A long-acting analgesic composition based on a biodegradable polymer delivery system

Abstract

This invention provides a long-acting analgesic composition based on a biodegradable polymer delivery system for postoperative analgesia. The composition combines the local anesthetic bupivacaine with the nonsteroidal anti-inflammatory drug lornoxicam, significantly enhancing the analgesic effect through synergistic action. It comprises a sustained-release polymer, a viscosity modifier, and aprotic polar solvent, enabling long-term drug release with an analgesic effect lasting up to 72 hours. In vitro and in vivo studies have verified the excellent analgesic properties and stable sustained-release characteristics of this composition. This composition is suitable for various administration methods, including local injection, and exhibits high safety and significant therapeutic effects, providing an innovative and reliable solution for postoperative pain management and demonstrating broad clinical application potential.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulations, specifically relating to a long-acting analgesic composition based on a biodegradable polymer delivery system for the prevention and treatment of long-acting local analgesia after surgery. Background Technology

[0002] Postoperative pain refers to pain caused by acute trauma from surgical procedures, damage to internal organs, and inflammatory stimulation of nerve endings. It appears after the patient awakens from anesthesia and can adversely affect cardiovascular, respiratory, neuroendocrine, immune, and psychological functions in the short term. If postoperative pain is not effectively controlled during the acute phase, it may develop into chronic postoperative pain, lasting for up to six months or even decades. Therefore, postoperative pain management is crucial for ensuring effective postoperative analgesia. However, the abuse and addiction of opioids have made the clinical need for safe, effective, and non-addictive drugs increasingly urgent. Local anesthetics have gained attention compared to other types of analgesics due to fewer systemic adverse reactions, but their analgesic effect and duration are insufficient to cover the peak of postoperative pain. The development of long-acting analgesics is therefore critical. In recent years, long-acting postoperative analgesics such as bupivacaine liposomes and bupivacaine / meroxetine formulations have gradually entered the market, but their clinical application still faces some challenges and controversies.

[0003] Bupivacaine / Meloxicam Extended-Release Solution (trade name: Zynrelef) is a combination formulation of the local anesthetic bupivacaine and the nonsteroidal anti-inflammatory drug meloxicam. It reduces postoperative pain and inflammation through a dual mechanism of action combining local anesthetic and nonsteroidal anti-inflammatory drugs—anesthesia and anti-inflammation. However, meloxicam is a selective COX-2 inhibitor, and its use requires special attention to cardiovascular risks, including serious cardiovascular thrombotic events, myocardial infarction, and stroke. These risks may increase with prolonged use. Patients with cardiovascular disease or cardiovascular risk factors may face greater risks.

[0004] Lornoxicam, a potent COX-1 / COX-2 dual-inhibitory nonsteroidal anti-inflammatory drug, offers strong analgesia and rapid onset of action, giving it certain advantages over meloxicam. However, lornoxicam's short half-life (3-4 hours) and the need for multiple daily dosings limit the development of long-acting formulations; currently, no long-acting formulations have been approved. Therefore, effectively prolonging the analgesic duration of lornoxicam and developing safe, long-acting postoperative analgesics to better meet the needs of postoperative pain management remains a direction worthy of further exploration. Summary of the Invention

[0005] To address the aforementioned issues, this invention provides a long-acting analgesic composition based on a biodegradable polymer delivery system, specifically comprising a bupivacaine and lornoxicam composition. This delivery system enables stable and long-lasting release of bupivacaine and lornoxicam, overcoming the shortcomings of existing pain management drugs and delivery systems, and providing a safer and more effective treatment option for pain patients, especially those experiencing postoperative pain.

[0006] One objective of this invention is to provide a bupivacaine and lornoxicam composition based on a biodegradable polymer delivery system, comprising:

[0007] (a) The active pharmaceutical ingredient is selected from a combination of bupivacaine and lornoxicam;

[0008] (b) Aprotic polar solvents;

[0009] (c) A sustained-release polymer having a molecular weight of 4000-12000 Mw g / mol, with the structural formula shown in Formula I:

[0010]

[0011] Where A is a residue of a diol, and the residue of the diol is selected from: C 1-10 Straight-chain alkyl groups or their acetals, C 1-10 Branched alkanes or their alcohol condensations, C 4-10 cyclic alkanes or their alcohol condensations;

[0012] R is H or C 1-4 Alkyl groups;

[0013] The degree of aggregation n is an integer from 0 to 7;

[0014] X and Y are values ​​in the molar ratio range of 10 to 90, and satisfy X + Y = 100.

[0015] According to an embodiment of the present invention, the residue of the diol is: -(CH2)a-, or -[(CH2CH2)b-O]c-, where a is an integer from 2 to 10; b is an integer from 2 to 5; c is an integer from 2 to 4; the degree of polymerization n is an integer from 2 to 7; further, the diol is: ethylene glycol, propylene glycol, butanediol, hexanediol, decanediol or its acetal; R is hydrogen or methyl; the polymer has a molecular weight of 5000 Mw g / mol to 9000 Mw g / mol; the molar ratios X and Y are in the range of: 70 ≤ X ≤ 90, 10 ≤ Y ≤ 30;

[0016] Further, the diol is: ethylene glycol, propylene glycol, hexanediol, decanediol, diethylene glycol, or triethylene glycol; R is hydrogen or methyl; the polymer has a molecular weight of 5000 Mw g / mol to 10000 Mw g / mol; the molar ratios X and Y are in the range of: 75 ≤ X ≤ 85, 15 ≤ Y ≤ 25;

[0017] Further, the diol is propylene glycol or triethylene glycol; R is hydrogen; the polymer has a molecular weight of 6000 Mw g / mol to 8000 Mw g / mol; the molar ratios X and Y are in the range of X = 80 and Y = 20.

[0018] According to an embodiment of the present invention, bupivacaine accounts for 0.5-10% w / w of the total composition of the active pharmaceutical ingredient; lornoxicam accounts for 0.01-1% w / w of the total composition of the active pharmaceutical ingredient.

[0019] The bupivacaine concentration in the composition ranges from about 0.5 wt% to 10 wt%, and in some embodiments, it is in the range of about 0.5 wt% to 7.5 wt%, 0.5 wt% to 5 wt%, 0.5 wt% to 2.5 wt%, and 0.5 wt% to 1.5 wt%.

[0020] The concentration of lornoxicam in the composition ranges from about 0.01 wt% to 1 wt%, and in some embodiments, it is in the ranges of about 0.01 wt% to 0.85 wt%, 0.01 wt% to 0.70 wt%, 0.01 wt% to 0.55 wt%, 0.01 wt% to 0.40 wt%, 0.01 wt% to 0.25 wt%, and 0.01 wt% to 0.10 wt%.

[0021] According to an embodiment of the present invention, the aprotic polar solvent accounts for 3-30% w / w of the total composition.

[0022] According to an embodiment of the present invention, the aprotic polar solvent is selected from one or more of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, and acetone.

