A pharmaceutical composition and its use in the manufacture of a medicament for the treatment of major depressive disorder

Abstract

The application discloses a kind of pharmaceutical composition and its purposes in preparation for treating major depressive disorder of drug. The pharmaceutical composition includes esketamine and yohimbine. The yohimbine in the pharmaceutical composition provided by the application can effectively promote the antidepressant effect of esketamine, significantly reduce the dosage of esketamine when it plays the antidepressant effect, prolong the duration of antidepressant effect, and a certain dosage of yohimbine can promote the antidepressant effect of less dosage of esketamine.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition and its use in the preparation of a medicament for treating major depressive disorder, belonging to the field of pharmaceutical technology. Background Technology

[0002] Traditional antidepressants, such as monoamine kinase inhibitors, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs), have slow onset of action, low cure rates, and numerous adverse reactions. Therefore, there is an urgent need for an antidepressant with rapid onset and long-lasting effect. In 2019, ketamine was officially approved by the FDA as an emerging antidepressant and began clinical use. Unlike traditional antidepressants, ketamine has a rapid onset and long-lasting effect, representing a major discovery in the treatment of depression this century. However, as a general anesthetic and antipsychotic, ketamine has many adverse reactions during use, such as psychotic-like symptoms, double vision, nausea, vomiting, and dizziness. Therefore, reducing the dosage of ketamine and prolonging its duration of action are solutions to reduce its adverse reactions. Summary of the Invention

[0003] The main objective of this invention is to provide a pharmaceutical composition and its use in the preparation of a medicament for treating major depressive disorder, thereby overcoming the shortcomings of the prior art.

[0004] To achieve the aforementioned objectives, the technical solution adopted by this invention includes: This invention provides a pharmaceutical composition for treating major depressive disorder, comprising: esketamine and yohimbine.

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

[0006] Compared with the prior art, the beneficial effects of the present invention are as follows: yohimbine in the pharmaceutical composition of the present invention can effectively promote the antidepressant effect of esketamine and significantly reduce the dosage of esketamine when it exerts its antidepressant effect, prolonging the duration of the antidepressant effect. At the same time, a certain dose of yohimbine can promote the antidepressant effect of a smaller dose of esketamine. Attached Figure Description

[0007] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0008] Figure 1A This is a graph showing the results of a dose screening experiment for the antidepressant effect of esketamine in normal mice in a typical embodiment of the present invention; Figure 1B This is a graph showing the effect of different doses of yohimbine on the resting time of normal mice in a forced swimming experiment in a typical embodiment of the present invention; Figure 1C This is a graph showing the effect of yohimbine dosage on the antidepressant effect of esketamine in a typical embodiment of the present invention; Figure 1D This is a graph showing the effect of yohimbine on the duration of esketamine antidepressant effects (day 4) in a typical embodiment of the present invention; Figure 1E This is a graph showing the effect of yohimbine on the duration of esketamine antidepressant effects (day 10) in a typical embodiment of the present invention; Figure 2A This 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 Implementation

[0009] In view of the deficiencies of the prior art, the inventors of this case, through long-term research and extensive practice, have proposed the technical solution of this invention. The technical solution of this invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0010] Specifically, as one aspect of the technical solution of the present invention, a pharmaceutical composition is involved in the treatment of major depressive disorder, comprising: esketamine and yohimbine.

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

[0012] The structural formula of yohimbine in this invention is shown below: .

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

[0014] In some preferred embodiments, the pharmaceutical composition further includes a pharmaceutically acceptable carrier and / or excipient; wherein the pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, cocrystals, radiolabeled forms, and combinations thereof.

[0015] Furthermore, the carrier and / or excipient can be any known pharmaceutically acceptable carrier and excipient suitable for such use. The term "pharmaceutical carrier" as used herein has the 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 delay agents, salts, preservatives, pharmaceuticals, pharmaceutical stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, similar substances, and combinations thereof.

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

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

[0018] In some preferred embodiments, the pharmaceutical composition is at least able to increase the time mice struggle in the water during a forced swimming experiment.

[0019] In some preferred embodiments, the pharmaceutical composition is at least able to reduce the time mice remain still in the water during forced swimming experiments.

[0020] In some preferred embodiments, the use of yohimbine in the pharmaceutical composition alone does not affect the time mice spend struggling in the water during forced swimming experiments.

[0021] In some preferred embodiments, the use of yohimbine in the pharmaceutical composition alone does not affect the time mice remain still in the water during forced swimming experiments.

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

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

[0024] In some preferred embodiments, the effective dosage of yohimbine in the pharmaceutical composition for mice is 15 mg / kg body weight.

[0025] In the pharmaceutical composition of this invention, yohimbine and esketamine are used by promoting a non-susceptible mechanism.

[0026] This invention is the first to discover that the combined use of yohimbine and esketamine can effectively reduce the dosage of esketamine to exert its antidepressant effect during forced swimming, prolong its antidepressant effect duration, and the combined use of these drugs provides a new solution for the treatment of depression, with significant prospects for clinical antidepressant efficacy.

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be further described in detail below with reference to the accompanying drawings and several preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this 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 are commercially available, for example: I. Experimental Procedure 1. Laboratory animals: C57BL / 6J mice were purchased from Changzhou Cavens Laboratory Animal Technology Co., Ltd., and bred at Xuzhou Medical University. The mice were housed in a standard animal room with a temperature of 23±2 degrees Celsius and a humidity of 40±10%, following a 12h / 12h (8:00 AM lighting) diurnal rhythm, and were allowed free access to food. This experiment was approved by the Animal Ethics Committee of Xuzhou Medical University and was conducted strictly in accordance with the guidelines for laboratory animal care and use.

