Long-acting analgesic composition based on lipid liquid crystal technology and application

Abstract

The invention provides a long-acting analgesic composition based on a lipid liquid crystal technology and application. The composition mainly comprises an analgesic drug, fat-soluble vitamin, phospholipid and a non-aqueous solvent. The long-acting analgesic composition is prepared by loading amide local anesthetics such as bupivacaine hydrochloride in the sustained-release medicine storage cavern lipid liquid crystal microspheres, the long-acting analgesic composition is locally injected to a painful part, the analgesic medicine is slowly released in a long-acting manner by controlling the internal crystal form of the microspheres and the size of the microspheres, the more lasting and stable analgesic effect is achieved compared with a conventional preparation, and the long-acting analgesic composition is suitable for clinical application. The action time of the medicine can be effectively prolonged, and the administration frequency is reduced.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and relates to a long-acting analgesic composition based on lipid liquid crystal technology and its application, which is mainly used for long-acting local analgesia by local application or injection. Background Art

[0002] Long-Acting Formulations (LAF) refer to pharmaceutical preparations that can slowly release drugs in the body, prolong drug effects, and reduce the frequency of dosing, and are designed to provide continuous or controlled drug release. Among them, long-acting injectables (LAIs) are particularly suitable for drugs with short biological half-lives, poor oral absorption, poor gastrointestinal stability, and rapid metabolism. This type of preparation can significantly reduce the frequency of dosing and provide long-term efficacy, and is therefore widely used in the treatment of a variety of chronic diseases, such as diabetes, schizophrenia, hormonal disorders, and cancer. Long-acting analgesics occupy an important place in pain management. Their purpose is to provide long-lasting and stable pain control, keep the concentration of the drug in the blood stable, thereby avoiding the discomfort caused by frequent dosage adjustments and reducing the risk of complications caused by improper pain management.

[0003] Lipid Liquid Crystalline (LLC) technology is a unique drug delivery system based on lipid self-assembly to form a system with a specific microstructure, consisting of water, lipids and possible excipients. These structures are between solid crystals and fluids, with unique rheological properties and physicochemical stability. In water or biological fluids, lipid molecules can self-assemble into a variety of ordered structures, such as lamellar, cubic, hexagonal, etc., through the action of their hydrophilic heads and hydrophobic tails. These structures are highly ordered and diverse, can effectively encapsulate drugs, and regulate the release behavior of drugs by controlling their phase transitions. Their formation is affected by factors such as lipid type, concentration, temperature, pH value and ionic strength.

[0004] Lidocaine, bupivacaine, ropivacaine and mepivacaine are widely used amide local anesthetics. Although their existing preparations can effectively provide anesthesia and analgesia in the short term, they still have problems such as short duration of action, poor in vivo stability and low safety, which seriously affect patients' medication compliance and prognosis, and bring great pressure to the medical system. Based on lipid liquid crystal technology, researchers have successfully prepared long-acting preparations that can slowly release these analgesics, and verified their controlled release and analgesic effects in vitro and in animal models. By adjusting the composition and structure of lipid liquid crystal prescriptions, the in vitro release efficiency and analgesic effect of the analgesics contained can be significantly improved. Summary of the invention

[0005] The purpose of the present invention is to provide a long-acting analgesic composition based on lipid liquid crystal technology, which mainly includes analgesics, fat-soluble vitamins, phospholipids and non-aqueous solvents, wherein the mass percentage of the analgesics is 0.5% to 15%, the mass percentage of the fat-soluble vitamins is 21% to 75%, the mass percentage of the phospholipids is 21% to 75%, and the non-aqueous solvent is used to 100%.

[0006] The analgesic drug is lidocaine, bupivacaine, ropivacaine or mepivacaine and pharmaceutically acceptable salts thereof.

[0007] The fat-soluble vitamins are one or more of vitamin A, vitamin D, vitamin E or vitamin K and their derivatives.

[0008] The phospholipid is one or more of phosphatidylglycerol, phosphatidylinositol, phosphatidylcholine and phosphatidylserine.

[0009] The non-aqueous solvent is one or more of polyethylene glycol, ethanol, propylene glycol, glycerol, glycerol, benzyl alcohol, dimethyl sulfoxide, 2-pyrrolidone, and N-methylpyrrolidone.

[0010] Another object of the present invention is to provide the use of the composition in the preparation of long-acting local analgesic injection.

