Gluconic acid pentazocine benzoate as well as preparation method and application thereof

Abstract

The invention relates to gluconic acid pentazocine benzoate as shown in a formula (I), and a preparation method, a pharmaceutical preparation and medical application thereof. The invention provides application of the compound in preparation of medicines for treating moderate and severe acute and chronic pains, and the compound has the effects of high efficacy and low side effect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to pentazocine gluconate benzoate, a preparation method thereof, a pharmaceutical preparation thereof and medical use thereof. Background Art

[0002] Opioids, as the main category of analgesics, are the most effective drugs for relieving moderate to severe pain. However, as we all know, their potential for addiction and abuse seriously hinders the clinical use of this type of drugs, and a large number of pain patients cannot receive timely and effective drug treatment at the same time. Therefore, it is of great significance to develop opioid analgesics with abuse-restraining properties.

[0003] Due to the inherent abuse potential, any pharmaceutical composition containing an opioid agonist should be as abuse-resistant or abuse-deterrent as possible. Illegal users often attempt to circumvent the sustained-release properties of these dosage forms by injecting or otherwise abusing the product to achieve immediate release of the opioid agonist.

[0004] Patients who take opioid analgesics for pain relief may inadvertently become addicted. As tolerance to opioids develops, more of the drug is needed to relieve pain and produce the feeling of well-being initially achieved with the prescribed dose. This leads to an increase in dosage, which can quickly lead to addiction if not controlled. In some cases, patients have become extremely addicted in as little as 30 days. Pentazocine tablets for oral use are currently the only orally available opioid receptor agonist antagonist analgesics. Drugs, 1973, 5(1): 6-91. Oral pentazocine takes effect within 1 hour and can last for 5 hours after a single dose. The oral bioavailability is low, accounting for only 20%.

[0005] CN201410252094 applied by the inventor mentioned that the phenolic hydroxyl group at position 8 was condensed with o-propionyloxy-cis-phenylacrylic acid to form an ester prodrug, which can reduce the first-pass effect of pentazocine hydrochloride, significantly increase the blood concentration of pentazocine, and improve the bioavailability. However, it did not mention that it remains inert in the stomach, and the gastrointestinal irritation is relatively large. Generally, the drug must be discontinued after 3 months, and the tolerance is poor.

[0006] CN202010207219 applied for by the inventor mentions pentazocine phosphate prodrug and its preparation method, which can be used for surgical anesthesia analgesia, postoperative analgesia, and analgesia for cancer patients, but cannot be used for routine oral use.

[0007] US4457933 mentions that a method for preventing the abuse of pentazocine is to use a compound composition of pentazocine and naloxone, and US7201920 mentions a method and composition for preventing the abuse of dosage forms containing opioids.

[0008] Despite the addictive properties and abuse potential of morphine-like drugs, codeine, hydrocodone, and pentazocine have been routinely prescribed in recent decades for the treatment of severe acute and chronic pain. This is partly because there are no alternatives to relieve severe pain that is resistant to other less effective analgesics, such as nonsteroidal anti-inflammatory drugs. In this regard, there is a need to reduce the potential for abuse. Unfortunately, the approaches taken so far have not completely solved the problem. Summary of the invention

[0009] The present invention unexpectedly discovered that the pentazocine gluconate benzoate molecule shown in formula (I) remains inert when passing through the stomach, but is absorbed in the small intestine, thereby reducing the side effects to a minimum or even eliminating them. Affected by a small amount of first-pass effect, the benzyl ester on the molecule of formula (I) falls off, thereby releasing the metabolite pentazocine, thereby greatly improving the bioavailability. At the same time, pentazocine gluconate benzoate has good physical and chemical properties and is suitable for use as an oral preparation.

