Application of jujuboside in the preparation of analgesic drugs / drugs for reducing addiction

Abstract

The present invention relates to the field of pharmaceutical technology, and particularly to the application of jujuboside in the preparation of analgesic drugs / drugs for reducing addiction; the solution includes: using jujuboside as an adjuvant drug and compounding it with opioid analgesics to form a compound analgesic drug, or using jujuboside as an active ingredient for separate preparation to reduce the addiction caused by opioid analgesics. Experiments have shown that jujuboside can effectively enhance the analgesic effect of opioid analgesics, prolong the analgesic duration, inhibit the formation of opioid analgesic addiction memory, and jujuboside itself has no addiction. Therefore, the present invention can provide better analgesic efficacy while reducing the dosage of opioid analgesics, prolonging the drug administration interval, eliminating / reducing the addiction of opioid analgesics, improving the drug safety of opioid analgesics, and reducing various side effects caused by the overdose of opioid analgesics.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to the application of jujuboside in the preparation of analgesic drugs / drugs for reducing addiction. Background Art

[0002] Pain is a complex physiological and psychological activity. Chronic pain, in particular, is considered a common neurological disease and one of the most common symptoms in clinical practice. It is reported that approximately 20% of adults are troubled by chronic pain. Common chronic pains include joint pain, migraine, and cancer pain, etc. These pains not only lead to the weakening or loss of behavioral ability but also bring consequences such as depression, sleep disorders, and suicidal tendencies, seriously affecting people's physical and mental health and causing a huge social and economic burden. Opioid drugs are currently the most widely used and effective analgesic drugs in clinical practice, but such drugs have a high degree of addiction, greatly limiting their clinical application. In addition, respiratory depression caused by overdose of opioid drugs in addicts leading to death has become an important medical and public safety issue. Therefore, enhancing the analgesic effect of opioid drugs and inhibiting their addiction is a major focus and difficulty in drug development.

[0003] Modern chemical and pharmacological studies have confirmed that jujube seed has the effects of sedation and hypnosis, anti - anxiety, anti - depression, anti - arrhythmia, protecting cardiomyocytes, and inhibiting atherosclerosis, etc., and is widely used in the treatment of diseases related to the cardiovascular, nervous, and immune systems. However, there are currently no studies and reports on the effects of jujuboside on the analgesic effect and addiction of opioid analgesic drugs. Summary of the Invention

[0004] (1) Technical Problems to be Solved

[0005] In view of the above - mentioned disadvantages and deficiencies of the prior art, the present invention provides the application of jujuboside as an adjuvant in the preparation of analgesic drugs. The analgesic drug is an analgesic drug with an opioid analgesic as the active ingredient. Compounding jujuboside with an opioid analgesic to form a compound preparation or using them in combination can effectively enhance the analgesic effect of the opioid analgesic, prolong the duration of the analgesic effect, inhibit the formation of addictive memory of the opioid analgesic, and jujuboside itself has no addiction and good safety. The proposal of the solution of the present invention can effectively alleviate the addiction brought by opioid analgesics and other side effects caused by overdose.

[0006] (2) Technical Solutions

[0007] In a first aspect, the present invention relates to the application of jujuboside as an adjuvant in the preparation of analgesic drugs; the analgesic drug is a compound analgesic drug with an opioid analgesic as the active ingredient.

[0008] According to a preferred embodiment of the present invention, the compound analgesic drug is an oral preparation or an injection.

[0009] According to a preferred embodiment of the present invention, the compound analgesic drug is an analgesic drug with morphine or oxycodone hydrochloride as the active ingredient.

[0010] According to a preferred embodiment of the present invention, the jujuboside is jujuboside A, jujuboside B, or a combination of jujuboside A and jujuboside B.

[0011] In the solution provided by the above scheme, taking jujuboside as an adjuvant or adjuvant in an analgesic drug with an opioid analgesic as the active ingredient can effectively enhance the analgesic effect of the opioid analgesic, prolong the duration of the analgesic effect, inhibit the formation of addictive memory of the opioid analgesic, and jujuboside itself has no addiction, with good safety. The proposal of the solution of the present invention can effectively alleviate the addiction caused by opioid analgesics and other side effects caused by excessive use.

[0012] In a second aspect, the present invention relates to the use of jujuboside in the preparation of a drug for reducing addiction; the addiction is the addiction caused by an opioid analgesic.

[0013] Preferably, the addiction is the addiction caused by morphine or oxycodone hydrochloride.