[0023] According to an embodiment of the present invention, the composition may further comprise a viscosity modifier, wherein the viscosity modifier comprises 1-40% w / w of the total composition;

[0024] According to an embodiment of the present invention, the viscosity modifier is one or more of triglycerides, triethyl citrate, PEG300, mPEG550, isopropyl adipate, benzyl alcohol, propylene glycol fatty acid esters, medium-chain triglycerides, and benzyl benzoate; preferably triglycerides or triethyl citrate.

[0025] According to an embodiment of the present invention, the viscosity of the composition is from about 2000 mPa·S to 20000 mPa·S.

[0026] The sustained-release polymer serves as a delivery carrier, comprising 40-80% w / w of the total composition, with some embodiments using 40-70% w / w, 40-60% w / w, or 40-50% w / w, and having a molecular weight of 4000-12000 Mw g / mol, with some embodiments using 5000-10000 Mw g / mol, and more preferably 6000-8000 Mw g / mol.

[0027] In some embodiments, the composition contains an acidic excipient selected from maleic acid or citric acid.

[0028] In some embodiments, the composition may also contain an alkaline modifier, such as magnesium hydroxide, ethanolamine, or tromethamine. The amount of each component is adjusted according to the specific formulation.

[0029] A second objective of this invention is to provide a method for preparing a bupivacaine and lornoxicam composition based on a biodegradable polymer delivery system.

[0030] In some implementation methods, the preparation process is as follows: first, the sustained-release polymer and viscosity reducer (if any) are premixed at a certain temperature; then, bupivacaine, lornoxicam and acid excipient (if any) are dissolved in the corresponding solvent; finally, the drug solution is added to the sustained-release polymer mixture and stirred evenly.

[0031] In some implementation methods, the preparation process is as follows: first, the sustained-release polymer and viscosity reducer (if any) are premixed at a certain temperature; then, bupivacaine, lornoxicam and alkalinity regulator (if any) are dissolved in the corresponding solvents; finally, the drug solution is added to the sustained-release polymer mixture and stirred evenly.

[0032] The preparation process temperature is 50–100℃, more preferably 50–90℃, 50–80℃, or 50–70℃.

[0033] In some embodiments, the composition is an aqueous solution.

[0034] A third objective of this invention is to provide a pharmaceutical formulation comprising the bupivacaine and lornoxicam composition based on the biodegradable polymer delivery system.

[0035] The fourth objective of this invention is to provide an application of a bupivacaine and lornoxicam composition based on a biodegradable polymer delivery system in the preparation of products for local anesthesia, postoperative analgesia, and preventive treatment of pain.

[0036] The pain can be acute or chronic.

[0037] The compositions provided by this invention can be used for analgesia, for symptomatic treatment of mild to moderate acute pain, such as musculoskeletal pain, dysmenorrhea and toothache; for the treatment of moderate pain; and as an adjunct to opioid analgesics for managing moderate to severe pain.

[0038] The composition is administered by dispensing it from a needle.

[0039] The composition is injectable and suitable for intramuscular injection, transdermal injection, local injection, subcutaneous injection, peripheral nerve injection, intramuscular injection, or direct application to a wound.

[0040] The composition can provide drug release times ranging from 1 day to 8 weeks, approximately 1 day to 7 weeks, approximately 1 day to 6 weeks, approximately 1 day to 5 weeks, approximately 1 day to 4 weeks, approximately 1 day to 3 weeks, approximately 1 day to 2 weeks, approximately 1 day to 1 week, approximately 1 day to 6 days, approximately 1 day to 5 days, approximately 1 day to 4 days, approximately 1 day to 3 days, and approximately 1 day to 2 days.

[0041] Beneficial effects of this invention:

[0042] This invention innovatively combines the local anesthetic bupivacaine with the nonsteroidal anti-inflammatory drug lornoxicam, employing a biodegradable sustained-release polymer delivery system to create a novel long-acting analgesic combination. This combination significantly enhances analgesia through a synergistic mechanism, achieving sustained release for up to 3 days or longer, effectively covering the peak postoperative pain period. The optimized molecular weight of the sustained-release polymer and the scientifically designed formulation of the two active ingredients ensure stable drug release, improving therapeutic efficacy while reducing opioid use and related side effects at low doses. Local delivery reduces systemic adverse reactions, and the suitable viscosity facilitates injection and is applicable to various clinical scenarios. Furthermore, the simple and controllable manufacturing process, excellent stability, and suitability for large-scale industrial production demonstrate significant clinical value and broad application prospects. Attached Figure Description

[0043] Figure 1 These are the in vitro release curves of bupivacaine for prescriptions 1-3.

[0044] Figure 2 These are the in vitro release curves of lornoxicam for prescriptions 1-3.

[0045] Figure 3 These are the in vitro release curves of bupivacaine for prescriptions 4-7.

[0046] Figure 4 These are the in vitro release curves of lornoxicam for prescriptions 4 and 7.

[0047] Figure 5These are the in vitro release curves of bupivacaine from prescriptions 8 to 12.

[0048] Figure 6 This is the in vitro release curve of lornoxicam from prescription 8 to prescription 12. Detailed Implementation

[0049] The following detailed description, in conjunction with specific embodiments, provides a clear and complete account of a bupivacaine and lornoxicam composition based on a biodegradable polymer delivery system and its preparation method, to fully illustrate the purpose, features, and effects of the present invention. These specific embodiments are provided for further detailed explanation of the invention and are not intended to limit the scope of protection of the invention.

[0050] Example 1: Preparation of Intermediate 1 (Monomer)

[0051] Abbreviation: 3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane, abbreviated as BTU.

[0052]

[0053] Preparation method: BTU (993.0 g, 4.68 mol), potassium tert-butoxide (950.9 g, 8.48 mol), and ethylenediamine (6.0 L) were added to a 10 L reaction flask and heated to an internal temperature of 100–105 °C. The mixture was stirred for about 6–8 h and cooled to room temperature. The reaction solution was poured into a mixture of 5.0 L ice water and 5.0 L n-hexane, stirred and extracted, allowed to stand for separation, and the organic phase was collected. The aqueous phase was extracted with 3 L n-hexane and stirred. The organic phases were combined and washed successively with water (3 L) and saturated brine (3 L). The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to an oily substance on a rotary evaporator and transferred to a distillation flask. The solution was distilled under reduced pressure at 120–130 °C to obtain: intermediate 1 crude product (408.5 g, yield 41.1%). The crude intermediate 1 was dissolved in 2.5 L of n-hexane and stirred at 0–10 °C to induce crystallization. The resulting filter cake was distilled to remove residual solvent, yielding 229.0 g of intermediate 1 as a colorless liquid (overall yield 23%). ESI-MS m / z: 213.13 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ: 4.05 (q, J = 6.9 Hz, 2H), 3.91 (d, J = 1.4 Hz, 4H), 3.84 (d, J = 1.6 Hz, 4H), 1.48 (d, J = 6.8 Hz, 6H).

