Bupivacaine multivesicular liposome, gel, composition, and preparation method and application of bupivacaine multivesicular liposome, gel and composition

Abstract

The invention provides bupivacaine multivesicular liposome, gel and composition as well as a preparation method and application of the bupivacaine multivesicular liposome and gel. The bupivacaine polycystic liposome disclosed by the invention is prepared from the following components: 8 to 20 mg / mL of phosphoric acid, 5 to 15 mg / mL of dierucyl phosphatidylcholine, 0.5 to 5 mg / mL of dipalmitoyl phosphatidyl glycerol, 0.5 to 5 mg / mL of tricaprylin, 2 to 10 mg / mL of cholesterol, 15 to 35 mg / mL of bupivacaine, 25 to 140 mg / mL of lysine, 55 to 400 mg / mL of osmotic pressure regulator and 15 to 20 mg / mL of sodium chloride. The gel containing the bupivacaine multivesicular liposome and the composition provided by the invention can improve the analgesic effect, prolong the analgesic time and play a slow-release analgesic role, and can be applied to the field of postoperative slow-release long-acting multimode analgesia, and the used materials are non-toxic and non-irritant, and have good biocompatibility and degradability.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and in particular relates to a bupivacaine polycystic liposome, a gel, a composition, and a preparation method and application thereof. BACKGROUND

[0002] Postoperative pain refers to the pain reaction caused by inflammation, hyperalgesia or nerve injury secondary to surgical trauma accompanying the surgical process. Postoperative pain includes somatic pain and visceral pain, and the duration is usually about three to seven days.

[0003] Currently marketed analgesic drugs are mainly local anesthetics, non-steroidal anti-inflammatory drugs and opioid drugs, but the duration of action is short. Among them, opioid drugs have addiction, and opioid drugs and non-steroidal anti-inflammatory drugs penetrate the whole body and play their role in the central nervous system. Local anesthetics, whether local infiltration or used in regional anesthesia techniques, can be used to relieve postoperative pain. However, due to the short half-life of local anesthetics when used single time, and repeated application or high-dose application will increase the risk of systemic complications in patients.

[0004] Zynrelef is the only marketed dual-acting local anesthetic, which can provide up to 72 hours of analgesic effect for adult patients receiving total knee arthroplasty, bunionectomy, and inguinal hernia repair. It uses a combination of bupivacaine and meloxicam, and compared with bupivacaine alone, Zynrelef has better persistence and reduces the need for opioid drugs. However, some postoperative pain lasts longer, so a multi-modal analgesic method for sustained long-acting analgesia needs to be developed.

[0005] Bupivacaine is a local anesthetic that can block voltage-gated sodium channels, increase the electrical stimulation threshold of nerve fibers, reduce the slope of action potential, and reduce the generation and propagation of nerve impulses, producing local analgesic effect. Meloxicam is a cyclooxygenase inhibitor that preferentially binds to cyclooxygenase-2 (COX-2) at low doses to inhibit the synthesis of prostaglandins, reducing inflammation at the surgical site. Compared with other non-steroidal anti-inflammatory drugs, it has fewer gastrointestinal side effects. When meloxicam is used in combination with bupivacaine, the effect of meloxicam is that it can reduce local inflammation, restore the pH value to normal, keep bupivacaine in an alkaline form, promote the absorption of bupivacaine, and thus increase the ability of bupivacaine to penetrate the neuronal cell membrane, providing enhanced and sustained analgesic effect; secondly, meloxicam has strong analgesic effect and small dosage, which is convenient for compounding; thirdly, meloxicam has a very long half-life, which is conducive to single-dose analgesia to reduce local inflammation. This synergistic mechanism overcomes the problem of limited local anesthetic action time in an acidic inflammatory environment after surgery.

[0006] The multivesicular liposome is a spherical preparation composed of multiple non-concentric aqueous chambers, i.e. vesicles, which gradually release the drug by erosion and dissolution with the rupture of the inner vesicles. Bupivacaine multivesicular liposome EXPAREL has been approved in the United States and Europe for use as postoperative local analgesia and for use as interscalene brachial plexus block to produce postoperative regional analgesia, but the effective time is 72 h, the release time is short, and the purpose of drug sustained release is not fundamentally solved.

[0007] The temperature-sensitive gel has good biocompatibility, low toxicity and biodegradability, and can realize solution-gel transition according to the change of external temperature, i.e. can form a drug depot under the condition of body temperature, so as to achieve the purpose of long-term slow release of the drug. However, the bupivacaine multivesicular liposome gel prepared by the bupivacaine multivesicular liposome and the temperature-sensitive gel has very poor stability.

[0008] Poloxamer is a commonly used temperature-sensitive gel material, and even if an isotonic gel solution is prepared, the multivesicular liposome cannot remain stable in the gel solution. Chitosan is also a commonly used temperature-sensitive gel material, and is widely used in drug delivery due to its biocompatibility, biodegradability, non-toxicity, promotion of wound healing and antibacterial effect. However, chitosan has the disadvantages of low mechanical strength and slow temperature response speed, and must be combined with other gelling agents to improve its performance. However, even if chitosan and β-glycerophosphate disodium are used as temperature-sensitive gel materials, the multivesicular liposome is still broken in the gel system. SUMMARY

[0009] The technical problem to be solved by the present application is to overcome the defects of the existing postoperative analgesic drugs, such as short action time, low analgesic effect and poor stability of bupivacaine multivesicular liposome gel, and to provide a bupivacaine multivesicular liposome, a gel, a composition and a preparation method and application thereof. The bupivacaine multivesicular liposome, the gel and the composition of the present application can effectively prolong the action time of the drug analgesia, improve the analgesic effect of the drug, and the stability of the bupivacaine multivesicular liposome gel is excellent.

[0010] The technical problem to be solved by the present application is solved by the following technical scheme.

[0011] In a first aspect, the present application provides a bupivacaine multivesicular liposome comprising the following concentrations of components:

[0012] Phosphoric acid 8-20 mg / mL,

[0013] Dijoyoylphosphatidylcholine 5-15 mg / mL,

[0014] Dipalmitoylphosphatidylglycerol 0.5-5 mg / mL,

[0015] Tricaprylin 0.5-5 mg / mL,

[0016] Cholesterol 2-10 mg / mL,

[0017] Bupivacaine 15-35 mg / mL,

[0018] Lysine 25-140 mg / mL,

[0019] Osmotic pressure regulator 55-400 mg / mL, and

[0020] Sodium chloride 15-20 mg / mL.

[0021] In the present invention, the concentration of the phosphate in the bupivacaine polycystic liposomes is preferably 9-18 mg / mL, more preferably 9.38-17.81 mg / mL, such as 14.07 mg / mL or 16.63 mg / mL.

[0022] In the present invention, the concentration of the dierucylphosphatidylcholine in the bupivacaine polycystic liposomes is preferably 6-13 mg / mL, more preferably 6.57-12.67 mg / mL, such as 9.86 mg / mL or 11.45 mg / mL.

[0023] In the present invention, the concentration of the dipalmitoylphosphatidylglycerol in the bupivacaine polycystic liposomes is preferably 1-3 mg / mL, more preferably 1.4-2.77 mg / mL, such as 2.10 mg / mL or 2.43 mg / mL.

[0024] In the present invention, the concentration of the glyceryl trioctanoate in the bupivacaine polycystic liposomes is preferably 1-3 mg / mL, more preferably 1.53-2.97 mg / mL, such as 2.30 mg / mL or 2.67 mg / mL.

[0025] In the present invention, the concentration of the cholesterol in the bupivacaine polycystic liposomes is preferably 3-7 mg / mL, more preferably 3.56-6.73 mg / mL, such as 5.34 mg / mL or 6.19 mg / mL.

[0026] In the present invention, the concentration of the bupivacaine in the bupivacaine polycystic liposomes is preferably 16-31 mg / mL, more preferably 16.25-30.88 mg / mL, such as 24.37 mg / mL or 28.30 mg / mL.

[0027] In the present invention, the concentration of the lysine in the bupivacaine polycystic liposomes is preferably 30-135 mg / mL, more preferably 30-134.58 mg / mL, such as 61.2 mg / mL, 31.5 mg / mL or 71.25 mg / mL.

[0028] In the present application, the concentration of the osmotic pressure adjusting agent in the bupivacaine multivesicular liposomes is preferably 63-377 mg / mL, more preferably 63-376.04 mg / mL, for example 144 mg / mL or 166.25 mg / mL.

[0029] In the present application, the concentration of the sodium chloride in the bupivacaine multivesicular liposomes is preferably 15-19 mg / mL, more preferably 15-18 mg / mL, for example 17 mg / mL.

[0030] In the present application, preferably, the osmotic pressure adjusting agent is one or more of glucose, sucrose and sodium chloride, for example glucose.

[0031] In some preferred embodiments of the present application, the bupivacaine multivesicular liposomes comprise the following concentrations of components:

[0032] Phosphoric acid 9-18 mg / mL,

[0033] Dierucoylphosphatidylcholine 6-13 mg / mL,

[0034] Dipalmitoylphosphatidylglycerol 1-3 mg / mL,

[0035] Tricaprylin 1-3 mg / mL,

[0036] Cholesterol 3-7 mg / mL,

[0037] Bupivacaine 16-31 mg / mL,

[0038] Lysine 30-135 mg / mL,

[0039] Osmotic pressure adjusting agent 63-377 mg / mL, and,

[0040] Sodium chloride 15-19 mg / mL.

[0041] In some more preferred embodiments of the present application, the bupivacaine multivesicular liposomes comprise the following concentrations of components:

[0042] Phosphoric acid 9.38-17.81 mg / mL,

[0043] Dierucoylphosphatidylcholine 6.57-12.67 mg / mL,

[0044] Dipalmitoylphosphatidylglycerol 1.4-2.77 mg / mL,

[0045] Tricaprylin 1.53-2.97 mg / mL,

[0046] Cholesterol 3.56-6.73 mg / mL,

[0047] Bupivacaine 16.25-30.88 mg / mL,

[0048] Lysine 30-134.58 mg / mL,

[0049] Osmotic pressure regulator 63-376.04 mg / mL, and

[0050] Sodium chloride 15-19 mg / mL.