[0014] Preferably, the drug is an oral preparation or an injection preparation.

[0015] Preferably, the jujuboside is jujuboside A, jujuboside B, or a combination of jujuboside A and jujuboside B.

[0016] In the drug for reducing addiction provided by the above scheme, jujuboside is made into a drug alone as the active ingredient, and this drug is taken or injected simultaneously with an opioid analgesic, which can effectively enhance the analgesic effect of the opioid analgesic, prolong the duration of the analgesic effect, inhibit the formation of addictive memory of the opioid analgesic, and jujuboside itself has no addiction, with good safety. The proposal of the solution of the present invention can effectively alleviate the addiction caused by opioid analgesics and other side effects caused by excessive use.

[0017] (III) Beneficial effects

[0018] The present invention discloses for the first time using jujuboside as an adjuvant for opioid analgesics or taking or injecting a drug containing jujuboside (as a drug to reduce addiction) simultaneously with an opioid analgesic. Animal experiments show that: when the dosage of the opioid analgesic is the same, jujuboside can effectively enhance the analgesic effect of the opioid analgesic, prolong the analgesic duration, inhibit the formation of opioid analgesic addiction memory, and jujuboside itself has no addiction. Therefore, the proposed technical solution of the present invention can provide better analgesic efficacy while reducing the dosage of opioid analgesics, prolonging the drug administration interval, eliminating / reducing the addiction of opioid analgesics, improving the drug safety of opioid analgesics, reducing various side effects caused by overdose of opioid analgesics, and further solving the problem of chronic pain. Description of the Drawings

[0019] Figure 1 For Example 1, the experimental method and experimental results of studying the enhancement of morphine analgesic effect by jujuboside using the hot plate method.

[0020] Figure 2 For Example 2, the experimental method and experimental results of studying the prolongation of morphine analgesic duration by jujuboside using the hot plate method.

[0021] Figure 3 For Example 3, the structural schematic diagram of the conditioned place preference test chamber for the conditioned place preference test of mice.

[0022] Figure 4 For Example 3, after interference by injecting jujuboside A and jujuboside B, the conditioned place preference test method and test results of mice after morphine-associated training.

[0023] Figure 5 For Example 4, the conditioned place preference test results of mice after morphine-associated training after interference by injecting gradient doses of jujuboside A.

[0024] Figure 6 For Example 5, the conditioned place preference test results of mice after morphine-associated training with jujuboside A and jujuboside B injection.

[0025] Figure 7 For Example 6, the experimental method and experimental results of studying the enhancement of oxycodone hydrochloride analgesic effect by jujuboside using the hot plate method.

[0026] Figure 8 For Example 7, the experimental method and experimental results of studying the prolongation of oxycodone hydrochloride analgesic duration by jujuboside using the hot plate method. Detailed Description of the Invention

[0027] For a better explanation and understanding of the present invention, the present invention will be described in detail below in conjunction with the accompanying drawings and through specific embodiments.

[0028] In the following examples, unless otherwise specified, all reagents used in the context of the present invention are commercially available. For animal experiments, the relevant procedures and methods comply with the requirements of medical ethics. The experimental methods used in the present invention are all conventional methods and techniques in the art.

[0029] In the biological experiment replicates, representative results are presented in the context drawings, and the data are shown as mean ± SD and mean ± SEM as specified in the drawings. All experiments were repeated at least three times. The data were analyzed using GraphPad Prism 5.0 or SPSS 22.0 software. Conventional medical statistical methods such as t-tests, chi-square tests, and analysis of variance were used to compare the mean differences between two or more groups. p < 0.05 was considered a significant difference. In this example, the experimental mice C57BL / 6J used were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0030] Example 1

[0031] This example uses the hot plate method for the experiment. The hot plate method is a commonly used method in the screening of analgesic drugs. As Figure 1 shown in Figure (A), mice were intraperitoneally injected with jujuboside A (injection dose 5 mg / kg mouse body weight) or jujuboside B (injection dose 10 mg / kg mouse body weight), and 30 minutes later, morphine (10 mg / kg mouse body weight) was intraperitoneally injected. At 0 min, 10 min, 20 min, and 40 min after the injection of morphine, the mice were placed on a hot plate at 55 ± 0.5 °C, and the hot stimulation of the mouse's foot produced a pain response, namely the foot licking response. The time when the mouse showed foot licking was used as the pain response threshold to judge the analgesic effect of the drug. The experiment also used the injection of an equal volume of physiological saline as a control.

