Novel analogenic injection composition

Abstract

The invention provides a novel analgesic injection composition. The composition comprises tapentadol in an active ingredient quick release form and a quick-acting and long-acting composition of bistapentadol sebacate in an active ingredient slow release form. The invention also relates to a method for preparing the quick-acting and long-acting injection composition and application of the prepared dosage form in preparation of medicines for treating chronic or acute pain, such as preoperative and postoperative administration. The quick-acting and long-acting injection composition provided by the invention has ideal pharmaceutical technology and clinical attributes.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology. Specifically, it relates to a novel analgesic injection pharmaceutical composition, its preparation method, and its use for preparing a medicament for treating postoperative pain. The pharmaceutical composition has rapid release and controllable long-acting effects, improves the drug utilization rate, reduces the toxic risk of drug accumulation, has a long-acting analgesic effect, and can be used in the fields such as treating postoperative pain. Background Art

[0002] Tapentadol is a novel strong central analgesic with dual modes of action of opioid receptor agonism and norepinephrine reuptake inhibition. In 2008, the US Food and Drug Administration (FDA) accepted the new drug marketing application for immediate-release tablets of tapentadol hydrochloride, and in 2011, it approved the marketing of tapentadol extended-release tablets for the treatment of moderate to severe acute pain. The research results show that tapentadol does not rely on metabolic activation, has no active metabolites, has good effects on acute, inflammatory, and chronic neuropathic pain models, its efficacy is between that of morphine and tramadol, satisfactory blood drug concentrations can be obtained by intravenous injection or oral administration, and it is less likely to produce analgesic tolerance and physical dependence than morphine, and can improve side effects (especially gastrointestinal side effects) more than strong opioid drugs with equivalent analgesic doses. It has been proven to have extremely high therapeutic value in clinical use, especially for treating acute pain and diabetic peripheral neuropathy that require opioid analgesics. The Chinese chemical name of tapentadol is: 3 - ((1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl)phenol, and the structural formula is as follows:

[0003]

[0004] Ditapentadol sebacate is a unique active structure unexpectedly discovered by the present inventors among numerous ester prodrugs. Its application number is 202510180368.9, and the structural formula is as follows:

[0005]

[0006] The longer the treatment time, the higher the need for a more convenient dosing regimen, as the efficacy of long-term treatment is closely related to patient compliance, among other factors. Therefore, there is a need to provide a pharmaceutical composition that can reduce the dosing frequency, for example as a controlled-release injection. A long-acting analgesic effect is particularly desirable for patients suffering from pain, such as postoperative pain, post-traumatic pain and burn pain, which may last for at least about 3 days. Tapentadol has a strong but short-acting analgesic activity. Prolonging the duration of action would make tapentadol more valuable in the clinical treatment of pain. Developing a long-acting tapentadol injection makes sense. There is a great need to improve the compliance factor, especially in the treatment of postoperative pain. The development of a long-acting formulation of tapentadol for once-weekly or even less frequent injections would mark an important step forward in ensuring a continuous and stable supply of an effective drug. This form of analgesic is designed to improve drug compliance to obtain better treatment options and treat patients who lack insight or have poor compliance with currently available oral medications. In addition, long-acting analgesics help to apply the principle of the lowest effective dose, thus reducing the frequency of adverse events such as drug overdose and improving the quality of life of patients.

[0007] There are several long-acting injections available clinically for pain: Liposomal bupivacaine injection, a long-acting sustained-release preparation developed by Pacira, was approved by the FDA for marketing in 2011 under the trade name Exparel. It can be directly injected into the surgical site to help control postoperative pain with a continuous analgesic duration of up to 72 hours. Given the clinical advantages of Exparel, in 2018, the FDA approved its expanded use for adult interscalene brachial plexus block to produce postoperative local analgesia. In 2021, the FDA further approved Exparel for children 6 years of age and older. Ropivacaine was first developed by Astra, first marketed in the Netherlands in 1996 and approved for marketing in the United States the same year under the trade name Naropin. In 2019, TLC Pharmaceutical Industries Limited in Taiwan, China, presented the I / II phase clinical trial data of TLC590 at the annual meeting of the American Society of Anesthesiologists, showing that a single dose can provide a long-acting postoperative pain relief effect for 4 to 7 days and reduce the use of opioids.