[0054] Example 2: Preparation of Intermediate 2 (components of triethylene glycol and glycolide)

[0055]

[0056] Preparation method: Heat a 2L reaction flask to 80℃, dry under reduced pressure for 1h, cool to room temperature, purge with nitrogen to remove the vacuum, add triethylene glycol (450.6g, 3mol) and glycolide (348.3g, 3mol) to the reaction flask, evacuate with nitrogen to replace the reaction system to an anhydrous and oxygen-free environment, heat to 175-185℃ and keep reacting for 22-24h, cool to room temperature, purge with nitrogen to remove the vacuum, transfer the sample to a high-density polyethylene bottle to obtain approximately 682.8g of intermediate 2 of this type, with a yield of 93%, and store sealed under nitrogen protection. 1 H-NMR (400MHz, CDCl3) δ: 4.75-4.71 (m, 1H), 4.38-4.27 (m, 4H), 4.19 (t, J = 2.8Hz, 2H), 3.75-3.57 (m, 10H).

[0057] Example 3: Preparation of sustained-release polymer (Mw approx. 6500)

[0058]

[0059] Preparation method: A 20L reactor was heated to 80℃ and dried under reduced pressure for 1 hour. The mixture was then cooled to room temperature, and nitrogen gas was introduced to remove the vacuum. Triethylene glycol (1200.0 g, 7.99 mol), intermediate 2 (532.0 g, 2.00 mol), and 6L of tetrahydrofuran were added to the reactor, and stirring was started. Intermediate 1 (1995.6 g, 9.40 mol) was dissolved in 6L of tetrahydrofuran and slowly added dropwise to the reactor, maintaining the internal temperature at 25–50℃. After the addition was complete, the polymerization reaction was maintained at this temperature for 3–5 hours. The reaction system was cooled to room temperature, and nitrogen gas was introduced to remove the vacuum. The reaction solution was transferred to a 20L single-necked flask, and residual solvent was removed by rotary evaporation under reduced pressure. Finally, the sample was transferred to a high-density polyethylene bottle, yielding approximately 3392.1 g of slow-release polymer, with a yield of 91%. The molecular weight and distribution of the product were determined by gel permeation chromatography (GPC). Tetrahydrofuran was used as the mobile phase, and a differential detector was employed. Molecular weight calibration curves were constructed using polystyrene standards with molecular weights of 1000, 2000, 4000, 10000, and 20000. The sustained-release polymer obtained in this example had a molecular weight (Mw) of 6608 g / mol, a number-average molecular weight (Mn) of 4253 g / mol, a dispersion index of 1.55, and a 10000-2500 Mw percentage (%) of 67.74%. The GPC chromatogram showed a purity of 97.13%. The molar ratios of X and Y were 80% and 20%, respectively.

[0060] Example 4: Preparation of sustained-release polymer (Mw approx. 4500)

[0061] Preparation method: A 10L reaction flask was heated to 85℃ and dried under reduced pressure for 1 hour. After cooling to room temperature, nitrogen gas was introduced to remove the vacuum. Triethylene glycol (600.0 g, 4.00 mol), intermediate 2 (266.0 g, 1.00 mol), and 3L of tetrahydrofuran were added to the reaction flask, and stirring was started. Intermediate 1 (934.1 g, 4.4 mol) was dissolved in 4L of tetrahydrofuran and slowly added dropwise to the flask, maintaining the internal temperature at 25–50℃. After the addition was complete, the polymerization reaction was maintained at this temperature for 3–4 hours. The reaction system was cooled to room temperature, nitrogen gas was introduced to remove the vacuum, and the reaction solution was transferred to a 20L single-necked flask. Residual solvent was removed by rotary evaporation under reduced pressure. Finally, the sample was transferred to a high-density polyethylene bottle, yielding approximately 1656.1 g of slow-release polymer, with a yield of 92%. Gel permeation chromatography was used to determine the molecular weight and distribution of the product. The sustained-release polymer obtained in this example has a molecular weight (Mw) of 4250 (g / mol), a number-average molecular weight (Mn) of 2832 (g / mol), a dispersion index of 1.50, and a percentage (%) of 68.20% for the 10000-2500 Mw range. The GPC chromatogram shows a purity of 94.59%. The molar ratios of X and Y are 80% and 20%, respectively.

[0062] Example 5: Preparation of sustained-release polymer (Mw approx. 8500)

[0063] Preparation method: A 10L reaction flask was heated to 85℃ and dried under reduced pressure for 1 hour. After cooling to room temperature, nitrogen gas was introduced to remove the vacuum. Triethylene glycol (630.8g, 4.80mol), intermediate 2 (319.4g, 1.20mol), and 3L of tetrahydrofuran were added to the reaction flask, and stirring was started. Intermediate 1 (1235.6g, 5.82mol) was dissolved in 5L of tetrahydrofuran and slowly added dropwise to the flask, maintaining the internal temperature at 25-50℃. After the addition was complete, the polymerization reaction was maintained at this temperature for 4-5 hours. The reaction system was cooled to room temperature, nitrogen gas was introduced to remove the vacuum, and the reaction solution was transferred to a 20L single-necked flask. Residual solvent was removed by rotary evaporation under reduced pressure. Finally, the sample was transferred to a high-density polyethylene bottle, yielding approximately 1967.2g of slow-release polymer, with a yield of 90%. Gel permeation chromatography was used to determine the molecular weight and distribution of the product. The sustained-release polymer obtained in this example has a molecular weight (Mw) of 8135 (g / mol), a number-average molecular weight (Mn) of 5410 (g / mol), a dispersion index of 1.50, and a percentage (%) of 60.42% for the 10000-2500 Mw range. The GPC chromatogram shows a purity of 96.08%. The molar ratios of X and Y are 80% and 20%, respectively.

[0064] Example 6: Preparation of sustained-release polymer (Mw approx. 10000)

[0065] Preparation method: A 20L reactor was heated to 85℃ and dried under reduced pressure for 1 hour. After cooling to room temperature, nitrogen gas was introduced to remove the vacuum. Triethylene glycol (1243.7g, 8.28mol), intermediate 2 (550.0g, 2.07mol), and 4L of tetrahydrofuran were added to the reactor, and stirring was started. Intermediate 1 (2176.1g, 10.25mol) was dissolved in 3L of tetrahydrofuran and slowly added dropwise to the reactor, maintaining the internal temperature at 25-50℃. After the addition was complete, the polymerization reaction was maintained at this temperature for 4-5 hours. The reaction system was cooled to room temperature, nitrogen gas was introduced to remove the vacuum, and the reaction solution was transferred to a 20L single-necked flask. Residual solvent was removed by rotary evaporation under reduced pressure. Finally, the sample was transferred to a high-density polyethylene bottle, yielding approximately 3572.8g of slow-release polymer, with a yield of 90%. Gel permeation chromatography was used to determine the molecular weight and distribution of the product. The sustained-release polymer obtained in this embodiment has a molecular weight (Mw) of 9927 (g / mol), a number-average molecular weight (Mn) of 6051 (g / mol), a dispersion index of 1.64, and a percentage (%) of 54.77% for the 10000-2500 Mw range. The GPC spectrum shows a purity of 1%. The molar ratios of X and Y are 80% and 20%, respectively.