[0032] The experimental results are as Figure 1 shown in Figure (B). When the morphine injection dose was exactly the same, compared with the mice injected with physiological saline + morphine, the mice injected with jujuboside A and morphine had the largest pain response threshold, followed by the mice injected with jujuboside B and morphine. This shows that the injection of jujuboside A and jujuboside B can significantly enhance the analgesic effect of morphine; among them, jujuboside A has a better effect at a lower dose than jujuboside B, indicating that jujuboside A has a better characteristic of enhancing the analgesic effect of morphine. In addition, it can also be seen from the experimental drawings that jujuboside A / B itself also has a certain analgesic effect.

[0033] Example 2

[0034] This example also uses the hot plate method for experiments. As Figure 2 shown in Figure (A) of Figure 2 , mice were intraperitoneally injected with jujuboside A (injection dose: 5 mg / kg of mouse body weight) or jujuboside B (injection dose: 10 mg / kg of mouse body weight), and 30 minutes later, morphine (10 mg / kg of mouse body weight) was intraperitoneally injected. At 0.5 h, 1 h, 2 h, and 4 h after morphine injection respectively, the mice were placed on a hot plate at 55 ± 0.5 °C, and the heat stimulation caused a pain response in the mouse's foot, namely the foot licking response. The time when the mouse showed foot licking was used as the pain response threshold to judge the analgesic effect of the drug. In the experiment, an equal volume of normal saline was also injected as a control.

[0035] The experimental results are as Figure 2 shown in Figure (B) of Figure 2 . When the morphine injection dose was exactly the same and the waiting time after morphine injection was also the same, compared with the mice injected with normal saline + morphine, the mice injected with jujuboside A and morphine had the largest pain response threshold, followed by the mice injected with jujuboside B and morphine. In addition, for the mice injected with jujuboside A / B and then morphine, after waiting for 4 h, the pain threshold latency of the mice was still significantly increased compared with 0 h (P < 0.001). This shows that injecting jujuboside A and jujuboside B can effectively prolong the analgesic time of morphine, and the efficacy of jujuboside A is better than that of jujuboside B.

[0036] Example 3

[0037] The addiction memory experiment was carried out using the conditioned place preference model (CPP). The conditioned place preference model (CPP) is based on the classical Pavlovian conditioning principle and is a classical experimental model for evaluating the rewarding effect of drugs and psychological dependence. It has widely become an effective tool for studying anti-drug-seeking behavior. The experimental arrangements and conditions are as follows:

[0038] (1) The mouse conditioned place preference test system consists of a conditioned place preference test chamber, a video receiving system, and a computer data acquisition system. As Figure 3 shown, the test chamber consists of two identical chambers (inner diameter: length × width × height, 16 cm × 16 cm × 30 cm). The chambers are made of resin material. One side of the chamber wall has black and white vertical alternating stripes, and the floor is a rough grid plastic floor. The other side of the chamber wall has black and white horizontal alternating stripes, and the floor is a smooth grid plastic floor. There is a pullable baffle at the connection of the two chambers, and there is a passage at the bottom of the baffle for the mouse to shuttle back and forth between the two chambers. The experimental environment requires sound insulation and light insulation to fully exclude the interference of external factors on the experimental mice.

[0039] (2) Establishment of morphine-induced conditioned place preference in mice (unbiased design). As Figure 4As shown in (A) of , for the pretest, the experimental mice were placed in the conditioned place preference box at 8:00 am and 16:00 pm on the first day to allow the mice to adapt to the preference box for 15 minutes each time, and the activity time of the mice in the two boxes was recorded. Mice with a preference score greater than 150 s were excluded. The eligible mice were grouped according to the principles of random control and equal balance, ensuring 10 - 12 mice in each group, and evenly distributed to the left and right boxes as the preference sides for training. The formation period (conditioned training period) was from the second to the seventh day, lasting for 6 days.

[0040] Training method for the experimental group (including Group JuA and Group JuB): Each mouse received two conditional alternating trainings per day, with a 6 - hour interval between the two. After intraperitoneal injection of 10 mg / Kg morphine, the mouse was placed in the preference box (drug - paired box), and the left and right channels of the preference box were closed. Each training lasted for 45 minutes. That is, on the morning of the first day, the mouse was injected with morphine (10 mg / kg) and placed on one side of the drug - paired box (denoted as M), and in the afternoon, the mouse was injected with normal saline and placed on one side of the non - drug - paired box (10 mg / kg, placed on one side of the non - drug - paired box, denoted as S). On the morning of the second day, the mouse was injected with normal saline (10 mg / kg, placed on one side of the non - drug - paired box, denoted as S), and in the afternoon, the mouse was injected with morphine (10 mg / kg, placed on one side of the drug - paired box, denoted as M). And so on, for a total of 6 days of training.

