A kind of pentazocine gluconate benzoate and its preparation method and use

Abstract

The present invention relates to pentazocine gluconate benzoate represented by formula (I), its preparation method, its pharmaceutical preparation, and its medical use. The present invention provides the use of this compound in the preparation of a drug for treating moderate to severe acute and chronic pain, which has high efficacy and low side effects. #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 uses thereof. Background Art

[0002] Opioids, a major class of analgesics, are the most effective medications for relieving moderate to severe pain. However, their potential for addiction and abuse has severely hampered their clinical use, leaving many pain patients without timely and effective treatment. Therefore, developing opioid analgesics with abuse-resistant properties is of great significance.

[0003] Because of 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 medication is needed to relieve pain and produce the feeling of well-being initially achieved with the prescribed dose. This leads to escalating doses, which, if left unchecked, can quickly lead to addiction. In some cases, patients have become highly addicted in as little as 30 days. Pentazocine tablets for oral administration 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. Oral bioavailability is low, accounting for only 20%.

[0005] CN201410252094, filed by the present inventors, describes an ester prodrug formed by condensing the phenolic hydroxyl group at the 8-position with o-propionyloxy-cis-phenylacrylic acid. This ester prodrug can reduce the first-pass effect of pentazocine hydrochloride, significantly increase its blood concentration, and enhance its bioavailability. However, it does not address its ability to remain inert in the stomach. Consequently, the drug can cause significant gastrointestinal irritation, typically requiring discontinuation after three months, and is poorly tolerated.

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

[0007] US4457933 mentions a method for preventing the abuse of pentazocine by using 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 potential for abuse of morphine-like drugs, codeine, hydrocodone, and pentazocine have been routinely prescribed for the treatment of severe acute and chronic pain in recent decades. This is partly due to the lack of alternatives for relieving severe pain that is resistant to other less effective analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs). In this regard, there is a need to reduce the potential for abuse. Unfortunately, the approaches taken so far have not fully addressed the problem. Summary of the Invention

[0009] The present invention unexpectedly discovered that the pentazocine gluconate benzoate molecule represented by formula (I) remains inert during passage through the stomach and is absorbed in the small intestine, thereby minimizing or eliminating side effects. A small amount of first-pass effect causes the benzyl ester on the molecule of formula (I) to detach, releasing the metabolite pentazocine, thereby significantly improving bioavailability. Furthermore, pentazocine gluconate exhibits favorable physical and chemical properties, making it suitable for oral use.

[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. 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 a diffraction angle (2θ) of at least 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 at least 8.6±0.2 and 13.2±0.2 (°) diffraction angles (2θ) 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, and 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 route of administration 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 ingredient pentazocine gluconate benzoate or the above-mentioned pentazocine gluconate benzoate crystal form and related pharmaceutical excipients according to a general method in pharmaceutical pharmacy. The excipients include those necessary in pharmaceutical pharmacy, such as diluents, binders, disintegrants, lubricants, flavoring agents, fragrances or preservatives.

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

[0031] The pentazocine gluconate benzoate obtained by the present 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 2This is the hydrogen spectrum of pentazocine gluconate benzoate.

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

[0035] Figure 4 The 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] 72 g of pentazocine (0.25 mol) was added to a 1000 ml three-necked flask, 400 ml of toluene and 42 ml (0.3 mol) of triethylamine were added to the reactor, and the mixture was stirred. The temperature was raised to 75°C to 80°C, and 38 g (0.27 mol) of benzoyl chloride was slowly added dropwise. After the addition was complete, the temperature was raised to reflux and the mixture was stirred for 2 h. TLC (petroleum ether-ethyl acetate = 4:5) showed that the reaction was complete. The mixture was cooled to room temperature, 50 ml of water was added, and the mixture was stirred for 10 min. The mixture was allowed to stand for stratification, and the aqueous layer was discarded. The organic layer was washed successively with saturated sodium carbonate solution (20 ml) and 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate for 30 min, filtered, and concentrated to dryness under reduced pressure at a temperature <45°C to obtain 86.7 g 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 flask, 600 ml of acetone was added to the reaction flask, and the mixture was stirred at room temperature to dissolve. The temperature was raised 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 at this temperature for 1 hour, and the mixture was first cooled to room temperature, then cooled to 0°C to 5°C and maintained for 4 hours to completely crystallize. The solid 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 pentazocine benzoate gluconate with a yield of 93% and a purity of 97.8%.