[0051] In the present application, preferably, the osmotic pressure of the bupivacaine polycystic liposomes is 500-600 mOsmol / kg, for example, 517 mOsmol / kg, 564 mOsmol / kg or 583 mOsmol / kg.

[0052] In the present application, preferably, the average particle size of the bupivacaine polycystic liposomes is 9-18 μm, for example, 9.65 μm, 12.5 μm or 14.1 μm.

[0053] In the second aspect, the present application further provides bupivacaine polycystic liposomes with an osmotic pressure of 500-600 mOsmol / kg.

[0054] In the present application, the osmotic pressure of the bupivacaine polycystic liposomes is, for example, 517 mOsmol / kg, 564 mOsmol / kg or 583 mOsmol / kg.

[0055] In the present application, preferably, the average particle size of the bupivacaine polycystic liposomes is 9-18 μm, for example, 9.65 μm, 12.5 μm or 14.1 μm.

[0056] In the third aspect, the present application further provides a preparation method of bupivacaine polycystic liposomes, which comprises the following steps:

[0057] Mixing the inner water phase and the lipid phase to obtain a primary emulsion; mixing the primary emulsion and the outer water phase to obtain a complex emulsion; and concentrating the complex emulsion by ultrafiltration to obtain the bupivacaine polycystic liposomes.

[0058] Preferably, the inner water phase comprises phosphoric acid and water, and the concentration of the phosphoric acid in the inner water phase is preferably 25-45 mg / mL.

[0059] Preferably, the lipid phase comprises dioleoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, glyceryl trioctanate, cholesterol and bupivacaine, and an organic solvent; and the concentration of the bupivacaine in the lipid phase is preferably 42-78 mg / mL.

[0060] Preferably, the outer aqueous phase comprises water, an osmotic pressure regulator and lysine; the concentration of the osmotic pressure regulator in the outer aqueous phase is preferably 42-95 mg / mL; the concentration of the lysine in the outer aqueous phase is preferably 20-34 mg / mL.

[0061] In the present application, the inner aqueous phase generally uses pure water as the solvent.

[0062] In the present application, preferably, the organic solvent in the lipid phase is a halogenated hydrocarbon solvent, such as chloroform or dichloromethane.

[0063] In the present application, preferably, the concentration of the diarachidonoyl phosphatidylcholine in the lipid phase is 17-32 mg / mL.

[0064] In the present application, preferably, the concentration of the dipalmitoyl phosphatidylglycerol in the lipid phase is 3.5-7 mg / mL.

[0065] In the present application, preferably, the concentration of the trioctanoin in the lipid phase is 4-7.5 mg / mL.

[0066] In the present application, preferably, the concentration of the cholesterol in the lipid phase is 9-17 mg / mL.

[0067] In the present application, preferably, the concentration of the bupivacaine in the lipid phase is 54-72 mg / mL.

[0068] In the present application, preferably, the mixing of the inner aqueous phase and the lipid phase is by dropwise addition of the inner aqueous phase to the lipid phase.

[0069] In the present application, preferably, the mixing of the inner aqueous phase and the lipid phase is accompanied by high-speed shearing.

[0070] Preferably, the speed of the high-speed shearing is 10,000-15,000 rpm.

[0071] Preferably, the time of the high-speed shearing is 20-30 min.

[0072] In the present application, the volume ratio of the inner aqueous phase to the lipid phase is preferably 1:(0.8-1.2), more preferably 1:1.

[0073] In the present application, the outer aqueous phase generally uses pure water as the solvent.

[0074] In the present application, preferably, the osmotic pressure regulator is one or more of glucose, sucrose and sodium chloride, for example, glucose.

[0075] In the present application, preferably, the concentration of the lysine in the outer aqueous phase is 21-30 mg / mL.

[0076] In the present application, preferably, the mixing of the colostrum and the outer aqueous phase is by dropwise adding the colostrum into the outer aqueous phase.

[0077] In the present application, preferably, the mixing of the colostrum and the outer aqueous phase is accompanied by high-speed shearing.

[0078] In the present application, preferably, the speed of the high-speed shearing is 4000-6000 rpm.

[0079] In the present application, preferably, the time of the high-speed shearing is 80-100 s, for example, 90 s.

[0080] In the present application, preferably, the volume ratio of the colostrum to the outer aqueous phase is 1:(2-5), more preferably 1:(2-3).

[0081] In the present application, the colostrum is generally a water-in-oil colostrum.

[0082] In the present application, the multiple emulsion is generally a water-in-oil-in-water multiple emulsion.

[0083] In the present application, before the ultrafiltration concentration of the multiple emulsion, the multiple emulsion generally further comprises a step of aeration.

[0084] In the present application, the aeration is generally by adding the multiple emulsion into a glucose solution and aerating with nitrogen. Preferably, the concentration of the glucose solution is 55-100 mg / mL, for example, 61 mg / mL, 92 mg / mL or 95 mg / mL. The purpose of the aeration is to remove the organic solvent.

[0085] In the present application, preferably, the ultrafiltration concentration is by a medium control fiber column ultrafiltration concentration.

[0086] In the present application, preferably, the displacement solution for the ultrafiltration concentration is a sodium chloride solution. The sodium chloride solution can be used to displace the glucose solution used in the aeration.

[0087] In the present application, preferably, the concentration of the sodium chloride solution is 15-20 mg / mL, more preferably 15-18 mg / mL, for example, 15 mg / mL, 17 mg / mL and 19 mg / mL.

[0088] In a fourth aspect, the present application further provides a bupivacaine polycystic liposome prepared by the preparation method of the bupivacaine polycystic liposome. Preferably, the bupivacaine polycystic liposome prepared by the preparation method has an osmotic pressure of 500-600 mOsmol / kg, for example, 517 mOsmol / kg, 564 mOsmol / kg or 583 mOsmol / kg. Preferably, the bupivacaine polycystic liposome has an average particle size of 9-18 μm, for example, 9.65 μm, 12.5 μm or 14.1 μm.

[0089] In the present application, the components and contents of the bupivacaine polycystic liposome prepared by the preparation method of the bupivacaine polycystic liposome are as described in the first aspect of the present application.

[0090] In the present application, the recovery rate in the preparation method of the bupivacaine polycystic liposome is generally above 90%, preferably 90%-95%.

[0091] In a fifth aspect, the present application further provides a bupivacaine polycystic liposome gel, which comprises the bupivacaine polycystic liposome as described above and a temperature-sensitive gel.

[0092] In the present application, the osmotic pressure of the temperature-sensitive gel is 650-800 mOsmol / kg.

[0093] In the present application, the volume ratio of the bupivacaine polycystic liposome to the temperature-sensitive gel is 1:(1.5-2.5).

[0094] In the present application, preferably, the volume ratio of the bupivacaine polycystic liposome to the temperature-sensitive gel is 1:2.

[0095] In the present application, preferably, the osmotic pressure of the temperature-sensitive gel is 677-776 mOsmol / kg, for example, 711 mOsmol / kg.

[0096] In the present application, preferably, the temperature-sensitive gel comprises chitosan.

[0097] In the present application, preferably, the concentration of the chitosan in the temperature-sensitive gel is 27-37.5 mg / mL.

[0098] In the present application, preferably, the temperature-sensitive gel comprises β-glycerophosphate disodium.

[0099] In the present application, preferably, the concentration of the β-glycerophosphate disodium in the temperature-sensitive gel is 76.5-90 mg / mL.

[0100] In some preferred embodiments of the present application, the temperature-sensitive gel comprises the following components: chitosan 27-37.5 mg / mL and β-glycerophosphate disodium 76.5-90 mg / mL.

[0101] In the present application, the phase transition temperature of the temperature-sensitive gel is preferably 30-37℃, more preferably 31-35℃.

[0102] In the present application, the osmolality of the bupivacaine multivesicular liposome gel is preferably 600-650 mOsmol / kg, for example 604 mOsmol / kg, 614 mOsmol / kg or 619 mOsmol / kg.

[0103] In the present application, the concentration of the phosphoric acid in the bupivacaine multivesicular liposome gel is preferably 3.13-5.94 mg / mL, for example 4.69 mg / mL.

[0104] In the present application, the concentration of the diarachidoyl phosphatidylcholine in the bupivacaine multivesicular liposome gel is preferably 2.19-4.22 mg / mL, for example 3.29 mg / mL.

[0105] In the present application, the concentration of the dipalmitoyl phosphatidylglycerol in the bupivacaine multivesicular liposome gel is preferably 0.47-0.92 mg / mL, for example 0.70 mg / mL.

[0106] In the present application, the concentration of the glyceryl trioctanoate in the bupivacaine multivesicular liposome gel is preferably 0.51-0.99 mg / mL, for example 0.77 mg / mL.

[0107] In the present application, the concentration of the cholesterol in the bupivacaine multivesicular liposome gel is preferably 1.19-2.24 mg / mL, for example 1.78 mg / mL.

[0108] In the present application, the concentration of the bupivacaine in the bupivacaine multivesicular liposome gel is preferably 5.42-10.29 mg / mL, for example 8.12 mg / mL.

[0109] In the present application, the concentration of the lysine in the bupivacaine multivesicular liposome gel is preferably 10-44.86 mg / mL, for example 20.40 mg / mL or 10.50 mg / mL.

[0110] In the present application, the concentration of the osmolality regulator in the bupivacaine multivesicular liposome gel is preferably 21-125.35 mg / mL, for example 48.00 mg / mL.

[0111] In the present application, the concentration of the sodium chloride in the bupivacaine multivesicular liposome gel is preferably 5-6.33 mg / mL, for example 5.67 mg / mL.