[0008] Currently, with the progress of pharmaceutical preparation technologies, various drug sustained-release and long-acting technologies are being developed to improve patient compliance. Compared with immediate-release formulations, sustained-release and long-acting formulations reduce the number of administrations, while effectively eliciting the potential effects of the drug by maintaining the drug action, and have many benefits in terms of effectiveness and safety, such as reducing side effects or toxicity. However, for analgesics that require immediate action, etc., it is also necessary to rapidly reach the effective blood concentration after administration to exhibit rapid-acting characteristics such as analgesic effects. Therefore, there is a need to develop formulations that simultaneously possess rapid-acting and long-acting characteristics.

[0009] Existing technical literature related to long-acting analgesia:

[0010] CN119280165: Long-acting analgesic composition based on lipid liquid crystal technology and its application

[0011] CN115463084A: A compound oil solution preparation for long-acting analgesia and its preparation method

[0012] CN116239516A: A eutectic and its use in the preparation of drugs for long-acting analgesia or / and long-acting local anesthesia

[0013] CN114980890A: Injectable long-acting analgesic drug composition, its preparation method and use

[0014] CN108653311A: Drug composition for long-acting analgesia, nanoformulation, its preparation method and application

[0015] US5716631: Long acting narcotic analgesics and antagonists

[0016] US5750534: Nalbuphine esters having long acting analgesic action and method of use

[0017] WO / 2003 / 084482: ANTIDEPRESSANTS AND THEIR ANALOGUES AS LONG-ACTING LOCAL ANESTHETICS AND ANALGESICS

[0018] To date, there has been no report of a tapentadol-related structure for rapid-acting and long-acting pain treatment approved on the global market. In addition, it is necessary to successfully optimize the determination of key parameters of various clinical candidate drugs or molecules related to drug development, such as selecting appropriate doses, appropriate dosage forms, appropriate administration routes, appropriate dosing regimens, and the effects on animals and humans. Therefore, there is an unmet need. Summary of the Invention

[0019] On the one hand, the present invention provides an analgesic composition, comprising: a) tapentadol or a pharmaceutically acceptable salt thereof and ditapentadol sebacate, b) a pH regulator, c) a wetting agent, d) a suspending agent, e) a dispersing agent, f) a tonicity regulator, g) a preservative, and h) one or more injection solvents.

[0020] Preferably, the tapentadol or a pharmaceutically acceptable salt thereof in the composition includes, but is not limited to, maleic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, fumaric acid, phenylpropionic acid, ascorbic acid, oxalic acid, dimethyl salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, amidosulfonic acid, phosphoric acid, nitric acid, etc. Further, it refers to tapentadol base, tapentadol hydrochloride or tapentadol tartrate.

[0021] Preferably, the ditapentadol sebacate in the composition is sterile.

[0022] In certain non-limiting embodiments, the composition further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of emulsifiers, co-solvents, oils, thickeners, antioxidants, and surface modifiers.

[0023] In certain non-limiting embodiments, the injection solvent in the composition is selected from the group consisting of water, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, glycerol, propylene glycol, and mixtures thereof. Preferably, the injection solvent is selected from water. Further preferably, the water content is 0.5 - 5 ml.

[0024] In certain non-limiting embodiments, the composition does not contain any alcohol-based excipients.

[0025] In certain non-limiting embodiments, the pH value of the composition is about 6.8 to about 7.2, the osmotic pressure is 100 to about 400 mOsm / kg, and the average particle size of the sterile ditapentadol sebacate in the composition is less than about 200 μm.

