Pharmaceutical composition and use thereof in preparing drug for preventing and / or treating major depressive disorder

Abstract

A pharmaceutical composition and use thereof in preparing a drug for preventing and / or treating major depressive disorder. The pharmaceutical composition comprises: ketamine, and a pharmaceutically acceptable idazoxan salt or a derivative thereof. The idazoxan hydrochloride in the pharmaceutical composition can effectively promote the antidepressant effect of ketamine, and significantly reduce the dose of ketamine required to exert the antidepressant effect, thereby prolonging the duration of the antidepressant effect.

Description

A pharmaceutical composition and its use in preparing a medicament for preventing and / or treating major depressive disorder

[0001] This application is based on and claims priority from a Chinese patent application with application number 202311569488.5 filed on November 22, 2023, and invention name “A pharmaceutical composition and its use in the preparation of a medicament for the prevention and / or treatment of major depressive disorder”. Technical Field

[0002] The present application specifically relates to a pharmaceutical composition and its use in preparing a medicament for preventing and / or treating major depressive disorder, belonging to the field of biomedicine technology. Background Art

[0003] Major depressive disorder, also known as clinical depression, is characterized by symptoms such as anhedonia, behavioral despair, social withdrawal, cognitive impairment, and, in severe cases, suicidal behavior. Epidemiological surveys show that the number of cases worldwide has increased by nearly 50% over the past 30 years, currently affecting approximately 280 million people of all ages. However, traditional antidepressants, such as tricyclic antidepressants, tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and norepinephrine reuptake inhibitors (NEIs), suffer from slow onset of action, low cure rates, and numerous adverse reactions. It wasn't until 2019 that esketamine was officially approved as an emerging antidepressant. Unlike traditional antidepressants, ketamine offers rapid onset and long-lasting effects, marking a landmark scientific discovery in the treatment of depression this century. However, as a general anesthetic and antipsychotic, ketamine carries significant side effects, including the risk of drug dependence, psychotic symptoms, nausea and vomiting, dizziness, ulcerative cystitis, diplopia, and blurred vision. Therefore, reducing ketamine's dosage and prolonging its duration of action are crucial approaches to minimizing its adverse reactions. Combination medication is a common strategy to reduce drug side effects, so the development of auxiliary drugs that directly regulate the duration of ketamine's effectiveness and the amount of drug used, that is, providing a new antidepressant combination, has become an urgent problem to be solved. It also has important practical significance for the clinical use effect of antidepressants.

[0004] Summary of the Invention

[0005] The main purpose of this application is to provide a pharmaceutical composition and its use in the preparation of antidepressant drugs to overcome the shortcomings of the existing technology.

[0006] To achieve the aforementioned application objectives, the technical solutions adopted in this application include:

[0007] The embodiments of the present application provide a pharmaceutical composition comprising: ketamine, and a pharmaceutically acceptable imidazoxan salt or a derivative thereof.

[0008] The present application also provides an embodiment of the use of the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating major depressive disorder.

[0009] Compared with the prior art, the beneficial effects of the present application are as follows: the present application proposes for the first time the use of a pharmaceutical composition (including ketamine and a pharmaceutically acceptable idazoxan salt or its derivatives) in the preparation of a drug for the prevention and / or treatment of major depressive disorder. Experiments have shown that intraperitoneal injection of idazoxan hydrochloride in mice can promote the antidepressant effect of ketamine, and idazoxan hydrochloride can significantly reduce the dosage of ketamine used to exert its antidepressant effect, prolong the duration of the antidepressant effect, and increase the social area residence time, sugar water preference index and struggling time of susceptible mice during treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments recorded in this application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0011] Figures 1A, 1B, and 1C-1D are diagrams showing the results of a dose screening experiment on the antidepressant effect of ketamine in normal mice, the effect of idazoxan hydrochloride on the dose of ketamine's antidepressant effect, and the effect of idazoxan hydrochloride on the duration of ketamine's antidepressant effect, respectively, in a typical embodiment of the present application;

[0012] Figures 2A-2B, 2C, 2D, and 2E are respectively diagrams showing the results of a dose screening experiment on the antidepressant effect of ketamine on depressed mice in a typical embodiment of the present application, idazoxan hydrochloride increasing the time susceptible mice spend in the social area during ketamine treatment, idazoxan hydrochloride increasing the sugar water preference index of susceptible mice during ketamine treatment, and idazoxan hydrochloride increasing the struggling time susceptible mice spend in water during ketamine treatment;