[0010] In one aspect, the present invention provides a pentazocine gluconate benzoate represented by formula (I):

[0011]

[0012] The present invention synthesizes a series of pentazocetate derivatives:

[0013]

[0014]

[0015] The results of further screening of commonly used salt forms of pentazocine benzoate are as follows:

[0016]

[0017] Another aspect of the present invention provides a method for preparing pentazocine benzoate, characterized in that it comprises the following steps:

[0018] Pentazocine and benzoyl chloride or N-benzyl succinimide are esterified in an organic solvent and a base acid-binding agent, and the reaction formula is as follows:

[0019]

[0020] Another aspect of the present invention provides a method for preparing pentazocine gluconate benzoate, characterized in that it comprises the following steps:

[0021] Pentazocine and benzoyl chloride or N-benzyl succinimide are esterified in an organic solvent and an alkaline acid-binding agent, and then salted with gluconolactone or gluconic acid solution to obtain the product. The reaction formula is as follows:

[0022]

[0023] Another aspect of the present invention is to provide a crystalline form of pentazocine gluconate benzoate, which has a characteristic peak at least at a diffraction angle (2θ) of 8.6±0.2 (°) in x-ray powder diffraction.

[0024] Preferably, another aspect of the present invention is to provide a crystalline form of pentazocine gluconate benzoate, which has characteristic peaks at least at diffraction angles (2θ) of 8.6±0.2 and 13.2±0.2 (°) in x-ray powder diffraction.

[0025] Preferably, another aspect of the present invention is to provide a crystalline form of pentazocine gluconate benzoate, which has characteristic peaks at least at diffraction angles (2θ) of 8.6±0.2, 13.2±0.2, 13.6±0.2 (°) in x-ray powder diffraction.

[0026] Preferably, DSC shows that the melting point of the crystalline form is 112.98°C.

[0027] Preferably, TGA shows that the crystalline form begins to melt and decompose at about 238.48°C.

[0028] Another aspect of the present invention is to provide a pharmaceutical composition containing pentazocine gluconate benzoate, which contains pentazocine gluconate benzoate or the above-mentioned pentazocine gluconate benzoate crystal form and pharmaceutically acceptable excipients. Preferably, the administration route is oral, and more preferably, the dosage form includes sustained-release tablets or sustained-release capsules.

[0029] The oral preparation is prepared from the active raw material pentazocine gluconate benzoate or the above-mentioned pentazocine gluconate benzoate crystal form and related pharmaceutical excipients according to the general method in pharmaceutical pharmacy. The excipients include those necessary in pharmaceutical pharmacy, such as diluents, binders, disintegrants, lubricants, flavoring agents, aromatics or preservatives.

[0030] Another aspect of the present invention is to provide the use of pentazocine gluconate benzoate for preparing drugs for moderate to severe acute and chronic pain.

[0031] The pentazocine gluconate benzoate obtained by the invention has the advantages of good efficacy and low toxicity, can significantly increase the bioavailability of pentazocine, has significant chemical stability, and simultaneously remains inert in the stomach, has almost no irritation to the gastrointestinal tract, and has good tolerance. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 HPLC analysis of pentazocine gluconate benzoate.

[0033] Figure 2It is the hydrogen spectrum of pentazocine gluconate benzoate.

[0034] Figure 3 This is the carbon spectrum of pentazocine gluconate benzoate.

[0035] Figure 4 Mass spectrum of pentazocine gluconate benzoate.

[0036] Figure 5 It is DSC of pentazocine gluconate benzoate.

[0037] Figure 6 It is pentazocine gluconate benzoate TG.

[0038] Figure 7 This is the XRPD of pentazocine gluconate benzoate.

[0039] Figure 8 It is pentazocine gluconate benzoate IR. DETAILED DESCRIPTION

[0040] The present invention is further described in the following examples; however, these examples should not be construed as limiting the scope of the present invention.

[0041] Example 1 Preparation of Pentazocine Benzoate

[0042]

[0043] 72g of pentazocine (0.25mol) was added to a 1000ml three-necked flask, 400ml of toluene and 42ml (0.3mol) of triethylamine were added to the reactor, stirred, heated to 75℃~80℃, 38g (0.27mol) of benzoyl chloride was slowly added dropwise, and after the addition was completed, the temperature was raised to reflux, and the reaction was stirred for 2h. TLC (petroleum ether-ethyl acetate=4:5) showed that the reaction was complete, cooled to room temperature, 50ml of water was added and stirred for 10min, and the mixture was allowed to stand for stratification, the aqueous layer was discarded, and the organic layer was washed with saturated sodium carbonate solution (20ml) and 50ml of saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate for 30min, filtered, and concentrated to dryness under reduced pressure at a temperature <45℃ to obtain 86.7g of an off-white oily substance, pentazocine benzoate, with a yield of 89.1%.

