Pharmaceutical composition and application thereof

Abstract

The invention discloses a pharmaceutical composition and application thereof, and belongs to the field of medicines. The pharmaceutical composition is prepared from active ingredients, and the active ingredients are prepared from telaprevir and tidutinib. The pharmaceutical composition disclosed by the invention has an excellent effect of preventing, improving and / or treating cognitive impairment, and the telaprevir and the sidumatinib are combined for use to show a synergistic effect, so that a more excellent curative effect can be obtained, the dosage of the medicine is reduced, the clinical medication safety is improved, and the pharmaceutical composition has a relatively good clinical application prospect; in addition, the pharmaceutical composition disclosed by the invention is expected to enrich the types of clinically available drugs in the field of cognitive impairment, so that the problems of drug resistance, safe medication and the like can be better solved.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition and its application, in particular to a pharmaceutical composition and its application in the preparation of prevention, improvement and / or treatment of cognitive dysfunction, belonging to the field of medicine. BACKGROUND

[0002] Dementia is a syndrome characterized by progressive, acquired decline in multiple cognitive functions, and leads to significant decline in the patient's daily life, social and work ability. The core cognitive function impairment often includes impaired memory, executive function, language ability, visual spatial ability, and leads to personality or behavior changes. There are many types of dementia, including Alzheimer's disease, vascular dementia (VaD), frontotemporal dementia (FTD), Lewy body dementia (DLB), and other types (such as normal pressure hydrocephalus and dementia caused by infection, poisoning, metabolic disease) etc.

[0003] Alzheimer's disease (AD) is a common central nervous system degenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. Clinically, it is manifested as learning and memory decline, cognitive dysfunction, visual spatial impairment, personality and behavior changes, and severe cases enter a complete dementia state. Alzheimer's disease is characterized by β-amyloid deposition in cell matrix to form senile plaques, tau protein overphosphorylation to form neurofibrillary tangles, neuronal degeneration and loss, and glial proliferation. AD lacks effective therapeutic drugs. The existing drugs can only partially relieve symptoms and delay the course of the disease but cannot cure AD, and have obvious side effects. With the intensification of population aging, the incidence of AD will increase year by year, and it is of great significance to seek effective drugs for treating AD.

[0004] Telaprevir (T) is a hepatitis C virus (HCV) NS3 / 4A serine protease inhibitor with antiviral effect of inhibiting HCV replication. The present inventors' team previously found that telaprevir can be used for preparing a drug for treating or preventing ischemia / reperfusion injury and AD (see CN202110943155.9, WO2023020488A1).

[0005] Cerdulatinib (C) is an oral multi-target tyrosine kinase inhibitor that can inhibit spleen tyrosine kinase (SYK) and Janus kinase (JAK), significantly reduce the cell activity of some non-Hodgkin's lymphoma (NHL) cell lines, and induce apoptosis of NHL cell lines with BCR signals, and can be used for treating peripheral T-cell lymphoma. The inventors' team found in previous studies that cerdulatinib can be used for preparing a drug for treating or preventing AD (see CN117618433A).

[0006] However, according to the prior art, it cannot be expected whether the combination of telaprevir and cerdulatinib has a preventive, improving and / or therapeutic effect on dementia and its related cognitive dysfunction, and whether the combination of telaprevir and cerdulatinib can produce a synergistic effect. SUMMARY

[0007] In view of the deficiencies of the prior art, the purpose of the present application is to provide a pharmaceutical composition with more excellent preventive, improving and / or therapeutic effect on cognitive dysfunction and applications thereof.

[0008] To solve the above technical problems, the technical solutions of the present application are as follows: A pharmaceutical composition comprises an active ingredient, wherein the active ingredient comprises telaprevir and cerdulatinib.

[0009] Further, the mass ratio of the telaprevir and the cerdulatinib is 1000:1-1:1000, further 100:1-1:100, more further 65:1-1:65, still further 60:1-1:60.

[0010] Further, the mass ratio of the telaprevir and the cerdulatinib is 8-50:1, preferably 10-45:1, more preferably 12-42:1.

[0011] Further, the mass ratio of the telaprevir and the cerdulatinib is 15-35:1, preferably 20-32:1, more preferably 25-30:1.