[0066] Example 7: Preparation of sustained-release polymer (Mw approx. 12000)

[0067] Preparation method: A 20L reactor was heated to 85℃ and dried under reduced pressure for 1 hour. The mixture was then cooled to room temperature, and nitrogen gas was introduced to remove the vacuum. Triethylene glycol (901.2g, 6.00mol), intermediate 2 (referring to intermediate 2 in Example 2, 400g, 1.50mol), and 3L of tetrahydrofuran were added to the reactor, and stirring was started. Intermediate 1 (1768.5g, 8.33mol) was dissolved in 4L of tetrahydrofuran and slowly added dropwise to the reactor, maintaining the internal temperature at 25-50℃. After the addition was complete, the polymerization reaction was maintained at this temperature for 5-6 hours. The reaction system was cooled to room temperature, and nitrogen gas was introduced to remove the vacuum. The reaction solution was transferred to a 20L single-necked flask, and residual solvent was removed by rotary evaporation under reduced pressure. Finally, the sample was transferred to a high-density polyethylene bottle, yielding approximately 2793.4g of slow-release polymer, with a yield of 91%. Gel permeation chromatography was used to determine the molecular weight and distribution of the product. The sustained-release polymer obtained in this example has a molecular weight (Mw) of 12560 (g / mol), a number-average molecular weight (Mn) of 8047 (g / mol), a dispersion index of 1.56, and a percentage (%) of 28.67% for the 10000-2500 Mw range. The GPC chromatogram shows a purity of 96.42%. The molar ratios of X and Y are 80% and 20%, respectively.

[0068] Example 8: Preparation of sustained-release polymer (Mw approximately 5000, components are diethylene glycol and lactide)

[0069] Step S1: Preparation of intermediate 2 (diethylene glycol and lactide)

[0070]

[0071] Preparation method: Heat a 2L reaction flask to 80℃, dry under reduced pressure for 1h, cool to room temperature, purge with nitrogen to remove the vacuum, and add diethylene glycol (159.2g, 1.5mol) and lactide (216.2g, 1.5mol) to the reaction flask in a 1:1 molar ratio. Evacuate the system and replace with nitrogen to create an anhydrous and oxygen-free environment. Heat to 180℃ and maintain the temperature for 20-21h. Cool to room temperature, purge with nitrogen to remove the vacuum, and transfer the sample to a high-density polyethylene bottle to obtain approximately 337.9g ​​of intermediate 2 of this type, with a yield of 90%. Store in a sealed container under nitrogen protection.

[0072] Step S2: Preparation of the sustained-release polymer

[0073]

[0074] Preparation method: A 2L reaction flask was heated to 80℃ and dried under reduced pressure for 1 hour. After cooling to room temperature, nitrogen gas was introduced to remove the vacuum. Intermediate 1 (382.1g, 1.8mol), diethylene glycol (148.5g, 1.4mol), intermediate 2 (referring to intermediate 2 in step S1 of this embodiment, 150.1g, 0.6mol), and tetrahydrofuran were added to the reaction flask in 1000mL, and stirring was started. Intermediate 1 (382.1g, 1.8mol) was dissolved in 1000mL of tetrahydrofuran and slowly added dropwise to the reaction flask, maintaining the internal temperature at 25-50℃. After the addition was complete, the polymerization reaction was maintained at this temperature for 3-5 hours. The reaction system was cooled to room temperature, nitrogen gas was introduced to remove the vacuum, and the reaction solution was transferred to a 20L single-necked flask. Residual solvent was removed by rotary evaporation under reduced pressure. Finally, the sample was transferred to a high-density polyethylene bottle, yielding approximately 612.6g of slow-release polymer, with a yield of 90%. The molecular weight and distribution of the product were determined by gel permeation chromatography (GPC). Tetrahydrofuran was used as the mobile phase, and a differential detector was employed. Molecular weight calibration curves were prepared using polystyrene standards with molecular weights of 1000, 2000, 4000, 10000, and 20000. The sustained-release polymer obtained in this example had a molecular weight (Mw) of 5065 g / mol, a number-average molecular weight (Mn) of 3084 g / mol, a dispersion index of 1.64, and a 10000-2500 Mw percentage (%) of 67.42%. The GPC chromatogram showed a purity of 91.73%. The molar ratios of X and Y were 70% and 30%, respectively.

[0075] Example 9: Preparation of a sustained-release polymer (Mw approximately 9000, components: diethylene glycol and glycolide)

[0076] Step S1: Preparation of intermediate 2 (diethylene glycol and glycolide)

[0077]

[0078] Preparation method: Heat a 3L reaction flask to 80℃, dry under reduced pressure for 1h, cool to room temperature, purge with nitrogen to remove the vacuum, add diethylene glycol (265.3g, 2.5mol) and glycolide (290.3g, 2.5mol) to the reaction flask, evacuate with nitrogen to replace the reaction system to an anhydrous and oxygen-free environment, heat to 180-185℃ and keep at that temperature for 21-22h, cool to room temperature, purge with nitrogen to remove the vacuum, transfer the sample to a high-density polyethylene bottle to obtain approximately 522.3g of intermediate 2 of this type, with a yield of 94%, and store in a sealed container under nitrogen protection.

[0079] Step S2: Preparation of the sustained-release polymer

[0080]

[0081] Preparation method: A 10L reaction flask was heated to 80℃ and dried under reduced pressure for 1 hour. After cooling to room temperature, nitrogen gas was introduced to remove the vacuum. Diethylene glycol (445.6g, 4.20mol), intermediate 2 (400.0g, 1.80mol), and 2L of tetrahydrofuran were added to the reaction flask, and stirring was started. Intermediate 1 (1248.3g, 5.88mol) was dissolved in 2L of tetrahydrofuran and slowly added dropwise to the reaction flask, maintaining the internal temperature at 25–50℃. After the addition was complete, the polymerization reaction was maintained at this temperature for 3–4 hours. The reaction system was cooled to room temperature, nitrogen gas was introduced to remove the vacuum, and the reaction solution was transferred to a 10L single-necked flask. Residual solvent was removed by rotary evaporation under reduced pressure. Finally, the sample was transferred to a high-density polyethylene bottle, yielding approximately 1884.5g of slow-release polymer, with a yield of 90%. Gel permeation chromatography was used to determine the molecular weight and distribution of the product. The sustained-release polymer obtained in this embodiment has a molecular weight (Mw) of 9457 (g / mol), a number-average molecular weight (Mn) of 6693 (g / mol), a dispersion index of 1.41, and a percentage (%) of 55.80% for the 10000-2500 Mw range. The GPC chromatogram shows a purity of 100.00%. The molar ratios of X and Y are 70% and 30%, respectively.

[0082] Example 10: Preparation of a sustained-release polymer (Mw approximately 12000, components: decanediol and lactide)

[0083] Step S1: Preparation of intermediate 2 (decanediol and lactide)

[0084]

[0085] Preparation method: Heat a 3L reaction flask to 80℃, dry under reduced pressure for 1h, cool to room temperature, purge with nitrogen to remove the vacuum, add decanediol (348.6g, 2mol) and lactide (288.2g, 2mol) to the reaction flask, evacuate with nitrogen to replace the reaction system to an anhydrous and oxygen-free environment, heat to 180-185℃ and keep at that temperature for 23-24h, cool to room temperature, purge with nitrogen to remove the vacuum, transfer the sample to a high-density polyethylene bottle to obtain approximately 573.1g of intermediate 2 of this type, with a yield of 90%, and store in a sealed container under nitrogen protection.

