, 10.90, 9.95). This indicates that epirubicin can produce a synergistic effect with the three mitochondrial autophagy activators ( Figure 6 ).

[0071] The above are only preferred embodiments of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A composition for treating liver cancer, comprising CCCP and epirubicin. The mass ratio of epirubicin to CCCP is (0.1~1.6):(0.62~10).

2. Use of the composition according to claim 1 in the preparation of anti-liver cancer drugs.

3. The use according to claim 2, characterized in that The anti-liver cancer effect includes inhibiting tumor cell activity and / or promoting tumor cell apoptosis.

4. A drug for treating liver cancer, comprising the composition according to claim 1 and a pharmaceutically acceptable excipient.

5. The drug according to claim 4, characterized in that The dosage form is a gastrointestinal dosage form and / or a parenteral dosage form; The dosage form for administration via the gastrointestinal tract is powder, tablet, granule, capsule, solution, emulsion or suspension; The non-gastrointestinal administration dosage form is an injection dosage form, a respiratory tract administration dosage form, a skin administration dosage form, a mucosal administration dosage form or a cavity administration dosage form.

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