Transdermal patches comprising dihydrocannabidiol di(hetero)arylate derivatives, methods for their preparation and use

Abstract

This invention belongs to the field of biomedical technology, specifically relating to transdermal patches containing dihydrocannabidiol (DHC) di(hetero)carbamate derivatives, their preparation methods, and applications. The patch comprises a drug-containing layer, a backing layer, and an anti-adhesive protective layer; the drug-containing layer contains DHC di(hetero)carbamate derivatives or pharmaceutically acceptable salts thereof, humectants, medical pressure-sensitive adhesives, and composite penetration enhancers; and the application of the transdermal patch in the preparation of a medicament for treating pain, specifically thermal pain or pain associated with limb rigidity. The prepared transdermal patch significantly increases the thermal pain threshold in mice and prolongs the latency of the pain response, demonstrating its clear analgesic effect. The prepared transdermal patch significantly shortens the time of limb rigidity and activity cessation caused by pain, indicating its effective improvement of pain-related pathological behaviors.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to transdermal patches containing dihydrocannabidiol di(hetero)carbamate derivatives, their preparation methods, and applications. Background Technology

[0002] Pain is one of the most common clinical symptoms, severely impacting patients' quality of life. Traditional oral analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, while effectively relieving pain, suffer from significant first-pass effects, delayed onset of action, large fluctuations in blood drug concentrations, and systemic side effects such as gastrointestinal, hepatotoxic, and nephrotoxic effects. Long-term use may also lead to drug tolerance and dependence. Therefore, developing a safe, non-invasive, locally administered, long-lasting, and highly compliant topical analgesic is a key focus of current research and development for postoperative neuropathic pain medications.

[0003] Transdermal patches, as a novel topical drug delivery formulation, apply medication to the skin surface, allowing the drug to penetrate the skin's stratum corneum barrier, enter the systemic circulation, or directly act on local tissues to produce a therapeutic effect. They achieve continuous and stable drug release through the skin barrier, avoiding the systemic toxicity of oral medications. They also have advantages such as convenient use, high patient compliance, and long-term drug delivery, showing significant application prospects in the treatment of local pain and nerve damage-related diseases.

[0004] The applicant has previously developed a series of dihydrocannabidiol (DHC) di(hetero)carbamate derivatives, namely PSF1-5, as detailed in 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 application of PSF1-5 in pain treatment, nor does it address its development and application as a transdermal patch.

[0005] PSF1-5 has been demonstrated by the applicant to possess potential anti-inflammatory, analgesic, and neuroprotective activities. However, developing these promising compounds into a transdermal patch capable of effective transdermal delivery, stable release, and precise analgesia still faces numerous technical challenges, including drug transdermal efficiency, matrix compatibility, formulation stability, and optimization of the manufacturing process.

[0006] Therefore, developing a novel transdermal patch containing PSF1-5 series compounds and systematically evaluating its analgesic effect is of great significance, providing a safe, effective, and convenient new option for pain treatment. Summary of the Invention

[0007] This invention aims to solve the problems of large side effects and inconvenience of use of existing oral analgesics, and provides a transdermal patch containing a di(hetero)aryl carbamate derivative of dihydrocannabidiol. The patch has good analgesic effect, is safe and convenient to use, and provides its preparation method and application.

[0008] The transdermal patch containing a di(hetero)aryl ester derivative of dihydrocannabidiol according to the present invention includes a drug-containing layer, a backing layer and an anti-adhesive protective layer. The drug-containing layer comprises a di(hetero)aryl ester derivative of dihydrocannabidiol or a pharmaceutically acceptable salt thereof, a humectant, a medical pressure-sensitive adhesive, and a composite penetration enhancer; The general structural formula of the di(hetero)arylformate derivative of dihydrocannabidiol is shown in Formula I below:

[0009] Formula I; Where R can be any of the following structures: (1); (2); (3); (4);

[0014] (5).

[0015] Specifically, the di(hetero)arcarbamate derivatives of dihydrocannabidiol are any one of the following compounds:

[0016] PSF1: Dihydrocannabidiimidazol carbamate;

[0017] PSF2: Dihydrocannabidiol-2,6-dioxapiperazine carboxylate;

[0018] PSF3: dihydrocannabidioxanone dinicotinate;

[0019] PSF4: dihydrocannabidiol difuranose ester;

[0020] PSF5: Dihydrocannabidiol dibenzoate; all subsequent uses are abbreviated by number.