[0086] Step S2: Preparation of the sustained-release polymer

[0087]

[0088] Preparation method: A 10L reaction flask was heated to 80℃ and dried under reduced pressure for 1 hour. After cooling to room temperature, nitrogen gas was introduced to remove the vacuum. Decanediol (925.5 g, 5.31 mol), intermediate 2 (565.0 g, 1.77 mol), and 2.5 L of tetrahydrofuran were added to the reaction flask, and stirring was started. Intermediate 1 (1653.8 g, 7.79 mol) was dissolved in 2.5 L of tetrahydrofuran and slowly added dropwise to the flask, maintaining the internal temperature at 25–50℃. After the addition was complete, the polymerization reaction was maintained at this temperature for 3–4 hours. The reaction system was cooled to room temperature, nitrogen gas was introduced to remove the vacuum, and the reaction solution was transferred to a 10L single-necked flask. Residual solvent was removed by rotary evaporation under reduced pressure. Finally, the sample was transferred to a high-density polyethylene bottle, yielding approximately 2767.0 g of slow-release polymer, with a yield of 88%. Gel permeation chromatography was used to determine the molecular weight and distribution of the product. The sustained-release polymer obtained in this embodiment has a molecular weight (Mw) of 12431 (g / mol), a number-average molecular weight (Mn) of 7900 (g / mol), a dispersion index of 1.57, and a percentage (%) of 28.72% for the 10000-2500 Mw range. The GPC chromatogram shows a purity of 92.25%. The molar ratios of X and Y are 75% and 25%, respectively.

[0089] Example 11: Preparation of a sustained-release polymer (Mw approximately 8000, components: propylene glycol and glycolide)

[0090] Step S1: Preparation of intermediate 2 (propylene glycol and glycolide)

[0091]

[0092] Preparation method: Heat a 3L reaction flask to 80℃, dry under reduced pressure for 1h, cool to room temperature, purge with nitrogen to remove the vacuum, add propylene glycol (190.3g, 2.5mol) and glycolide (290.3g, 2.5mol) to the reaction flask, evacuate with nitrogen to replace the reaction system to an anhydrous and oxygen-free environment, heat to 180-185℃ and keep reacting for 22-23h, cool to room temperature, purge with nitrogen to remove the vacuum, transfer the sample to a high-density polyethylene bottle to obtain approximately 442.2g of intermediate 2 of this type, with a yield of 92%, and store sealed under nitrogen protection.

[0093] Step S2: Preparation of the sustained-release polymer

[0094]

[0095] Preparation method: A 10L reaction flask was heated to 80℃ and dried under reduced pressure for 1 hour. After cooling to room temperature, nitrogen gas was introduced to remove the vacuum. Propylene glycol (633.2 g, 8.32 mol), intermediate 2 (400.0 g, 2.08 mol), and tetrahydrofuran (3.5 L) were added to the reaction flask, and stirring was started. Intermediate 1 (2118.7 g, 9.98 mol) was dissolved in 3.5 L of tetrahydrofuran and slowly added dropwise to the flask, maintaining the internal temperature at 25–50℃. After the addition was complete, the polymerization reaction was maintained at this temperature for 3–4 hours. The reaction system was cooled to room temperature, nitrogen gas was introduced to remove the vacuum, and the reaction solution was transferred to a 10L single-necked flask. Residual solvent was removed by rotary evaporation under reduced pressure. Finally, the sample was transferred to a high-density polyethylene bottle, yielding approximately 2805.2 g of slow-release polymer, with a yield of 89%. Gel permeation chromatography was used to determine the molecular weight and distribution of the product. The sustained-release polymer obtained in this example has a molecular weight (Mw) of 8135 (g / mol), a number-average molecular weight (Mn) of 5410 (g / mol), a dispersion index of 1.50, and a percentage (%) of 60.42% for the 10000-2500 Mw range. The GPC chromatogram shows a purity of 96.08%. The molar ratios of X and Y are 80% and 20%, respectively.

[0096] Experimental Example 1: Screening of the Dosage of the Sustained-Release Polymer

[0097] Formulated preparations were prepared using sustained-release polymers at different dosages as shown in Table 1, and the effects on in vitro release were studied.

[0098] Preparation method: The sustained-release polymer and triethyl glycerol are preheated and stirred together at 70°C. Bupivacaine, lornoxicam and maleic acid are added to DMSO and dissolved at 70°C. Then they are added to the sustained-release polymer and triethyl glycerol and stirred until homogeneous to obtain the final product.

[0099] Table 1. Composition of Prescriptions 1-3

[0100]

[0101] In vitro release studies:

[0102] Immersion method: Weigh approximately 200 mg of sample and spread it evenly on the immersion cell, cover it with a filter membrane, secure it with a gasket, place it in a release cup, add 100 mL of release medium (pH 7.4 PBS solution), and place it on a constant temperature incubator with a shaker set to 37°C and a shaking frequency of 120 rpm. Samples were taken at preset time points to detect the release amount.

[0103] Table 2. In vitro release data of bupivacaine from prescriptions 1-3.

[0104]

[0105]

[0106] Table 3. In vitro release data of lornoxicam for prescriptions 1-3

[0107] Time (h) Prescription 1 Prescription 2 Prescription 3 0 0.00％ 0.00％ 0.00％ 1 5.22％ 12.51％ 3.36％ 2 7.07％ 16.62％ 5.50％ 4 12.73％ 25.51％ 9.25％ 8 19.88％ 36.43％ 16.58％ 24 49.38％ 55.08％ 40.56％ 48 79.36％ 85.38％ 70.15％ 72 92.41％ 96.03％ 82.35％

[0108] The results are shown in Tables 2 and 3. Figure 1 , Figure 2 As shown, in Formulation 1, the amount of the sustained-release polymer was 62.35%, and bupivacaine and lornoxicam were released at 91.31% and 92.41% respectively after 72 hours. In Formulation 2, by reducing the amount of the sustained-release polymer, the release of bupivacaine and lornoxicam increased, reaching 98.08% and 96.03% respectively after 72 hours. In contrast, in Formulation 3, the amount of the sustained-release polymer was increased to 79.95%, and the release of bupivacaine and lornoxicam decreased after 72 hours, reaching 83.15% and 82.35% respectively. These results indicate that the amount of the sustained-release polymer affects the release rate of bupivacaine and lornoxicam: as the amount of the sustained-release polymer increases, the release rate slows down; while reducing the amount of the sustained-release polymer accelerates the release rate. However, all three formulations achieved sustained-release effects within 72 hours, and the cumulative release of bupivacaine and lornoxicam both exceeded 75%, meeting the basic requirements for sustained-release formulations.

