Use of di(hetero)arylate derivatives of dihydrocannabidiol in the preparation of a medicament for preventing, alleviating or treating depression

Abstract

This invention belongs to the field of biomedical technology, specifically relating to the use of dihydrocannabidiol di(hetero)carbamate derivatives in the preparation of medicaments for the prevention, relief, or treatment of depression. The medicaments are used to improve symptoms of reduced spontaneous activity and / or behavioral hopelessness caused by depression. It also includes an antidepressant oral suspension comprising: a dihydrocannabidiol di(hetero)carbamate derivative or a pharmaceutically acceptable salt thereof as the active ingredient, an emulsifier, a suspending agent, and a pharmaceutically acceptable aqueous buffer. This invention demonstrates, using a classic behavioral hopelessness mouse model, that oral administration of the suspension of this invention can dose-dependently improve depressive symptoms, i.e., significantly increase total distance traveled, activity time, and decrease rest time. In particular, the high-dose PSF1 suspension shows a significantly superior overall antidepressant effect compared to the first-line clinical drug fluoxetine hydrochloride, demonstrating great potential for new drug development.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of dihydrocannabidiol di(hetero)carbamate derivatives in the preparation of drugs for the prevention, relief or treatment of depression. Background Technology

[0002] Depression is a mental disorder characterized by persistent low mood, loss of interest, anhedonia, and reduced spontaneous activity. It is characterized by high prevalence, high relapse rate, and high disability rate, severely impacting patients' quality of life and social functioning. First-line clinical drugs mainly include selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). However, these traditional chemically synthesized drugs generally suffer from a series of problems. First, their onset of action is delayed, typically requiring 2-4 weeks to become effective; second, their overall efficacy is limited, and some patients develop resistance; and third, they are often accompanied by adverse reactions such as gastrointestinal reactions, sleep disturbances, and sexual dysfunction, leading to poor patient adherence. Therefore, finding new antidepressants with faster onset of action, better efficacy, and fewer side effects is an urgent need in the field of neuropsychiatry.

[0003] In recent years, natural products and their derivatives have attracted much attention in the development of antidepressants due to their multi-target effects, good biocompatibility and low toxicity.

[0004] Traditional treatments often suffer from drawbacks such as delayed onset of action (2-4 weeks), limited efficacy, and adverse effects on gastrointestinal function, sleep disturbances, and sexual function, making them difficult to meet clinical needs. In recent years, non-targeted small molecules, bioactive materials, and novel carrier substances have attracted attention in the regulation of mental disorders. Dihydrocannabidiol di(hetero)carbamate derivatives (PSF) have become a research hotspot for candidate intervention substances for central nervous system diseases due to their good biocompatibility, degradability, and neuromodulation potential.

[0005] The applicant has previously developed a series of dihydrocannabidiol (DHC) di(hetero)carbamate derivatives, namely PSF1-5, see patents CN116983265A (PSF2), CN116983266A (PSF4), CN116983267A (PSF3), CN116983263A (PSF1), and CN116983264A (PSF5). These patents confirm that PSF1-5, as a DHC di(hetero)carbamate derivative, has a protective effect against oxidative damage to nerve cells and can alleviate insulin resistance. However, the aforementioned prior art does not disclose the role of PSF1-5 in antidepressants, nor does it address its development and application as an oral suspension. PSF1-5 compounds are typically yellow and oily at room temperature and are extremely poorly soluble in water. This extremely poor water solubility leads to highly unstable absorption in the gastrointestinal tract and low bioavailability, severely limiting the development and clinical translation of its oral formulations.

[0006] Therefore, the technical problem to be solved by this invention is how to overcome the physicochemical defects of PSF1-5's water insolubility, develop an oral formulation that is process-stable, industrially scalable, and can ensure effective absorption and central drug efficacy in vivo, and demonstrate its antidepressant effect. Summary of the Invention

[0007] This invention aims to address the difficulty of oral administration caused by the water insolubility of PSF1-5, and provides a stable, uniformly sized oral emulsion suspension and its preparation method. This invention also aims to confirm the antidepressant efficacy of this oral suspension, providing a novel antidepressant treatment regimen with rapid onset of action and superior efficacy compared to existing drugs.