[0021] The composite penetration enhancer contains azone and propylene glycol.

[0022] The mass ratio of azone to propylene glycol is (2.0~4.0):(6.0~9.0).

[0023] The two penetration-enhancing components can work synergistically to effectively penetrate the stratum corneum and break through the skin barrier, significantly improving the transdermal absorption efficiency of PSF1-5, while effectively reducing the risk of skin irritation when using a single penetration enhancer at high doses.

[0024] The moisturizer is glycerin.

[0025] Based on the total weight of the drug-containing layer, the drug-containing layer contains 2%-8% of dihydrocannabidiol di(hetero)carbamate derivatives or pharmaceutically acceptable salts thereof, 6%-12% of a compound penetration enhancer, 3%-7% of glycerin, and the remainder is medical pressure-sensitive adhesive.

[0026] Among them, the moisturizer is used to maintain the stability of the matrix moisture, prevent the patch from drying and cracking and falling off, and improve the product storage stability; the medical pressure-sensitive adhesive, as the core matrix of the formulation, can not only stably carry PSF1-5 drugs and various excipients, but also give the patch good skin adhesion properties.

[0027] The drug-containing layer contains a di(hetero)carbamate derivative of dihydrocannabidiol, namely dihydrocannabidiimidazocarbamate or dihydrocannabidibenzoate.

[0028] The method for preparing the transdermal patch containing a di(hetero)arylformate derivative of dihydrocannabidiol according to the present invention includes the following steps: (1) The di(hetero)aryl ester derivatives of dihydrocannabidiol or its pharmaceutically acceptable salts, humectants, medical pressure-sensitive adhesives and composite penetration enhancers are stirred at a constant temperature of 35~40°C to form a uniform paste mixture; (2) The paste mixture is evenly coated on the backing layer to form a drug-containing layer; (3) Dry the coated semi-finished product at a constant temperature of 45°C; (4) After the dried semi-finished product has cooled to room temperature, cover it with an anti-stick protective layer and cut it into the predetermined size.

[0029] The coating thickness of the drug-containing layer in step (2) is 0.1~0.2 mm.

[0030] This method effectively ensures the activity of the drug and the quality of the formulation by mixing, coating, drying and molding the active ingredient with the excipients under mild conditions.

[0031] The application of the transdermal patch containing a dihydrocannabidiol di(hetero)carbamate derivative described in this invention in the preparation of a medicament for treating pain.

[0032] Furthermore, the pain is pain caused by heat stimulation or pain related to limb stiffness.

[0033] Compared with the prior art, the beneficial effects of the present invention are as follows: 1) The results of the hot plate experiment show that the PSF1-5 transdermal patch can significantly increase the thermal pain threshold and prolong the latency of pain response in mice, proving that it has a clear analgesic effect.

[0034] 2) The mouse freeze time experiment results of the present invention show that the prepared transdermal patch can significantly shorten the limb stiffness and activity cessation time caused by pain, indicating that it can effectively improve pain-related pathological behaviors.

[0035] 3) After a single dose, the transdermal patch of the present invention maintained a stable analgesic effect during the observation period of up to 12 hours, demonstrating good long-acting sustained-release characteristics.

[0036] 4) The topical transdermal patch prepared by this invention avoids the first-pass effect of the liver and gastrointestinal irritation of oral administration, as well as the pain and inconvenience of injection administration, thus improving the safety of medication and patient compliance.

[0037] 5) This invention provides a complete, mild and controllable preparation process. By optimizing the penetration enhancer formulation, stirring temperature, coating thickness and drying conditions, a transdermal patch product with stable quality and uniform efficacy has been successfully prepared, which has good industrialization prospects. Attached Figure Description

[0038] Figure 1 This is a comparison of the average arrest time of mice in each group at different time points after drug administration.

[0039] Figure 2 A comparison of the latency of thermal pain threshold at different time points after drug administration in mice of different groups. Detailed Implementation

[0040] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0041] The processes, conditions, reagents, and experimental methods used in implementing this invention, except as specifically mentioned below, are all common knowledge and general knowledge in the field, and this invention does not have any particular limitations. Experimental methods in the embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0042] Unless otherwise stated, all technical terms and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. However, in the event of any conflict, the specification containing the definitions shall prevail.

