Escketamine and mirtazapine synergistic antidepressant pharmaceutical composition and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an esketamine and mirtazapine synergistic antidepressant pharmaceutical composition and application thereof. The antidepressant pharmaceutical composition comprises the following active components: esketamine and mirtazapine, the esketamine is an N-methyl-D-aspartic acid receptor antagonist, and the mirtazapine is an adrenergic alpha2-AR antagonist. According to the anti-depression pharmaceutical composition containing esketamine and mirtazapine, through the synergistic effect of esketamine and mirtazapine, the effects of reducing dosage, prolonging aging and reducing adverse reactions are achieved, and major depressive disorder is safely and effectively prevented and treated.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an antidepressant composition and its application of esketamine and mirtazapine synergistically. Background Technology

[0002] Major depressive disorder, also known as severe depression, is characterized by symptoms such as anhedonia, social avoidance, and hopelessness; in severe cases, it can even lead to suicidal behavior. Epidemiological surveys show that more than 300 million people worldwide suffer from depression, and approximately 95 million people in my country currently suffer from it, placing a heavy burden on individuals and society.

[0003] In 2019, esketamine was officially approved by the FDA as an emerging antidepressant and has been used clinically. It works by antagonizing the N-methyl-D-aspartate receptor (NMDAR), with a rapid onset and relatively long duration of action, bringing a major breakthrough to the treatment of depression. However, esketamine is derived from general anesthetics and antipsychotics, and adverse reactions such as psychotic symptoms, double vision, nausea and vomiting, and dizziness may occur during its use, which limits the safety of its clinical application. Therefore, how to reduce the dosage and prolong the duration of action of esketamine while ensuring its antidepressant efficacy, thereby reducing the incidence of adverse reactions, has become a current research focus in this field.

[0004] In view of this, the present invention is hereby proposed. Summary of the Invention

[0005] This invention addresses the problems of high dosage, numerous adverse reactions, and limited duration of action associated with existing esketamine treatments for major depressive disorder. It provides a synergistic antidepressant composition and application of esketamine and mirtazapine, achieving reduced dosage, prolonged duration of action, and fewer adverse reactions through their synergistic effect. Effective, safe and efficient prevention and treatment of major depressive disorder.

[0006] To overcome the shortcomings of the prior art, the present invention provides the following technical solution: An antidepressant composition synergistically combining esketamine and mirtazapine, comprising the active ingredients esketamine and mirtazapine; the chemical structure of esketamine is shown in Formula I: Formula I; The chemical structure of mirtazapine is shown in Formula II: Formula II.

[0007] Furthermore, the ratio of esketamine to mirtazapine is 2.5:1.

[0008] Furthermore, the dosage of esketamine is 2.5 mg / kg, and the dosage of mirtazapine is 1 mg / kg.

[0009] Furthermore, the clinical dosage form of esketamine is a nasal spray or injection, and the clinical dosage form of mirtazapine is an oral tablet or orally disintegrating tablet.

[0010] In addition, the present invention also provides the use of the antidepressant pharmaceutical composition described above in the preparation of a medicament for the prevention and / or treatment of major depressive disorder.

[0011] Furthermore, the antidepressant drug composition is administered separately; the time interval between the administration of esketamine and mirtazapine does not exceed 30 minutes.

[0012] Furthermore, the antidepressant composition is suitable for patients with major depressive disorder who require a reduction in the risk of adverse reactions to esketamine; the adverse reactions include psychotic symptoms, diplopia, nausea and vomiting, and dizziness.