[0011] The long-acting local analgesic injection of the present invention is a microsphere based on lipid liquid crystal technology, which is prepared by the following steps: (1) completely dissolving the phospholipids and fat-soluble vitamins in a non-aqueous solvent, adding an analgesic drug, and mixing them uniformly to obtain a lipid liquid crystal precursor solution; (2) adding the obtained lipid liquid crystal precursor solution to the aqueous phase for emulsification, removing the aqueous phase after emulsification, and collecting the obtained microspheres to obtain the long-acting local analgesic injection.

[0012] The dissolving and mixing method in step (1) is one or more of vortexing, stirring and ultrasound.

[0013] The aqueous phase in step (2) is a mixture of water and a non-aqueous solvent, wherein the mass percentage of the non-aqueous solvent is in the range of 0% to 50%; an O / W type emulsifier or an auxiliary emulsifier, such as sodium dodecyl sulfate, Tween 80, etc., can be added to the aqueous phase; the emulsification method includes stirring, shearing, homogenization and microfluidics, etc., and the size of the obtained microspheres can be controlled by adjusting the emulsification method; the method for removing the aqueous phase includes dialysis, ultrafiltration and freeze-drying, etc.

[0014] The long-acting local analgesia of the present invention is achieved by using the long-acting lipid liquid crystal microspheres or directly using the lipid liquid crystal precursor solution obtained in the preparation process. The administration form of the injection is local injection.

[0015] The long-acting local analgesic injection of the present invention can use the structure of lipid liquid crystal to slow down the release rate of the analgesic drug. It can be slowly released at the application site, significantly prolonging the analgesic effect. And by adjusting the proportion of prescription components and the size of microspheres, the drug release rate can be adjusted, and then the length of the analgesic time can be regulated to meet different analgesic needs. The lipid liquid crystal microspheres can reduce the frequency of administration of analgesic preparations, improve the pain management effect of patients, improve the quality of life of patients, and reduce the work pressure of medical staff. And its preparation method is simple, the material cost used is low, the biocompatibility is good, and it has a high clinical transformation potential. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The following are photos of lipid liquid crystal precursor solutions of various prescriptions (A, B, C, D, E from left to right).

[0017] Figure 2 It is a summary diagram of the small-angle X-ray scattering experimental results and analyzed crystal structure parameters of lipid liquid crystals in various prescriptions.

[0018] Figure 3 These are photos of the lipid liquid crystal precursor solutions of various prescriptions after being injected into the release medium (from left to right: A, B, C, D, E).

[0019] Figure 4 These are photos of lipid liquid crystals of various formulations after 24 hours in the release medium.

[0020] Figure 5 These are photos of lipid liquid crystals of various formulations after 7 days in the release medium.

[0021] Figure 6 is the drug release profile of lipid liquid crystal precursor solution of each prescription.

[0022] Figure 7 Schematic diagram of microfluidic preparation of lipid liquid crystal microspheres.

[0023] Figure 8 This is the appearance picture (left) and microscopic picture (right) of bupivacaine hydrochloride lipid liquid crystal microspheres.

[0024] Fig. 9 This is a microscopic examination image of ropivacaine lipid liquid crystal microspheres.

[0025] Fig.10 This is a microscopic examination image of lidocaine hydrochloride lipid liquid crystal microspheres.

[0026] Fig.11 This is a microscopic examination image of mepivacaine lipid liquid crystal microspheres.

[0027] Fig.12 This is a graph showing the in vitro release results of bupivacaine hydrochloride lipid liquid crystal microspheres of various prescriptions.

[0028] Fig.13 The effect of particle size and specific surface area on the in vitro release of lipid liquid crystal microspheres.

[0029] Fig.14 Evaluation of the rapid-acting local analgesic effect of bupivacaine hydrochloride lipid liquid crystal precursor solution.

[0030] Fig.15 To evaluate the long-acting local analgesic effect of bupivacaine hydrochloride lipid liquid crystal precursor solution.

[0031] Fig.16 This is an evaluation of the rapid-acting local analgesic effect of bupivacaine hydrochloride lipid liquid crystal microspheres.

[0032] Fig.17 The purpose is to evaluate the long-acting local analgesic effect of bupivacaine hydrochloride lipid liquid crystal microspheres. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is described in detail below in conjunction with the accompanying drawings and embodiments. It is necessary to point out that the following embodiments are only used to explain and illustrate the present invention and are not used to limit the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above invention content still belong to the protection scope of the present invention.