[0041] Among them:

[0042] Group JuA: 30 minutes before each morphine injection, intraperitoneal injection of 5 mg / Kg of jujuboside A once; 30 minutes later, intraperitoneal injection of 10 mg / kg of morphine.

[0043] Group JuB: 30 minutes before each morphine injection, intraperitoneal injection of 10 mg / Kg of jujuboside B once; 30 minutes later, intraperitoneal injection of 10 mg / kg of morphine.

[0044] Saline control group (Control group): Equal volume of normal saline was injected regardless of whether it was the drug - paired side training or the non - drug - paired side training.

[0045] (3) On the eighth day, the preference test was conducted and the test results were obtained. The method of the preference test was to place the above - trained mice in the preference box, open the middle baffle, and let the mice shuttle freely. When testing the conditioned place preference score (CPPscores), the activity time of the mice in the two boxes within 15 minutes needed to be recorded. The conditioned place preference score = the activity time in the drug - paired box minus the activity time in the non - drug - paired box.

[0046] The experimental statistical results are as Figure 4As shown in (B). In the pre-test, the mice participating in the experiment did not show obvious place preference. After the training period, the mice injected with jujuboside A and then morphine did not show obvious drug-paired chamber preference after training. Secondly, the mice injected with jujuboside B and then morphine had a lower degree of drug-paired chamber preference than the control group (Control). The above experiments show that jujuboside A can significantly inhibit the formation of morphine addiction memory, and jujuboside B also has a certain inhibitory effect, but the effect is not as good as that of jujuboside A.

[0047] Example 4

[0048] The experimental method was referred to Example 3. Only the conditions of the JuA group in the experimental group were changed to: intraperitoneally inject 1 mg / kg, 5 mg / kg or 10 mg / kg of jujuboside A to mice, and then intraperitoneally inject 10 mg / kg of morphine 30 minutes later, and observe its effect on morphine-induced CPP.

[0049] The experimental statistical results are as Figure 5 shown. In the pre-test, the mice participating in the experiment did not show obvious place preference. After the training period, the mice only injected with 1 mg / kg of jujuboside A and then morphine still had a relatively high conditioned place preference score. As the injection dose of jujuboside A increased to 5 mg / kg, the conditioned place preference score decreased. When the injection dose of jujuboside A increased to 10 mg / kg, the conditioned place preference score decreased slightly compared with that at 5 mg / kg. This shows that the injection dose of jujuboside A at 5 mg / kg can significantly inhibit the formation of morphine addictive memory. The above experimental results show that the inhibition of morphine addiction memory formation by jujuboside A is dose-dependent.

[0050] Example 5

[0051] This experiment observed whether jujuboside A and jujuboside B have addiction. The experimental method was referred to Example 3. Only the conditions of the JuA group in the experimental group were changed to: intraperitoneally inject 5 mg / kg of jujuboside A to mice and no longer inject morphine. The JuB condition was changed to: intraperitoneally inject 10 mg / kg of jujuboside B to mice and no longer inject morphine. The control group was injected with morphine (10 mg / kg) and no jujuboside A / B was injected before injecting morphine. Observe the CPP values of the three groups of mice.

[0052] The experimental statistical results are as Figure 6As shown in the figure. In the pre-test, the mice participating in the experiment did not show obvious place preference. After the training period, the mice injected with morphine (control group) had the highest conditional place preference score; while the CPP values of the JuA group were basically the same as those of the JuB group and the pre-test, indicating that the mice did not develop addiction before and after training. The above experiments proved that neither jujuboside A nor jujuboside B could induce the formation of CPP in mice and had no addictive property.

[0053] Example 6

[0054] In this example, the hot plate method was used for the experiment. The hot plate method is a commonly used method in the screening of analgesic drugs. Jujuboside A (injection dose: 5 mg / kg body weight of mice) or jujuboside B (injection dose: 10 mg / kg body weight of mice) was intraperitoneally injected into mice. After 30 min, oxycodone hydrochloride (10 mg / kg body weight of mice) was intraperitoneally injected. At 0 min, 10 min, and 30 min after the injection of oxycodone hydrochloride, the mice were placed on a hot plate at 55 ± 0.5 °C, and the feet of the mice were thermally stimulated to produce a pain response, namely the foot licking response. The time when the mice showed foot licking was used as the pain response threshold to judge the analgesic effect of the drug. In the experiment, the injection of an equal volume of normal saline was also used as a control.