[0026] In certain non-limiting embodiments, the mass ratio of tapentadol or a pharmaceutically acceptable salt thereof to ditapentadol sebacate in the composition is 1:9 to 2:1.

[0027] On the other hand, the present invention provides an analgesic injection composition

[0028] comprising:

[0029] a) About 10% to 70% w / v of tapentadol or a pharmaceutically acceptable salt thereof, as the active ingredient in an immediate-release form;

[0030] b) About 30% to 90% w / v of ditapentadol sebacate, as the active ingredient in a sustained-release form;

[0031] Preferably, the composition further contains one or more pH regulators selected from the group consisting of sodium dihydrogen phosphate, sodium hydrogen phosphate, citric acid, sodium citrate, glacial acetic acid, hydrochloric acid, or a combination thereof;

[0032] Preferably, the composition further contains about 0.01% to 1% w / v of one or more suspending agents selected from the group consisting of hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl methyl cellulose, or a combination thereof;

[0033] Preferably, the composition further contains about 0.01% to 0.5% w / v of one or more wetting agents selected from the group consisting of sodium dodecyl sulfate, polysorbate, poloxamer, or a combination thereof, preferably polysorbate 80.

[0034] Preferably, the composition further contains one or more tonicity regulators selected from the group consisting of sodium acetate, sodium chloride, glucose, sodium lactate, calcium chloride, sodium bicarbonate, potassium chloride, or a combination thereof, present in an amount of about 0.01% to 2% w / v to provide an osmotic pressure of about 100 to 400 mOsm / kg.

[0035] The injection of the present invention refers to a route selected from subcutaneous (SC), intravenous (IV), intramuscular (IM), intradermal (ID), intraperitoneal (IP), long-acting injection, or through an implanted pump, etc.

[0036] Further features and advantages of the present invention will become apparent from the following detailed description, in conjunction with the accompanying drawings, wherein: the composition acts immediately and continuously releases tapentadol for at least 5 days, and wherein the composition has pharmacokinetic characteristics in vivo with substantially no burst release of tapentadol. It has a rapid onset of action and a smooth long-lasting effect, without a burst release effect, and has ideal pharmaceutical technology and clinical properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0038] Figure 1Cumulative drug release curves of Examples 1-3 of the present invention;

[0039] Figure 2 Cumulative drug release curves of Examples 4-10 of the present invention;

[0040] Figure 3 Average plasma concentration-time curve of tapentadol in rats. Detailed implementation manners

[0041] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0042] The present invention will be further explained below in conjunction with specific implementation manners.

[0043] The following examples can further describe the present invention. However, these examples should not be construed as limiting the scope of the present invention.

[0044] Example 1:

[0045] 1. Prescription:

[0046] Table 1 Prescription of Example 1

[0047]

[0048] 2. Preparation process:

[0049] 1) Place the required injection water volume in a clean and dry glass container and purge with nitrogen for 30 minutes to reduce the dissolved oxygen content;

[0050] 2) Take about 90% of the batch of injection water in step 1 and prepare the disodium hydrogen phosphate hydrate / sodium dihydrogen phosphate buffer solution [pH 5-8] according to the prescription;

[0051] 3) Slowly add the prescribed amount of tapentadol base and stir until completely dissolved;

[0052] 4) Slowly add the prescribed amounts of Tween 80, benzalkonium chloride, disodium ethylenediaminetetraacetate, and sodium chloride, and stir until completely dissolved;

[0053] 5) Filter the above solution in step 4 twice through a 0.22 μm filter to sterilize;

[0054] 6) Add the sterile raw material ditapentadol sebacate to the above steps;

[0055] 7) The above suspension is subjected to high-shear mixing at 5000 - 20000 RPM for 10 - 30 minutes;

[0056] 8) After high-shear mixing, the above suspension is homogenized at 10000 - 30000 psi for 5 cycles;

[0057] 9) Make up to 100% batch with water for injection, stir for 10 minutes, fill while maintaining a low-speed stirring cycle state, and keep a small flow of nitrogen filling in the headspace to obtain the product.