[0109] Experimental Example 2: Screening of Viscosity Reducing Agents

[0110] According to the formulation composition in Table 4 and the different viscosity modifiers in Table 5, bupivacaine-lornoxicam formulations were prepared using different viscosity reducers, following the same preparation method as in Example 1. The properties were observed, and the viscosity of the formulations was measured. A digital rotary viscometer was used, with rotor #21 selected and the rotation speed set to 5 rpm. The formulation was added to the sample cell, ensuring the sample submerged the rotor. Once the sample temperature reached 25°C, the sample viscosity was measured. After the value stabilized, the data was recorded.

[0111] Table 4. Viscosity regulator formulation composition

[0112]

[0113]

[0114] Table 5. Properties and viscosity results of prescription formulations prepared with different viscosity modifiers.

[0115] viscosity modifier Properties viscosity Glyceryl monooleate Turbid, not clear / castor oil Turbid, not clear / PEG200 Turbid, not clear / PEG300 Clarification, transparency 10027 mPa·S benzyl benzoate Clarification, transparency 1232 mPa·S mPEG550 Clarification, transparency 8936 mPa·S Isopropyl adipate Clarification, transparency 3725 mPa·S benzyl alcohol Clarification, transparency 9366 mPa·S Triethyl citrate Clarification, transparency 8018 mPa·S Triethylglycerol Clarification, transparency 6720 mPa·S Tripropylglyceride Clarification, transparency 5099 mPa·S Tributyl glyceride Clarification, transparency 4334 mPa·S

[0116] Table 5 shows the preparation of bupivacaine-lornoxicam formulations using different viscosity modifiers. The formulations prepared using PEG300, benzyl benzoate, mPEG550, isopropyl adipate, benzyl alcohol, triethyl citrate, triethyl glycerol, tripropyl glycerol, and tributyl glycerol as viscosity modifiers were all clear and transparent, with viscosities ranging from approximately 3000 to 12000 mPa·s. This formulation requires a certain viscosity to adhere to the administration site for an extended period, achieving a sustained-release effect for up to three days, providing prolonged analgesia. It also needs to maintain a certain degree of fluidity for easy formulation preparation and to ensure the permeability of the delivery device. Therefore, to control the viscosity of the formulation within the range of 4000-10000 mPa·s, triglycerides and triethyl citrate were selected as viscosity modifiers for further research.

[0117] Formulated preparations were prepared using different types of triglycerides and triethyl citrate as shown in Table 6, and their effects on in vitro release were studied.

[0118] Table 6. Formulation composition of prescriptions 4-7

[0119]

[0120] The results of the in vitro release study are shown in Tables 7 and 8.

[0121] Table 7. In vitro release data of bupivacaine from prescriptions 4-7.

[0122] Time (h) Prescription 4 Prescription 5 Prescription 6 Prescription 7 0 0.00％ 0.00％ 0.00％ 0.00％ 1 8.01％ 10.08％ 12.66％ 5.51％ 2 11.97％ 13.24％ 17.44％ 9.62％ 4 17.13％ 19.07％ 25.57％ 12.57％ 8 25.85％ 28.99％ 35.60％ 18.89％ 24 52.58％ 56.88％ 63.32％ 45.88％ 48 77.31％ 80.25％ 84.75％ 72.25％ 72 92.01％ 95.01％ 99.67％ 89.01％

[0123] Table 8. In vitro release data of lornoxicam for prescriptions 4-7

[0124] Time (h) Prescription 4 Prescription 5 Prescription 6 Prescription 7 0 0.00％ 0.00％ 0.00％ 0.00％ 1 7.12％ 9.18％ 11.07％ 4.58％ 2 10.89％ 11.43％ 15.44％ 6.24％ 4 16.23％ 18.87％ 23.80％ 10.97％ 8 24.00％ 28.93％ 33.98％ 17.89％ 24 50.19％ 54.80％ 60.20％ 44.88％ 48 78.13％ 81.25％ 84.89％ 72.25％ 72 90.11％ 94.57％ 98.69％ 88.93％

[0125] Research indicates that the longer the ester chain of a triglyceride viscosity modifier, the better it reduces formulation viscosity. Formulation 6 uses tributyl glycerol as a viscosity modifier, resulting in a formulation viscosity of 4334 mPa·s. Its release rate is slightly faster than formulations using triethyl and tripropyl glycerol as viscosity modifiers (Formulations 4 and 5), but it still achieves a 72-hour sustained-release effect. Formulation 7 uses triethyl citrate as a viscosity modifier, resulting in a formulation viscosity of 8018 mPa·s. Its release rate is slightly slower than formulations using triglycerides as viscosity modifiers, but the 72-hour release rate of bupivacaine and lornoxicam is >85%. Therefore, when the formulation viscosity is between 4000-10000 mPa·s, the drug can achieve a 72-hour sustained-release effect.

[0126] Experimental Example 3: Study on the effect of sustained-release polymer molecular weight on in vitro drug release

[0127] Formulated preparations were prepared using sustained-release polymers of different molecular weights according to Table 9, and the effect of molecular weight on drug release in vitro was studied.

[0128] Table 9. Composition of Prescriptions 8-12

[0129]

[0130] The in vitro release method is the same as in Example 1, and the results are shown in Tables 10 and 11. Figure 3 and Figure 4 ,

[0131] Table 10. In vitro release data of bupivacaine from prescriptions 8-12

[0132] time Prescription 8 Prescription 9 Prescription 10 Prescription 11 Prescription 12 0 0.00％ 0.00％ 0.00％ 0.00％ 0.00％ 1 17.87％ 9.50％ 8.20％ 5.12％ 3.22％ 2 24.17％ 12.33％ 11.23％ 7.40％ 4.81％ 4 33.24％ 16.24％ 14.25％ 11.96％ 7.49％ 6 40.92％ 21.10％ 18.59％ 15.74％ 10.38％ 8 47.94％ 27.69％ 23.24％ 19.21％ 14.03％ 24 82.09％ 55.26％ 46.30％ 38.54％ 30.11％ 48 97.85％ 82.06％ 75.79％ 60.71％ 46.26％ 72 99.85％ 94.17％ 88.67％ 72.69％ 55.32％

[0133] Table 11. In vitro release data of lornoxicam from prescriptions 8-12

[0134]

[0135]

[0136] Based on in vitro release results, the sustained-release polymer in Formula 8 has a low molecular weight of 2426 g / mol, resulting in rapid release of both bupivacaine and lornoxicam, with cumulative release exceeding 95% after 48 hours, essentially complete release, but failing to achieve the 72-hour sustained-release effect. The sustained-release polymers used in Formulas 11 and 12 have molecular weights above 10000 g / mol, resulting in slower in vitro release of both bupivacaine and lornoxicam, with cumulative drug release below 85% after 72 hours; Formula 12 releases only 50% of the drug. The sustained-release polymers in Formulas 9 and 10 have molecular weights of 6608 and 8135 g / mol, respectively, with moderate release rates, exhibiting slow release over 72 hours. Therefore, sustained-release polymers with molecular weights in the range of 5000-9000 g / mol can be selected to prepare formulations, enabling the drug to achieve a sustained-release effect.