[0034] Example 1 Preparation of bupivacaine hydrochloride lipid liquid crystal precursor solution

[0035] Table 1 The mass ratio of phospholipids, α-tocopherol and ethanol in the five groups of prescriptions: Group No. A B C D E S100 6 5 4 3 4 α-Tocopherol 2 3 4 5 2 Ethanol 2 2 2 2 2

[0036] According to the prescription, different proportions of soybean lecithin (S100), α-tocopherol, and ethanol were placed in a centrifuge tube, and ultrasonic and vortexed. After fully dissolved, bupivacaine hydrochloride was added to make the solution contain 1% of the drug, and ultrasonicated to fully mix ( Figure 1 ). The precursor solutions of all the prescriptions were yellow transparent liquids with good fluidity.

[0037] Example 2 Determination of crystal structure In this example, based on Example 1, 100 μL of drug-loaded lipid liquid crystal precursor solution was injected into 10 ml of pure water, and the solution was allowed to stand at room temperature for 12 h to allow the ethanol to diffuse completely and form lipid liquid crystals. A small amount of lipid liquid crystal sample was taken and small-angle X-ray scattering (XEUSS SAXS / WAXS system, XENOCS SA) was used to obtain detailed information on the LLC crystal structure. The sample was wrapped with KAPTOM film and fixed in a sample holder. The X-ray wavelength ( Figure 2). The ordinate of the result is the scattering intensity (I), in arbitrary units; the abscissa is the scattering vector "q" (q = 4πsinθ / λ), in units of nm-1; θ is the scattering angle, in degrees (°); λ is the X-ray wavelength, λCuKa = 0.15418nm. The liquid crystal type formed by each prescription can be examined by calculating each peak (Table 2).

[0038] Table 2 LLC crystal parameters of each prescription

[0039] Example 3 Observation of Release Properties of Bupivacaine Hydrochloride Lipid Liquid Crystalline Precursor Solution In this example, based on Example 1, 5 groups of LLC precursor solutions were injected into 5 mL of 0.9% saline as a release medium, and the properties of each formulation were observed at 0 h, 24 h, and 7 days. Figure 3 , 4 , 5). After injection of the release medium and incubation for 24 hours, the precursor solution of prescription A was light yellow opaque lumps, while the other prescriptions were bright yellow and transparent. After 7 days of incubation, the liquid crystals of all prescriptions began to sink, the yellow color of the liquid crystals of prescription A deepened, and the color of the liquid crystals of the other prescriptions changed from bright yellow to orange-yellow.

[0040] Example 4 Determination of in vitro drug release rate of bupivacaine hydrochloride lipid liquid crystal precursor solution In this example, based on Example 1, 100 μL of drug-loaded precursor solution is injected into 5 ml of release medium (normal saline), and the mass of the injected precursor solution is recorded. Place in a dual-function water bath constant temperature oscillator and vibrate horizontally at 37°C and 50 r / min. At regular intervals, take out all the release medium in the centrifuge tube and add to an equal volume, i.e., 5 ml of normal saline. The taken out release solution is filtered through a 0.22 μm water filter membrane and collected, and placed in a 0°C refrigerator for subsequent content determination. The concentration of BUP-HCl is determined by HPLC, and the drug concentration is multiplied by the volume of the release medium to calculate the drug release amount and cumulative release amount. Finally, the cumulative release amount is divided by the total amount of drug to obtain the cumulative release rate of the drug ( Figure 6 ). Prescription A released faster and had a stronger burst release effect; while Prescription B released slower in the early stage, but the release rate was more constant, and its release rate was higher than Prescription A in the later stage. Prescriptions C, D, and E showed similar release patterns, with overall slower release, and nearly 50% of the drug was still not released after one week.

[0041] HPLC conditions were: Mobile phase: 0.05 mol / L potassium dihydrogen phosphate aqueous solution: acetonitrile = (65:35), 1.0 mL / min; detection wavelength: 263 nm; chromatographic column: SinoChrom ODS-BP C18 Column (5 μm, 150 mm×4.6 mm).

[0042] Example 5 Preparation of Bupivacaine Hydrochloride Lipid Liquid Crystalline Microspheres In this embodiment, on the basis of embodiment 1, a lipid liquid crystal precursor solution of bupivacaine hydrochloride is prepared, which is used as the oil phase, and a certain volume of anhydrous ethanol is added thereto to increase the solubility of bupivacaine hydrochloride in the solution system and improve the fluidity of the oil phase; an aqueous solution containing 0.1% SDS and 20% ethanol is used as the water phase. The oil phase and the water phase are driven by a flow pump, and are rapidly sheared in a mixer at a specific flow rate and flow rate ratio. The water phase with a faster flow rate applies shear stress to the oil phase, shearing the oil phase into micron-sized droplets, and the droplets form lipid liquid crystal microspheres ( Figure 7 ). The formed microspheres are subjected to ultrafiltration to remove ethanol and unencapsulated free drugs, thereby obtaining lipid liquid crystal microspheres loaded with bupivacaine hydrochloride.