[0012] Alternatively, the mass ratio of the telaprevir and the cerdulatinib is 45:1, 44:1, 43:1, 42:1, 41:1, 40:1, 39:1, 38:1, 37:1, 36:1, 35:1, 34:1, 33:1, 32:1, 31:1, 30:1, 29:1, 28:1, 27:1, 26:1, 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 12:1, 11:1 or 10:1.

[0013] Optionally, the molar ratio of the telaprevir and the sedutinib is 0.01-100:1, further 0.3-60:1, more further 0.5-55:1, still further 0.6-50:1, yet further 0.8-45:1, more further 0.9-42:1, preferably 5-33:1.

[0014] Further, the molar ratio of the telaprevir and the sedutinib is 8-30:1, more further 10-28:1, still further 13-27:1, preferably 12-25:1, more preferably 16-22:1, still preferably 18-20:1.

[0015] Further, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, diluent or carrier.

[0016] Further, the pharmaceutically acceptable salt is a salt commonly used in pharmacy, preferably, the salt is selected from one or more of acetate, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, benzoic acid, fumarate, maleate, succinate, tartaric acid, citrate, oxalic acid, glyoxylic acid, aspartic acid, tartrate, 2,5-dihydroxybenzoic acid, methanesulfonate, ethanesulfonate, benzenesulfonate, mesitylenesulfonate, hydroquinonesulfonate and p-toluenesulfonate, or a salt with a carboxylic acid (such as formic acid, acetic acid or propionic acid).

[0017] Further, the pharmaceutical composition can be prepared into any one of pharmaceutically acceptable dosage forms according to known techniques, optionally, the dosage form of the pharmaceutical composition is one or more of suspension, injection (i.e. injection solution or extemporaneous injection solution), gel, oil, tablet, suppository, powder, capsule, granule, suspension, emulsion, polymer, nanoparticle, microsphere, rectal capsule, enema, paste, ointment, cream, plaster, drink, implant, spray, aerosol. Preferably, the dosage form is one of injection, capsule, tablet, granule, powder, spray, liposome, oral liquid, drop pill.

[0018] Optionally, the administration is 1-3 times or even more times per day, and the continuous administration is 1 month to several months.

[0019] In the present application, unless otherwise specified, the telaprevir refers to one of telaprevir compound (drug) or its pharmaceutically acceptable salt or ester or its isomer or its semi-synthetic derivative or one of its salts (salt of the compound or salt of the semi-synthetic derivative) or one of its esters or one of its ester salts (salt of the ester of the compound or salt of the ester of the semi-synthetic derivative) or deuterated compound (deuterated telaprevir) or isotope-labeled compound thereof.

[0020] In the present application, unless otherwise specified, the seduximab refers to a seduximab compound (drug) or a pharmaceutically acceptable salt, or a co-crystal thereof, any stereoisomer, tautomer, hydrate, solvate thereof.

[0021] Alternatively, in the present application, unless otherwise specified, the telaprevir includes a free form thereof or a form of isomer, pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, prodrug, deuterium compound or isotope marker, etc.

[0022] Alternatively, in the present application, unless otherwise specified, the seduximab includes a free form thereof or a form of isomer, pharmaceutically acceptable salt, co-crystal, solvate, hydrate, isomer (including stereoisomer, tautomer) or prodrug, etc.

[0023] Alternatively, the telaprevir is a telaprevir compound. Alternatively, the seduximab is a seduximab compound.

[0024] Further, the telaprevir is a telaprevir compound or an isomer or a pharmaceutically acceptable salt thereof, and the seduximab is a seduximab compound or an isomer or a pharmaceutically acceptable salt thereof.

[0025] Generally, the structural formula of the telaprevir compound is shown as Formula I, and the molecular formula is C 36 H 53 N7O6, and the molecular weight is 679.85.

[0026] Formula I.

[0027] Generally, the structural formula of the seduximab compound is shown as Formula , and the molecular formula is C 20 H 27 N7O3S, and the molecular weight is 445.54.

[0028] Formula .

[0029] The pharmaceutical composition as described above is used for preparing a drug for preventing, improving and / or treating cognitive dysfunction.

[0030] Further, the cognitive dysfunction includes one or more of Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), Lewy body dementia (DLB), mild cognitive impairment (MCI) and other types of dementia.