[0008] In a first aspect, the present invention provides the use of a dihydrocannabidiol di(hetero)carbamate derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention, relief or treatment of depression, wherein the general structural formula of the dihydrocannabidiol di(hetero)carbamate derivative is shown in Formula I below:

[0009] Formula I; Where R can be any of the following structures: (1); (2); (3); (4); (5); Specifically, the di(hetero)arylcarbamate derivative of the active pharmaceutical ingredient dihydrocannabidiol is any one of the following compounds:

[0015] PSF1: Dihydrocannabidiol diimidazocarbamate;

[0016] PSF2: Dihydrocannabidiol-2,6-dioxapiperazine carboxylate;

[0017] PSF3: dihydrocannabidioxanone dinicotinate;

[0018] PSF4: dihydrocannabidiol difuranose ester;

[0019] PSF5: Dihydrocannabidiol dibenzoate; all subsequent uses are abbreviated by number.

[0020] The medication is used to improve symptoms of reduced voluntary activity and / or behavioral hopelessness caused by depression.

[0021] The dosage of PSF1-5 is 200 mg / kg to 400 mg / kg body weight.

[0022] A second aspect of the present invention provides an antidepressant oral suspension comprising: a di(hetero)carbamate derivative of dihydrocannabidiol or a pharmaceutically acceptable salt thereof as an active ingredient, an emulsifier, a suspending agent, and a pharmaceutically acceptable aqueous buffer solution; The suspending agent is mannitol, and the emulsifier is poloxamer 188.

[0023] The content of poloxamer 188 is 0.5%-2.0% w / v, and the content of mannitol is 2.0%-8.0% w / v.

[0024] The oral suspension of the present invention forms a stable emulsified suspension system in an aqueous buffer solution through a specific combination of the nonionic emulsifier poloxamer 188 and the suspending stabilizer mannitol. Preferably, the concentration of poloxamer 188 in the suspension is 1.0% (w / v), and the concentration of mannitol is 5.0% (w / v). This system can effectively encapsulate the oily PSF1-5 compounds, preventing oil droplet aggregation and stratification.

[0025] The particle size D90 of the oil droplets dispersed in the suspension is ≤10μm.

[0026] The aqueous buffer solution is a citrate-sodium citrate buffer solution.

[0027] The suspension has a pH of 6.0-6.5 and an osmotic pressure of 250-600 mOsmol / kg.

[0028] A third aspect of the present invention provides a method for preparing an antidepressant oral suspension, comprising the following steps: a) Dissolve the emulsifier and suspending agent in an aqueous buffer solution to prepare an aqueous matrix; b) Disperse a di(hetero)aryl ester derivative of dihydrocannabidiol or a pharmaceutically acceptable salt thereof in the aqueous matrix and stir to obtain a colostrum; c) The primary emulsion is subjected to high-pressure homogenization, with the temperature controlled at ≤25℃, until the oil droplet size D90≤10 μm, to obtain an emulsified suspension.

[0029] In step c), the pressure of the high-pressure homogenization process is 400-600 bar, and the homogenization is repeated 3 to 6 times, preferably 500 bar, 3 to 4 times.

[0030] This method includes the preparation of the aqueous matrix, the initial emulsification of the oil phase, and the high-pressure homogenization microemulsification process. By controlling the pressure and number of cycles of high-pressure homogenization, the particle size of the dispersed oil droplets is strictly controlled to ensure uniform absorption by the gastrointestinal tract after oral administration.