[0043] Example 6 Observation of the Appearance of Bupivacaine Hydrochloride Lipid Liquid Crystalline Microspheres In this example, based on Example 5, bupivacaine hydrochloride lipid liquid crystal microspheres were dispersed in physiological saline, and observed and photographed under an optical microscope. It can be seen that the bupivacaine hydrochloride lipid liquid crystal microsphere suspension is opaque white, and under the microscope, it can be seen that the microsphere particles are regular and uniform, and the middle is transparent ( Figure 8 ).

[0044] Example 7 Preparation and Observation of Ropivacaine Lipid Liquid Crystal Microspheres A lipid liquid crystal precursor solution was prepared with 400 mg DMPG, 400 mg vitamin E acetate, 400 mg anhydrous ethanol, and 80 mg ropivacaine, which was used as the oil phase; an aqueous solution containing 40% ethanol was used as the water phase. The oil phase and the water phase were driven by a flow pump and rapidly sheared in a mixer at a specific flow rate and flow rate ratio. The faster flowing water phase applied shear stress to the oil phase, shearing the oil phase into micron-sized droplets, which formed lipid liquid crystal microspheres in a relatively short period of time. The formed microspheres were subjected to ultrafiltration to remove ethanol and unencapsulated free drugs, and lipid liquid crystal microspheres loaded with bupivacaine hydrochloride were obtained. The obtained microspheres were dispersed in physiological saline, observed and photographed under an optical microscope ( Fig. 9 ).

[0045] Example 8 Preparation and Observation of Lidocaine Hydrochloride Lipid Liquid Crystal Microspheres A lipid liquid crystal precursor solution was prepared with 200 mg of S100, 600 mg of vitamin D, 300 mg of anhydrous ethanol, and 100 mg of lidocaine hydrochloride as the oil phase; an aqueous solution containing 10% ethanol was used as the water phase. The oil phase was gradually added to the water phase and sheared at high speed to disperse the oil phase into micron-sized droplets. After the shearing was completed, the resulting emulsion was stirred at a low speed to allow the ethanol to fully diffuse and form lipid liquid crystal microspheres. The formed microspheres were subjected to ultrafiltration to remove ethanol and unencapsulated free drugs, and then observed and photographed under an optical microscope ( Fig.10 ).

[0046] Example 9 Preparation and Observation of Mepivacaine Lipid Liquid Crystal Microspheres Prepare lipid liquid crystal precursor solution with E80 600mg, vitamin E 200mg, N-methylpyrrolidone 200mg, and mepivacaine 20mg, and use it as the oil phase; gradually add the oil phase into pure water and homogenize it to disperse the oil phase into micron-sized emulsion droplets. After completion, dilute the obtained emulsion with pure water, stir at a low speed to fully diffuse the ethanol, and form lipid liquid crystal microspheres. The formed microspheres are subjected to ultrafiltration to remove ethanol and unencapsulated free drugs, and then observed and photographed under an optical microscope ( Fig.11 ).

[0047] Example 10 In vitro release of bupivacaine hydrochloride lipid liquid crystal microspheres In this example, on the basis of Examples 4 and 5, bupivacaine hydrochloride lipid liquid crystal microspheres of different prescriptions were dispersed in physiological saline and dispensed into centrifuge tubes at 5 mL / tube. All centrifuge tubes were placed in a dual-function water bath constant temperature oscillator and vibrated horizontally at 37°C and 50 r / min. At regular intervals, all the release media in the centrifuge tubes were taken out and supplemented with an equal volume of physiological saline. The taken out release solution was collected after filtration through a 0.22 μm water filter membrane and frozen in a 0°C refrigerator for subsequent content determination. The concentration of BUP-HCl was determined by the HPLC method described in Example 4. The drug concentration was multiplied by the volume of the release medium to calculate the drug release amount and the cumulative release amount. Finally, the cumulative release amount was divided by the total amount of drug to obtain the cumulative release rate of the drug ( Fig.12 ).