[0047] 1 H-NMR (400 MHz, 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); 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);

[0049] 1 C-NMR (400 MHz, DMSO / TMS, ppm):

[0050] 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;

[0051] MS:m / z[M+H] + 390.5

[0052] DSC: This product does not contain crystal water, and its melting point is 112.98℃

[0053] TGA: This product does not contain crystalline water and begins to melt and decompose at about 238.48℃.

[0054] XRD: Test conditions: 40kV 30mA Slit: 1.0 / 1.0 / Ni / 0.1 Step size: 0.02° Target: Cu Range: 5.00-90.00 Deg Scan Rate: 10.00 Deg / min

[0055] 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

[0056] IR:

[0057]

[0058]

[0059] Example 3 Preparation of Pentazocine Benzoate

[0060]

[0061] 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, and heated to 55°C to 60°C. 11 g (0.05 mol) of 2,5-dioxopyrrolidin-1-yl benzoate was added, and the reaction was stirred for 1.5 h. TLC (petroleum ether-ethyl acetate = 4:5) showed that the reaction was complete. The mixture was cooled to room temperature, and 15 ml of a 0.01 mol / L aqueous sodium hydroxide solution was added and stirred for 10 min. The mixture was allowed to stand for stratification, and the aqueous layer was discarded. The organic layer was washed sequentially with a saturated sodium carbonate solution (30 ml) and a saturated sodium chloride solution (30 ml), 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%.

[0062] Example 4 Preparation of Pentazocine Gluconate Benzoate

[0063]

[0064] 17 g (0.044 mol) of pentazocine benzoate was added to a 200 ml reaction flask, 100 ml of methanol was added to the reaction flask, and the mixture was stirred at room temperature to dissolve. The temperature was raised to 40°C to 45°C, and 7.9 g (0.045 mol) of glucurone lactone was added. The mixture was stirred at this temperature for 1 hour, and then cooled to room temperature, and then cooled to 0°C to 5°C and maintained for 4 hours for complete crystallization. The mixture was filtered, and the solid was washed with cold methanol and dried in vacuo 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%.

[0065] Example 5 Stability of Pentazocine Gluconate Benzoate

[0066] After oral administration, the drug first enters the stomach, where the pH is approximately 1-2, the small intestine has a pH of approximately 5-7, and the colon has a pH of approximately 5-9. In addition to varying pH values, enzymes in the body may also affect drug degradation. Therefore, we investigated the stability of the prodrug of the present invention in the gastrointestinal tract after oral administration by incubating it with buffers of varying pH values, as well as simulated gastric fluid (SGF, pH 2) and simulated intestinal fluid (SIF, pH 6.8). Drugs absorbed from gastrointestinal mucosal epithelial cells enter the bloodstream via the portal vein and are then transported to various sites within the circulatory system. Furthermore, a portion of orally administered pentazocine gluconate benzoate may be metabolized in the liver before being absorbed into the bloodstream. Therefore, we investigated the stability of pentazocine and the prodrug of the present invention in the blood and liver after oral administration by incubating it with plasma and liver tissue homogenates.

[0067] 1 Chemical stability in buffers of different pH values

[0068] 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 respectively, and refrigerated for use after preparation. Accurately weigh pentazocine benzoate gluconate, add an appropriate amount of ultrapure water and ultrasonically dissolve it to obtain a 1.0 mg / mL pentazocine benzoate gluconate prodrug solution. Use a pipette to add 0.1 mL of pentazocine benzoate gluconate solution (1.0 mg / mL) to a 10 mL volumetric flask, and then dilute it 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 benzoate gluconate was measured by HPLC to detect the drug concentration, and the degradation rate constant was calculated by substituting it into the first-order kinetic model.

[0069] 2. Stability in artificial intestinal fluid and artificial gastric fluid

[0070] 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 and 10 g of pepsin, add water to 1000 mL to obtain artificial gastric juice containing pepsin.