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) This invention successfully overcomes the physicochemical defects of PSF1-5, which is poorly soluble in water and has an oily state. By screening and optimizing excipients and using high-pressure homogenization process, an emulsion suspension with uniform particle size, isotonicity, and suitable pH was prepared. The process is stable and controllable and has the potential for industrial scale-up, providing a reliable formulation platform for the oral delivery of lipid-soluble PSF1-5.

[0032] (2) This invention demonstrates, through a classic behavioral despair mouse model, that oral administration of the suspension of this invention can dose-dependently improve depressive symptoms, namely, significantly increase total distance traveled and activity time, and reduce rest time. In particular, the overall antidepressant effect of high-dose PSF1 suspension is significantly better than that of the first-line clinical drug fluoxetine hydrochloride, showing great potential for new drug development.

[0033] (3) This invention compared the antidepressant effects of the natural product CBD in parallel. The experimental results surprisingly showed that the derivatives PSF1 and PSF5, especially PSF1, had significantly better antidepressant activity than their equivalent doses of the analogue CBD. This result indicates that specific di(hetero)aryl esterification modification not only improves the physicochemical properties but also achieves an unexpected enhancement of central nervous system activity.

[0034] (4) The present invention clarifies the activity differences of different substituents R, the pharmacodynamic gradient: PSF1 > PSF5 > PSF2 / 3 / 4, and the dose-effect characteristics that require medium to high doses (≥200 mg / kg) to fully exert the central mood regulation effect, providing a scientific basis for the setting of subsequent clinical drug doses. Specific Embodiments

[0035] To further elaborate on the technical means and effects adopted by the present invention, the following further illustrates the technical solutions of the present invention in combination with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0036] In the process of implementing the present invention, conditions, reagents, experimental methods, etc., except for the specifically mentioned content below, are all common knowledge and well-known common sense in the art, and the present invention has no particularly restricted content. For the experimental methods without specific conditions indicated in each embodiment, they are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0037] Unless otherwise specified, the meanings of all professional terms and scientific terms used in this specification are the same as those generally understood by those skilled in the technical field to which the present invention belongs. However, in case of conflict, this specification including the definitions shall prevail.

[0038] Test Substances: The preparations of PSF1-5 refer to the embodiments of the following patents: PSF1: CN116983263A, PSF2: CN116983265A, PSF3: CN116983267A, PSF4: CN116983266A, PSF5: CN116983264A. PSF1-5 are yellow oily substances with a purity greater than 98%.

[0039] Positive Control: Fluoxetine Hydrochloride Tablets, batch number: 202508141, specification: 10 mg * 14 tablets / box, expiration date: 2027.08.13; product of Changzhou Pharmaceutical Co., Ltd.

[0040] Cannabidiol (CBD) reference substance: purity ≥ 99%, purchased externally.

[0041] Experimental Animals: 210 SPF-grade male ICR mice, weighing 18 - 22 g, experimental animal use license number: SYXK (Xiang) 2025 - 0008.

[0042] Main Reagents: Pure water, produced by Youpu water purification machine.

[0043] Main Instruments: ME2002E / 02 electronic balance, Mettler Company product; Dig Behv animal behavior analysis system, Shanghai Jiliang Software Technology Co., Ltd. product; JL Behv forced swimming video analysis system, Shanghai Jiliang Software Technology Co., Ltd. product.

[0044] Example Preparation of antidepressant oral suspension: PSF1-5 is a yellow oily substance with a purity ≥98%. It is aseptically dispensed, sealed, and protected from light. Store at 4°C. Excipients meet oral pharmaceutical standards: mannitol 5.0 g, poloxamer 188 1.0 g, and an appropriate amount of 0.1 mol / L citrate-sodium citrate buffer.

[0045] Preparation of 0.1 mol / L citric acid-sodium citrate buffer: Take appropriate amounts of citric acid and sodium citrate, dissolve them in purified water and adjust the pH to 6.2 to prepare a 0.1 mol / L buffer solution. After preparation, filter the solution through a 0.45 μm pre-filter and a 0.22 μm hydrophilic PES filter cartridge for sterilization. Store at room temperature.