[0013] Compared with the prior art, the technical solution of the present invention has at least the following technical effects: (1) Synergistic effect: The combination of 2.5 mg / kg esketamine and 1 mg / kg mirtazapine had the same antidepressant effect as 10 mg / kg esketamine monotherapy and significantly shortened the resting time of mice in the forced swimming test; (2) Reduced dose: By combining with mirtazapine, the effective dose of esketamine was reduced from 10 mg / kg to 2.5 mg / kg, which reduced the risk of adverse reactions caused by high dose; (3) Prolonged duration of action: The antidepressant effect of esketamine monotherapy disappears on day 10, while the effect of low-dose esketamine can be maintained until day 10 after combination with mirtazapine; (4) Improved safety: By reducing the dosage of esketamine, the incidence of adverse reactions such as psychotic symptoms and double vision is significantly reduced; (5) High clinical value: It provides a new, safe and effective treatment for moderate to severe depression and has broad application prospects. Attached Figure Description

[0014] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. Wherein: Figure 1 A bar chart showing the effect of different doses of esketamine on the time of immobility during forced swimming in mice; Figure 2 , 3Figures 4 and 5 show the effects of different doses of mirtazapine on the time of forced swimming stillness in mice on days 1, 3, 5, and 7 after administration. Figure 6 , 7 8 is a bar chart showing the effect of mirtazapine combined with esketamine on resting time in mice on days 2, 4, and 10 after administration. Detailed Implementation

[0015] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions in the embodiments of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Those skilled in the art should understand that the embodiments described are merely illustrative of the invention and should not be considered as specific limitations thereof. 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. Process parameters not specifically specified in the following embodiments are generally performed under conventional conditions.

[0016] The endpoints and any values ​​of the ranges disclosed in this invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this invention.

[0017] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0018] According to a first aspect of the present invention, an antidepressant pharmaceutical composition is provided, comprising the active ingredients esketamine and mirtazapine; the chemical structure of esketamine is as follows: ; Mirtazapine: This is a multi-receptor antidepressant that, in addition to blocking α2-AR, also blocks serotonin (5-HT) receptors (mainly 5-HT2A, 5-HT2C, and 5-HT3 receptors). Mirtazapine is primarily metabolized by the hepatic CYP450 enzyme system (such as CYP1A2 and CYP2D6). Its chemical structure is as follows: .

[0019] Esketamine regulates the glutamatergic system by blocking NMDAR, while mirtazapine promotes the release of neurotransmitters such as norepinephrine by antagonizing α2-AR. Although their mechanisms of action are different, they synergistically enhance the antidepressant effect: (1) mirtazapine can enhance the antidepressant activity of esketamine, so that a low dose of esketamine (2.5 mg / kg) can exert a significant effect; (2) mirtazapine can prolong the duration of action of esketamine, extending the short-term effect of the single drug to at least 10 days.

[0020] The core mechanism of synergy is as follows: Depression is a common mental disorder with complex pathological mechanisms. Its pathogenesis is closely related to multiple factors, including dysfunction of the monoamine neurotransmitter system, decreased neuroplasticity, and abnormal neurotrophic factor signaling. Studies have shown that the density of high-affinity alpha-adrenergic receptors (α2-AR) in peripheral blood platelets of patients with depression is significantly increased, suggesting that α2-AR may play an important role in the development of the disease. As an autoreceptor, this type of receptor is mainly located on the presynaptic membrane of noradrenergic neurons and participates in the negative feedback regulation of neurotransmitter release. Therefore, its functional state is closely related to the activity of the norepinephrine (NE) system.

[0021] Mirtazapine is a norepinephrine-specific serotonergic antidepressant (NaSSA) with norepinephrine and specific serotonergic effects. Its mechanism of action primarily involves antagonizing central α2-AR receptors, thereby enhancing the release of norepinephrine and serotonin. Simultaneously, mirtazapine can block 5-HT2 and 5-HT3 receptors, reducing anxiety, improving sleep, and decreasing serotonin-related side effects. Its antidepressant efficacy is believed to be closely related to enhancing central norepinephrine and serotonergic neurotransmission. Furthermore, studies have shown that α2-AR antagonists such as mirtazapine can promote hippocampal neurogenesis, support the morphological maturation of new neurons, and upregulate the expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), thereby improving neural plasticity and cellular repair capabilities.