[0071] Prepare artificial intestinal fluid (containing pancreatic enzymes): 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; also weigh 2 g of pancreatic enzymes, dissolve them in water, mix the two liquids, and add water to 200 mL.

[0072] Accurately weigh 20 mg of pentazocine gluconate benzoate and dissolve it in ultrapure water. Dilute to a 2 mg / mL pentazocine gluconate benzoate solution and set aside. Dilute the solution with the prepared artificial gastric juice and artificial intestinal fluid. The remaining steps are the same as in step 1. Calculate the half-life of pentazocine gluconate benzoate in artificial intestinal fluid and artificial gastric juice by HPLC analysis. 1 / 2 (h).

[0073] 3 Results

[0074] Table 1 Half-life of pentazocine gluconate benzoate in different media 1 / 2 (h) (Mean±SD, n=3)

[0075]

[0076] Conclusion: The present invention's pentazocine gluconate benzoate is particularly stable in gastric acid, with a half-life of 41.3 hours. It is also relatively stable at pH values ​​of 4.5, 6.8, and 7.4, essentially existing as a prodrug with no significant degradation. It can be inferred that the prodrug does not degrade during gastric emptying time and maintains excellent stability in the intestine. The original drug pentazocine showed no significant degradation in buffers with different pH values, indicating that the varying pH environments of the gastrointestinal tract do not lead to pentazocine degradation. Furthermore, stability in simulated gastrointestinal fluid showed a long half-life, essentially existing as the original drug. This suggests that the presence of pepsin and pancreatic enzymes in the gastrointestinal tract does not affect the stability of the present invention's prodrug.

[0077] Example 6 Pharmacokinetic study in rats

[0078] 1. Rat dosing regimen and blood sample collection

[0079] Healthy Sprague-Dawley rats weighing 180-220 g were randomly divided into six groups of six. Rats were fasted overnight before the experiment, with ad libitum access to water. Group 1 received an intravenous injection of 6 mg / kg pentazocine (pentazocine in aqueous solution with lactic acid), group 2 received an oral gavage of 24 mg / kg pentazocine (pentazocine dissolved in PBS buffer), and groups 3 through 5 received different doses of pentazocine gluconate benzoate (pentazocine gluconate benzoate dissolved in PBS buffer). Blood samples (0.2 ml each) were collected from the retroorbital plexus of the rats at 5, 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 10, 24, and 48 hours after administration. Rats were anesthetized with ether. All samples were placed in heparinized tubes. Plasma was collected after centrifugation at 5000 rpm at 4°C for 10 minutes and frozen at -20°C until analysis.

[0080] 2 Data processing

[0081] All data were analyzed using a two-compartment model using DAS2.0 software. Plasma concentrations at different times were expressed as mean ± standard deviation (SD), and mean concentration-time curves were plotted. Maximum plasma concentration (Cmax) and Tmax were directly observed from the concentration-time curves. The area under the curve (AUC0-t) was calculated using the linear-trapezoidal rule with extrapolation to infinity. The results are shown below.

[0082] Table 2 Pharmacokinetic parameters of each group after administration according to the dosing regimen (n=6)

[0083]

[0084] 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.

[0085] Example 7 Experimental study on cytotoxicity of normal human hepatocytes in vitro

[0086] 1 Experimental Materials

[0087] 1.1 Cells: LO2 cells, a human liver cell line

[0088] 1.2 Drug: Compound of the present invention, HPLC purity 97.8%

[0089] 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

[0090] 2 Experimental methods

[0091] 2.1 Reagent preparation

[0092] 2.1.1 Preparation of MTT: Weigh 0.25 g of MTT using 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. Sterilize by filtering through a 0.22 μm microporous filter membrane. Aliquot and store in a refrigerator at 4°C away from light.

[0093] 2.1.2 Preparation of cell freezing solution Cell freezing solution was prepared by mixing 20% ​​serum, 10% DMSO and 70% 1640 culture medium and stored at -20℃.

[0094] 2.1.3 Preparation of the Compounds of the 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 to be ≤0.1%.