[0046] a) Take 5.0 g of mannitol and 1.0 g of poloxamer 188, add about 80 mL of sterile buffer, stir magnetically at room temperature until completely dissolved, add sterile buffer to 90 mL, let stand for 20 min to remove bubbles until no visible bubbles are visible on the liquid surface, and obtain the aqueous phase matrix.

[0047] b) In a Class A clean environment, while stirring at 500 rpm, slowly add 2.0 g of yellow oily PSF1-5 dropwise to the above aqueous matrix. After all the dropwise addition is complete, continue stirring at low speed for 5 min, then adjust the speed to 3000 rpm and stir at high speed for 15 min to obtain the colostrum.

[0048] c) Transfer the colostrum to a high-pressure homogenizer, set the homogenization pressure to 500 bar, turn on the low-temperature circulating cooling, and control the liquid temperature to ≤25 ℃ throughout the process. Homogenize 3 to 4 times. After each homogenization cycle, take a sterile sample and use a laser particle size analyzer to detect the oil droplet size. The qualified standard is D90≤10 μm. If the particle size does not meet the standard, 1 to 2 more homogenization cycles can be added, with a total number of cycles not exceeding 6.

[0049] After homogenization, add sterile buffer to a final volume of 100 mL, stir magnetically for 5 min, and retest the system. The pH should be 6.0–6.5, and the osmotic pressure should be controlled between 250–600 mOsmol / kg. Thoroughly mix the suspension and filter it through a 10 μm titanium rod filter at a low pressure of ≤0.15 MPa to remove any accidentally introduced insoluble foreign matter. Filters with pore sizes smaller than 10 μm are strictly prohibited to avoid trapping active oil droplets.

[0050] Transfer the filtrate to a Class 10,000 clean environment, aseptically dispense it into sterile brown bottles, seal and label them (indicating compound number, preparation date, and theoretical concentration of 20 mg / mL), and temporarily store at 4°C protected from light for no more than 7 days. Shake well before use; discard if obvious oil-water separation occurs.

[0051] Before dispensing, samples were taken to test the actual PSF content in the drug solution, and the animal dosage was calculated based on the measured corrected concentration.

[0052] Test methods 1. Grouping and Dosing Two hundred and ten SPF-grade male ICR mice, weighing 18–22 g and meeting quarantine standards, were randomly assigned to four groups based on their weight: a normal control group, a model control group, a fluoxetine hydrochloride tablet group (2.6 mg / kg), low, medium, and high dose PSF1-5 groups (100, 200, and 400 mg / kg), and low, medium, and high dose CBD groups (100, 200, and 400 mg / kg), with ten mice in each group. Mice in the normal and model control groups were administered pure water by gavage, while mice in the other groups were administered the corresponding drug solution by gavage at a volume of 20 mL / kg, once daily for seven consecutive days. After the last administration, tail suspension and forced swimming tests were performed to establish the ICR model, followed by open field testing.

[0053] 2. Dosage setting The PSF1-5 dosage was set at 100, 200, and 400 mg / kg; the CBD dosage was set at 100, 200, and 400 mg / kg; the clinical dosage of fluoxetine hydrochloride tablets was 20 mg / day; the equivalent dose for mice, calculated based on the body surface area conversion between humans and mice, was 20 mg × 0.0026 / 0.02 kg. 2.6 mg / kg, animal grouping and dosage design are shown in Table 1.

[0054] Table 1 Animal grouping and dosage design

[0055] 3. Detection indicators Tail suspension test: After the last administration, mice in each group underwent forced tail suspension test, and the immobility time of the mice was recorded for 5 minutes.

[0056] Forced swimming test: After the last administration, mice were subjected to forced swimming behavior tests, and the immobility time of the mice was recorded for 5 minutes.