[0022] On the other hand, esketamine, as an N-methyl-D-aspartate receptor (NMDAR) antagonist, has received widespread attention in recent years due to its rapid and potent antidepressant effects. Although its mechanism of action differs from mirtazapine, studies have shown that it can also promote BDNF release and activate downstream signaling pathways, ultimately leading to synaptic remodeling and a rapid antidepressant effect.

[0023] From a synergistic drug perspective, α2-AR antagonists can also enhance the efficacy of norepinephrine reuptake inhibitors (NRIs). NRIs increase NE levels in the synaptic cleft by inhibiting the reuptake of NE at the presynaptic membrane. However, elevated NE concentrations activate presynaptic α2-AR autoreceptors, triggering a negative feedback mechanism that inhibits further NE release, thus limiting the drug's effect. When used in combination with α2-AR antagonists, this autofeedback pathway can be blocked, effectively enhancing the extracellular NE accumulation induced by NRIs and producing a synergistic antidepressant effect.

[0024] In summary, antagonizing α2-AR can not only directly regulate the release of monoamine neurotransmitters and promote neurotrophic signaling pathways, but may also enhance the efficacy of existing antidepressants through combination therapy strategies. Therefore, it is considered a promising treatment approach, providing a theoretical basis for the development of new, rapid, and effective antidepressant regimens.

[0025] In the technical solution of this invention, the optimal combination therapy of esketamine and mirtazapine is as follows: the dosage ratio of esketamine to mirtazapine is 2.5:1; optionally, the dosage of esketamine is 2.5 mg / kg, and the dosage of mirtazapine is 1 mg / kg. These two dosage combinations, through synergistic effects of different mechanisms of action, have been verified in mouse models to significantly enhance efficacy, providing a clear dosage basis for clinical translation. During clinical translation, the human dosage needs to be adjusted according to the dosage conversion formula from animal experiments (such as the body surface area method).

[0026] In the above technical solution, as a preferred embodiment, the clinical dosage form of esketamine is a nasal spray or injection, and the clinical dosage form of mirtazapine is an oral tablet or orally disintegrating tablet.

[0027] According to a second aspect of the invention, the use of the antidepressant pharmaceutical composition as described above in the preparation of a medicament for the prevention and / or treatment of major depressive disorder is provided.

[0028] In the above applications, as a preferred embodiment, esketamine and mirtazapine are administered separately; the time interval between the administration of esketamine and mirtazapine does not exceed 30 minutes, which can achieve a rapid and synergistic antidepressant effect.

[0029] In the above applications, as a preferred embodiment, the antidepressant drug composition is suitable for patients with major depressive disorder who need to reduce the risk of adverse reactions to esketamine; the adverse reactions include psychotic symptoms, diplopia, nausea and vomiting, and dizziness.

[0030] In the above application, as a preferred embodiment, the antidepressant drug composition exerts its antidepressant effect through a synergistic effect; the synergistic effect includes achieving a comparable antidepressant effect when 2.5 mg / kg esketamine is used in combination with 1 mg / kg mirtazapine, and the duration of the antidepressant effect is extended to at least 10 days.

[0031] The present invention will now be described in detail with reference to embodiments thereof. These examples are provided by way of explanation and not by way of limitation. In fact, those skilled in the art will recognize that modifications and variations can be made to the present invention without departing from its scope or spirit. For example, a feature shown or described as part of one embodiment may be used in another embodiment to produce yet another embodiment. Therefore, it is desirable that the present invention encompass such modifications and variations that fall within the scope of the appended claims and their equivalents.

[0032] In the embodiments of the present invention, unless otherwise specified, the experimental methods used are conventional methods, and the materials and reagents used are commercially available unless otherwise specified. Example

[0033] I. Experimental Materials and Methods 1. Laboratory animals: Breed and specifications: C57BL / 6J mice, 7-8 weeks old, weighing 20-25g; purchased from Changzhou Cavens Laboratory Animal Technology Co., Ltd., and bred at the animal facility of Xuzhou Medical University.

