CN112707806B

CN112707806B - EphB2 small-molecule inhibitor and application thereof

Info

Publication number: CN112707806B
Application number: CN202010811142.1A
Authority: CN
Inventors: 王淑珍; 陈依军; 徐亚婷; 韩月晴; 高琪
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2020-08-13
Filing date: 2020-08-13
Publication date: 2022-06-17
Anticipated expiration: 2040-08-13
Also published as: CN112707806A

Abstract

The invention belongs to the technical field of biological medicine; the invention discloses EphB2 small molecule inhibitor idebenone and application thereof in treating hepatic fibrosis; the invention discovers that idebenone selectively inhibits the expression and activity of EphB2 kinase, reduces collagen deposition, inhibits fibroplasia, regulates the biochemical index of liver injury and the level of inflammation-related factors, down-regulates the expression of hepatic fibrosis-related protein and genes, and plays a role in resisting hepatic fibrosis. Therefore, idebenone can be used for treating hepatic fibrosis.

Description

EphB2 small-molecule inhibitor and application thereof

Technical Field

The invention relates to EphB2 small-molecule inhibitor Idebenone (Idebenone, 6- (10-hydroxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone, 6- (10-hydroxydececyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone) and application of the compound in treatment of hepatic fibrosis. The invention belongs to the technical field of biological medicines.

Background

The liver is the most important organ for human metabolism and foreign body removal, and the function of the liver directly affects human health and life. Hepatic fibrosis is a chronic liver disease caused by various factors, including viruses, alcohol, obesity, drugs, autoimmunity, and the like. After these etiologies continue to act on the liver, chronic inflammation of the liver occurs, breaking the balance between synthesis and degradation of extracellular matrix (ECM), which is excessively deposited in the liver, leading to structural damage of hepatic parenchymal cells and liver dysfunction, leading to liver fibrosis. The process and mechanism by which liver inflammation leads to liver fibrosis is widely recognized by the scientific community. If hepatic fibrosis is not treated in a timely manner, cirrhosis may further progress, eventually leading to liver cancer (HCC) or liver failure. Liver fibrosis is a reversible process before chronic hepatitis progresses to cirrhosis, but once cirrhosis progresses, only liver transplantation is clinically a treatment. Therefore, prevention and treatment of hepatic fibrosis is of great importance in the treatment of chronic liver diseases. At present, the treatment method for chronic liver diseases is mainly disease treatment, no specific and effective medicine is available for treating liver fibrosis, and the existing clinical treatment medicines are poor in curative effect due to serious adverse reactions, lack of specific targeting of liver and the like.

Activation of Hepatic Stellate Cells (HSCs) is widely recognized as a key factor in the development of liver fibrosis. In normal bodies, HSCs are in a quiescent state, and when the liver is damaged, Kuppfer cells and apoptotic hepatocytes release cytokines such as TGF- β, tumor necrosis factor- α (TNF- α), and Reactive Oxygen Species (ROS), among others, which stimulate the activation of HSCs from a quiescent state into Myofibroblasts (MFs). HSCs are the main precursors of activated MF, the main cell that produces ECM proteins during liver fibrosis. Static HSCs store lipid droplets containing vitamin a, while HSCs lose lipid droplets after being activated. Therefore, controlling the activation process of HSCs is an important strategy for treating liver fibrosis.