[0095] 2.2 LO2 cell culture Normal human LO2 cells were placed in a 25 cm 2 Add approximately 4-5 mL of RPMI-1640 medium containing 10% FBS to the cell culture flask and incubate in a 37°C cell culture incubator with 5% CO2 saturated humidity. Change the medium every two days and observe cell growth daily. Passage or cryopreserve cells when they reach 80% confluency. Select cells from passages 5-7 for formal experiments.

[0096] 2.3 Grouping and Dosing The experiment was divided into a normal cell control group, and different concentrations of the drug-dosing groups of the present invention were set according to the results of the preliminary experiment, with concentrations of 4.0, 8.0, 16.0, 32.0, 64.0, 128, 256, 512, 800, and 1000 μmol / L, respectively.

[0097] 2.4 Hepatocyte MTT Colorimetry: LO2 cells in the logarithmic growth phase were prepared and plated into a cell suspension of 5.0 × 10 cells / mL in a 96-well plate. A normal control group and groups treated with the compound of the present invention at various concentrations of 4.0, 8.0, 16.0, 32.0, 64.0, 128, 256, 512, 800, and 1000 μmol / L were set up. After 24 hours of incubation, the culture medium was aspirated and the cells were washed two to three times with PBS. The compounds of the present invention were then added at various concentrations, with eight replicate wells per well for each concentration. The cells were incubated in a 37°C, 5% CO2 incubator. After 24, 48, and 72 hours of incubation, MTT solution was added at each time point and incubated for 4 hours in the dark. After 4 hours, the supernatant was aspirated and 150 μL of DMSO solvent was added to each well to dissolve the thiazolyl blue crystals. The plates were gently shaken to ensure uniform dissolution. The absorbance of each well was measured at 490 nm using a microplate reader. The absorbance value of each well reflects the number of cells, and the two are directly proportional. The experiment was repeated 3 times. The cell viability rate was calculated as follows: Cell viability rate (%) = absorbance of each group (OD490) × 100 / absorbance of control group (OD490)

[0098] 2.5 Statistical Analysis All data are expressed as mean ± standard deviation and processed using SPSS 17.0 statistical software package. Statistical analysis was performed using the t-test. Paired t-tests were used for intragroup comparisons, and unpaired t-tests were used for intergroup comparisons. P < 0.05 was the standard.

[0099] 3 Experimental results

[0100] Group Dosage concentration / (μmol / L) OD value Survival rate / % 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

[0101] Conclusion: 72 hours after administration of different concentrations of the present invention, the OD values ​​of cells in each group 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 treated with different concentrations of the present invention had no inhibitory effect on the cells. Compared with the normal group, the cell survival rate was greater than 90%. Within the range of 4.0-1000 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. The crystal of pentazocine gluconate benzoate according to claim 1, wherein: It has characteristic peaks at least at diffraction angles (2θ) of 8.6±0.2, 13.2±0.2, 13.4±0.2, 13.6±0.2, 13.5±0.2, and 13.6±0.2 (°) in X-ray powder diffraction.

3. The crystal of pentazocine gluconate benzoate according to claim 2, wherein: It has characteristic peaks at diffraction angles (2θ) of at least 8.66, 8.68, 8.70, 13.22, 13.24, 13.28, 13.30, 13.32, 13.40, 13.42, 13.44, 13.46, 13.48, 13.50, 13.52, 13.54, 13.56, 13.58, 13.60, 13.62, 13.64, 13.66, 13.68, 13.70, and 13.72 (°) in X-ray powder diffraction.

4. The crystal of pentazocine gluconate benzoate according to claim 2, wherein Its XRPD is shown in Figure 7.

5. 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 a base acid-binding agent. The reaction formula is as follows:

6. 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:

7. A pharmaceutical composition comprising the pentazocine benzoate gluconate according to claim 1 or the pentazocine benzoate gluconate crystal according to claim 2, 3 or 4, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 7 , which is administered orally.

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

10. Use of the pentazocine gluconate benzoate according to claim 1, or the pentazocine gluconate benzoate crystal according to claim 2, 3, or 4, or the pharmaceutical composition according to claim 7, 8, or 9 for preparing a drug for moderate to severe acute and chronic pain.

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