[0057] Open field test: After the tail suspension test and forced swimming test, the mice were placed in an activity box and allowed to adapt to the environment for 3 minutes. Then, the Dig Behv animal behavior analysis system was used to record the mice’s spontaneous activities within 10 minutes.

[0058] 4. Experimental Results 4.1 Effects of PSF1-5, fluoxetine hydrochloride, and CBD on open field testing in a mouse model of behavioral despair As shown in Table 2, compared with the normal control group, the total distance, average speed, and activity time of the mice in the model control group were significantly reduced. P ≤0.01), the number of activities and rest time increased significantly ( P ≤0.01); Compared with the model control group, mice in the fluoxetine hydrochloride tablet group, PSF1 medium-high dose group, and PSF5 high dose group had significantly increased total distance, average speed, and activity time, and significantly decreased activity frequency and rest time; mice in the PSF1 low dose group, PSF2-4 medium-high dose group, PSF5 medium dose group, and CBD medium dose group had significantly decreased activity frequency. P ≤0.05); the improvement in various indicators was particularly significant in the high-dose PSF1 group ( P ≤0.01), with overall activity superior to the fluoxetine hydrochloride tablet group; PSF2-4 only showed significant improvement in the high-dose group ( P The CBD group showed a significant dose-dependent effect, with no statistically significant difference in any of the tested indicators in the low-dose group (P>0.05). The medium-dose group showed a significant improvement only in the number of activities. The high-dose group showed significant improvements in total distance, average speed, activity time, and rest time, but the overall efficacy was lower than that of the high-dose PSF5 group. The low-dose groups of each test substance showed weak overall improvement. Only the low-dose PSF1 group showed a statistically significant difference in the number of activities. The low-dose PSF2-5 and low-dose CBD groups showed no statistically significant differences in any of the tested indicators (P>0.05). This indicates that the antidepressant effects of the PSF series compounds and CBD are both significantly dose-dependent. Only high-dose administration can comprehensively improve the depressive-like manifestations of spontaneous activity inhibition in model mice. The overall activity gradient was: PSF1 > fluoxetine hydrochloride > PSF5 > high-dose CBD > high-dose PSF2 / 3 / 4.

[0059] Table 2 Effects of PSF1-5 and CBD on open field tests in a behavioral despair mouse model ( X±SEM, n=10)

[0060] Note: Compared with the normal control group, ++ P ≤0.01, compared with the model control group, * P ≤0.05,** P ≤0.01.

[0061] This invention targets the yellow, oily, water-insoluble active ingredient PSF1-5 and successfully establishes a complete preparation process for an industrially scalable, aseptically controllable, and uniformly sized oral emulsion suspension of PSF1-5. Through precise control of oil droplet size, construction of an isotonic buffer system, high-pressure homogenization microemulsification, and aseptic operation throughout the process, a stable and mildly physicochemically mild oral suspension is obtained, providing a reliable dosage form basis for animal gavage efficacy evaluation and subsequent clinical translation of new oral antidepressants.

[0062] From a formulation perspective, poloxamer 188, when combined with mannitol, forms an emulsified-suspension isotonic system. As a nonionic emulsifier, poloxamer 188 can fully encapsulate the water-insoluble oily PSF1-5, improving the wetting properties of the oil phase and effectively inhibiting oil droplet flotation and oil-water separation. High-pressure homogenization can break large oil droplets into a uniform particle size range, ensuring uniform gastrointestinal absorption and stable in vivo effects after oral administration. With the system pH controlled at 6.0-6.5 and the osmotic pressure maintained at 280-320 mOsmol / kg, coupled with aseptic filtration, the overall physicochemical parameters are adapted to the gastrointestinal oral tolerance environment, making it suitable for long-term gavage administration and animal efficacy studies.