[0043] Experimental materials: PSF1-5 is a yellow oily substance with a purity of ≥98%. It is free of pyrogens and impurities, exhibits good batch stability, and meets the quality standards for pharmaceutical raw materials.

[0044] The preparation method of the oily substance PSF1-5 is described in the following patent examples: PSF1: CN116983263A, PSF2: CN116983265A, PSF3: CN116983267A, PSF4: CN116983266A, PSF5: CN116983264A The composite penetration enhancer uses azone (pharmaceutical grade) and propylene glycol (pharmaceutical grade), both conforming to the pharmaceutical excipient standards of the Chinese Pharmacopoeia; the humectant is pharmaceutical grade glycerin with a water content ≤0.5% and good stability; the matrix material uses medical pressure-sensitive adhesive, possessing good biocompatibility, skin adhesion, and breathability, and is non-irritating to the skin; the backing material is medical sterile non-woven fabric, which is soft, breathable, and tensile-resistant; the anti-stick protective layer uses medical silicone paper, which has a smooth surface and excellent anti-stick properties, effectively isolating external contaminants. All excipients undergo drying and impurity removal pretreatment and are stored in sealed, light-proof containers for later use.

[0045] Example Preparation of the transdermal patch: (1) Raw material pretreatment Accurately weigh the prescribed amount of yellow, oily PSF1-5 pharmaceutical raw material and place it in a clean, sterile mixing container for later use. Prepare the compound penetration enhancer in advance: weigh 2.8% (by weight of the total drug-containing layer) of azone and 4.2% of propylene glycol, mix thoroughly, with a mass ratio of azone to propylene glycol of 4:6; separately weigh 2% (by weight of the total drug-containing layer) of PSF1-5 pharmaceutical raw material and add it to the azone and propylene glycol mixture. Since PSF1-5 is an oily substance and insoluble in water, it can be completely dissolved in the azone and propylene glycol mixture. Stir until a homogeneous oil phase solution is formed. Subsequently, add 5% (by weight of the total drug-containing layer) of pharmaceutical humectant glycerin and 86% (by weight of the total drug-containing layer) of medical pressure-sensitive adhesive to the above system.

[0046] (2) Stir and mix at a constant temperature and speed. The mixed raw material system was placed in a temperature-controlled stirrer, and the stirring container was sealed to prevent impurities from being introduced and solvents from evaporating. The constant temperature of the stirring system was set at 35~40 ℃, which is the stable temperature range of PSF1-5 drug, effectively preventing the decomposition and inactivation of the active pharmaceutical ingredient due to high temperature, while ensuring that the excipient components are fully integrated. The stirring speed was adjusted to 350 r / min, and stirring was carried out continuously at a constant temperature for 30 min. During the stirring process, the state of the system was continuously observed until the raw materials were completely dispersed, with no visible particles, lumps, or stratification, forming a uniform paste-like mixture with consistent color, fine texture, and moderate fluidity. Uniform stirring ensures that the PSF1-5 drug particles are evenly dispersed in the matrix, avoiding local enrichment or uneven distribution of the drug, and ensuring uniform release of the drug efficacy in subsequent formulations.

[0047] (3) Precision coating and molding Clean, dry, and sterile medical nonwoven fabric was selected as the backing material and fixed flat on the worktable of a high-precision coating machine, ensuring that the backing was wrinkle-free, without shifting, and without damage. The prepared paste mixture was uniformly added to the coating machine's hopper, and the coating equipment was started. The coating thickness was strictly controlled at 0.1~0.2 mm, and in this embodiment, it was strictly controlled at 0.15 mm. This coating thickness was optimized and verified through multiple experiments: when the coating thickness was less than 0.1 mm, the drug loading per unit area was insufficient, the effective duration of drug action was shortened, and the analgesic effect decreased; when the coating thickness was greater than 0.2 mm, the coating was too thick, and the internal moisture and solvent were difficult to dry completely, making the patch prone to softening and stickiness, and significantly reducing skin adhesion. The coating thickness of 0.15 mm can ensure that the drug loading per unit area meets the treatment requirements, while also taking into account both drying effect and patch adhesion. During the coating process, the coating speed is maintained at 3 m / min, and the operation is uniform and stable to ensure that the mixture is coated evenly, with consistent thickness, no missed coating, and no accumulation on the nonwoven fabric backing surface, thus ensuring the uniformity of the formulation.