The EphB family of tyrosine kinases was originally identified as axon-oriented factors, and its ligands, Ephrins, play important roles in neurological diseases such as development of the central nervous system, senile dementia, and lesion repair. With the progress of research, it was found that EphB family is involved in various non-neuronal physiopathological processes through abnormal activation of kinase activity and overexpression of proteins. EphB2 and its ligand, EphrinB, were first discovered in liver cancer cell lines, and signaling between them mediates many important physiological processes, with effects on regulating liver monocyte infiltration, hepatitis, tissue remodeling and fibrosis recently reported. Studies have shown that inflammatory injury leads to upregulation of EphB2 expression in liver-activated Kupffer cells and macrophages (M phi), thereby promoting monocyte infiltration, releasing cytokines and chemokines to stimulate HSC cell proliferation, migration and activation. Inhibition of EphB2 expression or activity can prevent liver cell damage caused by inflammatory cell infiltration, effectively prevent and reverse the progress of hepatic fibrosis, and suggest that EphB2 is expected to become a brand-new target for hepatic fibrosis treatment (Mimche PN, et al. hepatology.2015,62(3):900-14.), and EphB2 inhibitor is also expected to bring a new direction for hepatic fibrosis treatment. However, since the EphB receptor family has multiple members and the amino acid sequence homology of the members of the same family is high, no compound which selectively inhibits EphB2 activity has been reported, and only non-selective pan-family inhibiting compounds have been reported in the literature. Therefore, the development of the highly selective inhibitor of EphB2 provides a new treatment option for hepatic fibrosis patients, and has good application prospect and clinical value in the field of hepatic fibrosis treatment.

The invention screens a compound library consisting of more than 500 small molecules, and unexpectedly discovers that Idebenone (Idebenone, 6- (10-hydroxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone) can selectively inhibit EphB2(IC 2)₅₀30nM), effectively inhibits the activation of HSC, reduces collagen deposition and inhibits fibroplasia, regulates the biochemical index of liver injury and the level of inflammation-related factors, and regulates the expression of hepatic fibrosis-related proteins and genes by specifically inhibiting the activity and the expression of EphB2 kinase. At the same time, in the well-known carbon tetrachloride (CCl)₄) The induced hepatic fibrosis mouse model shows obvious therapeutic effect. Therefore, idebenone can be used as a novel medicine for preventing and treating hepatic fibrosis and can be used for preventing and treating hepatic fibrosis.

The key role of antioxidants in the treatment and prevention of many systemic and local inflammatory diseases is well known. Idebenone, an intelligent facilitator developed by the japanese martial arts pharmaceutical (Takeda) and approved for marketing in 1988, is one of the commonly used antioxidants for clinical applications and is capable of acting as an electron carrier in the mitochondrial electron transport chain. The traditional Chinese medicine composition is mainly used for treating central nervous system degeneration diseases related to oxidative stress in clinic, such as Alzheimer disease, multi-infarct dementia, cerebral ischemia, cerebral failure and the like, and is also used for treating diseases caused by mitochondrial dysfunction, such as Friedreich's ataxia, Leber's hereditary optic neuropathy, Duchenne muscular dystrophy and the like. At present, no research and report shows that idebenone has the effect of resisting hepatic fibrosis, and no related experimental data show that idebenone can play the effect of resisting hepatic fibrosis by inhibiting the activity and expression of EphB2 kinase.

Although previous studies (Cell Physiol biochem. 2015; 35(6): 2402-. In addition, it has been reported (Cell Death Discov.2019; 5:146) that idebenone can ameliorate lung injury caused by bleomycin and relieve symptoms of pulmonary fibrosis. However, the content described in this document is fundamentally different from the present invention: (1) due to the difference of tissue pathology, the occurrence and development processes of pulmonary fibrosis are different or not completely consistent with hepatic fibrosis; (2) the direct relationship between pulmonary inflammation and pulmonary fibrosis has not been elucidated, while hepatic fibrosis is a direct result of chronic hepatitis; (3) bleomycin can induce lung injury, is a common model for researching pulmonary fibrosis, but whether the influence on the formation of hepatic fibrosis is not determined, even if the influence of bleomycin on liver function is reported in literature (radio. Oncol.2019,53:415 + 426); (4) while idebenone is used for preventing and treating pulmonary fibrosis, whether the idebenone has the effect of resisting hepatic fibrosis is unknown. Therefore, the contents and results reported in the literature are combined, and have no direct relevance to the contents of the invention.

Disclosure of Invention

The invention aims to provide a new application of EphB2 small-molecule inhibitor idebenone.