[0044] Example 2 Preparation of Pentazocine Gluconate Benzoate

[0045]

[0046] 86 g (0.22 mol) of pentazocine benzoate was added to a 1000 ml reaction bottle, 600 ml of acetone was added to the reaction bottle, and the mixture was stirred at room temperature to dissolve. The mixture was heated to 40°C to 45°C, and 90 g (0.23 mol) of a 50% aqueous solution of gluconic acid was added. The mixture was stirred for 1 h at this temperature, and the mixture was cooled to room temperature, and then cooled to 0°C to 5°C and kept for 4 h to completely crystallize. The mixture was filtered, and the solid was washed with cold acetone and dried in vacuo at 55°C to 60°C to obtain 120 g of white gluconic acid pentazocine benzoate with a yield of 93% and a purity of 97.8%.

[0047] 1 H-NMR (400MHz, DMSO / TMS, ppm):

[0048] δ8.15~8.13(2H,d,J=8.2Hz); δ7.77~7.60(3H,m); δ7.22~7.02(3H,m); δ5.21~5.18(1H,t);

[0049] δ4.51~3.32(2.57H,m); δ3.10~2.92(4H,m); δ2.69~2.63(1H,m); δ2.52~2.46(1H,m ); δ1.97~1.81(2H,m); δ1.76~1.65(7H,m); δ1.32~1.25(4H,m); δ0.80~0.78(3H,m);

[0050] 1 C-NMR (400MHz, DMSO / TMS, ppm):

[0051] 176.14,165.17,149.43,143.66,134.74,134.43,134.15,130.23,129.66,129.44,128.54,122.93,119.48,118.93,80.61,73.80,73.22,69.82,63.32,56.85,52.33,45.24,42.11,41.45,36.79,26.19,25.60,23.83,18.38,14.37;

[0052] MS:m / z[M+H] + 390.5

[0053] DSC: This product does not contain crystal water, and its melting point is 112.98℃

[0054] TGA: This product does not contain crystal water and begins to melt and decompose at about 238.48℃.

[0055] XRD: Test conditions: 40kv 30mA Slit: 1.0 / 1.0 / Ni / 0.1 Step size: 0.02° Target type: CuRange: 5.00-90.00Deg Scan Rate: 10.00Deg / min

[0056] 2θ angle Relative Strength 8.66 146 8.68 138 8.70 142 8.66 146 13.22 146 13.24 170 13.28 196 13.30 210 13.32 238 13.40 336 13.42 332 13.44 340 13.46 378 13.48 392 13.50 388 13.52 384 13.54 382 13.56 354 13.58 286 13.60 290 13.62 228 13.64 196 13.66 190 13.68 168 13.70 158 13.72 174

[0057] IR:

[0058]

[0059]

[0060] Example 3 Preparation of Pentazocine Benzoate

[0061]

[0062] 14 g of pentazocine (0.05 mol) was added to a 500 ml three-necked flask, 200 ml of toluene and 30 ml of pyridine were added to the reactor, stirred, heated to 55°C-60°C, 11 g (0.05 mol) of 2,5-dioxopyrrolidin-1-yl benzoate was added, stirred for 1.5 h, TLC (petroleum ether-ethyl acetate = 4:5) showed that the reaction was complete, cooled to room temperature, 15 ml of 0.01 mol / L sodium hydroxide aqueous solution was added, stirred for 10 min, allowed to stand for stratification, the aqueous layer was discarded, the organic layer was washed with saturated sodium carbonate solution (30 ml) and 30 ml of saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate for 30 min, filtered, and concentrated to dryness under reduced pressure at a temperature <45°C to obtain 17.7 g of an off-white oily substance, pentazocine benzoate, with a yield of 91.2%.

[0063] Example 4 Preparation of Pentazocine Gluconate Benzoate

[0064]

[0065] 17 g (0.044 mol) of pentazocine benzoate was added to a 200 ml reaction bottle, 100 ml of methanol was added to the reaction bottle, and the mixture was stirred at room temperature to dissolve. The mixture was heated to 40°C to 45°C, and 7.9 g (0.045 mol) of glucurone lactone was added. The mixture was stirred for 1 h at this temperature, and the mixture was first cooled to room temperature, and then cooled to 0°C to 5°C and kept for 4 h to completely crystallize. The solid was filtered, and washed with cold methanol. The solid was dried under vacuum at 55°C to 60°C to obtain 24.7 g of white gluconate pentazocine benzoate with a yield of 96.2% and a purity of 99.3%.