[0048] (4) Constant temperature drying to remove solvent The coated semi-finished products were carefully transferred to a forced-air constant-temperature drying oven, arranged evenly with adequate ventilation gaps to avoid uneven drying caused by stacking. The drying temperature was set to 45 ℃ and maintained for 18 minutes. This low-temperature forced-air drying process can thoroughly remove residual moisture and trace solvents from the system while maximizing the preservation of the bioactivity of PSF1-5 drugs, preventing drug denaturation and reduced efficacy caused by high-temperature drying. Continuous ventilation was maintained during the drying process to ensure stable airflow circulation within the drying oven, ensuring that the formulation coating is thoroughly dried, firm, and free from defects such as stickiness, softening, or cracking.

[0049] (5) Lamination, cutting and sealing packaging After the semi-finished formulation is completely dry and naturally cooled to room temperature, a medical silicone paper anti-stick protective layer is quickly applied. During the application process, ensure the protective layer is flat, adheres well, and is free of bubbles and wrinkles. This effectively protects the drug layer, preventing contamination, oxidation, and peeling, while also preventing adhesion during storage. Subsequently, using aseptic cutting equipment, the patches are cut to fixed sizes according to clinical usage specifications. After cutting, qualified patches with a smooth appearance, no damage, no delamination, and uniform color are selected. These are then individually sealed using an aseptic sealing packaging machine to isolate them from air, moisture, and microbial contamination. They are then stored in a cool, dry place away from light to obtain the final PSF1-5 transdermal patch.

[0050] Analgesic efficacy verification laboratory animals Healthy SPF-grade Kunming mice, half male and half female, weighing 18–22 g, were selected and housed in an environment with a temperature of 22–25 °C and a relative humidity of 50% ± 5%, maintaining normal diurnal rhythms and free access to food and water. All mice were acclimatized for 3 days before the experiment was conducted, and the experimental procedures complied with animal ethics guidelines.

[0051] Test drug and instrument Test drug: self-made PSF1-5 transdermal patch; experimental instruments: hot plate pain threshold tester, stopwatch, mouse restraint device, electronic balance.

[0052] Experimental methods and procedures 1. Mouse arrest time experiment The overall analgesic and pain-relieving effects of the PSF1-5 transdermal patch were evaluated using a mouse stiffness behavior observation method. Experimental mice were randomly divided into a blank control group, a PSF1-5 treatment group, and a CBD group, with 10 mice in each group. In the treatment group, after hair removal on the backs of the mice, a PSF1-5 transdermal patch was evenly applied and fixed to prevent dislodgement. The blank control group received no drug intervention but underwent the same hair removal and fixation treatment. Mice in all groups were routinely fed and continuously treated with the drug.

[0053] Unified dosing standards: Area of ​​hair removal on the mouse's back: 2 cm × 2 cm; Cut the finished patch to size: 2 cm × 2 cm, ensuring a complete fit to the hair removal area with no excess or gaps; The total amount of drug-loaded material per patch is approximately 1.8 mg. Application and fixation method: Medical breathable tape is used to wrap around the edge of the patch to prevent mice from scratching or rubbing it off. The patch is not changed for 12 hours and the medication is administered continuously.

[0054] The time of rigidity in mice was observed and recorded at 2 h, 4 h, 6 h, 8 h and 12 h after administration. The criteria for rigidity were limb curling, cessation of activity, stiff posture and significant reduction of spontaneous activity. The duration of a single rigidity in each group of mice was accurately recorded using a stopwatch. The average time of rigidity in each group was calculated and the differences between the groups were compared to evaluate the effect of the preparation on improving pain-induced rigidity.