[0034] Husbandry conditions: Mice were housed in a standard animal room with a temperature of 23±2℃ and a humidity of 40±10%, with a 12h / 12h (lighting at 8:00) diurnal rhythm and free access to food.

[0035] Approval: This experiment was approved by the Animal Ethics Committee of Xuzhou Medical University and was conducted in strict accordance with the Laboratory Animal Care and Use Guidelines of the Institute of Hospital Management of the National Health Commission.

[0036] Sample size and statistics: The sample size for each group was n=8, and one-way ANOVA was used for statistical analysis.

[0037] 2. Experimental reagents: Mirtazapine: Purchased from Glpbio, USA; Esketamine: Meets clinical pharmaceutical standards; Physiological saline: used as a control reagent.

[0038] 3. Experimental Design: Administration route: Esketamine and mirtazapine are both administered systemically via intraperitoneal injection; Dosage: Mirtazapine was administered in four dose groups: 1 mg / kg, 3 mg / kg, 5 mg / kg, and 10 mg / kg; Esketamine was administered in three dose groups: 2.5 mg / kg, 5 mg / kg, and 10 mg / kg. Dosing interval: The interval between the two administrations is 10 minutes; Behavioral testing time: The mice began emotional and behavioral testing on the second day after injection.

[0039] 4. Emotional and behavioral tests (forced swimming experiment) Experimental environment: The experiment was conducted in a quiet behavioral room, where mice were placed 24 hours in advance to acclimatize to the environment; Experimental setup: an open transparent acrylic bucket (25cm high, 12.5cm in diameter), with a water depth of 15cm and a water temperature of 25±1℃; Experimental procedure: Mice were placed individually in an acrylic container for a total of 6 minutes, with the first minute being the adaptation period and the resting time of the mice in the water recorded for the next 5 minutes. Result interpretation: It is generally believed that mice will instinctively exhibit struggling and escaping behavior in the water. Prolonged periods of stillness indicate increased depressive-like symptoms (behavioral despair), while shortened periods of stillness indicate improved depressive-like symptoms.

[0040] 5. Data Analysis All values ​​are expressed as mean plus or minus standard error (SEM). P < 0.05 was considered statistically significant.

[0041] II. Experimental Results 1. Screening of effective and sub-effective doses of esketamine and mirtazapine 1.1 Screening of esketamine dosage: The effects of different dose gradients (1, 2.5, 5, 10, 100 mg / kg) of esketamine on the resting time in forced swimming tests in normal mice were observed. The results are as follows: Figure 1As shown, 10 mg / kg esketamine significantly reduced the stillness time in water in normal mice, indicating that 10 mg / kg esketamine can effectively improve depressive-like mood in mice (P<0.05), which is called the effective dose; mice injected with 5 mg / kg esketamine did not exhibit this effect, which is called the subeffective dose; doses of 2.5 mg / kg and below had no antidepressant effect. 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 an effective measure to reduce its adverse reactions. The experimental data on the screening of esketamine dosage (the effect of different doses on stillness time in the forced swimming experiment in mice) are shown in Table 1 below: Table 1

[0042] In Table 1, the first row from left to right represents the control group, and the six groups containing 9 mice each, with esketamine at concentrations of 1 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, and 100 mg / kg. The time for the mice to remain motionless during forced swimming is measured in seconds. The subsequent experiments each have eight mice per group, and the unit is mg / kg, measured in seconds.