[0066] Example 5 Stability of Pentazocine Gluconate Benzoate

[0067] After oral administration, the drug first enters the stomach, where the pH value is about 1-2, the pH value of the small intestine is about 5-7, and the pH value of the colon is about 5-9. In addition to different pH values, enzymes in the body may also affect the degradation of the drug. Therefore, the prodrug of the present invention was incubated with different pH buffers and simulated gastric fluid (SGF, pH2) and simulated intestinal fluid (SIF, pH6.8) to evaluate the stability of the prodrug in the gastrointestinal tract after oral administration. The drug absorbed from the gastrointestinal mucosal epithelial cells enters the blood circulation through the portal vein and is then transported to various parts of the body with the circulatory system. In addition, a portion of the orally administered pentazocine gluconate benzoate may be metabolized in the liver before it is absorbed into the blood circulation. Therefore, we investigated the incubation of the present invention with plasma and liver tissue homogenate to evaluate the stability of pentazocine and the prodrug of the present invention in the blood and liver after oral administration.

[0068] 1 Chemical stability in buffers of different pH values

[0069] According to the steps in the 2020 edition of the Chinese Pharmacopoeia, hydrochloric acid solution (pH = 1.2) and a series of phosphate buffer solutions with different pH values ​​(pH = 4.5, 6.8, 7.4) were prepared and refrigerated for use. Accurately weigh pentazocine gluconate benzoate, add an appropriate amount of ultrapure water for ultrasonic dissolution, and obtain a 1.0 mg / mL pentazocine gluconate benzoate prodrug solution. Use a pipette to add 0.1 mL of pentazocine gluconate benzoate solution (1.0 mg / mL) to a 10 mL volumetric flask, and then dilute with hydrochloric acid solution (pH = 1.2) and phosphate buffer solution (pH = 4.5, 6.8, 7.4). The volumetric flask was placed in a water bath for constant temperature incubation at 37 ° C, and samples were taken at regular intervals. After filtering with a filter membrane, the sample was analyzed. The peak area of ​​the compound pentazocine gluconate benzoate was measured by HPLC, the drug concentration was detected, and the degradation rate constant was calculated by substituting into the first-order kinetic model.

[0070] 2. Stability in artificial intestinal fluid and artificial gastric fluid

[0071] Preparation of artificial gastric juice (containing pepsin): According to the steps in the 2020 edition of the "Chinese Pharmacopoeia", accurately measure 1.64 mL of dilute hydrochloric acid, 10 g of pepsin, add water to 1000 mL to obtain artificial gastric juice containing pepsin.

[0072] Preparation of artificial intestinal fluid (containing pancreatic enzyme): According to the 2020 edition of the "Chinese Pharmacopoeia", weigh 1.36 g of potassium dihydrogen phosphate, add 100 mL of water to dissolve it, and adjust the pH to 6.8 with 0.1 mol / L NaOH; weigh 2 g of pancreatic enzyme, add water to dissolve it, mix the two liquids, and add water to 200 mL.

[0073] Weigh 20 mg of gluconate pentazocine benzoate accurately, add ultrapure water to dissolve, dilute to obtain a 2 mg / mL gluconate pentazocine benzoate solution for later use. Dilute the solution with the prepared artificial gastric juice and artificial small intestinal juice, and the other steps are the same as 1. Calculate the half-life t of gluconate pentazocine benzoate in artificial small intestinal juice and artificial gastric juice by HPLC analysis. 1 / 2 (h).

[0074] 3 Results

[0075] Table 1 Half-life of pentazocine gluconate benzoate in different media 1 / 2 (h) (Mean±SD, n=3)

[0076]

[0077] Conclusion: The gluconate pentazocine benzoate of the present invention is particularly stable in the gastric acid environment, with a half-life of 41.3h. It is also relatively stable under the conditions of pH 4.5, 6.8, and 7.4, and basically exists in the form of a prodrug without significant degradation. It can be inferred that the prodrug does not degrade during the gastric emptying time, but can maintain good stability in the intestine. The original drug pentazocine has no significant degradation in buffers of different pH values, indicating that the different pH environments of the gastrointestinal tract will not cause the degradation of pentazocine. In addition, the stability in simulated gastrointestinal fluid shows that its half-life is relatively long, and it basically exists in the form of a prototype drug. It shows that the pepsin and pancreatic enzymes present in the gastrointestinal tract will not affect the stability of the prodrug of the present invention.