[0031] Further, the cognitive dysfunction refers to one or more of Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementia and mild cognitive impairment.

[0032] Further, the cognitive dysfunction refers to Alzheimer's disease.

[0033] Alternatively, the pharmaceutical composition of telaprevir and sedutinib, for simultaneous use, separate use or use with time interval, is used as a medicine, in particular for preventing, improving and / or treating an individual with cognitive dysfunction. It should be understood that for simultaneous use, the compounds contained in the pharmaceutical composition of the compounds can be mixed together or physically separated, for separate use or use with time interval, the compounds present must be physically separated.

[0034] According to one embodiment of the present application, the amount of telaprevir in the pharmaceutical composition can be 0.01 mg to 6000 mg / mg sedutinib, preferably 1 mg to 600 mg (telaprevir) / mg sedutinib.

[0035] Alternatively, the telaprevir and sedutinib of the pharmaceutical composition can be a common dosage form between them. Also according to the present application, the telaprevir and sedutinib of the composition can be the same dosage form or different dosage forms.

[0036] Therefore, it should be understood that according to the present application, when the telaprevir and sedutinib of the composition are in a common dosage form, they can be administered simultaneously (i.e. at the same time) and use the same administration route.

[0037] It should also be understood that according to the present application, the telaprevir and sedutinib of the composition are in the same dosage form or different dosage forms, they can be administered simultaneously, sequentially or separately using the same or different administration routes.

[0038] Preferably, when administered sequentially, the telaprevir and sedutinib are administered within a time interval of not more than about 1 hour (preferably not more than about 10 minutes, and even more preferably not more than about 1 minute).

[0039] According to the present application, telaprevir and sedutinib can be used in combination with one or more acceptable excipients or inert carriers, i.e. excipients which are pharmaceutically inactive and non-toxic, with the aim of imparting a certain consistency or other specific physical or taste characteristics to the finished product. Saline solutions, isotonic solutions, physiological solutions, buffered solutions, etc. which are compatible with pharmaceutical use and known to those skilled in the art are included. The pharmaceutical compositions of the present application can comprise one or more agents or vehicles selected from the group consisting of solubilizers, dispersants, stabilizers, sweeteners, preservatives, flavorings, lubricants, anti-caking agents, disintegrants, adsorbents, etc. In particular, agents or vehicles which can be used for the formulation (liquid and / or injectable and / or solid) are: methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, polysorbate 80, cyclodextrins, gelatin, mannitol, lactose, PEG, animal or vegetable oils, etc. The pharmaceutical compositions of the present application can be prepared in the form of suspensions or ready-to-use or extemporaneous injectable solutions, oils, gels, tablets, powders, suppositories, capsules, granules, emulsions, suspensions, polymers, microspheres, nanoparticles, rectal capsules, enemas, pastes, creams, ointments, plasters, implants, drinks, sprays, aerosols, etc.; optionally, controlled and / or sustained release by means of the dosage form or device. For this type of formulation, agents such as carbonates, celluloses or starches are advantageously used.

[0040] In a particular embodiment, the pharmaceutical composition can be prepared in the form of a powder, reconstituted for intravenous injection.

[0041] Alternatively, administration of the above-mentioned pharmaceutical compositions in the present application can be carried out by any method known to those skilled in the art, preferably oral or parenteral administration, for example by intramuscular injection, intravenous administration, subcutaneous injection, intra-arterial injection, intraperitoneal injection, intracerebral injection or intrathecal injection, oral administration, sublingual administration, intralesional or intracerebral or implanted delivery, spray administration. Intramuscular injection, intravenous administration, subcutaneous injection, oral or sublingual administration are preferred. For long-term treatment, the preferred route of administration is oral, sublingual or transdermal.

[0042] For injection, the compounds can be packaged as a suspension or liquid solution, injectable using a syringe or infusion device. It will be understood that the amount to be administered or the amount and / or rate of injection can be adjusted by those skilled in the art depending on the pathology, the mode of administration, the individual, etc. It will be understood that repeated administration can be carried out in combination with other active ingredients and / or any pharmaceutically acceptable carrier (buffer, isotonic solution, saline solution, in the presence of stabilizers, etc.).

[0043] According to certain aspects, the pharmaceutical compositions of the present application can be administered before, during or after the occurrence of the cognitive disorder.