[0013] FIG3A , FIG3B , and FIG3C are graphs showing the experimental results of a typical embodiment of the present application showing that idazoxan hydrochloride does not affect the emotional state of susceptible animals (social interaction test, sugar water preference test, forced swimming test). DETAILED DESCRIPTION

[0014] In view of the shortcomings of the prior art, the applicant of this case, after long-term research and extensive practice, was able to propose the technical solution of this application. The technical solution of this application will be clearly and completely described below. Obviously, the embodiments described are part of the embodiments of this application, but not all of them. Based on the embodiments of this application, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of this application.

[0015] Specifically, as one aspect of the technical solution of the present application, it relates to a pharmaceutical composition comprising: ketamine, and a pharmaceutically acceptable imidazoxan salt or a derivative thereof.

[0016] In some preferred embodiments, the molar ratio of ketamine to pharmaceutically acceptable imidazolin salt or derivative thereof is 1.23-4.94:1.

[0017] In some preferred embodiments, the pharmaceutical composition comprises 55-83 wt % of ketamine and 17-45 wt % of a pharmaceutically acceptable idazoxan salt or a derivative thereof.

[0018] In some preferred embodiments, the pharmaceutically acceptable idazoxan salt is idazoxan hydrochloride.

[0019] Furthermore, the mass ratio of ketamine to idazoxan hydrochloride is 2.5-5:1.

[0020] Furthermore, the idazoxan hydrochloride has a structure as shown in formula (I):

[0021] In some preferred embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0022] Another aspect of the embodiments of the present application further provides use of the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating major depressive disorder.

[0023] In some preferred embodiments, the drug is capable of at least reducing the water immobility time of susceptible mice in a forced swim test.

[0024] In some preferred embodiments, the drug is capable of at least increasing the struggling time in water of susceptible mice in a forced swimming test.

[0025] In some preferred embodiments, the drug is capable of at least increasing the time that susceptible mice spend in a social area during a social interaction experiment.

[0026] In some preferred embodiments, the drug is at least capable of increasing the sugar water preference index of susceptible mice in a sugar water preference test.

[0027] In some preferred embodiments, the dosage form of the drug includes tablets or injections.

[0028] In some preferred embodiments, the effective administration amount of the drug to mice is 2 mg / Kg body weight.

[0029] The idazoxan hydrochloride in the pharmaceutical composition of the present application can effectively promote the antidepressant effect of ketamine, and the ketamine antidepressant effect is an effect of reversing a depressive state induced by ketamine.

[0030] In some preferred embodiments, when the pharmaceutical composition is used, idazoxan hydrochloride can prolong the duration of action of ketamine.

[0031] In some preferred embodiments, when the pharmaceutical composition is used, idazoxan hydrochloride can enhance the antidepressant effect of ketamine.

[0032] In some preferred embodiments, when the pharmaceutical composition is used, idazoxan hydrochloride can reduce the dosage of ketamine and prolong the duration of action of ketamine.

[0033] In some preferred embodiments, when the pharmaceutical composition is used, idazoxan hydrochloride can increase the social area residence time, sugar water preference index and water struggling time of susceptible mice during ketamine treatment.

[0034] In some preferred embodiments, idazoxan hydrochloride alone does not affect the emotional state of susceptible individuals; wherein the behavioral indicators of the emotional state include the social area residence time, sugar water preference index or water immobility time in the social experiment.

[0035] The technical solution of the present application is further described in detail below in conjunction with several preferred embodiments and accompanying drawings. This embodiment is implemented on the premise of the technical solution of the application, and a detailed implementation method and specific operation process are given, but the scope of protection of the present application is not limited to the following embodiments.

[0036] Unless otherwise specified, the experimental materials used in the following examples can be purchased from conventional biochemical reagent companies.

[0037] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0038] Example 1

[0039] 1. Experimental steps

[0040] 1. Experimental Animals

[0041] C57BL / 6J mice were purchased from Changzhou Cavens Laboratory Animal Technology Co., Ltd. and bred at Xuzhou Medical University. Mice were housed in a standard animal room at a temperature of 23 ± 2°C and a humidity of 40 ± 10%, on a 12-hour / 12-hour circadian rhythm (lights on at 8:00 AM), with free access to food. This experiment was approved by the Animal Ethics Committee of Xuzhou Medical University and performed in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

[0042] 2. Reagents:

[0043] Idazoxan hydrochloride was purchased from MedChemExpress, USA.