An EphB2 small molecule inhibitor, wherein the EphB2 small molecule inhibitor is Idebenone ((Idebenone, 6- (10-hydroxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone)), and the structural formula of the inhibitor is shown in formula I

The EphB2 small molecule inhibitor is applied to the preparation of drugs for diseases related to EphB2 kinase.

The EphB2 kinase related disease is hepatic fibrosis.

The diseases of liver fibrosis include: chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune liver disease, and hepatic blood stasis.

The idebenone is a medicinal salt, a crystal form, a preparation and/or a medicinal composition consisting of the idebenone and an administration carrier.

A pharmaceutical composition characterized by: comprising said compound and at least one pharmaceutically acceptable carrier.

The application of the pharmaceutical composition in preparing medicines with the effects of preventing and treating hepatic fibrosis.

Specifically, the method comprises the following steps:

in order to achieve the above purpose, the invention adopts the following technical means:

the invention provides application of Idebenone in treating hepatic fibrosis, wherein the chemical structural formula of Idebenone is as shown in formula I:

preferably, idebenone reduces collagen deposition and fiber proliferation by inhibiting EphB2 kinase activity, regulates biochemical indexes of liver injury and levels of inflammation-related factors, and reduces expression of hepatic fibrosis-related proteins and genes, thereby achieving the purpose of treating hepatic fibrosis.

The diseases causing the liver fibrosis mainly include: chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune liver disease, hepatic blood stasis, and hereditary metabolic disease.

The idebenone is a medicinal salt, a crystal form, a preparation and/or a compound formed by the idebenone and an administration carrier, and is administered by different routes.

The medicinal salt form of idebenone comprises various salts and various crystal forms formed by the idebenone and inorganic acid, organic acid or inorganic base and organic base. Examples of acidic salts are acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphoriodate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, sulfinate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, malate, malonate, naphthalenesulfonate, nicotinate, nitrate, oxalate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, isopropionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate; examples of the basic salts are alkali metal (e.g., sodium, potassium) salts, basic divalent metal (e.g., magnesium, zinc) salts, ammonium salts and alkylammonium salts having 1 to 4 carbon atoms.

The concrete dosage forms of the idebenone provided by the invention comprise aqueous solution injection, oily suspension injection, oral capsules, oral tablets, oral aqueous solution, oral suspension, rectal suppositories, eye drops, eye ointments, skin creams, skin sprays, oral aerosols, nasal sprays, nasal aerosols and the like, and also comprise sustained-release agents and preparations for controlling release speed and dosage of the different dosage forms.

The idebenone or its pharmaceutically acceptable salts or crystal forms of the present invention can be used in various administration routes for its action. For example, it can be administered orally, parenterally, by inhalation through the mouth, transdermally, rectally, nasally, sublingually, buccally, vaginally, via an implantable container, etc. Parenteral administration in turn includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection and infiltration. One of ordinary skill in the pharmaceutical art can select the appropriate form and mode of administration depending on the disease state and other relevant circumstances. Such pharmaceutical formulations may contain, for example, from 0.05 to 90% by weight of the active ingredient, more usually between about 15 and 60% of the active ingredient, in combination with a carrier. The dosage of the compound of the invention can be 0.005-5000 mg/kg/day, and the dosage can be beyond the dosage range according to the severity of diseases or different dosage forms. The dosage used is influenced by various factors including age, body weight, health condition, sex, race, eating habits, administration time, frequency of urination and whether other drugs are used, etc.

