Pharmaceutical composition and application thereof in preparation of medicine for treating major depressive disorder

Abstract

The invention discloses a pharmaceutical composition and application thereof in preparation of a medicine for treating major depressive disorder. The pharmaceutical composition is prepared from esketamine and yohimbine. The yohimbine in the pharmaceutical composition provided by the invention can effectively promote the anti-depression effect of the esketamine, remarkably reduce the use dosage of the esketamine when the esketamine plays the anti-depression effect and prolong the duration of the anti-depression effect, and meanwhile, a certain dosage of yohimbine can promote a smaller dosage of esketamine to play the anti-depression effect.

Description

Technical Field

[0001] The invention relates to a pharmaceutical composition and use thereof in preparing a medicine for treating major depressive disorder, belonging to the technical field of medicine. Background Art

[0002] Traditional antidepressants, such as monoamine oxidase inhibitors, tricyclic antidepressants, and selective 5-HT reuptake inhibitors, have slow onset, low cure rates, and many adverse reactions, so there is an urgent need for an antidepressant that is fast-acting and long-lasting. It was not until 2019 that esketamine was officially approved by the FDA as an emerging antidepressant for marketing and clinical use. Unlike traditional antidepressants, ketamine has a rapid onset and lasting effect, and is a major discovery in the treatment of depression in this century. However, as a general anesthetic and antipsychotic drug, ketamine has many adverse reactions during use, such as psychotic symptoms, diplopia, nausea and vomiting, dizziness, etc. Therefore, how to reduce the dosage of esketamine and prolong the duration of action of esketamine has become a solution to reduce the adverse reactions of esketamine. Summary of the invention

[0003] The main purpose of the present invention is to provide a pharmaceutical composition and its use in preparing a drug for treating major depressive disorder, so as to make up for the deficiencies of the prior art.

[0004] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention includes: An embodiment of the present invention provides a pharmaceutical composition for treating major depressive disorder, comprising: esketamine and yohimbine.

[0005] The embodiment of the present invention also provides the use of the aforementioned pharmaceutical composition in preparing a drug for treating major depressive disorder.

[0006] Compared with the prior art, the beneficial effects of the present invention are as follows: the yohimbine in the pharmaceutical composition of the present invention can effectively promote the antidepressant effect of esketamine, and significantly reduce the dosage of esketamine used when exerting the antidepressant effect, prolong the duration of the antidepressant effect, and at the same time, a certain dose of yohimbine can promote a smaller dose of esketamine to exert the antidepressant effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0008] Figure 1A This is a diagram showing the results of a dose screening experiment on the antidepressant effect of esketamine in normal mice in a typical embodiment of the present invention; Figure 1B is a graph showing the effect of different doses of yohimbine on the immobility time of normal mice in a forced swimming test in a typical embodiment of the present invention; Figure 1C is a graph showing the effect of yohimbine on the antidepressant dose of esketamine in a typical embodiment of the present invention; Figure 1D is a graph showing the effect of yohimbine on the antidepressant duration (fourth day) of esketamine in a typical embodiment of the present invention; Figure 1E is a graph showing the effect of yohimbine on the antidepressant duration (tenth day) of esketamine in a typical embodiment of the present invention; Figure 2A is a graph showing the effect of different doses of yohimbine on the antidepressant effect of 2.5 mg / kg esketamine in a typical embodiment of the present invention; Figure 2B This is a graph showing the effect of different doses of yohimbine on the antidepressant effect of 5 mg / kg esketamine in a typical embodiment of the present invention. DETAILED DESCRIPTION

[0009] In view of the defects of the prior art, the inventor of this case has proposed the technical solution of the present invention after long-term research and extensive practice. The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0010] Specifically, as one aspect of the technical solution of the present invention, a pharmaceutical composition is provided for treating major depressive disorder, which comprises: esketamine and yohimbine.

[0011] The structural formula of esketamine in the present invention is shown below: .

[0012] The structural formula of Yohimbine in the present invention is shown below: .

[0013] In some preferred embodiments, the mass ratio of esketamine to yohimbine is 2.5-5:15.

[0014] In some preferred embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient; wherein the pharmaceutically acceptable derivative is selected from at least one of a pharmaceutically acceptable salt, a polymorph, a co-crystal, a radiolabeled form and a combination thereof.

[0015] Further, the carrier and / or excipient can be any known pharmaceutically acceptable carrier and excipient for those skilled in the art suitable for such use. The "pharmaceutical carrier" described in this specification has a meaning well known to those skilled in the art, and can include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, similar substances and combinations thereof.