[0044] 3. Preparation of Mouse Depression Model:

[0045] Chronic Social Defeat Model: The chronic social defeat stress depression model was developed using a method developed by the Nestler laboratory. CD1 mice were screened for aggressiveness for three consecutive days before the experiment began. Three days later, male C57BL / 6J experimental mice weighing 25-30 g were placed in a cage with individually housed CD1 mice for 5 minutes. The CD1 mice attacked the experimental C57BL / 6J mice, biting their necks, backs, and buttocks. The two mice were then separated by a perforated transparent acrylic partition but remained in the same cage for 24 hours to maintain sensory contact. The next day, the experimental C57BL / 6J mice were placed in a new cage with CD1 mice for 5 minutes, and the same experiment was repeated. This model was continued for 10 days. After day 10, the C57BL / 6J mice were individually housed for 24 hours. On day 11, the C57BL / 6J mice underwent a social interaction test. The mice were placed in a 45 x 45 cm white wooden box, which was divided into a social area and two corner areas based on the location of the social partner (a stranger CD1 mouse). Computer software (Smart C 3.0) was used to record the time the mice spent in these areas, their overall activity rate, and the distance they moved. The social ratio was calculated to divide the animals into susceptible and non-susceptible subgroups. After the social interaction experiment, the C57BL / 6J mice were housed individually until further use.

[0046] 4. Experimental Design

[0047] Idazoxan hydrochloride and ketamine were administered systemically via intraperitoneal injection at a dose of 2 mg / kg, and 2.5, 5, and 10 mg / kg, respectively. The emotional behavior test was performed 12 hours after the injections.

[0048] 5. Emotional behavior experiment:

[0049] The experiments on general emotional behavior specifically include social interaction experiments, sugar water preference experiments, and forced swimming experiments. All experiments are carried out in a quiet behavioral room, and mice are required to be placed in the room for 24 hours in advance to adapt. In the social interaction experiment, mice are placed in a 45*45cm white wooden box, which is divided into a social area and two corner areas according to the position of the social object (a strange CD1 mouse). The time the mice stay in the above-mentioned areas, the overall activity rate and the activity distance are recorded by computer software (Smart V 3.0). In the sugar water preference experiment, mice are adapted to drinking water with two bottles 48 hours before the start of the experiment. On the day of the experiment, one of the bottles is replaced with 1% sucrose solution. The amount of drinking of the mice after 24 hours is observed, and the sugar water preference index is calculated as sucrose drinking amount / (sucrose drinking amount + water drinking amount)*100%. For the forced swimming test, mice were placed individually in an open transparent acrylic bucket (bucket height 25 cm, diameter 12.5 cm, water depth 15 cm, water temperature 25°C, error ± 1°C). The mice were placed in the water to adapt for 1 min, and the immobility time of the mice in the water was recorded for the next 5 min.

[0050] 6. Data Analysis:

[0051] All values ​​are expressed as mean ± standard deviation (SD). P < 0.05 was considered statistically significant.

[0052] 2. Experimental Results

[0053] 1. Effects of Idazoxan Hydrochloride on the Dose and Duration of Ketamine's Antidepressant Effect

[0054] The applicant first investigated the effects of different doses of ketamine (2.5, 5, and 10 mg / kg) on ​​normal mice in a forced swim test. The results, as shown in Figure 1A, show that ketamine doses of 5 mg / kg and 10 mg / kg significantly reduced the immobility time of normal mice in the water. At a sub-effective dose of ketamine (2.5 mg / kg), the immobility time of mice injected intraperitoneally with saline or idazoxan hydrochloride was measured. The results, as shown in Figure 1B, show that on day 2 after administration, the immobility time of mice injected intraperitoneally with idazoxan hydrochloride was significantly reduced compared to mice injected with saline, indicating that systemic administration of idazoxan hydrochloride can enhance the antidepressant effect of ketamine. The immobility time in water of mice injected intraperitoneally with normal saline or idazoxan hydrochloride was tested at an effective dose of ketamine (10 mg / kg). The results are shown in Figures 1C and 1D. On the 4th day after administration, the immobility time in water of mice injected intraperitoneally with idazoxan hydrochloride was significantly reduced, similar to that of the mice injected with normal saline. However, on the 10th day after administration, the immobility time in water of mice injected intraperitoneally with idazoxan hydrochloride was still significantly reduced compared with that of the mice injected with normal saline, indicating that systemic administration of idazoxan hydrochloride can prolong the antidepressant effect of ketamine.