[0043] Screening for 1.2 mizapine: The effects of different doses (1, 3, 5, 10 mg / kg) of mirtazapine on immobility time in normal mice during the forced swimming test were investigated. The results are as follows: Figure 2 , 3 As shown in Tables 2, 3, 4, and 5, after injecting different doses of mirtazapine into normal mice for 12 hours, doses of 3, 5, and 10 mg / kg significantly reduced the time the mice remained still in water. This effect disappeared on day seven. This indicates that doses of 3, 5, and 10 mg / kg mirtazapine can effectively improve depressive-like mood in mice, and this is referred to as the effective dose. Mice injected with a dose of 1 mg / kg mirtazapine did not exhibit this effect, and this is referred to as the sub-effective dose. The experimental data for screening mirtazapine doses (the effect of different doses on the time remaining still in the mouse forced swimming experiment) are shown in Tables 2, 3, 4, and 5 below. Table 2

[0044] Table 3

[0045] Table 4

[0046] Table 5

[0047] 2. Effect of mirtazapine on the dosage of esketamine for its antidepressant effect Under low-dose esketamine (2.5 mg / kg) conditions, the resting time in water of normal mice after intraperitoneal injection of physiological saline and sub-effective doses of mirtazapine (1 mg / kg) was measured. The results are as follows: Figure 6 As shown, on the second day after administration, compared with the mice injected with saline, the mice injected with sub-effective doses of mirtazapine and low-dose esketamine showed significantly reduced resting time in water, indicating that mirtazapine injection can promote the antidepressant effect of esketamine and exert a synergistic amplification effect. The data from the forced swimming experiment in mice after dose reduction are shown in Table 6: Table 6

[0048] Effect of mirtazapine on the duration of the antidepressant effect of esketamine Under sub-effective doses of mirtazapine (1 mg / kg), the resting time in water of normal mice at different time points after intraperitoneal injection of saline and esketamine (2.5, 10 mg / kg) was measured. The results are as follows: Figure 7 , 8 As shown, on the fourth day after administration, both esketamine alone and the low-dose esketamine / mirtazapine 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 mirtazapine, the low-dose esketamine still exerted a significant antidepressant effect. This indicates that mirtazapine injection can prolong the duration of the antidepressant effect of esketamine. The forced swimming test data for mice on day 4 and day 10 after administration are shown in Tables 7 and 8. Table 7

[0049] Table 8

[0050] The foregoing has described and evaluated some embodiments of the present invention. It should be understood that the present invention is not limited to the specific embodiments described above. Any person skilled in the art can make many possible variations and modifications to the technical solutions of the present invention, or modify them into equivalent embodiments, without departing from the scope of the present invention. This does not affect the essential content of the present invention. Therefore, any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention, without departing from the content of the present invention, still fall within the protection scope of the present invention.

Claims

1. A synergistic antidepressant composition of esketamine and mirtazapine, characterized in that, It includes the active ingredients esketamine and mirtazapine; the chemical structure of esketamine is shown in Formula I: Formula I; The chemical structure of mirtazapine is shown in Formula II: Formula II.

2. The antidepressant composition according to claim 1, characterized in that, The ratio of esketamine to mirtazapine used is 2.5:

1.

3. The antidepressant composition according to claim 2, characterized in that, The dosage of esketamine is 2.5 mg / kg, and the dosage of mirtazapine is 1 mg / kg.

4. The antidepressant composition according to claim 1, characterized in that, The clinical dosage form of esketamine is a nasal spray or injection, and the clinical dosage form of mirtazapine is an oral tablet or orally disintegrating tablet.

5. The use of the antidepressant pharmaceutical composition according to any one of claims 1-4 in the preparation of a medicament for the prevention and / or treatment of major depressive disorder.

6. The application according to claim 5, characterized in that, The antidepressant drug composition is administered separately; the time interval between the administration of esketamine and mirtazapine does not exceed 30 minutes.

7. The application according to claim 5, characterized in that, The antidepressant drug composition exerts its antidepressant effect through a synergistic effect; the synergistic effect includes achieving a comparable antidepressant effect when 2.5 mg / kg esketamine is used in combination with 1 mg / kg mirtazapine, and the duration of the antidepressant effect is extended to at least 10 days.

8. The application according to claim 5, characterized in that, The antidepressant composition is indicated for patients with major depressive disorder who require a reduction in the risk of adverse reactions to esketamine; these adverse reactions include psychotic-like symptoms, diplopia, nausea and vomiting, and dizziness.

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