[0137] Experimental Example 4: Effect of Bupivacaine and Lornoxicam Dosage on Efficacy

[0138] Prescription formulations were prepared according to different dosages of bupivacaine and lornoxicam as shown in Tables 12 and 13, and their effects on the treatment of pain in a rat model were investigated.

[0139] (1) Prescriptions 13-16: The prescription dosage of bupivacaine was fixed, and the dosage of lornoxicam was screened.

[0140] (2) Prescriptions 17-18: The dosage of lornoxicam was fixed, and the dosage of bupivacaine was screened.

[0141] Table 12. Formulation composition of prescriptions 13-16

[0142]

[0143]

[0144] Table 13. Composition of Formulations 17-18

[0145]

[0146] (3) Proof of long-lasting efficacy

[0147] SD rats weighing approximately 300g were selected as experimental animals, with 10 rats per group, to study the efficacy of formulations 13-18, as well as the bupivacaine-loaded group, lornoxicam-loaded group, and blank-loaded group. Before the experiment, hair was removed from the right hind leg ankle joint of each rat using depilatory cream, and the initial pain threshold at the ankle joint was measured using a digital push-pull force meter as baseline data. Subsequently, rats were anesthetized with isoflurane. The model group was induced by injection of 200μL of 25mg / mL sodium urate suspension, while the control group was injected with 200μL of PBS. After successful modeling, the model group was subcutaneously injected with 200μL of the corresponding carrier, and each drug-loaded group was subcutaneously injected with 200μL of each drug-loaded carrier. After administration, the changes in pain threshold of each group of rats were measured using a digital push-pull force meter at time points of 1h, 3h, 8h, 24h, 72h, 120h, and 240h, and the changes and duration of analgesic efficacy were recorded.

[0148] Data analysis employed ANOVA or t-test to compare differences between different groups.

[0149] Experimental Example 5 Solvent Screening

[0150] According to Table 14, bupivacaine lornoxicam formulations were prepared using dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylacetamide as solvents, respectively.

[0151] Table 14. Formulation composition of prescriptions 19-21

[0152]

[0153]

[0154] The results are shown in the table above. Dimethyl sulfoxide and N,N-dimethylacetamide can both be selected as solvents for formulation preparation.

[0155] Example 6: Preparation of a bupivacaine-lornoxicam sustained-release composition

[0156] (1) Preparation of the composition of Formula 22:

[0157] Table 15 Formulation Composition of Formula 22

[0158]

[0159] Preparation process: First, polyorthoester and triethyl glycerol are premixed at 70°C. Then, at 70°C, the prescribed amounts of bupivacaine, lornoxicam and maleic acid are added to DMSO to dissolve. After complete dissolution, the drug solution is added to the polyorthoester and triethyl glycerol mixture and stirred until homogeneous.

[0160] (2) Preparation of the composition of Formula 23:

[0161] Table 16 Formulation 23 Preparation Composition

[0162]

[0163] Preparation process: First, polyorthoester and triethyl glycerol are premixed at 60°C. Then, at 60°C, the prescribed amounts of bupivacaine, lornoxicam and maleic acid are added to DMSO to dissolve. After complete dissolution, the drug solution is added to the polyorthoester and triethyl glycerol mixture and stirred until homogeneous.

[0164] (3) Preparation of the composition of prescription 24:

[0165] Table 17 Formulation 24 Composition

[0166]

[0167] Preparation process: First, polyorthoester and triethyl glycerol are premixed at 70°C. Then, at 70°C, the prescribed amounts of bupivacaine, lornoxicam and maleic acid are added to DMSO to dissolve. After complete dissolution, the drug solution is added to the polyorthoester and triethyl glycerol mixture and stirred until homogeneous.

[0168] (4) Preparation of Formula 25 composition:

[0169] Table 18 Formulation 25 Composition

[0170]

[0171] Preparation process: First, polyorthoester and triglyceride are premixed at 70°C. Then, at 70°C, the prescribed amounts of bupivacaine, lornoxicam and maleic acid are added to DMSO to dissolve. After complete dissolution, the drug solution is added to the polyorthoester and triglyceride mixture and stirred until homogeneous.

[0172] (5) Preparation of the composition of Formula 26:

[0173] Table 19 Formulation 26 Preparation Composition

[0174]

[0175]

[0176] Preparation process: First, polyorthoester and triethyl citrate are premixed at 70°C. Then, at 70°C, the prescribed amounts of bupivacaine, lornoxicam and maleic acid are added to DMSO and dissolved. After complete dissolution, the drug solution is added to the polyorthoester and triethyl citrate mixture and stirred until homogeneous.

[0177] (6) Preparation of the composition of Formula 27:

[0178] Table 20 Formulation 27 Preparation Composition

[0179]

[0180] Preparation process: First, polyorthoester and triethyl glycerol are premixed at 60°C. Then, at 60°C, the prescribed amounts of bupivacaine, lornoxicam and maleic acid are added to N,N-dimethylformamide and dissolved. After complete dissolution, the drug solution is added to the polyorthoester and triethyl glycerol mixture and stirred until homogeneous.

[0181] (7) Preparation of the composition of Formula 28:

[0182] Table 21 Formulation 28 Composition

[0183]

[0184] Preparation process: First, polyorthoester and triethyl glycerol are premixed at 50°C. Then, at 50°C, the prescribed amounts of bupivacaine, lornoxicam and maleic acid are added to DMSO and dissolved. After complete dissolution, the drug solution is added to the polyorthoester and triethyl glycerol mixture and stirred until homogeneous.

[0185] (8) Preparation of the composition of Formula 29:

[0186] Table 22 Formulation 29 Composition

[0187]

[0188] Preparation process: First, polyorthoester and triethyl glycerol are premixed at 60°C. Then, at 60°C, the prescribed amounts of bupivacaine, lornoxicam and maleic acid are added to DMSO to dissolve. After complete dissolution, the drug solution is added to the polyorthoester and triethyl glycerol mixture and stirred until homogeneous.

[0189] (9) Preparation of Formula 30 composition:

[0190] Table 23 Formulation Composition of Formula 30

[0191]

[0192] Preparation process: First, polyorthoester and triethyl glycerol are premixed at 70°C. Then, at 70°C, the prescribed amounts of bupivacaine, lornoxicam and maleic acid are added to DMSO to dissolve. After complete dissolution, the drug solution is added to the polyorthoester and triethyl glycerol mixture and stirred until homogeneous.

[0193] (10) Preparation of the composition of Formula 31:

[0194] Table 24 Formulation 31 Composition

[0195]

[0196]

[0197] Preparation process: First, polyorthoester and triethyl glycerol are premixed at 70°C. Then, at 70°C, the prescribed amounts of bupivacaine, lornoxicam and maleic acid are added to DMSO to dissolve. After complete dissolution, the drug solution is added to the polyorthoester and triethyl glycerol mixture and stirred until homogeneous.