[0055] 2. Effects of Idazoxan Hydrochloride on Emotional Behavior of Susceptible Mice During Ketamine Treatment

[0056] The applicant in this case first investigated the effects of different doses of ketamine (2.5, 5, and 10 mg / kg) on ​​susceptible mice in social interaction and forced swim tests. The results, as shown in Figures 2A and 2B, show that a 10 mg / kg ketamine dose significantly reduced the time susceptible mice spent immobile in the water. The emotional and behavioral states of susceptible mice injected intraperitoneally with saline or idazoxan hydrochloride were tested in social interaction, saccharide preference, and forced swim tests, respectively, at a sub-effective dose of ketamine (5 mg / kg). The results, as shown in Figures 2C, 2D, and 2E, show that compared with mice injected with saline, mice injected intraperitoneally with idazoxan hydrochloride spent significantly more time in the social area, had an increased saccharide preference index, and spent less time immobilized in the water, indicating that systemic administration of idazoxan hydrochloride can enhance the antidepressant effect of ketamine.

[0057] 3. Systemic administration of idazoxan hydrochloride does not affect the emotional state of susceptible animals

[0058] In order to rule out the possible impact of idazoxan hydrochloride on the emotional and behavioral indicators of susceptible mice when used alone, the applicant in this case first explored whether systemic administration of idazoxan hydrochloride (intraperitoneal injection) affects the emotional state of susceptible animals. The results in Figures 3A-3C show that there was no significant difference between the susceptible mice in the idazoxan hydrochloride group and the susceptible mice in the saline group in terms of indicators such as the time spent in the social area of ​​the social interaction experiment (Figure 3A), the sugar water preference index of the sugar water preference experiment (Figure 3B), and the immobility time of the forced swimming experiment (Figure 3C), indicating that idazoxan hydrochloride does not affect the emotional state of depressed animals.

[0059] In addition, the applicant of this case also referred to the aforementioned embodiments and conducted experiments using other raw materials, process operations, and process conditions described in this specification, and obtained relatively ideal results.

[0060] It should be understood that the technical solution of the present application is not limited to the above-mentioned specific implementation cases. Any technical variations made according to the technical solution of the present application without departing from the scope of protection of the purpose of the present application and the claims shall fall within the scope of protection of the present application.

Claims

1. A pharmaceutical composition, characterized in that include: Ketamine, and pharmaceutically acceptable imidazoxan salts or derivatives thereof.

2. The pharmaceutical composition according to claim 1, characterized in that: The molar ratio of ketamine to pharmaceutically acceptable imidazolide salt or its derivative is 1.23-4.94:1; And / or, the pharmaceutical composition comprises 55-83 wt % of ketamine and 17-45 wt % of a pharmaceutically acceptable imidazoxan salt or a derivative thereof.

3. The pharmaceutical composition according to claim 1, characterized in that: The pharmaceutically acceptable idazoxan salt is idazoxan hydrochloride.

4. The pharmaceutical composition according to claim 1, characterized in that Pharmaceutically acceptable excipients are also included.

5. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a medicament for preventing and / or treating major depressive disorder.

6. The use according to claim 5, characterized in that: The drug can at least reduce the immobility time in water of susceptible mice in a forced swimming test.

7. The use according to claim 5, characterized in that: The drug can at least increase the struggling time in water of susceptible mice in a forced swimming test.

8. The use according to claim 5, characterized in that: The drug can at least increase the time that susceptible mice stay in the social area in a social interaction experiment; And / or, the drug can at least increase the sugar water preference index of susceptible mice in a sugar water preference experiment.

9. The use according to claim 5, characterized in that: The dosage form of the drug includes tablets or injections.

10. The use according to claim 5, characterized in that: The effective dosage of the drug for mice is 2 mg / kg body weight.

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