[0058] 3. Appearance, properties and physical properties:

[0059] Table 2 Appearance, properties and physical properties of Example 1

[0060]

[0061] Example 2:

[0062] 1. Prescription:

[0063] Table 3 Prescription of Example 2

[0064]

[0065] 2. Preparation process:

[0066] Tank 1 (Grade C)

[0067] Take 10% of the water for injection in the prescription amount, add disodium hydrogen phosphate anhydrous, sodium chloride, disodium edetate respectively, adjust the liquid medicine to pH 6.8 - 7.2 with 1M hydrochloric acid solution, fill with nitrogen to below 3 mg / L, and add tapentadol hydrochloride in the prescription amount to dissolve. Keep nitrogen filling in the headspace; filter through a 0.22 - μm filter into Tank 3;

[0068] Tank 2 (Grade C)

[0069] 1) Solution 1: Add the suspending agent sodium carboxymethylcellulose + polyethylene glycol 3350 to 55% of the hot water (50 - 60 °C) in the prescription amount, swell and set aside;

[0070] 2) Solution 2: Add benzyl alcohol to 20% of the hot water (60 - 80 °C) in the prescription amount, stir to dissolve;

[0071] 3) Add Solution 1 to Solution 2 under stirring, stir evenly, and filter through a 0.22 - μm filter into Tank 3;

[0072] Tank 3 (Grade C + A) process

[0073] Dissolve the prescription amount of sterile Tween 80 in 3% of the prescription amount of sterilized water for injection. Disperse the sterile raw material buprenorphine decanoate into the Tween 80 solution and add it. Make up the volume to the full amount with sterilized water for injection that has been sterilized by filtration. After high-speed shearing, keep stirring at a low speed in a circulating state for filling. Keep a small flow of nitrogen purging in the headspace for protection, and thus obtain the product.

[0074] Table 4 Appearance, properties and physical properties of Example 2

[0075]

[0076] Example 3:

[0077] 1. Prescription:

[0078] Table 5 Prescription of Example 3

[0079]

[0080] 2. Preparation process:

[0081] Tank 1 (Grade C)

[0082] Take 10% of the prescription amount of water for injection, add disodium hydrogen phosphate anhydrous, sodium chloride, disodium edetate respectively, adjust the liquid medicine to pH 6.8 - 7.2 with 1M hydrochloric acid solution, purge with nitrogen to below 3 mg / L, and add the prescription amount of tapentadol tartrate to dissolve. Keep purging nitrogen in the headspace; filter through a 0.22 μm filter into Tank 3;

[0083] Tank 2 (Grade C)

[0084] 3) Solution 1: Add the suspending agent sodium carboxymethylcellulose + polyethylene glycol 4000 to 55% of the prescription amount of hot water (50 - 60 °C) to swell and then set aside;

[0085] 4) Solution 2: Add benzyl benzoate to 20% of the prescription amount of hot water (60 - 80 °C), and stir to dissolve;

[0086] 3) Add Solution 1 to Solution 2 under stirring, stir evenly, and filter through a 0.22 μm filter into Tank 3;

[0087] Tank 3 (Grade C + A) process

[0088] Dissolve the prescription amount of sterile Tween 80 in 3% of the prescription amount of sterilized water for injection. Disperse the sterile raw material buprenorphine decanoate into the Tween 80 solution and add it. Make up the volume to the full amount with sterilized water for injection that has been sterilized by filtration. After high-speed shearing, keep stirring at a low speed in a circulating state for filling. Keep a small flow of nitrogen purging in the headspace for protection, and thus obtain the product.