[0078] Example 6 Pharmacokinetic study in rats

[0079] 1. Dosing regimen and blood sample collection in rats

[0080] Healthy Sprague-Dawley rats with a body weight range of 180-220 g were selected and randomly divided into 6 groups, with 6 rats in each group. The rats were fasted overnight before the experiment, and drinking water was not restricted. The first group was intravenously injected with 6 mg / kg pentazocine (pentazocine + lactic acid aqueous solution), the second group was gavaged with 24 mg / kg pentazocine (pentazocine dissolved in PBS buffer), and the third to fifth groups were gavaged with different doses of gluconate pentazocine benzoate (gluconate pentazocine benzoate dissolved in PBS buffer). Blood was collected from the rat retro-orbital plexus with capillaries at 5, 15, 30, 45 min and 1, 1.5, 2, 3, 4, 6, 8, 10, 24, and 48 h after administration, 0.2 ml each time. During sampling, the rats were anesthetized with ether. All samples were placed in heparinized tubes. After centrifugation at 5000 rpm and 4°C for 10 minutes, plasma was collected and frozen at -20°C until analysis.

[0081] 2 Data processing

[0082] All data were analyzed by two-compartment model using DAS2.0 software. The blood drug concentration at different times was expressed as mean ± standard deviation (SD), and the average concentration-time curve was drawn. The maximum plasma concentration (Cmax) and Tmax were directly observed from the concentration-time curve. The area under (AUC0-t) was calculated using the linear-trapezoidal rule extrapolated to infinity. The specific results are shown below.

[0083] Table 2 Pharmacokinetic parameters of each group after administration according to the dosing regimen (n=6)

[0084]

[0085] Compared with pentazocine, the pharmacokinetic parameters of pentazocine gluconate benzoate have been significantly improved, which greatly improves the oral bioavailability of pentazocine and has good application prospects.

[0086] Example 7 Experimental study on cytotoxicity of normal human liver cells in vitro

[0087] 1 Experimental Materials

[0088] 1.1 Cells: LO2 cells, a human liver cell line

[0089] 1.2 Drug: Compound of the present invention, HPLC purity 97.8%

[0090] 1.3 Reagents and instruments Modified RPMI-1640 culture medium, penicillin-streptomycin double antibody solution, 0.25% trypsin-EDTA, fetal bovine serum, MTT, dimethyl sulfoxide, CO-150 carbon monoxide incubator, SW-CJ-2F medical clean bench, CKX-41-32 inverted microscope, CU600 electric constant temperature water bath, RT-2100C enzyme label analyzer

[0091] 2 Experimental methods

[0092] 2.1 Reagent preparation

[0093] 2.1.1 Preparation of MTT Weigh 0.25 g of MTT with a precision balance and place it in a 50 mL volumetric flask. Add an appropriate amount of PBS and place in a 50-60 °C water bath. Shake well to dissolve thoroughly. Add PBS to the mark to prepare a 5 mg / kg solution. Filter and sterilize with a 0.22 μm microporous filter membrane. After aliquoting, store in a dark refrigerator at 4 °C.

[0094] 2.1.2 Preparation of cell freezing solution Cell freezing solution was prepared by mixing 20% ​​serum, 10% DMSO and 70% 1640 culture medium evenly and stored at -20°C.

[0095] 2.1.3 Preparation of the compounds of the present invention The stock solution of the drug was prepared with DMSO, and then diluted with culture medium to the concentration of the drug to be used. The final concentration of DMSO was controlled at ≤0.1%.

[0096] 2.2 LO2 cell culture Normal human LO2 cells were placed in a 25 cm 2 Add about 4-5 mL of RPMI-1640 culture medium containing 10% FBS to the cell culture flask and place it in a 37°C cell culture incubator with 5% CO 2 Culture in a saturated humidity cell culture incubator. Change the culture medium every 2 days, observe the cell growth every day, and pass the cells or freeze them after 80% of the cells are confluent. Take the 5th to 7th generation cells for formal experiments.