[0044] Optionally, the amount of the pharmaceutical composition administered daily can be administered in one, two, three, four, five, six or more doses taken daily, or in a number of sub-doses taken at appropriate intervals throughout the day, as needed.

[0045] Optionally, the amount chosen can depend on a number of factors, in particular the route of administration, the duration of administration, the time at which the administration is carried out, the elimination rate of the compound, the different products used in combination with the composition, the age, weight and physical condition of the individual and the individual's medical history, the nature of the pathological situation or of the decline with which he or she is confronted, and any other information known in medicine.

[0046] Optionally, the physician's prescription can start with doses lower than those usually used and then gradually increase these doses in order to better control the side effects that can appear. Preferably, the pharmaceutical composition of the application can be administered for a period of 1 day to 20 years or even more, even more preferably for a period of 1 day to 3 years.

[0047] Further, the administration mode in the application is subcutaneous injection, intravenous injection, intramuscular injection, oral administration, sublingual administration or spray administration.

[0048] The present application also relates to a treatment method, which can comprise administering to a human or animal in need a therapeutically effective amount of a pharmaceutical composition comprising telaprevir and sedutinib.

[0049] The present application also relates to a method for preparing a pharmaceutical composition comprising telaprevir and sedutinib, in which the active ingredients of the pharmaceutical composition of the application are mixed with acceptable excipients, in particular pharmaceutically acceptable excipients, according to methods known per se.

[0050] Compared with the prior art, the present application has the following advantages: The pharmaceutical composition of the present application has excellent effects in preventing, improving and / or treating cognitive dysfunction, the combination of telaprevir and sedutinib shows a synergistic effect, which helps to obtain more excellent curative effects, reduces the amount of drugs, improves the safety of clinical medication, and has a good clinical application prospect; in addition, the pharmaceutical composition of the present application is also expected to enrich the types of clinically available drugs in the field of cognitive impairment, so as to better resist drug resistance, safe medication and other problems. BRIEF DESCRIPTION OF DRAWINGS

[0051] Figure 1 Case diagram of the ratio of the time spent in the new arm to the time spent in the old arm for mice in different groups in Example 1 (Y-maze).

[0052] Figure 2 Case diagram of escape latency for mice in different groups in Example 1 (Barnes maze experiment).

[0053] Figure 3The graph of the escape latency of the mice in different groups in Example 1 (water maze experiment).

[0054] Figure 4 The graph of the time spent in the target quadrant ratio of the mice in different groups in Example 1 (water maze experiment).

[0055] Figure 5 The graph of the number of times of crossing the platform of the mice in different groups in Example 1 (water maze experiment). DETAILED DESCRIPTION

[0056] The application will be described in detail below with reference to the examples. It should be noted that the examples in the application and the features in the examples can be combined with each other without conflict.

[0057] Use of a pharmaceutical composition containing telaprevir and sedutinib in the preparation of a medicament for treating Alzheimer's disease Example 1 Animal experiment: using APP / PS1 transgenic mouse Alzheimer's disease animal model to verify the anti-Alzheimer's disease effect of the pharmaceutical composition containing telaprevir and sedutinib.

[0058] Experimental drugs: telaprevir (compound) and sedutinib (compound) were purchased from MedChemExpress (MCE) reagent company, and were dissolved and prepared according to the company's reagent instructions.

[0059] 1. Experimental animals and methods 1.1 Experimental animals: APP / PS1 transgenic mice (Alzheimer's disease animal model, mouse background is C57BL / 6J mice), male, 5 months old, body weight 24-30 g, and C57BL / 6J mice of the same age (male, 5 months old, body weight 26-30 g), purchased from Beijing Huafukang Biotechnology Co., Ltd. All experimental animals were raised in a SPF level feeding room with a temperature of 22℃±2℃, a relative humidity of 45%±15%, free water, and a 12-hour light / dark cycle.

[0060] 1.2 Experimental grouping and administration method: 5-month-old APP / PS1 transgenic mice were randomly divided into groups, 6 in each group, and gavage administration was started from the age of 5 months, once a day, and continuous administration for 2 months; the normal control group and the APP / PS1+vehicle group of mice were given the same volume of vehicle [the vehicle was a 0.5% (w / v) aqueous solution of sodium carboxymethyl cellulose], and the specific grouping and single administration amount are as follows: Normal control group: APP / PS1 transgenic background mice (C57BL / 6J mice) + vehicle gavage.