[0016] In some preferred embodiments, the dosage form of the pharmaceutical composition includes any one of injection, oral solution, capsule, tablet, and granule.

[0017] Another aspect of the embodiments of the present invention further provides use of the aforementioned pharmaceutical composition in the preparation of a drug for treating major depressive disorder.

[0018] In some preferred embodiments, the pharmaceutical composition is at least capable of increasing the struggling time of mice in water in a forced swimming test.

[0019] In some preferred embodiments, the pharmaceutical composition is capable of at least reducing the immobility time in water of mice in a forced swimming test.

[0020] In some preferred embodiments, when yohimbine in the pharmaceutical composition is used alone, it does not affect the struggling time of mice in the water in the forced swimming test.

[0021] In some preferred embodiments, when yohimbine in the pharmaceutical composition is used alone, it does not affect the immobility time in water of mice in a forced swimming test.

[0022] In some preferred embodiments, the dosage form of the pharmaceutical composition includes tablets or injections.

[0023] In some preferred embodiments, the effective administration amount of esketamine in the pharmaceutical composition to mice is 2.5-5 mg / kg body weight.

[0024] In some preferred embodiments, the effective administration amount of yohimbine in the pharmaceutical composition to mice is 15 mg / Kg body weight.

[0025] The use of yohimbine and esketamine in the pharmaceutical composition of the present invention is achieved by promoting a non-susceptible mechanism.

[0026] The present invention discovers for the first time that the combined use of yohimbine and esketamine can effectively reduce the dosage of esketamine at which the antidepressant effect is exerted in forced swimming and prolong its antidepressant effect time. The combined use of the drugs provides a new solution for treating depression and has important development prospects for the clinical antidepressant effect.

[0027] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings and several preferred embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0029] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources, for example: 1. Experimental steps 1. Experimental Animals: 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 with a temperature of 23±2 degrees and a humidity of 40±10%, a 12h / 12h (light on at 8:00), and free access to food. This experiment was approved by the Animal Ethics Committee of Xuzhou Medical University and was performed in strict accordance with the Guide for the Care and Use of Laboratory Animals.

[0030] 2. Reagents: Yohimbine was purchased from Glpbio, USA.

[0031] 3. Experimental design: Yohimbine was administered systemically via intraperitoneal injection at doses of 1, 2, 5, 10, and 15 mg / kg, and esketamine was administered systemically via intraperitoneal injection at doses of 2.5 and 5 mg / kg. The mice were tested for emotional behavior the day after the injection.

[0032] 4. Emotional behavior test: The behavioral test for depression-like emotions used in this patent is the forced swimming test. The experiment is conducted in a quiet behavioral room, and the mice must be placed in the room 24 hours in advance to adapt. In the forced swimming test, the mice are placed individually in an open transparent acrylic bucket (the bucket is 25 cm high, 12.5 cm in diameter, the water depth in the tank is 15 cm, the water temperature is 25°C, and the error is ±1°C). The total experimental time for each mouse is 6 minutes, including 1 minute of adaptation in the water, and the mouse's static time in the water is recorded for the next 5 minutes. It is generally believed that mice will struggle to escape in the water out of instinct. If the static time is prolonged, it means that the behavior is desperate, and the mouse's depression-like emotion is stronger; and the static time is shortened, which means that the mouse's depression-like emotion has improved.

[0033] 5. Data Analysis: All values ​​are expressed as mean plus or minus standard error (SEM). P < 0.05 was considered statistically significant.

[0034] 2. Experimental Results 1. Effect of Yohimbine on the Antidepressant Dose and Duration of Esketamine's Antidepressant Effect First, in order to screen out the effective and sub-effective doses of esketamine for relieving depression-like emotions, different dose gradients of esketamine (1, 2.5, 5, 10, 100 mg / kg) were selected to observe the effects on the immobility time of normal mice in the forced swimming test. The results are as follows: Figure 1A As shown in the figure, 10 mg / kg of esketamine can significantly reduce the immobility time of normal mice in water, indicating that 10 mg / kg of esketamine can effectively improve the depressive mood of mice. Although esketamine has been approved by the FDA for clinical use, many of its adverse reactions remain to be resolved, such as psychotic symptoms, nausea and vomiting, diplopia, blurred vision, etc. Therefore, reducing the dosage of esketamine and prolonging the duration of esketamine action may be an effective measure to reduce the adverse reactions of esketamine.