[0055] Experimental results: The comparison of the average arrest time of mice in each group at different time points after drug administration is shown in the figure below. Figure 1 As shown, the duration of stiffness reflects the ability of the formulation to relieve pain-induced limb rigidity; the longer the duration, the stronger the analgesic effect. Multiple significance markers for intergroup comparisons show that PSF1 is labeled a, PSF5 is labeled b, and PSF2, PSF3, PSF4, and CBD are uniformly labeled c. The average duration of stiffness for PSF1 was significantly longer than all other active drug groups (P < 0.05), indicating the best anti-rigidity effect; PSF5 was the second most effective, significantly better than PSF2, PSF3, PSF4, and CBD (P < 0.05); there were no statistically significant differences among the four PSF2, PSF3, PSF4, and CBD groups (P > 0.05), showing only moderate analgesic activity. The model carrier group showed a highly significant difference compared to PSF1 and PSF5 (P < 0.01), demonstrating that the highly active components can effectively improve pain-induced rigidity.

[0056] 2. Thermal Pain Experiment The thermal pain threshold in mice was determined using the hot plate test to evaluate the analgesic effect of the PSF1-5 transdermal formulation on thermal pain. The hot plate pain threshold tester was preheated, with the hot plate temperature set to 55 ℃ ± 0.5 ℃, and the instrument was put into use after the temperature stabilized.

[0057] Mice were screened for suitability before the experiment: Mice were placed on a preheated hot plate, and the latency of pain responses such as licking, lifting, and jumping was recorded. Mice with a pain threshold latency of 5-30 seconds were selected for the experiment, while individuals with abnormal pain thresholds were excluded. Suitable mice were randomly divided into a blank control group, a PSF1-5 treatment group, and a CBD group, with 10 mice in each group. Mice in the treatment group received a PSF1-5 transdermal patch on their backs, while the blank control group received no treatment.

[0058] Thermal pain threshold tests were performed at 2 h, 4 h, 6 h, 8 h, and 12 h after drug administration. Mice were gently placed in the center of a constant-temperature hot plate, and timing began immediately. The latency period at which the mouse first exhibited obvious pain avoidance behavior was recorded as the thermal pain threshold. To avoid burns to the mice, the maximum testing time was set to 60 seconds. Mice were removed immediately if no pain response was observed after 60 seconds, and the pain threshold time was recorded as 60 seconds. Each time point in each group was tested three times, and the average value was taken. The analgesic effect was compared between groups.

[0059] All measurement data were analyzed using SPSS 26.0, and the results were expressed as xˉ±s. One-way ANOVA was used for the analysis of overall differences among multiple groups; for multiple comparisons between groups: Tukey test was used when the variances were homogeneous, and Tamhane T2 test was used when they were not, and the differences were marked using the letter marking method. P<0.05 was considered significantly different, and P<0.01 was considered extremely significantly different; different letters under the same index represented significantly different groups (P<0.05), and the same letters indicated no statistical difference (P>0.05).

[0060] Experimental results The comparison chart of the latency of thermal pain threshold at different time points after drug administration in each group of mice is shown in Figure 2 , and the higher the latency, the stronger the thermal pain tolerance ability of the mice. The significant markers in each group were consistent with those in the rigidity experiment: the analgesic effect of PSF1 was the most prominent, and the increase in pain threshold at each time point was significantly higher than that of the other groups; the analgesic effect of PSF5 was the second, significantly better than that of PSF2, PSF3, PSF4, and CBD; the thermal analgesic levels of the four groups of PSF2, PSF3, PSF4, and CBD were similar, with no obvious inter-group differences; the analgesic effect of the positive drug gabapentin was significantly weaker than that of all PSF series and CBD. The analgesic peak was reached 4 - 8 h after the administration of all active components, and the drug effect was persistent and stable.

[0061] The pharmacodynamic gradient laws of the two in vivo behavioral experiments were completely consistent. PSF1 had the best comprehensive analgesic performance, PSF5 was the second-best active component, PSF2, PSF3, PSF4, and CBD only had moderate analgesic effects, and the significant differences among the groups clearly distinguished the pharmacodynamic levels, confirming that PSF1 and PSF5 had excellent prospects for the development of topical analgesics.

[0062] Experimental example: Non-addictive evaluation 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 the open field test (OFT) and the elevated plus maze test (EPM).

[0063] 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 Spepharm Biotechnology Co., Ltd. [Production License Number: 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 Experimental Animal Ethics Committee.