The invention also claims a pharmaceutical composition, the main active ingredient of which is the idebenone or the pharmaceutically acceptable salt or crystal form thereof, and the pharmaceutical composition also comprises a clinically acceptable carrier or auxiliary material and a sustained-release preparation thereof. Such pharmaceutically acceptable carriers or excipients include ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates, glycine, sorbic acid, potassium sorbate, and the like), glycerolipids of partially saturated vegetable oils, mixtures of water and salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium oxide, and the like), zinc salts, colloidal silica gel, magnesium trisilicate, polyvinylpyrrolidone, celluloses, polyvinyl glycerol, sodium carboxymethylcellulose, polyimides, waxes, lanolin, and the like. The carrier or adjuvant for sustained or controlled release can be selected from cellulose derivatives (such as methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, etc.), non-cellulose polysaccharides (such as glucose, chitin, galactose, mannan, etc.), natural gums (pectin, sodium alginate, agar, potassium alginate, etc.), vinyl or acrylic polymers (such as polyvinyl alcohol, and polyvinyl 934), inert fats or waxes (such as beeswax, hydrogenated vegetable oils, stearic acid, and stearyl alcohol, etc.), polyethylene, polypropylene, silicone, and polyoxyethylene, etc.

Advantageous effects

1. The invention adopts a Kinase-Glo Kinase activity detection method to screen the influence of a compound library consisting of more than 500 small molecules on the EphB2 Kinase activity, and unexpectedly discovers that idebenone can selectively inhibit EphB2 and IC of the EphB2₅₀Was 30 nM. The interaction of idebenone with EphB2 was analyzed using computer modeling and molecular docking, and it was found that idebenone can intercalate into the pocket of the kinase domain of EphB2 and form hydrogen bonds with Asp739 near the pocket, indicating that idebenone can bind directly to EphB2 through this amino acid. Subsequently, human LX-2 cells activated by TGF-beta 1 stimulation are taken as a liver fibrosis cell model, and the influence of idebenone on the expression of liver fibrosis related proteins and genes in the LX-2 cells and a possible action mechanism of idebenone are examined. The result shows that idebenone can inhibit the expression level of fibrosis related protein and genes thereof in LX-2 cells in a dose-dependent and time-dependent manner, and plays a role in resisting fibrosis. The method comprises the steps of constructing a mouse hepatic fibrosis model by adopting a method of intraperitoneal injection of CCl4, taking mouse serum and liver tissues for analysis after idebenone is administered by gastric lavage, and finding that the idebenone can inhibit the expression and activity of EphB2 kinase, can relieve the hepatic fibrosis of mice, reduce collagen deposition and inhibit fibroplasia, regulate biochemical indexes of liver injury and the level of inflammation-related factors, reduce the expression of hepatic fibrosis-related proteins and genes, and play a role in resisting hepatic fibrosis in vivo. The invention discovers Idebenone (Idebenone) which is a specific inhibitor of EphB2 through systematic research of molecular, cell and animal experiments, and proves the effect of Idebenone in treating hepatic fibrosis.

Drawings

Figure 1 is a graph of idebenone and EphB2 interaction. A, molecule docking results; b, interaction diagram.

FIG. 2 shows the expression of liver fibrosis-associated proteins and genes in LX-2 cells of normal control group, model group and idebenone treatment group (IDE group). A, Western blot; b, RT-qPCR.

FIG. 3 shows the serum biochemical indices ALT, AST, T-Bil and hydroxyproline (Hyp) content of mice in the normal control group, model group and idebenone treatment group (IDE group).

Fig. 4 is a result of HE staining of liver tissues of mice in the normal control group, the model group, and the idebenone treatment group (IDE group), which shows that idebenone can effectively inhibit liver fibrosis of mice.

Fig. 5 shows MASSON staining results of mouse liver tissues of a normal control group, a model group and an idebenone treatment group (IDE group), and the results show that idebenone can effectively inhibit the degree of liver fibrosis of mice.

FIG. 6 shows the expression of fibrosis-associated proteins and genes in liver tissues of mice in the normal control group, model group and idebenone treatment group (IDE group).

Wherein: p <0.05, P <0.01, compared to model group

Detailed Description

The present invention is further described below in conjunction with specific examples, and the advantages and features of the present invention will become more apparent as the description proceeds. These examples are merely illustrative and do not set any limit to the scope of the invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.