[0035] The effects of different doses (1, 2, 5, 10, 15 mg / kg) of yohimbine on the immobility time of normal mice in the forced swimming test were investigated. Figure 1B As shown, different doses of yohimbine had no effect on the immobility time of mice in water, indicating that yohimbine neither has an antidepressant effect nor induces depressive-like behavior.

[0036] The immobility time of normal mice in water was measured after intraperitoneal injection of saline and yohimbine (15 mg / kg) under the background of sub-effective dose of esketamine (5 mg / kg). Figure 1CAs shown, on the second day after administration, the immobility time of mice in the group injected with yohimbine intraperitoneally in water was significantly reduced compared with that in the group injected with normal saline, indicating that the injection of yohimbine can promote the antidepressant effect of esketamine and exert a synergistic amplification effect.

[0037] In the context of an effective dose of esketamine (10 mg / kg), the immobility time of normal mice in water at different time points was measured after intraperitoneal injection of normal saline and yohimbine (15 mg / kg). The results are shown in Figure 1D and Figure 1E As shown in the figure, on the fourth day after administration, injection of esketamine alone and esketamine / yohimbine combination both effectively improved the depressive-like behavior of mice. On the tenth day after administration, the depression-relieving effect of esketamine alone disappeared, but when used in combination with yohimbine, esketamine still exerted a significant antidepressant effect. This indicates that the antidepressant effect of esketamine can be prolonged after injection of yohimbine.

[0038] 2. Effects of different doses of yohimbine on the antidepressant effects of different doses of esketamine The effective dose and sub-effective dose of esketamine were clarified, and yohimbine itself does not directly regulate depressive-like behavior, but can exert a synergistic amplification effect. Then, the optimal dosage combination of esketamine and yohimbine was explored to see whether an antidepressant effect could be exerted by using a smaller dose of esketamine in combination with yohimbine.

[0039] Next, we explored the minimum dose of yohimbine that could promote the antidepressant effect of 2.5 mg / kg esketamine. We combined this dose of esketamine with different doses of yohimbine (1, 2, 5, 10, 15 mg / kg) and observed the immobility time of mice in the forced swimming test. Figure 2A As shown, compared with the control mice, the intraperitoneal injection of 2.5 mg / kg esketamine and 15 mg / kg yohimbine combination regimen can significantly reduce the immobility time of mice in water, indicating that the minimum yohimbine dose that promotes the antidepressant effect of 2.5 mg / kg esketamine is 15 mg / kg.

[0040] Furthermore, the same protocol was used to explore the minimum dose of yohimbine that could promote the antidepressant effect of 5 mg / kg esketamine. Figure 2B As shown, compared with the mice injected with normal saline only, the combination of 1, 2, 5, and 10 mg / kg yohimbine and 5 mg / kg esketamine had no effect on the immobility time of mice, while the combination of 15 mg / kg yohimbine and 5 mg / kg esketamine significantly reduced the immobility time of mice, indicating that the minimum yohimbine dose that promotes the antidepressant effect of 5 mg / kg esketamine is also 15 mg / kg.

[0041] In addition, the inventors of this case also referred to the aforementioned embodiments and conducted experiments with other raw materials, process operations, and process conditions described in this specification, and obtained relatively ideal results.

[0042] It should be understood that the technical solution of the present invention is not limited to the above-mentioned specific implementation cases. Any technical deformation made according to the technical solution of the present invention without departing from the scope of protection of the purpose of the present invention and the claims shall fall within the protection scope of the present invention.

Claims

1. A pharmaceutical composition for treating major depressive disorder, characterized in that: include: Esketamine and yohimbine.

2. The pharmaceutical composition according to claim 1, characterized in that: The mass ratio of esketamine to yohimbine is 2.5-5:

15.

3. The pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient; Wherein, the pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, co-crystals, radiolabeled forms and combinations thereof.

4. The pharmaceutical composition according to claim 1, characterized in that: The dosage form of the pharmaceutical composition includes any one of injection, oral solution, capsule, tablet and granule.

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

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

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

8. The use according to claim 5, characterized in that: When the yohimbine in the pharmaceutical composition is used alone, it will not affect the struggling time of mice in the water in the forced swimming test.

9. The use according to claim 5, characterized in that: When the yohimbine in the pharmaceutical composition is used alone, it will not affect the immobility time of mice in the water in the forced swimming test.

10. The use according to claim 5, characterized in that: The effective dosage of esketamine in the pharmaceutical composition for mice is 2.5-5 mg / kg body weight; And / or, the effective administration amount of yohimbine in the pharmaceutical composition to mice is 15 mg / Kg body weight.

Images