[0061] APP / PS1 + vehicle group: APP / PS1 mice + vehicle gavage.

[0062] APP / PS1 + telaprevir low-dose group (+ telaprevir L): APP / PS1 mice + telaprevir (50 mg / kg) gavage administration.

[0063] APP / PS1 + telaprevir high-dose group (+ telaprevir H): APP / PS1 mice + telaprevir (100 mg / kg) gavage administration.

[0064] APP / PS1 + semedugnib group (+ semedugnib): APP / PS1 mice + semedugnib (2.5 mg / kg) gavage administration.

[0065] APP / PS1 + telaprevir low-dose and semedugnib combination composition 1 group (+ composition 1): APP / PS1 mice + composition 1 (the composition of composition 1 meets: after each administration, the amount of telaprevir administered at this time is 50 mg / kg, and the amount of semedugnib administered at this time is 2.5 mg / kg) gavage administration.

[0066] APP / PS1 + telaprevir high-dose and semedugnib combination composition 2 group (+ composition 2): APP / PS1 mice + composition 2 (the composition of composition 2 meets: after each administration, the amount of telaprevir administered at this time is 100 mg / kg, and the amount of semedugnib administered at this time is 2.5 mg / kg) gavage administration.

[0067] 1.3 Test the learning and memory ability and cognitive function of mice by Y maze, Barnes maze, Morris water maze experiment, etc.

[0068] (1) Y maze experiment The experiment was performed according to the reference [1] to detect the learning and memory ability of mice. The Y-shaped maze used in the experiment was made of gray organic plastic and consisted of three arms with an angle of 120° between adjacent arms. Each arm was 8 cm x 30 cm x 15 cm (width x length x height). The computer could automatically track and record the exploration process of the mouse according to the camera above the center of the maze. Three identical arms were randomly designated: (1) the starting arm, where the mouse started to explore (always open); (2) the novel arm (referred to as "new arm"), which was blocked during the first test but opened during the second test, and (3) the other arm (always open). The novel arm was closed, and the mouse was placed in the starting arm facing away from the center of the maze, allowing it to orientate and explore in the starting arm and the other arm for 3 min. After the orientation exploration, the mouse was taken out of the Y-maze and allowed to rest for 2 min. During this time, the maze was wiped with alcohol to remove the influence of the mouse's odor. After 2 min, the novel arm was opened, and the mouse was placed in the starting arm facing away from the center of the maze, allowing the mouse to freely explore the three arms for 1 min. The motion trajectory and behavior of the animal were recorded by the smart3.0 small animal analysis software system, and the time the mouse spent in the "novel arm" (i.e., "new arm") was recorded. The percentage of the time the mouse spent in the new arm to the total free exploration time (i.e., the ratio of the time spent in the new arm) was analyzed.

[0069] (2) Barnes maze The Barnes maze is a circular platform containing 20 holes, any of which can be connected to a dark box. A black dark box of a size just large enough to hold the mouse is also required. During the experiment, a hole is selected and connected to the dark box. The mouse is placed in the center of the circular platform and covered with the dark box for 5 seconds. After 5 seconds, the dark box is removed, and the mouse is allowed to freely explore the circular platform until it finds the dark box connected to the hole (escape box) and all four limbs enter the dark box, indicating that the mouse has found the target box. Each mouse is allowed to freely explore the circular platform for 3 minutes. If the animal has not found the dark box after 3 minutes, it is guided into the target box. Each mouse is trained once a day for 4 consecutive days. On the 5th day, the test is conducted, and the latency time for the mouse to find the escape box (referred to as latency period) is recorded.

[0070] The Barnes maze is used to evaluate the spatial learning and memory ability of mice.

[0071] (3) Morris water maze experiment.