Example 1 screening and validation of EphB2 Small molecule inhibitors

1. In vitro kinase assay: the half Inhibitory Concentration (IC) of a compound library consisting of more than 500 small molecules on EphB2 Kinase was screened by using Kinase-Glo Kinase activity assay kit (Kinase-Glo Plus luminescence Kinase Assays) from Promega corporation₅₀). The method is a chemiluminescence method, and is a method for detecting homogeneous luciferase through reaction of kinase and a substrate. The luciferase reaction needs the participation of ATP, the phosphorylation of a Kinase catalytic substrate needs the consumption of ATP, the Kinase reaction is finished, an equal volume of Kinase-Glo reagent is added, and the luminescence signal is measured. The luminescence signal is proportional to the remaining ATP in the system and inversely proportional to the kinase activity. After the kinase inhibitor is added, the kinase is inhibited, the activity is reduced, the consumed ATP is reduced, and when the kinase activity is reduced to half of the initial activity, the concentration of the inhibitor is the half inhibition concentration of the inhibitor on the kinase.

2. Molecule docking: taking idebenone as a ligand, EphB2 as a receptor, and adopting MOE (molecular Operating environment) software to carry out molecular docking, wherein the docking process is approximately as follows: downloading a crystal structure file of EphB2 from a PBD database, loading MOE, selecting a proper force field (MMFF94), executing an energy minimization module to obtain an optimized protein docking area, performing docking operation to obtain docking energy and possible binding sites of a ligand in different conformations, wherein the docking model with the highest score is the optimal docking model.

3. The experimental results are as follows:

the inhibition effect of a compound library consisting of more than 500 small molecules on EphB2 is screened by using a Kinase-Glo Kinase luminescence detection kit, and the optimal activity (IC) of idebenone is found to be shown₅₀30nM) of the total amount of the enzyme, and the results show that the idebenone has strong inhibition effect on EphB2 only and no significant inhibition effect on other kinases, thus indicating that the idebenone is a high-selectivity inhibitor of EphB 2.

To investigate the structural basis of the interaction of idebenone with EphB2 protein, idebenone was molecularly interfaced with the crystal structure of EphB2 using molecular simulation software MOE. Idebenone was found to intercalate into the pocket of the kinase domain of EphB2 and form hydrogen bonds with Asp739 near the pocket, suggesting that idebenone inhibits its activity by direct binding of this amino acid to EphB2 (see figure 1).

Example 2 use of idebenone in the treatment of liver fibrosis

1. Cell, animal and experimental reagent

Human hepatic stellate cell LX-2 (purchased from Xiangya medical college), mouse (strain: C57, purchased from Nanjing model animal research institute), carbon tetrachloride (CCl)₄Purchased from Sigma).

LX-2 cell induced activation

LX-2 cells were treated with compound solutions in the experimental group, DMEM medium containing TGF-. beta.1 (5 ng/mL final concentration) in the model group, and DMEM medium containing no compound and TGF-. beta.1 in the control group at 37 ℃ under 5% CO 2. Extracting cell protein and gene for detection.

3.CCl₄Construction of hepatic fibrosis induction model

30 healthy C57 male mice (weight 190-220g) are randomly divided into three groups according to the weight balance principle, namely a normal control group and a modelGroup, idebenone treatment group. All were raised in a standard feeding environment. The experiment period is six weeks in total, and mice of the model group and the idebenone treatment group are injected with CCl in the abdominal cavity₄The normal control group mice were injected intraperitoneally with corn oil as a solvent twice a week. Starting in the third week, idebenone treatment groups started gavage of idebenone (50mg/kg), and normal control and model mice were gavage of corn oil control once a day. After the test is finished, the left lobe of the liver is fixed by 4% paraformaldehyde, and the rest liver tissues are frozen in liquid nitrogen and then transferred to a minus 80 refrigerator for storage. Fixed liver tissue was pathologically stained.

4. Liver function testing

The serum sample is tested by using a full-automatic biochemical analyzer of Chemray 240 of Shenzhen Leidu Life technologies company, and the liver function is detected, wherein indexes comprise Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Total bilirubin (T-bil).