[0112] In the present application, the concentration of the chitosan in the bupivacaine multivesicular liposome gel is preferably 18-25 mg / mL, for example 20 mg / mL.

[0113] In the present application, the concentration of the β-glycerophosphate disodium in the bupivacaine multivesicular liposome gel is preferably 51-60 mg / mL, for example 54 mg / mL.

[0114] In some preferred embodiments of the present application, the bupivacaine multivesicular liposome gel comprises the following concentrations of components:

[0115] Phosphoric acid 3.13-5.94 mg / mL,

[0116] Dierucoylphosphatidylcholine 2.19-4.22 mg / mL,

[0117] Dipalmitoylphosphatidylglycerol 0.47-0.92 mg / mL,

[0118] Tricaprylin 0.51-0.99 mg / mL,

[0119] Cholesterol 1.19-2.24 mg / mL,

[0120] Bupivacaine 5.42-10.29 mg / mL,

[0121] Lysine 10-44.86 mg / mL,

[0122] Osmotic pressure regulator 21-125.35 mg / mL,

[0123] Sodium chloride 5-6.33 mg / mL,

[0124] Chitosan 18-25 mg / mL, and,

[0125] β-glycerophosphate disodium 51-60 mg / mL.

[0126] In a sixth aspect, the present application also provides a preparation method of a bupivacaine multivesicular liposome gel, comprising the following steps:

[0127] S1, using the preparation method of the bupivacaine multivesicular liposome as described above, to prepare the bupivacaine multivesicular liposome;

[0128] wherein the osmotic pressure of the bupivacaine multivesicular liposome is 500-600 mOsmol / kg;

[0129] S2, mixing the chitosan solution and the β-glycerophosphate disodium solution to obtain a temperature-sensitive gel;

[0130] wherein the osmotic pressure of the temperature-sensitive gel is 650-800 mOsmol / kg;

[0131] S3, mixing the bupivacaine polycystic liposomes obtained in S1 with the temperature-sensitive gel obtained in S2, to obtain the bupivacaine polycystic liposome gel;

[0132] The volume ratio of the bupivacaine polycystic liposomes to the temperature-sensitive gel is 1: (1.5-2.5).

[0133] The osmotic pressure of the bupivacaine polycystic liposome gel is 600-650 mOsmol / kg.

[0134] In the present application, preferably, the volume ratio of the bupivacaine polycystic liposomes to the temperature-sensitive gel is 1:2.

[0135] In S2 of the present application, preferably, the osmotic pressure of the temperature-sensitive gel is 677-776 mOsmol / kg, for example, 711 mOsmol / kg.

[0136] In S2 of the present application, preferably, the concentration of the chitosan in the temperature-sensitive gel is 27-37.5 mg / mL.

[0137] In S2 of the present application, preferably, the concentration of the β-glycerophosphate disodium solution in the temperature-sensitive gel is 76.5-90 mg / mL.

[0138] In S2 of the present application, preferably, the phase transition temperature of the temperature-sensitive gel is 30-37℃, more preferably 31-35℃.

[0139] In S2 of the present application, preferably, the pH of the temperature-sensitive gel is 7.0-7.2.

[0140] In S2 of the present application, the chitosan solution is generally used for chitosan swelling.

[0141] The chitosan swelling is generally achieved by dissolving chitosan powder in an acid solution.

[0142] The acid solution can be a hydrochloric acid solution or an acetic acid solution, preferably a hydrochloric acid solution.

[0143] The concentration of the acid solution can be 0.1 mol / L.

[0144] Preferably, the chitosan swelling is accompanied by stirring until complete swelling.

[0145] Preferably, the chitosan swelling is carried out at low temperature, generally below 4℃, for example, 4℃.

[0146] In S2 of the present application, the β-glycerophosphate disodium solution is generally obtained by dissolving β-glycerophosphate disodium in pure water.

[0147] Preferably, the dissolving of the beta-glycerophosphate disodium salt is carried out at low temperature, typically at 4℃ or below, such as 4℃.

[0148] In S2 of the present application, the mixing is typically carried out by adding the beta-glycerophosphate disodium salt solution to the chitosan solution.

[0149] In S2 of the present application, the mixing is typically carried out with stirring to ensure uniform mixing.

[0150] In S2 of the present application, the mixing is typically carried out at low temperature, typically at 4℃ or below, such as 4℃.

[0151] In S2 of the present application, after the mixing, the mixture is typically allowed to stand for 10-15h, such as 12h.

[0152] In S3 of the present application, the osmotic pressure of the bupivacaine polycapsular liposome gel can be 604mOsmol / kg, 614mOsmol / kg or 619mOsmol / kg.

[0153] In a seventh aspect, the present application also provides a bupivacaine polycapsular liposome composition comprising the bupivacaine polycapsular liposome, the meloxicam nanocrystal and the temperature-sensitive gel as described above.

[0154] In the meloxicam nanocrystal, the following components are included: meloxicam, a wetting agent, a stabilizer and an osmotic pressure regulator.

[0155] In the bupivacaine polycapsular liposome, the meloxicam nanocrystal and the temperature-sensitive gel, the volume ratio is 5:(0.05-0.08):(7.5-12.5).

[0156] In the bupivacaine polycapsular liposome composition, the osmotic pressure is 600-650mOsmol / kg.

[0157] Preferably, in the bupivacaine polycapsular liposome composition, the osmotic pressure is 604-648mOsmol / kg, such as 619mOsmol / kg.

[0158] Preferably, in the bupivacaine polycapsular liposome, the meloxicam nanocrystal and the temperature-sensitive gel, the volume ratio is 5:0.065:10.

[0159] Preferably, in the meloxicam nanocrystal, the concentration of the meloxicam is 40-60mg / mL.

[0160] In the present invention, preferably, the concentration of the wetting agent in the meloxicam nanocrystal is 4-6 mg / mL.

[0161] In the present invention, preferably, the concentration of the stabilizer in the meloxicam nanocrystal is 12-18 mg / mL.

[0162] In the present invention, preferably, the concentration of the osmotic pressure adjusting agent in the meloxicam nanocrystal is 120-148 mg / mL.

[0163] In the present invention, preferably, the wetting agent is sodium deoxycholate.

[0164] In the present invention, preferably, the stabilizer is povidone.

[0165] In the present invention, preferably, the osmotic pressure adjusting agent is sucrose.

[0166] In the present invention, the concentration of the phosphoric acid in the bupivacaine multivesicular liposome composition is preferably 3.11-5.91 mg / mL, for example 4.67 mg / mL or 5.52 mg / mL.

[0167] In the present invention, the concentration of the dierucoylphosphatidylcholine in the bupivacaine multivesicular liposome composition is preferably 2.18-4.20 mg / mL, for example 3.27 mg / mL or 3.80 mg / mL.

[0168] In the present invention, the concentration of the dipalmitoylphosphatidylglycerol in the bupivacaine multivesicular liposome composition is preferably 0.47-0.92 mg / mL, for example 0.70 mg / mL or 0.81 mg / mL.

[0169] In the present invention, the concentration of the trioctanoin in the bupivacaine multivesicular liposome composition is preferably 0.51-0.99 mg / mL, for example 0.76 mg / mL or 0.89 mg / mL.

[0170] In the present invention, the concentration of the cholesterol in the bupivacaine multivesicular liposome composition is preferably 1.18-2.23 mg / mL, for example 1.77 mg / mL or 2.05 mg / mL.

[0171] In the present invention, the concentration of the bupivacaine in the bupivacaine multivesicular liposome composition is preferably 5.39-10.25 mg / mL, for example 8.09 mg / mL or 9.39 mg / mL.

[0172] In the present application, the concentration of the lysine in the bupivacaine multivesicular liposome composition is preferably 9.96-44.67 mg / mL, for example 20.31 mg / mL, 10.45 mg / mL or 23.65 mg / mL.

[0173] In the present application, the concentration of the osmotic pressure regulator in the bupivacaine multivesicular liposome composition is preferably 20.91-124.81 mg / mL, for example 47.79 mg / mL, 21.0 mg / mL or 55.18 mg / mL.

[0174] In the present application, the concentration of the sodium chloride in the bupivacaine multivesicular liposome composition is preferably 4.98-6.31 mg / mL, for example 5.64 mg / mL or 6.31 mg / mL.

[0175] In the present application, the concentration of the chitosan in the bupivacaine multivesicular liposome composition is preferably 17.92-24.89 mg / mL, for example 19.91 mg / mL or 17.92 mg / mL.

[0176] In the present application, the concentration of the β-glycerophosphate disodium in the bupivacaine multivesicular liposome composition is preferably 50.78-59.74 mg / mL, for example 53.77 mg / mL or 59.74 mg / mL.

[0177] In the present application, the concentration of the sodium deoxycholate in the bupivacaine multivesicular liposome composition is preferably 0.017-0.026 mg / mL, for example 0.022 mg / mL.

[0178] In the present application, the concentration of the povidone in the bupivacaine multivesicular liposome composition is preferably 0.052-0.078 mg / mL, for example 0.065 mg / mL.

[0179] In the present application, the concentration of the meloxicam in the bupivacaine multivesicular liposome composition is preferably 0.0173-0.259 mg / mL, for example 0.216 mg / mL.

[0180] In the present application, the concentration of the sucrose in the bupivacaine multivesicular liposome composition is preferably 0.518-0.639 mg / mL, for example 0.578 mg / mL.