[0072] According to the requirements of the water maze experiment, the Morris water maze is divided into 4 quadrants, one of which is placed with a platform with a diameter of 12 cm and a height of 35 cm (i.e. the target quadrant), and the water is dyed black with carbon ink. After 5 days of positioning navigation experiment, the platform is removed for spatial exploration experiment, and the time for the mouse to reach the original platform position (i.e. latency), the time spent in the target quadrant (the time spent in the original hidden platform quadrant), and the number of times crossing the original platform are recorded, and the percentage of time spent in the target quadrant to the total exploration time is analyzed. The motion trajectory and behavior of the animal are recorded by smart3.0 small animal analysis software system, and the related data are analyzed.

[0073] 1.4 Statistical analysis: statistical analysis was performed using GraphPad Prism software. All data were expressed as mean ± standard error (± S.E.M). Independent sample Student's t test was used for comparison of means of two groups, one-way ANOVA was used for difference of multiple groups, and Tukey's test was used for post-hoc multiple comparisons, P <0.05 was considered statistically significant.

[0074] 2. Experimental results: 2.1 Y maze experiment results The experimental results are shown in Figure 1 As can be seen from the figure, compared with the normal control group of mice, the residence time of APP / PS1 + solvent group of mice in the "new arm" was significantly reduced, indicating that the learning and memory ability and cognitive function of APP / PS1 mice were weakened, and the residence time of APP / PS1 mice in the "new arm" was improved by giving low-dose and high-dose telaprevir, sedutinib and the combination of the two drugs, among which the combination of low-dose telaprevir and sedutinib composition 1 (T50mg / kg +C2.5mg / kg) and high-dose telaprevir and sedutinib composition 2 (T100mg / kg +C2.5mg / kg) can significantly improve the residence time of APP / PS1 mice in the "new arm", and the effect is better than that of telaprevir and sedutinib single drug, showing synergistic effect. Among them, the data are expressed as mean ± standard error, and the number of mice in each group n=6, P <0.01 vs normal control group; # P <0.05, ## P <0.01 vs APP / PS1 + solvent group; + P <0.05, ++ P <0.01 vs APP / PS1 + single drug group (telaprevir, sedutinib).

[0075] The results show that the pharmaceutical composition containing telaprevir and sedutinib of the application can significantly improve the learning and memory ability and cognitive function of Alzheimer's disease mice, and shows a synergistic effect, and the pharmaceutical composition of telaprevir and sedutinib can be applied to the preparation of a drug for preventing and treating Alzheimer's disease, and is used for treating Alzheimer's disease.

[0076] 2.2 Results of Barnes maze experiment The experimental results are shown in Figure 2 From the figure, it can be seen that compared with the normal control group of mice, the time for the APP / PS1+vehicle group of mice to find the escape box (escape latency) was significantly increased (see Figure 2 ), the time for the APP / PS1 mice treated with composition 1 and composition 2 to find the escape box (escape latency) was significantly reduced, and the APP / PS1+telaprevir low-dose and sedutinib composition 1 group, telaprevir high-dose and sedutinib composition 2 (T100mg / kg+C2.5mg / kg) can significantly reduce the time for the APP / PS1 mice to find the escape box (escape latency) (see Figure 2 ), and the effect is better than that of telaprevir and sedutinib alone, and shows a synergistic effect. The data are represented as mean ± standard error, and the number of mice in each group n=6. P <0.01 vs normal control group; ## P <0.01 vs APP / PS1+vehicle group; + P <0.05 vs APP / PS1+sedutinib group.

[0077] The results show that the pharmaceutical composition containing telaprevir and sedutinib of the application can significantly improve the learning and memory ability and cognitive function of Alzheimer's disease mice, and shows a synergistic effect, and the pharmaceutical composition of telaprevir and sedutinib can be applied to the preparation of a drug for preventing and treating Alzheimer's disease, and is used for treating Alzheimer's disease.

[0078] 2.3 Effect of telaprevir and sedutinib composition on spatial learning and memory ability and cognitive function of Alzheimer's disease model mice - results of Morris water maze experiment