[0063] Pharmacodynamic open-field experiments showed that the PSF series materials could improve symptoms of loss of spontaneous activity and behavioral hopelessness in a depression model mouse in a dose-dependent manner. The activity of different PSF structures differed significantly. Among them, PSF1 had the best overall antidepressant effect, and its efficacy at high doses was superior to that of the first-line clinical antidepressant fluoxetine hydrochloride. PSF5 was the second best, while PSF2, 3, and 4 only had weak intervention effects at high doses. CBD, as a positive control natural active substance, also showed a dose-dependent effect, and its overall activity was weaker than that of PSF5.

[0064] PSF family materials possess both good biocompatibility and neuromodulatory activity. This study demonstrates that oral administration of PSF1-5 can significantly alleviate depressive-like behavior in mice, compensating for the shortcomings of SSRIs, such as slow onset of action and numerous side effects. Further research can explore the molecular mechanisms by which it regulates central neurotransmitters and neuroplasticity, providing new insights for the development of novel oral antidepressant bioactive agents.

[0065] This invention successfully constructs a stable and industrially scalable method for preparing oral emulsified suspensions targeting the yellow, oily, and poorly soluble PSF1-5 series active substances. Through key processes such as oil-phase pre-emulsification, high-pressure homogenization and microemulsification, precise pH and osmotic pressure control, and aseptic filtration and dispensing, the resulting formulation exhibits uniform oil droplet size, stable physicochemical properties, and pH and osmotic pressure parameters suitable for gastrointestinal gavage administration, allowing for direct use in animal efficacy evaluation.

[0066] The pharmacodynamic experiments were carried out using a mouse behavioral despair model. Fluoxetine hydrochloride was set as a chemical positive control and CBD as a natural active control simultaneously. The results of open-field behavior confirmed that oral administration of PSF1-5 could dose-dependently improve the depressive-like manifestations such as reduced spontaneous activity and behavioral inhibition in depressive model mice. There were significant differences in the activities of different structural products: PSF1 had the best comprehensive antidepressant effect, and its efficacy at high doses was better than that of fluoxetine hydrochloride; PSF5 was the second; only the high-dose groups of PSF2, PSF3, and PSF4 had significant intervention effects. CBD also showed dose-dependent antidepressant activity, but the overall improvement effect was weaker than that of the high-dose group of PSF5. No obvious behavioral improvement effects were observed at low doses of all test substances, indicating that high-dose administration was required to fully exert the central mood regulation effect.

[0067] Combining the pharmaceutical technology and the in vivo pharmacodynamic results, the PSF1-5 oral suspension prepared by this process is easy to prepare, has good stability, and outstanding in vivo antidepressant activity. It has potential pharmacodynamic advantages compared with traditional SSRI drugs; at the same time, compared with CBD, it is confirmed that the PSF series materials have better development potential in the field of antidepressants, which can provide complete experimental basis and candidate development directions for the subsequent mechanism research, dosage form optimization and clinical transformation of new oral antidepressant bioactive preparations.

[0068] Experimental example: Evaluation of the non-addictive properties of the active ingredients PSF1-5 of the present invention To evaluate the drug addiction of the active ingredients PSF1-5 of the present invention, the present invention conducted a conditioned place preference (CPP) experiment to evaluate its psychological dependence, and evaluated its physical dependence after withdrawal through an open-field test (OFT) and an elevated plus-maze test (EPM).

[0069] 1. Experimental materials and methods 1.1 Experimental animals SPF-grade male Kunming mice, 6-8 weeks old, weighing 25-30 g, were purchased from Beijing Spey Foster Biotechnology Co., Ltd. [Production License No.: SCXK (Beijing) 2024-0001]. The animals were housed in an SPF-grade animal room at a temperature of 22-25 °C, with a 12 h light / 12 h dark cycle, and free access to food and water. All animal experiments followed the relevant regulations of the Animal Ethics Committee.