[0181] In some preferred embodiments of the present application, the bupivacaine multivesicular liposome composition comprises the following concentrations of components:

[0182] phosphoric acid 3.11-5.91 mg / mL,

[0183] Dierucoylphosphatidylcholine 2.18-4.20 mg / mL,

[0184] Dipalmitoylphosphatidylglycerol 0.47-0.92 mg / mL,

[0185] Tricaprylin 0.51-0.99 mg / mL,

[0186] Cholesterol 1.18-2.23 mg / mL,

[0187] Bupivacaine 5.39-10.25 mg / mL,

[0188] Lysine 9.96-44.67 mg / mL,

[0189] Osmotic pressure regulator 20.91-124.81 mg / mL,

[0190] Sodium chloride 4.98-6.31 mg / mL,

[0191] Chitosan 17.92-24.89 mg / mL,

[0192] Beta-glycerophosphate disodium 50.78-59.74 mg / mL,

[0193] Sodium deoxycholate 0.017-0.026 mg / mL,

[0194] Povidone 0.052-0.078 mg / mL,

[0195] Meloxicam 0.0173-0.259 mg / mL, and

[0196] Sucrose 0.518-0.639 mg / mL.

[0197] In an eighth aspect, the present application further provides a preparation method of the bupivacaine polycystic liposome composition, comprising the following steps:

[0198] S1, using the preparation method of the bupivacaine polycystic liposome, to prepare the bupivacaine polycystic liposome;

[0199] S2, dispersing and grinding the raw material liquid to obtain meloxicam nanocrystals;

[0200] Among them, the components in the raw material liquid include sodium deoxycholate, povidone, sucrose and meloxicam;

[0201] S3, using the preparation method of the temperature-sensitive gel, to prepare the temperature-sensitive gel;

[0202] S4, S1 bupivacaine polycystic liposomes, S2 meloxicam nanocrystals and S3 temperature-sensitive gel mixed, namely the bupivacaine polycystic liposome composition;

[0203] Wherein, the volume ratio of the bupivacaine polycystic liposome, the meloxicam nanocrystal and the temperature-sensitive gel is 5: (0.05-0.08): (7.5-12.5).

[0204] Wherein, the osmotic pressure of the bupivacaine polycystic liposome composition is 600-650 mOsmol / kg.

[0205] In the present application, preferably, the osmotic pressure of the bupivacaine polycystic liposome composition is 604-648 mOsmol / kg, for example, 619 mOsmol / kg.

[0206] In S2 of the present application, the solvent of the raw liquid is generally pure water.

[0207] In S2 of the present application, preferably, the concentration of meloxicam in the meloxicam nanocrystal is 40-60 mg / mL.

[0208] In S2 of the present application, preferably, the concentration of sodium deoxycholate in the meloxicam nanocrystal is 4-6 mg / mL.

[0209] In S2 of the present application, preferably, the concentration of povidone in the meloxicam nanocrystal is 12-18 mg / mL.

[0210] In S2 of the present application, preferably, the concentration of sucrose in the meloxicam nanocrystal is 120-148 mg / mL.

[0211] In S2 of the present application, in the preparation of the raw liquid, the sodium deoxycholate and the povidone are first dissolved, and then the sucrose and the meloxicam are added.

[0212] In S2 of the present application, the dispersion method is generally stirring.

[0213] In S2 of the present application, the grinding medium is generally zirconium oxide beads.

[0214] Wherein, preferably, the particle size of the zirconium oxide beads is 0.2 mm or 0.3 mm.

[0215] In S2 of the present application, preferably, the rotation speed of the grinding is 4000-5000 rpm.

[0216] In S2 of the present application, preferably, the grinding time is 30-60 min.

[0217] In the S2 of the present application, the meloxicam nanocrystal is generally in the state of suspension.

[0218] In the S2 of the present application, preferably, the average particle size of the meloxicam nanocrystal is 100-300 nm.

[0219] In a ninth aspect, the present application further provides a use of the bupivacaine polycystic liposome composition in the preparation of a postoperative sustained-release long-acting multimodal analgesic drug.

[0220] The bupivacaine polycystic liposome composition disclosed in the present application comprises bupivacaine polycystic liposomes, meloxicam nanocrystals, and chitosan / β-glycerophosphate disodium warm-sensitive gel. The local anesthetic drug bupivacaine is wrapped in polycystic liposomes with good biocompatibility and biodegradability, and the polycystic liposomes are dispersed in chitosan / β-glycerophosphate disodium warm-sensitive gel, and meloxicam nanocrystals with synergistic analgesic effect are added. When the gel solution is injected, it will gel into a semi-solid gel at body temperature, forming a drug depot to slowly release the drug, prolonging the analgesic time of the drug and improving the analgesic intensity of the drug, and reducing local inflammation. The synergistic administration of bupivacaine local anesthetic drug and non-steroidal anti-inflammatory drug meloxicam overcomes the problem of limited local anesthetic drug action time in postoperative inflammatory acidic environment.

[0221] On the basis of common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, thereby obtaining preferred examples of the present application.

[0222] The reagents and raw materials used in the present application are commercially available.

[0223] The positive progress effect of the present application is that:

[0224] The bupivacaine polycystic liposome gel disclosed in the present application comprises bupivacaine polycystic liposomes and chitosan / β-glycerophosphate disodium warm-sensitive gel. The bupivacaine polycystic liposomes can be stable in the gel system for a long time. The local anesthetic drug bupivacaine is wrapped in polycystic liposomes with good biocompatibility and biodegradability, and the polycystic liposomes are dispersed in chitosan / β-glycerophosphate disodium warm-sensitive gel. When the gel solution is injected, it will gel into a semi-solid gel at body temperature, forming a drug depot to slowly release the drug, prolonging the analgesic time of the drug.

[0225] The bupivacaine polycystic liposome composition of the present application has high osmotic pressure and the polycystic liposomes can be stable in the gel system for a long time with good stability. The meloxicam nanocrystals can reduce local inflammation. At the same time, chitosan can promote the absorption of the drug and prolong the action time of the drug in the body. The bupivacaine and meloxicam synergistically improve the analgesic effect and prolong the analgesic time. The new dosage form of the present application has a sustained-release effect, can effectively prolong the treatment time, can effectively relieve pain for at least 5 days, plays a role in sustained analgesia, and can be applied to the field of postoperative sustained-release long-acting multimodal analgesia.

[0226] Furthermore, the bupivacaine polycystic liposome gel and bupivacaine polycystic liposome composition of the present invention are made of non-toxic, non-irritating materials with good biocompatibility and biodegradability. Attached Figure Description

[0227] Figure 1 This is a stability diagram of the bupivacaine polycystic liposome composition prepared in Example 1 under an optical microscope.

[0228] Figure 2 In Example 1, the mechanical pain threshold and sensory blockade time were measured using von Frey fibers.

[0229] Figure 3 The exercise block score and duration are shown in Example 1.

[0230] Figure 4 The results of immunofluorescence of muscle tissue at the sciatic nerve gel reservoir site in Example 1 are shown.

[0231] Figure 5 For the effect example 1, a semi-quantitative analysis of inflammatory factors in the muscle tissue at the sciatic nerve gel reservoir site was performed (A is a semi-quantitative analysis of IL-6, and B is a semi-quantitative analysis of TNF-α).

[0232] Figure 6 The stability of the bupivacaine polycystic liposome gel prepared in Comparative Example 2 is shown under an optical microscope. Detailed Implementation

[0233] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0234] In this invention, the average particle size of bupivacaine polycystic liposomes was determined using a Mastersize-3000 laser particle size analyzer, and the average value of D50 obtained from 5 measurements was taken as the final average particle size.

[0235] In this invention, the average particle size of meloxicam nanocrystals was measured using a Nicomp Z3000 laser particle size analyzer, and the average value of D50 obtained from 5 measurements was taken as the final average particle size.

[0236] The abbreviations in the specific embodiments of this invention are explained as follows:

[0237]

[0238]

[0239] Example 1

[0240] The present example provides a bupivacaine polycystic liposome composition (H-MVL+MLX-GEL) and a preparation method thereof.

[0241] (1) Preparation of bupivacaine polycystic liposomes: 25 mL of a 37.5 mg / mL phosphoric acid solution was used as an internal aqueous phase, and 657 mg of dioleoylphosphatidylcholine, 139.5 mg of dipalmitoylphosphatidylglycerol, 153 mg of glyceryl tricaprylate, 355.5 mg of cholesterol, and 1625 mg of bupivacaine were precisely weighed into a 100 mL beaker, and 25 mL of dichloromethane was added to dissolve the lipids, obtaining a lipid phase; the internal aqueous phase was added to the lipid under high-speed shearing at 13000 rpm, and shearing was performed for 30 min to form a W / O primary emulsion; the primary emulsion was added to a solution of 150 mL of 27.28 mg / mL lysine and 64 mg / mL glucose as an external aqueous phase under high-speed shearing at 5400 rpm, and shearing was performed for 90 s to form a W / O / W multiple emulsion, which was then added to 1 L of a 92 mg / mL glucose solution and subjected to nitrogen aeration; the crude bupivacaine polycystic liposomes after aeration were subjected to ultrafiltration, and the external aqueous phase was replaced with a 17 mg / mL sodium chloride solution, followed by ultrafiltration and concentration to obtain high-osmotic-pressure bupivacaine polycystic liposomes with a volume of 60 mL and an osmotic pressure of 564 mOsmol / kg, and an average particle size of 12.5 μm.

[0242] The recovery rate of the bupivacaine polycystic liposome preparation method of the present example was 90%, and the contents of the components in the obtained high-osmotic-pressure bupivacaine polycystic liposomes were as follows:

[0243] phosphoric acid 14.07 mg / mL,

[0244] dioleoylphosphatidylcholine 9.86 mg / mL,

[0245] dipalmitoylphosphatidylglycerol 2.10 mg / mL,

[0246] glyceryl tricaprylate 2.30 mg / mL,

[0247] cholesterol 5.34 mg / mL,

[0248] bupivacaine 24.37 mg / mL,

[0249] lysine 61.2 mg / mL,

[0250] osmotic pressure regulator 144 mg / mL, and

[0251] sodium chloride 17 mg / mL.