[0079] The experimental results are shown in Figure 3 and Figure 4 From the figure, it can be seen that compared with the normal control group of mice, the time for the APP / PS1+vehicle group of mice to find the escape box (escape latency) was significantly increased (see Figure 3 ), the time for the APP / PS1+vehicle group of mice to find the escape box (escape latency) was significantly increased (see Figure 4 ), the time for the APP / PS1+vehicle group of mice to find the escape box (escape latency) was significantly increased (seeFigure 4 ), the time to find the original platform (escape latency) of the APP / PS1 mice treated with low-dose and high-dose telaprevir, sedutinib and their combinations 1 and 2 was significantly reduced, the time spent in the target quadrant and the ratio of the time spent were significantly increased, and the number of times of crossing the platform was significantly increased, wherein the combination of high-dose telaprevir and sedutinib combination 2 (T100mg / kg + C2.5mg / kg) can significantly reduce the time to find the original platform (escape latency) of the APP / PS1 mice (see Figure 3 ), and significantly increase the time spent in the target quadrant and the ratio of the time spent (see Figure 4 ), and significantly increase the number of times of crossing the platform (see Figure 5 ), and the effect is better than that of telaprevir and sedutinib alone, showing a synergistic effect. The data are represented as mean ± standard error, and the number of mice in each group n = 6, P <0.05, P <0.01 vs normal control group; # P <0.05, ## P <0.01 vs APP / PS1 + vehicle group; + P <0.05, ++ P <0.01 vs APP / PS1 + single drug group.

[0080] Conclusion: The pharmaceutical composition containing telaprevir and sedutinib of the present application can significantly improve the learning and memory ability and cognitive function of Alzheimer's disease mice, has a neuroprotective effect, and shows a synergistic effect. The pharmaceutical composition of telaprevir and sedutinib can be used for preparing a drug for preventing and treating Alzheimer's disease, and is used for treating Alzheimer's disease.

[0081] The above examples show that the pharmaceutical composition containing telaprevir and sedutinib can be used for treating Alzheimer's disease or cognitive impairment, and the effect of the combination of telaprevir and sedutinib is better than that of single drug, showing a synergistic effect, which helps to ensure the efficacy and reduce the drug dosage, improves the safety of clinical medication while ensuring the clinical treatment effect.

[0082] The above examples should be understood as examples only for more clearly illustrating the present application, and should not be used to limit the scope of the present application. After reading the present application, those skilled in the art can make various modifications to the equivalent forms of the present application, which fall within the scope defined by the appended claims.

[0083] 【1】Zou C, Mifflin L, Hu Z, Zhang T, Shan B, Wang H, Xing X, Zhu H, Adiconis X, Levin JZ, Li F, Liu CF, Liu JS, Yuan J. Reduction of mNAT1 / hNAT2 Contributes to Cerebral Endothelial Necroptosis and Ab Accumulation in Alzheimer's Disease. Cell Rep. 2020;33(10):108447.

Claims

1. A pharmaceutical composition comprising an active ingredient, characterized in that, The active ingredients include telaprevir and sedutinib.

2. The pharmaceutical composition of claim 1, wherein, The mass ratio of the telaprevir and sedutinib is 1000:1-1:1000, further 100:1-1:100, more further 65:1-1:65, again further 60:1-1:

60.

3. The pharmaceutical composition of claim 2, wherein, The mass ratio of the telaprevir and sedutinib is 8-50:1, preferably 10-45:1, again preferably 12-42:

1.

4. The pharmaceutical composition of claim 3, wherein, The mass ratio of the telaprevir and sedutinib is 15-35:1, preferably 20-32:1, again preferably 25-30:

1.

5. The pharmaceutical composition of claim 1, wherein, The molar ratio of the telaprevir and sedutinib is 0.01-100:1, further 0.3-60:1, more further 0.5-55:1, again further 0.6-50:1, again further 0.8-45:1, more further 0.9-42:1, preferably 5-33:

1.

6. The pharmaceutical composition of claim 5, wherein, The molar ratio of the telaprevir and sedutinib is 8-30:1, more further 10-28:1, again further 13-27:1, preferably 12-25:1, more preferably 16-22:1, again preferably 18-20:

1.

7. Use of the pharmaceutical composition according to any one of claims 1-6 in the preparation of a medicament for preventing, ameliorating and / or treating cognitive dysfunction.

8. Use according to claim 7, characterized in that, The cognitive dysfunction includes one or several of Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementia, mild cognitive impairment and other types of dementia.

9. Use according to claim 7, characterized in that, The cognitive dysfunction refers to one or several of Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementia and mild cognitive impairment.

10. Use according to claim 7, characterized in that, The cognitive dysfunction refers to Alzheimer's disease.

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