5. Determination of hydroxyproline content in liver tissue

The hydroxyproline content in liver tissues is determined according to the specification of a hydroxyproline (Hyp) determination kit by the alkali hydrolysis method of Nanjing institute of Biotechnology.

6. Results of the experiment

6.1 idebenone can reduce the expression level of liver fibrosis related protein and gene in LX-2 cell

Western Blot and RT-qPCR results are shown in figure 2, idebenone treatment can inhibit EphB2 kinase activity in LX-2 cells activated by TGF-beta 1 induction, inhibit phosphorylation of the kinase, and remarkably reduce expression of hepatic fibrosis related protein alpha-SMA and genes of the hepatic fibrosis related protein alpha-SMA.

6.2 idebenone can alleviate liver injury in mice

Serum biochemical detection is carried out on the liver function index by taking mouse serum, and the result is shown in figure 3, which shows that idebenone can remarkably reduce the levels of ALT, AST and T-Bil and reduce the liver injury of mice. The Hyp content in the liver tissue of the mice in the idebenone treatment group is remarkably reduced, which shows that the idebenone can reduce CCL₄The resulting liver damage reduces excessive deposition of collagen.

6.4 idebenone can reduce hepatic fibrosis in mice

The HE staining results are shown in fig. 4, in which the hepatocytes in the tissues of the control mice were irregular polygons, and the nuclei were rounded and located in the center of the cells; the liver cells are arranged and distributed in a cord shape, and the liver cell cords are arranged in a radial shape by taking a central vein as a center; the size of the hepatic blood sinus clearance in the tissue is uniform and does not expand; the tissue morphological structure is normal, and no obvious pathological change is seen. Part of liver cells in liver tissues of the mice in the model group are subjected to steatosis, round vacuoles with regular shapes are visible in the cells, and cell nuclei are extruded to the edge by the vacuoles, as shown by red arrows; fibrous tissue hyperplasia in the tissue section manifold area, with fibroblast and fibrocyte massive hyperplasia as shown by blue arrows; part of the vascular area is hyperplastic, part of the hyperplastic blood vessels expand and stagnate, and a large number of red blood cells and inflammatory cells are visible in the lumen, as indicated by the yellow arrows. Some hepatocellular edema, cell swelling, and plasma faint staining were seen in the liver tissues of the idebenone-treated mice, as indicated by the black arrows; the hepatocyte cords are radially arranged by taking the central vein as the center, and no disorder is seen; the hepatic blood sinus clearance is uniform in size and has no expansion.

MASSON staining as shown in fig. 5, there was only a small amount of blue collagen fiber deposition around the central vein wall of the liver lobules in the control mice. Model group mice in CCl₄After 6 weeks of intraperitoneal injection, obvious hepatic lobular fiber intervals can be seen, and obvious blue collagen fiber deposits are formed around the central venous duct and the manifold and are connected with adjacent intervals to surround the hepatic lobules. The deposition of collagen fibers around the central venous duct of the liver of the mice in the idebenone treatment group is reduced, and the fiber intervals are not obvious.

6.5 idebenone can reduce the expression level of liver fibrosis related protein and gene in liver tissue of mouse

Western Blot and RT-qPCR results are shown in FIG. 6, idebenone treatment can down-regulate CCl₄The expression level of fibrosis-related protein alpha-SMA and genes thereof in the liver tissue of the resulting liver fibrosis model mouse, and the expression and phosphorylation of EphB2 kinase are inhibited at the same time.

Claims

The application of the EphB2 small-molecule inhibitor in preparing the medicine for treating EphB2 kinase related diseases;

the EphB2 small-molecule inhibitor is idebenone, and the structural formula of the inhibitor is shown as formula I:
2. use according to claim 1, characterized in that: the EphB2 kinase related disease is hepatic fibrosis.
3. Use according to claim 2, characterized in that: the diseases of liver fibrosis include: chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune liver disease, and hepatic blood stasis.
4. Use according to claim 2, characterized in that: the idebenone is a medicinal salt, a crystal form, a preparation and/or a medicinal composition consisting of the idebenone and an administration carrier.