[0089] Table 6 Appearance, properties and physical properties of Example 3

[0090]

[0091] Examples 4 to 6:

[0092] 1. Prescription:

[0093] Table 7 Prescriptions of Examples 4 to 6

[0094]

[0095] 2. Preparation process

[0096] The preparation process is similar to the process disclosed in Example 1.

[0097] Examples 7 to 10:

[0098] 1. Prescription:

[0099] Table 8 Prescriptions of Examples 7 to 10

[0100]

[0101]

[0102] The preparation process is similar to the process disclosed in Example 2.

[0103] Example 11: Main physical and chemical properties:

[0104] Table 9 Main physical and chemical properties of Examples 1 to 10 Continued from the above table

[0105]

[0106]

[0107] Conclusion: The charge carried by the suspension injection of the present invention is negative, with an absolute value greater than 25 mv, and the system has good physical stability. Because the higher the charge carried by the particles, the greater the repulsion between the particles, the particles are not easily aggregated, and the system is more stable.

[0108] Example 12: In vitro release determination:

[0109] 1. Chromatographic conditions:

[0110] Chromatographic column: 150 mm × 4.6 mm end-capped octadecylsilyl-bonded silica gel column (5 μm)

[0111] Column temperature: 35 °C

[0112] Mobile phase: Mobile phase A: phosphoric acid - methanol - water = 0.1:10:90

[0113] Mobile phase B: Phosphoric acid - water - methanol = 0.1:10:90

[0114] Gradient elution time program;

[0115] Table 10 Gradient elution time sequence

[0116] Flow rate: 1.5 ml / min

[0117] Detection wavelength: 215 nm

[0118] Injection volume: 20 μl

[0119] 2. Method:

[0120] The in vitro release rate of this product was determined by the dialysis bag method. Samples of Example 1, Example 2 and Example 3 with the sample concentrations as shown in the following table were prepared respectively, placed in dialysis bags with a diameter of 22 mm and a length of about 10 cm, the air in the bags was removed, both ends were tied tightly with string, coiled and fixed on the stirring paddle of the dissolution apparatus. The stirring paddle was placed about 1.5 cm from the bottom of the dissolution cup. Using 900 mL of phosphate buffer solution with pH 7.4 as the dissolution medium, the temperature was maintained at (37.0 ± 0.5) °C, the stirring paddle speed was adjusted to 50 r / min, and 2 mL of samples were taken at 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 h respectively (while adding the same volume of release medium), filtered through a 0.45 μm microporous filter membrane, the subsequent filtrate was taken, injected according to the above chromatographic conditions, the peak areas were recorded, and the cumulative release percentage of the present invention at each time was calculated. Taking the release rate as the vertical coordinate and time as the horizontal coordinate. The calculation formulas for the release rate and cumulative release percentage are as follows: Release rate % = actual total release amount / total drug amount × 100%. The results are shown in the following table:

[0121] Time Mobile Phase A Mobile Phase B 0-2 100 0 2-44 100→61 0→39 44-44.5 61→0 39→100

[0122]

[0123] Results of the in vitro release rate study of the present invention

[0124] Table 11 Results of the in vitro release rate study of Examples 1 to 3

[0125]

[0126]

[0127] Table 12 Results of the in vitro release rate study of Examples 4 to 10

[0128]

[0129] The results show that when the drug is prepared into water-soluble suspensions with different average particle sizes, within a certain range, the decrease in particle size leads to a significant increase in the solubility and dissolution rate of the drug. The release amount of the present invention is stable in each time period, without burst release phenomenon, and the cumulative release rate after 6 days is greater than 70%, achieving the sustained release effect.

[0130] Example 13: Accelerated stability test:

[0131] The samples of Examples 1, 2, and 3 were subjected to an accelerated test. The self-made suspension injection was placed in a thermostatic and humid incubator, with the humidity set at 65% ± 5% and the temperature at 30°C ± 2°C, and an accelerated test was carried out for 6 months. Sampling was carried out at the end of 0, 1, 2, 3, and 6 months respectively, and the appearance properties, particle size distribution, content, related substances, and release degree of the samples were measured respectively.