[0252] (2) Preparation of meloxicam nanocrystal: 0.6 g of sodium deoxycholate and 1.8 g of povidone were precisely weighed and dissolved in 100 mL of pure water, then 6 g of meloxicam and 12 g of sucrose were precisely weighed and added to the above solution and stirred until uniformly dispersed, 70 mL of 0.2 mm zirconium oxide beads were taken as grinding medium and added to the above mixture in a grinder, the grinding speed was 4500 rpm, and the grinding time was 60 min, to obtain an average particle size of 140 nm.

[0253] The content of each component in the obtained meloxicam nanocrystal was:

[0254] sodium deoxycholate 6 mg / mL,

[0255] povidone 18 mg / mL,

[0256] meloxicam 60 mg / mL, and

[0257] sucrose 120 mg / mL.

[0258] (3) Preparation of temperature-sensitive gel: 300 mg of chitosan was precisely weighed in 9 mL of 0.1 M hydrochloric acid solution and stirred at low temperature to swell; 810 mg of β-glycerophosphate disodium was precisely weighed and dissolved in 1 mL of pure water and stirred at low temperature to dissolve, the β-glycerophosphate disodium solution was added dropwise to the above low-temperature stirred chitosan solution, stirred and mixed evenly, and left to stand for 12 h to obtain a blank temperature-sensitive gel, the osmotic pressure of the temperature-sensitive gel was 711 mOsmol / kg.

[0259] The content of each component in the obtained blank temperature-sensitive gel was:

[0260] chitosan 30 mg / mL, and

[0261] β-glycerophosphate disodium 81 mg / mL.

[0262] (4) 5 mL of bupivacaine multivesicular liposomes obtained in step (1) and 65 μL of meloxicam nanocrystal suspension obtained in step (2) were added to the blank temperature-sensitive gel obtained in step (3) and stirred evenly at low temperature to obtain H-MVL+MLX-GEL, the osmotic pressure was 604 mOsmol / kg, the pH was 7.0, and the gelation temperature was 33.9°C.

[0263] The content of each component in the obtained bupivacaine multivesicular liposome composition was:

[0264] phosphoric acid 4.67 mg / mL,

[0265] dierucoylphosphatidylcholine 3.27 mg / mL,

[0266] dipalmitoylphosphatidylglycerol 0.70 mg / mL,

[0267] Glycerol triacetate 0.76 mg / mL,

[0268] Cholesterol 1.77 mg / mL,

[0269] Bupivacaine 8.09 mg / mL,

[0270] Lysine 20.31 mg / mL,

[0271] Osmotic pressure regulator 47.79 mg / mL,

[0272] Sodium chloride 5.64 mg / mL,

[0273] Chitosan 19.91 mg / mL,

[0274] β-Glycerophosphate disodium 53.77 mg / mL,

[0275] Sodium deoxycholate 0.026 mg / mL,

[0276] Povidone 0.078 mg / mL,

[0277] Meloxicam 0.259 mg / mL, and,

[0278] Sucrose 0.518 mg / mL.

[0279] Example 2

[0280] The present example provides a bupivacaine polycapsule liposome composition (H-MVL+MLX-GEL) and a preparation method thereof.

[0281] (1) Preparation of bupivacaine polycapsule liposome: 25 mL of 25.0 mg / mL phosphoric acid solution was used as an inner aqueous phase, and 438 mg of dioleoyl phosphatidylcholine, 93 mg of dipalmitoyl phosphatidylglycerol, 102 mg of glycerol triacetate, 237 mg of cholesterol, and 1083 mg of bupivacaine were precisely weighed into a 100 mL beaker, and 25 mL of dichloromethane was added to dissolve the lipids to obtain a lipid phase; the inner aqueous phase was added to the lipid phase under high-speed shearing at 10,000 rpm for 30 min to form a W / O primary emulsion; the primary emulsion was added to an outer aqueous phase solution of 100 mL of 21 mg / mL lysine and 42 mg / mL glucose under high-speed shearing at 4000 rpm for 90 s to form a W / O / W multiple emulsion, and then the multiple emulsion was added to 1 L of a 61 mg / mL glucose solution and aerated with nitrogen gas; the crude bupivacaine polycapsule liposome after aeration was ultrafiltered, the outer aqueous phase was replaced with a 15 mg / mL sodium chloride solution, and finally ultrafiltration and concentration were performed to obtain a bupivacaine polycapsule liposome with high osmotic pressure, with a volume of 60 mL, an osmotic pressure of 517 mOsmol / kg, and an average particle size of 14.1 μm.

[0282] The recovery rate of the preparation method of the bupivacaine polycystic liposome in this embodiment is 90%, and the content of each component in the obtained bupivacaine polycystic liposome with high osmotic pressure is:

[0283] Phosphoric acid 9.38 mg / mL,

[0284] Dierucyophosphatidylcholine 6.57 mg / mL,

[0285] Dipalmitoylphosphatidylglycerol 1.40 mg / mL,

[0286] Tricaprylin 1.53 mg / mL,

[0287] Cholesterol 3.56 mg / mL,

[0288] Bupivacaine 16.25 mg / mL,

[0289] Lysine 31.5 mg / mL,

[0290] Osmotic pressure regulator 63 mg / mL, and

[0291] Sodium chloride 15 mg / mL.

[0292] (2) Preparation of meloxicam nanocrystals: 0.4 g of sodium deoxycholate and 1.2 g of povidone were precisely weighed and dissolved in 100 mL of pure water, then 4 g of meloxicam and 14.8 g of sucrose were precisely weighed and added to the above solution and stirred until uniformly dispersed, 70 mL of 0.3 mm zirconium oxide beads were taken as grinding medium and added to the grinding machine together with the above mixture, the grinding speed was 5000 rpm, and the grinding time was 30 min, and the average particle size was 232 nm.

[0293] The content of each component in the obtained meloxicam nanocrystals is:

[0294] Sodium deoxycholate 4 mg / mL,

[0295] Povidone 12 mg / mL,

[0296] Meloxicam 40 mg / mL, and

[0297] Sucrose 148 mg / mL.

[0298] (3) Preparation of temperature-sensitive gel: 375 mg of chitosan was precisely weighed in 9 mL of 0.1 M hydrochloric acid solution and low-temperature stirred to swell; 765 mg of β-glycerophosphate disodium was precisely weighed and dissolved in 1 mL of pure water and low-temperature stirred to dissolve, and the β-glycerophosphate disodium solution was added dropwise to the above low-temperature stirred chitosan solution, stirred and mixed uniformly, and then placed for 12 h to obtain a blank temperature-sensitive gel, and the osmotic pressure of the temperature-sensitive gel was 776 mOsmol / kg.

[0299] The content of each component in the obtained blank thermosensitive gel is:

[0300] Chitosan 37.5 mg / mL, and

[0301] β-glycerophosphate disodium 76.5 mg / mL.

[0302] (4) 5 mL of the bupivacaine polycapsular liposomes obtained in step (1) and 65 μL of the meloxicam nanocrystal suspension obtained in step (2) were added to the blank thermosensitive gel obtained in step (3) and stirred uniformly at low temperature to obtain H-MVL+MLX-GEL, the osmotic pressure of which was 619 mOsmol / kg, the pH was 7.1, and the gelation temperature was 32.5°C.

[0303] The content of each component in the obtained bupivacaine polycapsular liposome composition is:

[0304] Phosphoric acid 3.11 mg / mL,

[0305] Dierucoylphosphatidylcholine 2.18 mg / mL,

[0306] Dipalmitoylphosphatidylglycerol 0.47 mg / mL,

[0307] Tricaprylin 0.51 mg / mL,

[0308] Cholesterol 1.18 mg / mL,

[0309] Bupivacaine 5.39 mg / mL,

[0310] Lysine 10.45 mg / mL,

[0311] Osmotic pressure regulator 21.0 mg / mL,

[0312] Sodium chloride 4.98 mg / mL,

[0313] Chitosan 24.89 mg / mL,

[0314] β-glycerophosphate disodium 50.78 mg / mL,

[0315] Sodium deoxycholate 0.017 mg / mL,

[0316] Povidone 0.052 mg / mL,

[0317] Meloxicam 0.173 mg / mL, and

[0318] Sucrose 0.639 mg / mL.

[0319] Example 3

[0320] The present embodiment provides a bupivacaine polycystic liposome composition (H-MVL+MLX-GEL) and a preparation method thereof.

[0321] (1) Preparation of bupivacaine polycystic liposome: 25 mL of 42 mg / mL phosphoric acid solution was used as the inner aqueous phase, and 722.7 mg of dioleoylphosphatidylcholine, 153.45 mg of dipalmitoylphosphatidylglycerol, 168.3 mg of glycerol tricaprylate, 391.05 mg of cholesterol, and 1787.5 mg of bupivacaine were precisely weighed into a 100 mL beaker, and 25 mL of dichloromethane was added to dissolve the lipid phase; the inner aqueous phase was added to the lipid under high-speed shearing at 15000 rpm, and shearing was performed for 20 min to form a W / O primary emulsion; the primary emulsion was added to an outer aqueous phase solution of 150 mL of 30 mg / mL lysine and 70 mg / mL glucose under high-speed shearing at 6000 rpm, and shearing was performed for 90 s to form a W / O / W multiple emulsion, which was then added to 1 L of a 95 mg / mL glucose solution and subjected to nitrogen aeration; the crude bupivacaine polycystic liposome after aeration was subjected to ultrafiltration, and the outer aqueous phase was replaced with a 19 mg / mL sodium chloride solution, followed by ultrafiltration and concentration to obtain high-osmotic-pressure bupivacaine polycystic liposome with a volume of 60 mL and an osmotic pressure of 583 mOsmol / kg, and an average particle size of 9.65 μm.