[0070] 1.2 Drugs and reagents Each component of PSF1-5 (purity ≥ 98%, provided by the Institute of Agro-Products Processing, Chinese Academy of Agricultural Sciences); Morphine Hydrochloride Injection (commercial specification, positive control drug); Normal saline; DMSO (dimethyl sulfoxide, pharmaceutical grade); 75% alcohol.

[0071] Before administration, each of the PSF1, PSF2, PSF3, PSF4 and PSF5 components was dissolved in DMSO to prepare a stock solution. Before use, each solution was diluted with physiological saline to the required concentration (final DMSO concentration ≤ 5%) and administered via intraperitoneal injection.

[0072] 1.3 Main Instruments Conditional location preference box, open field test box, elevated cross maze and VisuTrack animal behavior video analysis software (Shanghai Xinruan Information Technology Co., Ltd.).

[0073] 1.4 Experimental grouping and dosing regimen Mice were randomly divided into the following groups, with 10 mice in each group: First batch: blank control group (physiological saline), solvent control group (5% DMSO), positive control group (morphine 3mg / kg), PSF1 group (10mg / kg), PSF5 group (10mg / kg).

[0074] The second batch consisted of: blank control group (physiological saline), solvent control group (5% DMSO), positive control group (morphine 3 mg / kg), PSF2 group (20 mg / kg), PSF3 group (20 mg / kg), and PSF4 group (20 mg / kg).

[0075] All medications were administered via intraperitoneal injection.

[0076] 2. Experimental Procedure 2.1 Conditional Place Preference (CPP) Experiment The experiment consisted of three phases: pre-test (3 days), training (12 days, drug-environment pairing), and post-test (1 day). The changes in the time mice spent in the drug-accompanied box before and after training (CPP score) were compared among the groups.

[0077] The training phase lasted for 12 days (days 1 to 12). A partition was inserted, and training was alternated between medication-accompanied and non-medication-accompanied boxes, 6 times each. On medication-accompanied box training days (days 1, 3, 5, 7, 9, and 11): Mice in each drug-treated group were intraperitoneally injected with the corresponding drug 30 minutes before training (PSF1-5 groups and the solvent control group were injected with the corresponding drug or 5% DMSO saline solution; the positive control group was injected with morphine; and the blank control group was injected with saline solution). After 30 minutes, the mice were placed in the medication-accompanied box and left for 35 minutes before being removed. On non-medication-accompanied box training days (days 2, 4, 6, 8, 10, and 12): Mice in all groups were not given any medication and were directly placed in the non-medication-accompanied box, left for 35 minutes, and then removed.

[0078] 2.2 Withdrawal Behavioral Experiments On days 7 and 8 after CPP training, the open field test (OFT) and elevated cross maze test (EPM) were conducted to evaluate voluntary activities and anxiety-like behaviors after drug withdrawal.

[0079] OFT metrics: total distance traveled, number of times entering the central zone, time spent in the central zone, average speed, and number of supporting stands.

[0080] EPM metrics: number of times the arm is opened and the dwell time in the arm.

[0081] 2.3 Statistical Analysis Experimental data are expressed as mean ± standard deviation (Mean ± SD). One-way ANOVA was used for comparisons among multiple groups; LSD method was used for pairwise comparisons when variances were homogeneous, and Dunnett's T3 method was used when variances were unequal. Paired t-tests were used to compare pre-test and post-test CPP scores. A p-value < 0.05 was considered statistically significant. GraphPad Prism 9.0 was used as the statistical software.

[0082] 3. Experimental Results 3.1 Results of the CPP experiment (evaluation of psychological dependence) The results are shown in Table 3. The positive control group (morphine) mice showed a significantly higher post-test CPP score than the pre-test score (P<0.001), indicating a clear conditional position preference. However, the post-test CPP scores of all PSF1-5 groups showed no significant difference compared to the pre-test scores (P>0.05), comparable to the blank control group and the solvent control group. These results indicate that none of the components of PSF1-5 induces psychological dependence.