[0132] Table 13 Results of the accelerated stability test of Examples 1 to 10

[0133]

[0134]

[0135] Conclusion: Under the accelerated test, for this product, in Examples 1, 2, and 3, layering occurred after storage, but it could be evenly dispersed after shaking, and the remixability was good. The particle size and related substances increased slightly with time, and the content decreased slightly, but it was overall stable and met the requirements of the clinical quality standard.

[0136] Example 14: Pharmacokinetic study in rats:

[0137] 1. In vivo high performance liquid chromatography analysis method:

[0138] Chromatographic column: 150 mm × 4.6 mm end-capped octadecylsilyl-bonded silica gel column (5 μm);

[0139] Column temperature: 35°C;

[0140] Mobile phase: Mobile phase A: phosphoric acid - methanol - water = 0.1:10:90;

[0141] Mobile phase B: phosphoric acid - water - methanol = 0.1:10:90;

[0142] Table 14 Gradient elution time sequence

[0143] Time Mobile Phase A Mobile Phase B 0-2 100 0 2-44 100→61 0→39 44-44.5 61→0 39→100

[0144] Flow rate: 1.5 ml / min;

[0145] Detection wavelength: 215 nm;

[0146] Injection volume: 20 μL;

[0147] 2. Preparation of plasma samples:

[0148] Blank plasma sample: Take blank plasma of rats. After thawing, accurately measure 100 μL and transfer it into a 1.5 mL centrifuge tube. Add 700 μL of 4% glacial acetic acid methanol, vortex mix for 5 min, centrifuge at 9000 rpm for 10 min to precipitate proteins. Aspirate the supernatant into a 1.5 mL centrifuge tube and dry it at 40 °C. Add 50 μL of phosphoric acid - methanol - water = 0.1:10:90 to dissolve the residue, vortex oscillate for 6 min, ultrasonicate for 15 min, centrifuge at 13000 rpm for 20 min. The supernatant is the blank plasma sample solution.

[0149] Plasma sample after drug administration: Take plasma of rats after drug administration. After thawing, accurately measure 100 μL and transfer it into a 1.5 mL centrifuge tube. Add 10 μL of internal standard (tramadol 2 μg / mL, dissolved in phosphoric acid - methanol - water = 0.1:10:90), vortex for 1 min to mix evenly. Add 700 μL of 4% glacial acetic acid methanol, vortex mix for 5 min, centrifuge at 9000 rpm for 1 min to precipitate proteins. Aspirate the supernatant into a 1.5 mL centrifuge tube and dry it at 40 °C. Add 50 μL of phosphoric acid - methanol - water = 0.1:10:90 to dissolve the residue, vortex oscillate for 6 min, ultrasonicate for 15 min to fully dissolve the drug, then centrifuge at 13000 rpm for 20 min. The supernatant is the plasma sample solution after drug administration.

[0150] 3. Drug administration regimen and sample collection:

[0151] Inject the suspension in Example 1 into the thigh muscles of 6 rats at a dose of 100 mg / kg. Collect blood from the orbital veins of rats at 0, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 h after drug administration. Each time, collect about 0.5 mL of blood and add it to an anticoagulant tube treated with sodium heparin. Centrifuge at 4000 rpm for 10 min, separate the upper plasma, and store it at -20 °C for analysis and detection.