[0064] 1.2 Drugs and reagents PSF1-5 components (purity ≥98%, provided by the Institute of Agricultural Product Processing, Chinese Academy of Agricultural Sciences); morphine hydrochloride injection (commercially available specification, positive control); physiological saline; DMSO (dimethyl sulfoxide, pharmaceutical grade); 75% alcohol.

[0065] 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.

[0066] 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.).

[0067] 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).

[0068] 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).

[0069] All medications were administered via intraperitoneal injection.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] EPM metrics: number of times the arm is opened and the dwell time in the arm.

[0075] 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.

[0076] 3. Experimental Results 3.1 Results of the CPP experiment (evaluation of psychological dependence) The results are shown in Table 1. The positive control group (morphine) mice showed a significantly higher post-test CPP score than the pre-test (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 (P>0.05), and were 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.

[0077] Table 1: Comparison of CPP scores before and after the test in each group of mice (s, Mean±SD, n=10)

[0078] 3.2 Results of the withdrawal behavior experiment (evaluation of physical dependence) Open field test (OFT) results (Table 2): 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).

[0079] Table 2: Comparison of Open Field Test (OFT) Results among Different Groups of Mice (Mean±SD, n=10)

[0080] The results of the elevated cross maze (EPM) test (Table 3) showed that the morphine withdrawal group had significantly less time spent in the open arm and fewer entries 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).

[0081] Table 3: Comparison of Elevated Cross Maze (EPM) results among different groups of mice (Mean±SD, n=10)

[0082] 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. A transdermal patch comprising a di(hetero)arylate derivative of dihydrocannabidiol, characterized in that, Includes a drug-containing layer, a backing layer, and an anti-sticking protective layer; The drug-containing layer comprises a di(hetero)aryl ester derivative of dihydrocannabidiol or a pharmaceutically acceptable salt thereof, a humectant, a medical pressure-sensitive adhesive, and a composite penetration enhancer; 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. The transdermal patch comprising the di(hetero)arylic acid ester derivative of dihydrocannabidiol according to claim 1, characterized in that, The composite penetration enhancer contains azone and propylene glycol.

3. The transdermal patch comprising the di(hetero)arylic acid ester derivative of dihydrocannabidiol according to claim 2, characterized in that, The mass ratio of azone to propylene glycol is (2.0~4.0):(6.0~9.0).

4. The transdermal patch containing a di(hetero)arylformate derivative of dihydrocannabidiol according to claim 1, characterized in that, The moisturizer is glycerin.

5. The transdermal patch containing a di(hetero)arylformate derivative of dihydrocannabidiol according to claim 4, characterized in that, Based on the total weight of the drug-containing layer, the drug-containing layer contains 2% to 8% of dihydrocannabidiol di(hetero)carbamate derivatives or pharmaceutically acceptable salts thereof, 6% to 12% of a composite penetration enhancer, 3% to 7% of glycerin, and the remainder is medical pressure-sensitive adhesive.

6. The transdermal patch comprising the di(hetero)arylic acid ester derivative of dihydrocannabidiol according to claim 1, characterized in that, The drug-containing layer contains a di(hetero)carbamate derivative of dihydrocannabidiol, namely dihydrocannabidiimidazocarbamate or dihydrocannabidibenzoate.

7. A method for preparing a transdermal patch comprising the di(hetero)arylate derivative of dihydrocannabidiol according to any one of claims 1 to 6, characterized in that, Includes the following steps: (1) Stir the di(hetero)aryl ester derivatives of dihydrocannabidiol or their pharmaceutically acceptable salts, humectants, medical pressure-sensitive adhesives and composite penetration enhancers to form a uniform paste mixture; (2) The paste mixture is evenly coated on the backing layer to form a drug-containing layer; (3) Dry the coated semi-finished product; (4) After the dried semi-finished product has cooled to room temperature, cover it with an anti-stick protective layer.

8. The method of preparing a transdermal patch comprising a di(hetero)arylate derivative of dihydrocannabidiol according to claim 7, characterized in that, The coating thickness of the drug-containing layer in step (2) is 0.1-0.2 mm.

9. The use of a transdermal patch comprising a di(hetero)carbamate derivative of dihydrocannabidiol as described in any one of claims 1 to 6 in the preparation of a medicament for treating pain.

10. The application according to claim 9, characterized in that, The pain is either caused by heat stimulation or is related to limb stiffness.

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