[0055] The experimental results are as Figure 7 shown. When the injection dose of oxycodone hydrochloride was exactly the same, compared with the mice injected with normal saline + oxycodone hydrochloride, the mice injected with jujuboside B and oxycodone hydrochloride had the largest pain response threshold, followed by the mice injected with jujuboside A and oxycodone hydrochloride. This indicated that the injection of jujuboside A and jujuboside B could significantly enhance the analgesic effect of oxycodone hydrochloride. The dosage of jujuboside A was 1 / 2 of that of jujuboside B, but its efficacy in enhancing the analgesic effect was only slightly lower than that of jujuboside B. This might suggest that, compared with jujuboside B, jujuboside A per unit dose had better efficacy.

[0056] Example 7

[0057] In this example, the hot plate method was also used for the experiment. Jujuboside A (injection dose: 5 mg / kg body weight of mice) or jujuboside B (injection dose: 10 mg / kg body weight of mice) was intraperitoneally injected into mice. After 30 min, oxycodone hydrochloride (10 mg / kg body weight of mice) was intraperitoneally injected. At 1 h, 2 h, and 4 h after the injection of oxycodone hydrochloride, the mice were placed on a hot plate at 55 ± 0.5 °C, and the feet of the mice were thermally stimulated to produce a pain response, namely the foot licking response. The time when the mice showed foot licking was used as the pain response threshold to judge the analgesic effect of the drug. In the experiment, the injection of an equal volume of normal saline was also used as a control.

[0058] The experimental results are as Figure 8As shown, when the injection dose of oxycodone hydrochloride is exactly the same and the waiting time after injecting oxycodone hydrochloride is also the same, compared with the mice injected with normal saline + oxycodone hydrochloride, the pain response threshold of the mice injected with jujuboside B and oxycodone hydrochloride is the largest, followed by the mice injected with jujuboside A and oxycodone hydrochloride. In addition, for the mice injected with jujuboside A / B and then injected with oxycodone hydrochloride, after waiting for 4 h, the pain threshold latency of the mice is still significantly increased compared with 0 h (P < 0.001). This shows that injecting jujuboside A and jujuboside B is beneficial to prolong the analgesic time of morphine.

[0059] The above experimental data results of mice show that both jujuboside A and jujuboside B can enhance the analgesic effect of morphine or oxycodone hydrochloride and prolong the analgesic duration of morphine or oxycodone hydrochloride. Therefore, jujuboside A / B can be used as an analgesic adjuvant for morphine or oxycodone hydrochloride to reduce the dosage or shorten the usage frequency of morphine or oxycodone hydrochloride.

[0060] Similarly, according to the experimental method of Example 3, the CPP experiment induced by oxycodone hydrochloride was carried out. The experimental results were the same as those of Example 3. Jujuboside A could significantly inhibit the formation of oxycodone hydrochloride addiction memory, and at the same time, jujuboside B also had a certain inhibitory effect.

[0061] The present invention confirmed through Examples 3 - 4 that even when the injection dose and usage frequency of morphine are constant, jujuboside A can also inhibit the formation of morphine addiction memory. Therefore, jujuboside A can achieve the effect of reducing morphine addiction through multiple ways such as enhancing the analgesic effect of morphine, reducing the dosage or frequency, and inhibiting the formation of morphine addiction memory. In clinical treatment, jujuboside A, jujuboside B or their combination can be used as an adjuvant to compound with opioid analgesics to produce a compound preparation or used as a single drug to reduce the addiction caused by excessive / long-term use of opioid analgesics, and used in combination with opioid analgesics to reduce the dosage of opioid analgesics, extend the dosing interval, reduce or eliminate addictive side effects, and solve the problem of human chronic pain.

[0062] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of jujuboside in the preparation of a drug for reducing addiction, characterized in that, The addiction is caused by opioid analgesics; the jujuboside is jujuboside A.

2. The application according to claim 1, wherein The addiction is caused by morphine or oxycodone hydrochloride.

3. The application according to claim 1, wherein The drug is an oral preparation or an injection preparation.

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