[0322] The recovery rate of the bupivacaine polycystic liposome preparation method of the present embodiment was 95%, and the contents of the components in the obtained high-osmotic-pressure bupivacaine polycystic liposome were as follows:

[0323] phosphoric acid 16.63 mg / mL,

[0324] dioleoylphosphatidylcholine 11.45 mg / mL,

[0325] dipalmitoylphosphatidylglycerol 2.43 mg / mL,

[0326] glycerol tricaprylate 2.67 mg / mL,

[0327] cholesterol 6.19 mg / mL,

[0328] bupivacaine 28.30 mg / mL,

[0329] lysine 71.25 mg / mL,

[0330] osmotic pressure regulator 166.25 mg / mL, and

[0331] sodium chloride 19 mg / mL.

[0332] (2) Preparation of meloxicam nanocrystal: 0.5 g of sodium deoxycholate and 1.5 g of povidone were precisely weighed and dissolved in 100 mL of pure water, then 5 g of meloxicam and 13.4 g of sucrose were precisely weighed and added to the above solution and stirred until uniformly dispersed, 70 mL of 0.2 mm zirconium oxide beads were taken as grinding medium and added to the above mixture in a grinder, the grinding speed was 4000 rpm, and the grinding time was 45 min, to obtain an average particle size of 264 nm.

[0333] The content of each component in the obtained meloxicam nanocrystal was:

[0334] sodium deoxycholate 5 mg / mL,

[0335] povidone 15 mg / mL,

[0336] meloxicam 50 mg / mL, and

[0337] sucrose 134 mg / mL.

[0338] (3) Preparation of temperature-sensitive gel: 270 mg of chitosan was precisely weighed in 9 mL of 0.1 M acetic acid solution and stirred at low temperature to swell; 900 mg of β-glycerophosphate disodium was precisely weighed and dissolved in 1 mL of pure water and stirred at low temperature to dissolve, then the β-glycerophosphate disodium solution was added dropwise to the above low-temperature stirred chitosan solution, stirred and mixed uniformly, and left to stand for 12 h to obtain a blank temperature-sensitive gel, and the osmotic pressure of the temperature-sensitive gel was 677 mOsmol / kg.

[0339] The content of each component in the obtained blank temperature-sensitive gel was:

[0340] chitosan 27 mg / mL, and

[0341] β-glycerophosphate disodium 90 mg / mL.

[0342] (4) 5 mL of bupivacaine multivesicular liposomes obtained in step (1) and 65 μL of meloxicam nanocrystal suspension obtained in step (2) were added to the blank temperature-sensitive gel obtained in step (3) and stirred uniformly at low temperature to obtain H-MVL+MLX-GEL, the osmotic pressure was 648 mOsmol / kg, the pH was 7.2, and the gelation temperature was 31.5°C.

[0343] The content of each component in the obtained bupivacaine multivesicular liposome composition was:

[0344] phosphoric acid 5.52 mg / mL,

[0345] dierucoylphosphatidylcholine 3.80 mg / mL,

[0346] dipalmitoylphosphatidylglycerol 0.81 mg / mL,

[0347] Glycerol triacetate 0.89 mg / mL,

[0348] Cholesterol 2.05 mg / mL,

[0349] Bupivacaine 9.39 mg / mL,

[0350] Lysine 23.65 mg / mL,

[0351] Osmotic pressure regulator 55.18 mg / mL,

[0352] Sodium chloride 6.31 mg / mL,

[0353] Chitosan 17.92 mg / mL,

[0354] β-Glycerophosphate disodium 59.74 mg / mL,

[0355] Sodium deoxycholate 0.022 mg / mL,

[0356] Povidone 0.065 mg / mL,

[0357] Meloxicam 0.216 mg / mL, and

[0358] Sucrose 0.578 mg / mL.

[0359] Example 4

[0360] This example provides a bupivacaine polycapsule liposome gel (H-MVL-GEL) and a preparation method thereof.

[0361] (1) Preparation of bupivacaine polycapsule liposome: same as Example 1.

[0362] (2) Preparation of temperature-sensitive gel: same as Example 1.

[0363] (3) 5 mL of bupivacaine polycapsule liposome obtained in step (1) was added to the blank temperature-sensitive gel obtained in step (2), and uniformly stirred at low temperature to obtain H-MVL-GEL, the osmotic pressure was 604 mOsmol / kg, the pH was 7.0, and the gelation temperature was 33.9°C.

[0364] The content of each component in the obtained bupivacaine polycapsule liposome gel was:

[0365] Phosphoric acid 4.69 mg / mL,

[0366] Dipalmitoyl phosphatidylcholine 3.29 mg / mL,

[0367] Dipalmitoyl phosphatidylglycerol 0.70 mg / mL,

[0368] Glycerol triacetate 0.77 mg / mL,

[0369] Cholesterol 1.78 mg / mL,

[0370] Bupivacaine 8.12 mg / mL,

[0371] Lysine 20.40 mg / mL,

[0372] Osmotic pressure regulator 48.00 mg / mL,

[0373] Sodium chloride 5.67 mg / mL,

[0374] Chitosan 20 mg / mL, and

[0375] β-Glycerophosphate disodium 54 mg / mL.

[0376] Example 5

[0377] This example provides a bupivacaine polycapsule liposome gel (H-MVL-GEL) and a method for preparing the same.

[0378] (1) Preparation of bupivacaine polycapsule liposome: same as Example 2.

[0379] (2) Preparation of temperature-sensitive gel: same as Example 2.

[0380] (3) 5 mL of the bupivacaine polycapsule liposome obtained in step (1) was added to the blank temperature-sensitive gel obtained in step (2), and stirred uniformly at low temperature to obtain H-MVL-GEL, the osmotic pressure was 619 mOsmol / kg, the pH was 7.1, and the gelation temperature was 32.5°C.

[0381] The content of each component in the obtained bupivacaine polycapsule liposome gel was as follows:

[0382] Phosphoric acid 3.13 mg / mL,

[0383] Dipalmitoyl phosphatidylcholine 2.19 mg / mL,

[0384] Dipalmitoyl phosphatidylglycerol 0.47 mg / mL,

[0385] Tricaprylin 0.51 mg / mL,

[0386] Cholesterol 1.19 mg / mL,

[0387] Bupivacaine 5.42 mg / mL,

[0388] Lysine 10.50 mg / mL,

[0389] Osmotic pressure regulator 21.00 mg / mL,

[0390] Sodium chloride 5 mg / mL,

[0391] Chitosan 25 mg / mL, and,

[0392] β-glycerophosphate disodium 51 mg / mL.

[0393] Example 6

[0394] The present example provides a bupivacaine multivesicular liposome (H-MVL) and a preparation method thereof.

[0395] The preparation conditions and parameters of the bupivacaine multivesicular liposome are the same as those in Example 2.

[0396] Comparative Example 1

[0397] Preparation of the bupivacaine multivesicular liposome: 25 mL of a 42 mg / mL phosphoric acid solution was used as the internal aqueous phase, and 722.7 mg of dioleoyl lecithin, 153.45 mg of dipalmitoyl phosphatidylglycerol, 168.3 mg of triolein, 391.05 mg of cholesterol, and 1787.5 mg of bupivacaine were precisely weighed into a 100 mL beaker, and 25 mL of dichloromethane was added to dissolve the lipid phase; the internal aqueous phase was added to the lipid under high-speed shearing at 15000 rpm for 20 min to form a W / O primary emulsion; the primary emulsion was added to an external aqueous phase solution of 150 mL of 30 mg / mL lysine and 70 mg / mL glucose under high-speed shearing at 6000 rpm for 90 s to form a W / O / W multiple emulsion, and then the multiple emulsion was added to 1 L of a 95 mg / mL glucose solution and subjected to nitrogen aeration; during the aeration, the multivesicular liposomes were broken, and phospholipids floated in the solution.

[0398] Comparative Example 2

[0399] The present comparative example provides a bupivacaine multivesicular liposome gel and a preparation method thereof.

[0400] (1) Bupivacaine multivesicular liposome: EXPAREL, an on-market drug, was selected.

[0401] (2) Preparation of the temperature-sensitive gel: the conditions and parameters were the same as those in Example 1.

[0402] 5 mL of EXPAREL was added to the blank temperature-sensitive gel obtained in step (2), and the mixture was stirred uniformly at low temperature 4°C to obtain the product.

[0403] Effect Example 1: postoperative analgesic effect

[0404] (1) Grouping of rats

[0405] Male rats were randomly divided into 4 groups (n=5), A, normal saline group, B, EXPAREL group, C, H-MVL+MLX-GEL group (the medicament obtained in Example 1), D, H-MVL-GEL group (the medicament obtained in Example 4). The rat sciatic nerve injury model was established, after the rats were anesthetized, a 1-2 cm opening was cut along the left leg sciatic, the fascia was separated, the muscle was bluntly separated, and the sciatic nerve trunk was exposed to the visual field. The drug was given around the sciatic nerve by a syringe, the needle was vertically inserted into the sciatic fossa between the sciatic and greater trochanter, the dose was 10 mg / kg, the sensory block and motor block of each group of preparations were evaluated, and the postoperative analgesic effect was evaluated. After 7 days of administration, the muscle tissue at the sciatic nerve administration site was taken, and immunohistochemical experiment was performed, and the influence of each group of preparations on local inflammatory factors IL-6 and TNF-α was semi-quantitatively analyzed.

[0406] (2) Sensory block determination

[0407] The "Up & Down" method introduced by Dixon was used to determine the 50% paw withdrawal threshold of rodents. After the rats were placed in the net cage and rested, a series of von frey fibers were used to test the rat paw withdrawal from 4.0 g, and the test was continued until the withdrawal reaction occurred or the withdrawal threshold was reached, and the positive sequence combination was recorded. The pain threshold determination area was fixed in the center of the paw bottom, avoiding the insensitive paw pad part. The calculation formula is:

[0408] 50% paw withdrawal threshold (g) = 10(xf+kδ) / 10000

[0409] Xf is the last test fiber number; δ is the average difference of each fiber after logarithmic transformation, δ is 0.26 in this study; k is the coefficient value obtained by looking up the table of the positive sequence combination obtained by measurement.