[0097] 2.3 Grouping and Dosing The experiment was divided into a normal cell control group, and different concentrations of the drug administration groups of the present invention were set according to the preliminary experimental results, and the concentrations were 4.0, 8.0, 16.0, 32.0, 64.0, 128, 256, 512, 800, and 1000 μmol / L, respectively.

[0098] 2.4 Hepatocyte MTT colorimetry LO2 cells in logarithmic growth phase were prepared into a cell suspension of 5.0×103 / mL and inoculated into a 96-well plate. A normal control group and different concentrations of 4.0, 8.0, 16.0, 32.0, 64.0, 128, 256, 512, 800, and 1000 μmol / L of the present invention were set up. After culturing for 24 hours, the culture medium was aspirated and discarded, and the cells were washed 2 to 3 times with PBS. The above-mentioned different concentrations of the present invention compound were added respectively, and 8 replicate wells were set for each concentration. The plates were placed at 37°C and 5% CO 2 Culture in an incubator. After culturing for 24, 48, and 72 hours, add MTT solution at different time periods and culture in the dark for 4 hours. After 4 hours, aspirate and discard the upper culture medium, then add 150LDMSO solvent to each well to dissolve the thiazolyl blue crystals, and gently shake the culture plate to dissolve evenly. Use an enzyme reader to measure the absorbance of each well at 490nm. The absorbance value of each well reflects the number of cells, and the two are directly proportional. Repeat the experiment 3 times. Calculate the cell viability rate: Cell viability rate (%) = absorbance of each group (OD490) × 100 / absorbance of control group (OD490)

[0099] 2.5 Statistical analysis All data were expressed as mean ± standard deviation, and SPSS17.0 statistical software package was used for data processing. t-test statistical analysis, paired t-test for self-comparison and unpaired t-test for inter-group comparison, test standard P < 0.05.

[0100] 3 Experimental results

[0101] Group Dosage concentration / (μmol / L) OD value Survival rate value / % Normal control group —— 0.773±0.024 100 The present invention 1000 0.733±0.026 101.1 800 0.784±0.041 99.9 512 0.751±0.057 98.7 256 0.786±0.063 103.6 128 0.761±0.118 97.2 64.0 0.776±0.11 96.4 32.0 0.791±0.133 1016 16.0 0.783±0.110 102.9 8.0 0.870±0.080 103.6 4.0 0.735±0.071 98.4

[0102] Conclusion: After 72 hours of administration of different concentrations of the present invention, the OD value of each group of cells showed an increasing trend, but the growth rate decreased, indicating that the cells were still in the growth stage and the growth rate was inhibited. The groups of different concentrations of the present invention had no inhibitory effect on the cells. Compared with the normal group, the survival rate of the cells was greater than 90%. In the range of 4.0 to 1000 μmol / L, there was almost no inhibition on cell growth and no toxicity to the cells.

Claims

1. Pentazocine gluconate benzoate represented by formula (I):

2. A crystal of pentazocine gluconate benzoate represented by formula (I), characterized in that: It has a characteristic peak at least at a diffraction angle (2θ) of 8.6±0.2(°) in x-ray powder diffraction.

3. A method for preparing pentazocine benzoate, characterized in that: The following steps are involved: Pentazocine and benzoyl chloride or N-benzyl succinimide are esterified in an organic solvent and a base acid-binding agent, and the reaction formula is as follows:

4. The method for preparing pentazocine gluconate benzoate according to claim 1, wherein: The following steps are involved: Pentazocine and benzoyl chloride or N-benzyl succinimide are esterified in an organic solvent and an alkaline acid-binding agent, and then salted with gluconolactone or gluconic acid solution to obtain the product. The reaction formula is as follows:

5. A pharmaceutical composition comprising the pentazocine gluconate benzoate according to claim 1 or the pentazocine gluconate benzoate crystal according to claim 2, and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, which is administered orally.

7. The pharmaceutical composition according to claim 5, which is in the form of a sustained-release tablet or a sustained-release capsule.

8. Use of the pentazocine gluconate benzoate according to claim 1 or the pentazocine gluconate benzoate crystal according to claim 2 or the pharmaceutical composition according to claim 5 for preparing drugs for moderate to severe acute and chronic pain.

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