[0152] 4. Detection and data processing of plasma samples:

[0153] Take the plasma samples after drug administration and process them according to the method under 2. Preparation of plasma samples. Inject the samples according to the chromatographic conditions under 1. In - vivo high - performance liquid chromatography analysis method. Substitute the ratio of the peak areas of the main drug and the internal standard peak into the standard curve to calculate the plasma drug concentration, and use Phoenix software to process the results and calculate the relevant pharmacokinetic parameters. The results are as follows:

[0154] Table 15 Concentrations at each time point in vivo after drug administration

[0155]

[0156] Table 16 Pharmacokinetic parameters after drug administration

[0157] Parameter Unit Example 1 AUC(0-t) h*mg / L 65.3 AUC(0-∞) h*mg / L 98.9 MRT(0-t) h 127.1 MRT(0-∞) h 146.6 Cmax mg / L 0.34 Tmax h 71.6 t1 / 2 h 95.7 Vz / F L / kg 2.3 CLz / F L / h / kg 0.7

[0158] The results show that, based on the results of pharmacokinetic studies, tapentadol base in the preparation of the present invention takes effect immediately. At the same time, the concentration of tapentadol increases slowly after injection, and the slow long-acting release maintains the tapentadol concentration within the required range, thus exerting a long-acting effect. At the same time, it is released smoothly, achieving a stable long-acting release for at least 5 days without a burst effect. Therefore, it is extremely advantageous in clinical treatment.

[0159] 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 for some or all of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An analgesic composition, characterized in that: The invention comprises: a) tapentadol or a pharmaceutically acceptable salt thereof and bis-tapentadol sebacate, b) a pH adjuster, c) a wetting agent, d) a suspending agent, e) a dispersing agent, f) a tonicity adjuster, g) a preservative and h) one or more injection solvents.

2. The analgesic composition according to claim 1, characterized in that The composition further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of emulsifiers, cosolvents, oils, thickeners, antioxidants, and surface modifiers.

3. The analgesic composition according to claim 1, characterized in that The injection solvent is selected from the group consisting of water, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, glycerol, propylene glycol and a mixture thereof. Preferably, the injection solvent is selected from water. More preferably, the water content is 0.5 to 5 ml.

4. The analgesic composition according to claim 1, characterized in that The composition does not contain any alcohol-based auxiliary materials.

5. The analgesic composition according to claim 1, characterized in that The pH value of the composition is about 6.8 to about 7.2, the osmotic pressure is 100 to about 400 mOsm / kg, and the average particle size of the sterile dipentadol sebacate in the composition is less than about 200 μm.

6. The analgesic composition according to claim 1, characterized in that The tapentadol or a pharmaceutically acceptable salt thereof refers to tapentadol, tapentadol hydrochloride or tapentadol tartrate; the tapentadol sebacate is sterile.

7. The analgesic composition according to claim 1, characterized in that The mass ratio of the tapentadol or a pharmaceutically acceptable salt thereof to the di-tapentadol sebacate is 1:9 to 2:

1.

8. The analgesic composition according to claim 1, characterized in that Include: a) about 10% to 70% w / v of tapentadol or a pharmaceutically acceptable salt thereof as the active ingredient in an immediate release form; b) about 30% to 90% w / v of ditapentadol sebacate as the active ingredient in a sustained release form; c) one or more pH adjusters selected from the group consisting of sodium dihydrogen phosphate, sodium hydrogen phosphate, citric acid, sodium citrate, glacial acetic acid, hydrochloric acid or a combination thereof; d) about 0.01% to 1% w / v of one or more suspending agents selected from the group consisting of hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, hydroxypropyl methyl cellulose, or a combination thereof; e) about 0.01% to 0.5% w / v of one or more wetting agents selected from the group consisting of sodium lauryl sulfate, polysorbate, poloxamer or a combination thereof, preferably polysorbate 80.

9. The analgesic composition according to claim 1, characterized in that: One or more tonicity adjusting agents selected from the group consisting of sodium acetate, sodium chloride, dextrose, sodium lactate, calcium chloride, sodium bicarbonate, potassium chloride, or a combination thereof, are present in an amount of about 0.01% to 2% w / v to provide an osmotic pressure of about 100 to 400 mOsm / kg.

10. Use of the analgesic composition according to any one of claims 1 to 9 for preparing a drug for treating chronic or acute pain, such as preoperative or postoperative administration.

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