[0030] 2. Reagents: Yuhimbine was purchased from Glpbio in the United States.

[0031] 3. Experimental Design: Yohimbine was administered systemically via intraperitoneal injection at doses of 1, 2, 5, 10, and 15 mg / kg, while esketamine was administered systemically via intraperitoneal injection at doses of 2.5 and 5 mg / kg. Emotional and behavioral tests were conducted on mice starting the day after injection.

[0032] 4. Emotional and behavioral tests: The behavioral test used in this patent to assess depressive-like symptoms is the forced swimming test. The experiment is conducted in a quiet behavioral testing room, and mice are placed in this room 24 hours in advance to acclimatize. In the forced swimming test, mice are individually placed in an open, transparent acrylic tank (25 cm high, 12.5 cm in diameter, 15 cm deep water, 25°C, with an error margin of ±1°C). The total test time for each mouse is 6 minutes, including 1 minute of acclimatization in the water. The time the mouse remains still in the water for the remaining 5 minutes is recorded. It is generally believed that mice, instinctively, will exhibit struggling and escape behaviors in the water. A prolonged period of stillness indicates behavioral despair and a stronger depressive-like emotion in the mouse; conversely, a shorter period of stillness indicates an improvement in the mouse's depressive-like emotion.

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

[0034] II. Experimental Results 1. Effects of yohimbine on the dose and duration of antidepressant effect of esketamine First, to screen for the effective and sub-effective doses of esketamine in alleviating depressive-like symptoms, different dose gradients (1, 2.5, 5, 10, 100 mg / kg) of esketamine were used to observe the effect on the resting time in normal mice during the forced swimming test. The results are as follows: Figure 1A As shown, a dose of 10 mg / kg esketamine significantly reduced the stillness time in water in normal mice, indicating that a dose of 10 mg / kg esketamine can effectively improve depressive-like symptoms in mice. Although esketamine has been approved by the FDA for clinical use, many of its adverse reactions remain to be addressed, such as psychotic-like symptoms, nausea and vomiting, diplopia, and blurred vision. Therefore, reducing the dosage of esketamine and prolonging its duration of action may be effective measures to reduce its adverse reactions.

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

[0036] Under sub-effective doses of esketamine (5 mg / kg), the resting time in water of normal mice after intraperitoneal injection of saline and yohimbine (15 mg / kg) was measured, and the results are as follows: Figure 1CAs shown, on the second day after administration, compared with the mice injected with saline, the mice injected with yohimbine intraperitoneally had a significantly reduced resting time in water, indicating that yohimbine injection can promote the antidepressant effect of esketamine and exert a synergistic amplification effect.

[0037] Under the premise of an effective dose of esketamine (10 mg / kg), the resting time in water of normal mice at different time points after intraperitoneal injection of physiological saline and yohimbine (15 mg / kg) were measured. The results are as follows: Figure 1D and Figure 1E As shown, on the fourth day after administration, both esketamine alone and the esketamine / yohimbine combination effectively improved depressive-like behavior in mice. However, on the tenth day after administration, the depressive-relieving effect of esketamine alone disappeared, but when used in combination with yohimbine, esketamine still exerted a significant antidepressant effect. This indicates that yohimbine injection can prolong the duration of the antidepressant effect of esketamine.

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

[0039] Next, we explored the minimum yohimbine dose that could promote the antidepressant effect of 2.5 mg / kg esketamine. This dose of esketamine was combined with different doses of yohimbine (1, 2, 5, 10, 15 mg / kg), and the immobility time in mice during the forced swimming test was observed. The results are as follows: Figure 2A As shown, compared with the control group, the combination of intraperitoneal injection of 2.5 mg / kg esketamine and 15 mg / kg yohimbine significantly reduced the immobility time of mice in water, indicating that the minimum dose of yohimbine to promote the antidepressant effect of 2.5 mg / kg esketamine is 15 mg / kg.

[0040] Furthermore, using the same protocol, the minimum yohimbine dose that could promote the antidepressant effect of 5 mg / kg esketamine was explored. The results are as follows... Figure 2B As shown, compared with mice injected with saline alone, the combination of 1, 2, 5, and 10 mg / kg yohimbine with 5 mg / kg esketamine did not affect the immobility time of mice, while the combination of 15 mg / kg yohimbine with 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 conducted experiments with other raw materials, process operations, and process conditions described in this specification, referring to the aforementioned embodiments, and obtained relatively ideal results in all cases.

[0042] It should be understood that the technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made to the technical solutions of the present invention without departing from the spirit and scope of the claims are within the scope of protection of the present invention.

Claims

1. Use of a pharmaceutical composition in the preparation of a medicament for treating major depressive disorder, characterized in that, The pharmaceutical composition comprises esketamine and yohimbine, wherein the mass ratio of esketamine to yohimbine is 2.5 to 5:15; the effective dosage of esketamine in mice is 2.5 to 5 mg / kg body weight; and the effective dosage of yohimbine in mice is 15 mg / kg body weight.

2. The use according to claim 1, characterized in that: The dosage form of the pharmaceutical composition is an injection.

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