[0198] (11) Preparation of the composition of prescriptions 32-39:

[0199] Table 25 Formulation Composition of Formula 32

[0200]

[0201] Table 26 Formulation 33 Preparation Composition

[0202]

[0203] Table 27 Formulation 34 Composition

[0204]

[0205] Table 28 Formulation 35 Composition

[0206]

[0207]

[0208] Table 29 Formulation 36 Composition

[0209]

[0210] Table 30 Formula 37 Preparation Composition

[0211]

[0212] Table 31 Formulation 38 Composition

[0213]

[0214] Table 32 Formulation Composition of Formula 39

[0215]

[0216]

[0217] The preparation methods for prescriptions 32-39 are the same as those for prescription 22.

[0218] Experimental Example 7: In vitro release study using the immersion tank method

[0219] An in vitro release study was conducted on the formulation composition of Test Example 6. Approximately 200 mg of sample was weighed and spread evenly on an immersion tank, covered with a filter membrane, secured with a gasket, placed in a release cup, and 100 mL of release medium (pH 7.4 PBS solution) was added. The tank was then placed on a constant-temperature incubator with a shaking setting of 37°C and a shaking frequency of 120 rpm. Samples were taken at preset time points to determine the release amount.

[0220] Stability Study of Experiment Example 8

[0221] The formulation composition from Experimental Example 6 was selected for stability studies. The study protocol included: long-term studies at 25℃±2℃ and 60%±5% relative humidity; studies on influencing factors at light intensity of 4500lx±500lx, high temperature of 60℃±2℃, high humidity of 75%±5%, and high humidity of 92.5%±5%; and accelerated studies at 40℃±2℃ and 75%±5% relative humidity. The assays included appearance, drug content and related substances, and polymer molecular weight.

[0222] Example 9: Proof of Long-Lasting Efficacy

[0223] SD rats weighing approximately 300g were selected as experimental animals, with 10 rats per group, to study the efficacy of the prescription composition in Experiment 6, as well as the bupivacaine-loaded group, lornoxicam-loaded group, and blank-loaded group. Before the experiment, hair was removed from the right hind leg ankle joint of each rat using depilatory cream, and the initial pain threshold at the ankle joint was measured using a digital push-pull force meter as baseline data. Subsequently, rats were anesthetized with isoflurane. The model group was induced by injection of 200μL of 25mg / mL sodium urate suspension, while the control group was injected with 200μL of PBS. After successful modeling, the model group was subcutaneously injected with 200μL of the corresponding carrier, and each drug-loaded group was subcutaneously injected with 200μL of each drug-loaded carrier. After administration, the changes in pain threshold of each group of rats were measured using a digital push-pull force meter at time points of 1h, 3h, 8h, 24h, 72h, 120h, and 240h, and the changes and duration of analgesic efficacy were recorded.

[0224] Data analysis employed ANOVA or t-test to compare differences between different groups.

[0225] Experimental Example 10 PK Verification

[0226] In vivo pharmacokinetic studies were conducted as follows. SD rats (approximately 300g) (n=6) were administered a single dose of 400μl of the composition. The composition included the formulation from Test Example 6, as well as bupivacaine-loaded and lornoxicam-loaded groups. Plasma samples were collected from each rat at 0 (immediately before drug administration), 24h, 48h, 72h, 96h, 120h, and 240h after subcutaneous injection. Bupivacaine and meloxicam in the plasma samples were subsequently analyzed by LC / MS / MS to calculate key pharmacokinetic parameters, such as peak concentration (C0.05). max Peak time (T) max Area under the curve (AUC) and half-life (t) 1 / 2 Data analysis utilized pharmacokinetic software to compare drug concentration-time curves between different groups to examine drug release characteristics and in vivo behavior.

Claims

1. A long-acting analgesic composition based on a biodegradable polymer delivery system, characterized in that, Include: (a) The active pharmaceutical ingredient is selected from a combination of bupivacaine and lornoxicam; (b) Aprotic polar solvents; (c) A sustained-release polymer having a molecular weight of 4000-12000 Mw g / mol, with the structural formula shown in Formula I: Where A is a residue of a diol, and the residue of the diol is selected from: C 1-10 Straight-chain alkyl groups or their acetals, C 1-10 Branched alkanes or their alcohol condensations, C 4-10 cyclic alkanes or their alcohol condensations; R is H or C 1-4 Alkyl groups; The degree of aggregation n is an integer from 0 to 7; X and Y are values ​​in the molar ratio range of 10 to 90, and satisfy X + Y = 100.

2. The sustained-release polymer according to claim 1, characterized in that, The residues of the diol are: -(CH2)a-, or -[(CH2CH2)b-O]c-, where a is an integer from 2 to 10; b is an integer from 2 to 5; c is an integer from 2 to 4; and the degree of polymerization n is an integer from 2 to 7. Further, the diol is: ethylene glycol, propylene glycol, butanediol, hexanediol, decanediol or its acetal; R is hydrogen or methyl; the polymer has a molecular weight of 5000 Mw g / mol to 10000 Mw g / mol; the molar ratios X and Y are in the range of 70 ≤ X ≤ 90, 10 ≤ Y ≤ 30; Further, the diol is: ethylene glycol, propylene glycol, hexanediol, decanediol, diethylene glycol, or triethylene glycol; R is hydrogen or methyl; the polymer has a molecular weight of 5000 Mw g / mol to 10000 Mw g / mol; the molar ratios X and Y are in the range of: 75 ≤ X ≤ 85, 15 ≤ Y ≤ 25; Further, the diol is propylene glycol or triethylene glycol; R is hydrogen; the polymer has a molecular weight of 6000 Mw g / mol to 8000 Mw g / mol; the molar ratios X and Y are in the range of X = 80 and Y = 20.

3. The composition according to claim 1, characterized in that, The active pharmaceutical ingredients include bupivacaine at 0.5-10% w / w of the total composition and lornoxicam at 0.01-1% w / w of the total composition.

4. The composition according to claim 1, characterized in that, The aprotic polar solvent accounts for 3-30% w / w of the total composition; the aprotic polar solvent is selected from one or more of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, and acetone.

5. The composition according to claim 1, characterized in that, The composition may further include a viscosity modifier, wherein the viscosity modifier accounts for 1-40% w / w of the total composition; the viscosity modifier is one or more of triglycerides, triethyl citrate, PEG300, mPEG550, isopropyl adipate, benzyl alcohol, propylene glycol fatty acid esters, medium-chain triglycerides, and benzyl benzoate; preferably triglycerides or triethyl citrate.

6. The composition according to claim 1, characterized in that, The slow-release polymer comprises 40-80% w / w of the total composition, and the viscosity of the composition is about 2000 mPa·s to 20000 mPa·s.

7. The composition according to claim 1, characterized in that, The composition may also contain an acidic excipient selected from maleic acid or citric acid.

8. The composition according to claim 1, characterized in that, The composition may also contain an alkalinity modifier, such as magnesium hydroxide, ethanolamine, or tromethamine.

9. A pharmaceutical preparation, characterized in that, The composition comprising any one of claims 1-8, wherein the formulation is administered by subcutaneous injection, peripheral nerve injection, intramuscular injection or direct application to a wound.

10. The composition according to any one of claims 1-8 is used in the preparation of products for local anesthesia, postoperative analgesia, and preventive treatment of pain.

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