[0410] The results are shown in Table 1: Figure 2 The sensory block time of EXPAREL was 3.6±0.5d, the sensory block time of H-MVL+MLX-GEL was 5.6±0.9d, the sensory block time of H-MVL-GEL was 4.4±0.5d, and the block time of H-MVL+MLX-GEL was the longest, and the analgesic effect was the best.

[0411] (3) Motor block determination

[0412] The evaluation of motor block used a 4-point scale. At a predetermined time, the tail of the experimental rat was raised, and the foot state was observed. The motor block time when the score was 2 was defined as the motor block time.

[0413] Table 1 Four-point scale evaluation of animal motor block based on visual observation Local analgesia experiment

[0414] Score Behavior 1 Normal appearance 2 Complete dorsiflexion of foot, impaired extension of toes 3 Plantar flexion, unable to extend toes 4 Complete loss of dorsiflexion, plantar flexion and gait impairment

[0415] Results are shown in Figure 3 Table 2. The motion block time of EXPAREL, H-MVL+MLX-GEL, H-MVL-GEL was 3.4±0.5d, 5.6±0.5d, 5.0±0.7d, respectively. The H-MVL+MLX-GEL group had the longest block time.

[0416] In summary, the H-MVL+MLX-GEL formulation had the longest sensory block time and motion block time, indicating the best analgesic effect.

[0417] (4) Sciatic nerve gel depot site muscle tissue immunofluorescence

[0418] Figure 4 To implement Example 1 sciatic nerve gel depot site muscle tissue immunofluorescence results, the red fluorescence in the picture is the inflammatory factor that needs to be labeled, and the blue fluorescence is the labeled nucleus. The weaker the red fluorescence, the smaller the inflammation. By comparing Figure 4 the red distribution area and intensity of the immunofluorescence results of the several groups, it can be preliminarily judged that the inflammatory results. The addition of bupivacaine multivesicular liposome composition can reduce local inflammatory factors IL-6 and TNF-α, neutralize the postoperative acidic environment, improve the analgesic effect and prolong the analgesic time.

[0419] The red fluorescence intensity and area in the immunofluorescence picture were semi-quantitatively analyzed by Imagine J software, and the average fluorescence intensity of the inflammatory factor was obtained. The results are shown in Figure 4 Table 3. From Figure 5 it can be known that the group with the addition of bupivacaine multivesicular liposome composition has the most reduction in the content of local inflammatory factors IL-6 and TNF-α, which indicates that the bupivacaine multivesicular liposome composition can significantly improve the analgesic effect and prolong the analgesic time. Figure 5

[0420] Effect Example 2: In vivo pharmacokinetic study

[0421] ​Male SD rats of 220-250g were selected and randomly divided into 4 groups, 5 rats in each group, and the dosage was 25mg / kg. A, H-MVL+MLX-GEL group (the medicament obtained in Example 2): subcutaneous injection of bupivacaine polycapsule liposome composition with high osmotic pressure, the dosage was 0.7mL; B, H-MVL-GEL group (the medicament obtained in Example 5): subcutaneous injection of bupivacaine polycapsule liposome gel with high osmotic pressure, the dosage was 0.7mL; C, H-MVL group (the medicament obtained in Example 6): subcutaneous injection of bupivacaine polycapsule liposome with high osmotic pressure, the dosage was 0.7mL; D, EXPAREL group: subcutaneous injection of marketed bupivacaine polycapsule liposome preparation, the dosage was 0.7mL. After subcutaneous injection, 0.5mL of blood was taken from the orbital vein, and the blood drug concentrations of bupivacaine and meloxicam at 5min, 10min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h after administration were determined.

[0422] The results show that: the pharmacokinetic results show that the half-life of the H-MVL+MLX-GEL preparation group is significantly prolonged, and there is a significant difference relative to the EXPAREL group, which prolongs the analgesic time.

[0423] Table 2: Pharmacokinetic parameter statistics of EXPAREL, H-MVL+MLX-GEL, H-MVL-GEL

[0424]

[0425] Table 3: Pharmacokinetic parameter statistics of H-MVL, meloxicam

[0426]

[0427] Effect Example 3: stability effect

[0428] The optical microscope images of the bupivacaine polycapsule liposome composition obtained in Example 1 at 2 days, 14 days, 28 days and two months are shown in Figure 1 It can be seen from Figure 1 that the bupivacaine polycapsule liposome composition obtained in Example 1 is in a spherical structure in the initial state, and after being placed in a 4°C refrigerator for 2 months, it is still in a spherical structure. This shows that the bupivacaine polycapsule liposome composition obtained in the present application has good stability.

[0429] The optical microscope images of the bupivacaine polycapsule liposome gel obtained in Comparative Example 2 at 0h and 12h are shown in Figure 6 It can be seen from Figure 6It can be seen that the bupivacaine polycystic liposome gel obtained in Comparative Example 2 has a spherical structure in the initial state, and when it is placed in a 4℃ refrigerator, it is observed that it has been broken after standing for 12h. This indicates that the bupivacaine polycystic liposome gel obtained by directly adding the marketed drug EXPAREL into the temperature-sensitive gel has relatively poor stability.

Claims

1. A bupivacaine multicystic liposome, characterized in that, It includes components at the following concentrations: Phosphoric acid 8-20 mg / mL Disorhodophosphatidylcholine 5-15 mg / mL Dipalmitoylphosphatidylglycerol 0.5-5 mg / mL, Trioctyl glycerol 0.5-5 mg / mL, Cholesterol 2-10 mg / mL Bupivacaine 15-35 mg / mL Lysine 25-140 mg / mL Osmotic pressure regulator 55-400 mg / mL, and, Sodium chloride 15-20 mg / mL.

2. The bupivacaine multicystic liposome as described in claim 1, characterized in that, The concentration of phosphate in the bupivacaine polycystic liposome is 9-18 mg / mL, preferably 9.38-17.81 mg / mL, for example 14.07 mg / mL or 16.63 mg / mL; And / or, the concentration of disqualylphosphatidylcholine in the bupivacaine polycystic liposome is 6-13 mg / mL, preferably 6.57-12.67 mg / mL, for example 9.86 mg / mL or 11.45 mg / mL; And / or, the concentration of dipalmitoylphosphatidylglycerol in the bupivacaine polycystic liposome is 1-3 mg / mL, preferably 1.4-2.77 mg / mL, for example 2.10 mg / mL or 2.43 mg / mL; And / or, the concentration of the tricaprylic acid glyceride in the bupivacaine polycystic liposome is 1-3 mg / mL, preferably 1.53-2.97 mg / mL, for example 2.30 mg / mL or 2.67 mg / mL; And / or, the concentration of cholesterol in the bupivacaine polycystic liposomes is 3-7 mg / mL, preferably 3.56-6.73 mg / mL, for example 5.34 mg / mL or 6.19 mg / mL; And / or, the concentration of bupivacaine in the bupivacaine multicyst liposome is 16-31 mg / mL, preferably 16.25-30.88 mg / mL, for example 24.37 mg / mL or 28.30 mg / mL; And / or, the concentration of lysine in the bupivacaine polycystic liposome is 30-135 mg / mL, preferably 30-134.58 mg / mL, for example 61.2 mg / mL, 31.5 mg / mL or 71.25 mg / mL; And / or, the concentration of the osmotic pressure regulator in the bupivacaine polycystic liposomes is 63- 377 mg / mL, preferably The concentration ranges from 63 to 376.04 mg / mL, for example, 144 mg / mL or 166.25 mg / mL; And / or, the concentration of sodium chloride in the bupivacaine polycystic liposome is 15-19 mg / mL, preferably 15-18 mg / mL, for example 17 mg / mL; And / or, the osmotic pressure regulator is one or more of glucose, sucrose and sodium chloride, for example, glucose; Preferably, the bupivacaine polycystic liposome comprises the following components at the following concentrations: Phosphoric acid 9-18 mg / mL, Disorhodophosphatidylcholine 6-13 mg / mL Dipalmitoylphosphatidylglycerol 1-3 mg / mL Trioctyl glycerol 1-3 mg / mL, Cholesterol 3-7 mg / mL Bupivacaine 16-31 mg / mL Lysine 30-135 mg / mL Osmotic pressure regulator 63-377 mg / mL, and, Sodium chloride 15-19 mg / mL; More preferably, the bupivacaine polycystic liposome comprises the following components at the following concentrations: Phosphoric acid 9.38-17.81 mg / mL Disorhodophosphatidylcholine 6.57-12.67 mg / mL, Dipalmitoylphosphatidylglycerol 1.4-2.77 mg / mL, Trioctyl glycerol 1.53-2.97 mg / mL, Cholesterol 3.56-6.73 mg / mL Bupivacaine 16.25-30.88 mg / mL Lysine 30-134.58 mg / mL Osmotic pressure regulator 63-376.04 mg / mL, and, Sodium chloride 15-19 mg / mL.

3. The bupivacaine multicystic liposome as described in claim 1, characterized in that, The osmotic pressure of the bupivacaine multicyst liposomes is 500-600 mOsmol / kg, for example, 517 mOsmol / kg, 564 mOsmol / kg or 583 mOsmol / kg. And / or, the average particle size of the bupivacaine polycystic liposomes is 9-18 μm, for example 9.65 μm, 12.5 μm or 14.1 μm.