[0083] Table 3: Comparison of CPP scores before and after the test in each group of mice (s, Mean±SD, n=10)

[0084] 3.2 Results of the withdrawal behavior experiment (evaluation of physical dependence) Open field test (OFT) results (Table 4): The total range of motion and central area activity of mice in the morphine withdrawal group were significantly reduced, while the number of times they supported themselves on their feet was significantly increased (P<0.05), exhibiting typical anxiety-like behavior. There were no significant differences in any behavioral indicators of mice in the PSF1-5 groups compared with the blank control group (P>0.05).

[0085] Table 4: Comparison of Open Field Test (OFT) Results among Different Groups of Mice (Mean±SD, n=10)

[0086] Results of the elevated cross maze (EPM) test (Table 5): The morphine withdrawal group mice spent significantly less time in the open arm and entered the maze fewer times than the blank control group (P<0.05). There were no significant differences between the PSF1-5 groups and the blank control group (P>0.05).

[0087] Table 5: Comparison of Elevated Cross Maze (EPM) results among different groups of mice (Mean±SD, n=10)

[0088] In summary, the active ingredients PSF1-5 involved in this invention do not induce psychological dependence in the conditional position preference test, do not cause anxiety-like behavior after withdrawal, and do not induce physical dependence. These results strongly demonstrate that the PSF1-5 series of compounds do not have addictive potential and possess the good safety profile required for use as a chronic pain treatment drug.

Claims

1. The use of a dihydrocannabidiol di(hetero)carbamate derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention, relief or treatment of depression, characterized in that, The general structural formula of the di(hetero)arylformate derivative of dihydrocannabidiol is shown in Formula I below: Formula I; Where R can be any of the following structures: （1）； （2）； （3）； （4）； （5）。 2. Use according to claim 1, characterized in that, The medication is used to improve symptoms of reduced voluntary activity and / or behavioral hopelessness caused by depression.

3. An antidepressant oral suspension characterized in that, It comprises: a di(hetero)carbamate derivative of dihydrocannabidiol as the active ingredient, or a pharmaceutically acceptable salt thereof, an emulsifier, a suspending agent, and a pharmaceutically acceptable aqueous buffer; the general structural formula of the di(hetero)carbamate derivative of dihydrocannabidiol is shown in Formula I below: Formula I; Where R can be any of the following structures: （1）； （2）； （3）； （4）； （5）。 4. The antidepressant oral suspension according to claim 3, characterized in that, The suspending agent is mannitol, and the emulsifier is poloxamer 188.

5. The antidepressant oral suspension according to claim 4, characterized in that, The content of poloxamer 188 is 0.5%-2.0% w / v, and the content of mannitol is 2.0%-8.0% w / v.

6. The antidepressant oral suspension according to claim 3, characterized in that, The particle size D90 of the oil droplets dispersed in the suspension is ≤10 μm.

7. The antidepressant oral suspension according to claim 3, characterized in that, The aqueous buffer solution is a citrate-sodium citrate buffer solution.

8. The antidepressant oral suspension according to claim 7, characterized in that, The suspension has a pH of 6.0-6.5 and an osmotic pressure of 250-600 mOsmol / kg.

9. A process for the preparation of an antidepressant oral suspension as claimed in any one of claims 3 to 8, characterized in that, Includes the following steps: a) Dissolve the stabilizer and suspending agent in an aqueous buffer solution to prepare an aqueous matrix; b) Disperse a di(hetero)aryl ester derivative of dihydrocannabidiol or a pharmaceutically acceptable salt thereof in the aqueous matrix and stir to obtain a colostrum; c) The primary emulsion is subjected to high-pressure homogenization until the oil droplet size D90 ≤ 10 μm, to obtain an emulsion suspension.

10. The method of preparing an antidepressant oral suspension according to claim 9, characterized in that, In step c), the pressure of the high-pressure homogenization process is 400-600 bar, and the homogenization is repeated 3 to 6 times.

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