4. A method for preparing bupivacaine polycystic liposomes as described in any one of claims 1-3, characterized in that, It includes the following steps: The inner aqueous phase and the lipid phase are mixed to obtain the colostrum; the colostrum is mixed with the outer aqueous phase to obtain the secondary emulsion; the secondary emulsion is concentrated by ultrafiltration to obtain bupivacaine polycystic liposomes. Preferably, the internal aqueous phase comprises phosphoric acid and water, wherein the concentration of phosphoric acid in the internal aqueous phase is 25-45 mg / mL; Preferably, the lipid phase comprises disqualyl phosphatidylcholine, dipalmitoyl phosphatidylglycerol, tricaprylic acid glyceride, cholesterol, and bupivacaine, as well as an organic solvent; the concentration of bupivacaine in the lipid phase is 42-78 mg / mL. Preferably, the external aqueous phase comprises water, an osmotic pressure regulator, and lysine; the concentration of the osmotic pressure regulator in the external aqueous phase is 42-95 mg / mL; and the concentration of lysine in the external aqueous phase is 20-34 mg / mL.

5. The method for preparing bupivacaine multicystic liposomes as described in claim 4, characterized in that, The replacement solution for ultrafiltration concentration is a sodium chloride solution; The concentration of the sodium chloride solution is preferably 15-20 mg / mL, more preferably 15-18 mg / mL, for example 15 mg / mL, 17 mg / mL and 19 mg / mL.

6. A bupivacaine polycystic liposome gel, characterized in that, It includes bupivacaine polycystic liposomes and thermosensitive gels as described in any one of claims 1-3.

7. The bupivacaine polycystic liposome gel as described in claim 6, characterized in that, The osmotic pressure of the temperature-sensitive gel is 650-800 mOsmol / kg; And / or, the volume ratio of the bupivacaine polycystic liposomes to the thermosensitive gel is 1:(1.5-2.5), preferably 1:2; And / or, the osmotic pressure of the thermosensitive gel may be 677-776 mOsmol / kg, for example 711 mOsmol / kg; And / or, the thermosensitive gel includes chitosan and / or disodium β-glycerophosphate; Preferably, the concentration of chitosan in the thermosensitive gel is 27-37.5 mg / mL; Preferably, the concentration of β-glycerophosphate disodium in the thermosensitive gel is 76.5-90 mg / mL; And / or, the thermosensitive gel comprises the following components: chitosan 27-37.5 mg / mL and β-glycerophosphate disodium 76.5-90 mg / mL; And / or, the phase transition temperature of the thermosensitive gel is 30℃-37℃, preferably 31-35℃; And / or, the osmotic pressure of the bupivacaine polycystic liposome gel is 600-650 mOsmol / kg, for example, 604 mOsmol / kg, 614 mOsmol / kg or 619 mOsmol / kg; And / or, the concentration of phosphate in the bupivacaine polycystic liposome gel is 3.13-5.94 mg / mL, for example 4.69 mg / mL; And / or, the concentration of discholarphosphatidylcholine in the bupivacaine polycystic liposome gel is 2.19-4.22 mg / mL, for example 3.29 mg / mL; And / or, the concentration of dipalmitoylphosphatidylglycerol in the bupivacaine polycystic liposome gel is 0.47-0.92 mg / mL, for example 0.70 mg / mL; And / or, the concentration of the tricaprylic acid glyceride in the bupivacaine polycystic liposome gel is 0.51-0.99 mg / mL, for example 0.77 mg / mL; And / or, the concentration of cholesterol in the bupivacaine polycystic liposome gel is 1.19-2.24 mg / mL, for example 1.78 mg / mL; And / or, the concentration of bupivacaine in the bupivacaine multicyst liposome gel is 5.42-10.29 mg / mL, for example 8.12 mg / mL; And / or, the concentration of lysine in the bupivacaine polycystic liposome gel is 10-44.86 mg / mL, for example 20.40 mg / mL or 10.50 mg / mL; And / or, the concentration of the osmotic pressure regulator in the bupivacaine polycystic liposome gel is 21-125.35 mg / mL, for example 48.00 mg / mL; And / or, the concentration of sodium chloride in the bupivacaine polycystic liposome gel is 5-6.33 mg / mL, for example 5.67 mg / mL; and / or, the concentration of chitosan in the bupivacaine polycystic liposome gel is 18-25 mg / mL, for example 20 mg / mL. And / or, the concentration of the β-glycerophosphate disodium in the bupivacaine polycystic liposome gel is 51-60 mg / mL, for example 54 mg / mL; Preferably, the bupivacaine polycystic liposome gel comprises the following components at the following concentrations: Phosphoric acid 3.13-5.94 mg / mL Disorhodophosphatidylcholine 2.19-4.22 mg / mL, Dipalmitoylphosphatidylglycerol 0.47-0.92 mg / mL, Trioctyl glycerol 0.51-0.99 mg / mL, Cholesterol 1.19-2.24 mg / mL Bupivacaine 5.42-10.29 mg / mL Lysine 10-44.86 mg / mL Osmotic pressure regulator 21-125.35 mg / mL, Sodium chloride 5-6.33 mg / mL Chitosan 18-25 mg / mL, and, β-glycerophosphate disodium 51-60 mg / mL.

8. A bupivacaine multi-capsule liposome composition, characterized in that, It includes bupivacaine polycystic liposomes, meloxicam nanocrystals, and thermosensitive gels as described in any one of claims 1-5.

9. The bupivacaine multi-capsule liposome composition as described in claim 8, characterized in that, And / or, the meloxicam nanocrystals comprise the following components: Meloxicam, wetting agents, stabilizers, and osmotic pressure regulators; Preferably, the concentration of meloxicam in the meloxicam nanocrystals is 40-60 mg / mL; Preferably, the concentration of the wetting agent in the meloxicam nanocrystals is 4-6 mg / mL; Preferably, the concentration of the stabilizer in the meloxicam nanocrystals is 12-18 mg / mL; Preferably, the concentration of the osmotic pressure regulator in the meloxicam nanocrystals is 120-148 mg / mL; Preferably, the wetting agent is sodium deoxycholate; Preferably, the stabilizer is povidone; Preferably, the osmotic pressure regulator is sucrose; And / or, the volume ratio of the bupivacaine polycystic liposomes, the meloxicam nanocrystals and the thermosensitive gel is 5:(0.05-0.08):(7.5-12.5), for example 5:0.065:10; And / or, the osmotic pressure of the bupivacaine multicapsule liposome composition is 600-650 mOsmol / kg, preferably 604-648 mOsmol / kg, for example 619 mOsmol / kg; And / or, the concentration of phosphate in the bupivacaine polycystic liposome composition is 3.11-5.91 mg / mL, for example 4.67 mg / mL or 5.52 mg / mL; And / or, the concentration of discholarphosphatidylcholine in the bupivacaine polycystic liposome composition is 2.18-4.20 mg / mL, for example 3.27 mg / mL or 3.80 mg / mL; And / or, the concentration of dipalmitoylphosphatidylglycerol in the bupivacaine multicyst liposome composition is 0.47-0.92 mg / mL, for example 0.70 mg / mL or 0.81 mg / mL; And / or, the concentration of the tricaprylic acid glyceride in the bupivacaine multicapsule liposome composition is 0.51-0.99 mg / mL, for example 0.76 mg / mL or 0.89 mg / mL; And / or, the concentration of cholesterol in the bupivacaine polycystic liposome composition is 1.18-2.23 mg / mL, for example 1.77 mg / mL or 2.05 mg / mL; And / or, the concentration of bupivacaine in the bupivacaine multicyst liposome composition is 5.39-10.25 mg / mL, for example 8.09 mg / mL or 9.39 mg / mL; And / or, the concentration of lysine in the bupivacaine multicyst liposome composition is 9.96-44.67 mg / mL, for example 20.31 mg / mL, 10.45 mg / mL or 23.65 mg / mL; And / or, the concentration of the osmotic pressure regulator in the bupivacaine multicapsule liposome composition is 20.91-124.81 mg / mL, for example 47.79 mg / mL, 21.0 mg / mL or 55.18 mg / mL; And / or, the concentration of sodium chloride in the bupivacaine multicyst liposome composition is 4.98-6.31 mg / mL, for example 5.64 mg / mL or 6.31 mg / mL; And / or, the concentration of chitosan in the bupivacaine multicapsule liposome composition is 17.92-24.89 mg / mL, for example 19.91 mg / mL or 17.92 mg / mL; And / or, the concentration of the β-glycerophosphate disodium in the bupivacaine multicapsule liposome composition is 50.78-59.74 mg / mL, for example 53.77 mg / mL or 59.74 mg / mL; And / or, the concentration of sodium deoxycholate in the bupivacaine polycystic liposome composition is 0.017-0.026 mg / mL, for example 0.022 mg / mL; And / or, the concentration of povidone in the bupivacaine multicapsule liposome composition is 0.052-0.078 mg / mL, for example 0.065 mg / mL; And / or, the concentration of meloxicam in the bupivacaine multicyst liposome composition is 0.0173-0.259 mg / mL, for example 0.216 mg / mL; And / or, the concentration of sucrose in the bupivacaine multicapsule liposome composition is 0.518-0.639 mg / mL, for example 0.578 mg / mL; Preferably, the bupivacaine multivesicular liposome composition comprises the following components at the following concentrations: Phosphoric acid 3.11-5.91 mg / mL Discholarphosphatidylcholine 2.18-4.20 mg / mL, Dipalmitoylphosphatidylglycerol 0.47-0.92 mg / mL, Trioctyl glycerol 0.51-0.99 mg / mL, Cholesterol 1.18-2.23 mg / mL Bupivacaine 5.39-10.25 mg / mL Lysine 9.96-44.67 mg / mL Osmotic pressure regulator 20.91-124.81 mg / mL, Sodium chloride 4.98-6.31 mg / mL, Chitosan 17.92-24.89 mg / mL β-glycerophosphate disodium 50.78-59.74 mg / mL Sodium deoxycholate 0.017-0.026 mg / mL Povidone 0.052-0.078 mg / mL Meloxicam 0.0173-0.259 mg / mL, and, Sucrose 0.518-0.639 mg / mL.

10. The use of a bupivacaine multicyst liposome composition as described in any one of claims 8-9 in the preparation of a postoperative sustained-release, long-acting, multimodal analgesic.

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