[0048] The results show that after being made into microspheres, the release rate of lipid liquid crystal microspheres of each prescription is accelerated. In contrast, the release rate of prescription A is still the fastest. The release rate of lipid liquid crystal microspheres of the other prescriptions is slower, and the rate is relatively constant.

[0049] Example 11 Effect of particle size on in vitro release of bupivacaine hydrochloride lipid liquid crystal microspheres In this example, on the basis of Examples 1 and 4, a lipid liquid crystal precursor solution of bupivacaine hydrochloride is prepared according to Prescription C. 100 μL of the precursor solution is drawn with a microsyringe and injected into centrifuge tubes containing 5 mL of normal saline at multiple points to form monodispersed, double-dispersed, nine-dispersed and sixteen-dispersed liquid crystal microspheres. All centrifuge tubes are placed in a dual-function water bath constant temperature oscillator and vibrated horizontally at 37°C and 50 r / min. At regular intervals, all the normal saline is taken out and an equal volume of normal saline is added. The released solution taken out is filtered through a 0.22 μm water filter membrane and collected, and stored in a refrigerator at 0°C for subsequent content determination. The concentration of BUP-HCl is determined by the HPLC method described in Example 4. The drug concentration is multiplied by the volume of the release medium to calculate the drug release amount and the cumulative release amount. Finally, the cumulative release amount is divided by the total amount of drug to obtain the cumulative release rate of the drug ( Fig.13 ).

[0050] The release results show that as the size of the microspheres decreases, the total surface area of ​​the reservoir increases and the release rate accelerates. The degree of increase in release rate is positively linearly correlated with the degree of increase in specific surface area. Therefore, the release rate of the encapsulated drug can be regulated by changing the size of the microspheres.

[0051] Example 12 Evaluation of the local analgesic effect of bupivacaine hydrochloride lipid liquid crystal precursor solution In this example, based on Example 1, 20 C57BL / 6 male mice were prepared and randomly divided into 5 groups, with 4 mice in each group. Groups Ⅰ, Ⅱ, Ⅲ and Ⅳ were set as the drug-administered groups, and group Ⅴ was the control group. The dosage of each mouse was 15 mg / kg (in terms of bupivacaine hydrochloride) by foot-stomach administration. Groups Ⅰ, Ⅱ and Ⅲ were injected with 2% bupivacaine hydrochloride lipid liquid crystal precursor solutions of prescriptions A, B and D, respectively, and group Ⅳ was injected with 2% bupivacaine hydrochloride in saline solution. Mice in group Ⅴ were injected with an equal volume of saline as a control.

[0052] Before drug administration, mice were subjected to Von Frey test to evaluate the initial average threshold of mice's response to Von Frey. For the experimental groups, Von Frey test was performed at 1h, 24h, 48h, 72h, 96h, 144h, and 168h after drug administration. Before each experiment, mice in each group were allowed to adapt to the environment 40min in advance, and the experiment was started after the mice's limbs were not active frequently. The soles of the mice were stimulated with Von Frey filaments of different intensities. If a positive result was shown, such as claw retraction and foot licking, the next lower value filament was used in the next stimulation test; if a negative result was shown, that is, the mice did not respond to the stimulation of the filament, a higher value Von Frey filament was used in the next test. Each test was separated by more than 5min. Each mouse was tested until a positive reaction occurred. If a negative reaction was shown, a higher value was continued for stimulation, and the steps were repeated until the mouse had a positive reaction, and the test was stopped. If the mouse still has no positive reaction to Von Frey filament No. 16 (26g), no further testing will be performed, and subsequent data calculations will be based on 26g. The average of the Von Frey filament values ​​for the first positive reaction of mice in the same group is taken, and an adjustment value of ±0.5 stimulation interval is added to calculate the paw withdrawal threshold (PWT) to evaluate the local analgesic effect. If the mouse has a negative reaction to the last filament tested, the adjustment factor is positive to obtain a PWT slightly higher than the fifth filament value; conversely, if the mouse has a positive reaction to the last filament tested, the adjustment factor is negative to obtain a PWT slightly lower than the fifth filament value. The 1-hour PWT data is used to evaluate the rapid-acting local analgesic effect, and the time-varying PWT data is used to evaluate the long-acting local analgesic effect ( Fig.14 , 15 ).

[0053] The rapid local analgesic effect of bupivacaine hydrochloride lipid liquid crystal precursor solution is stronger than that of bupivacaine hydrochloride solution, which may be because the ethanol in the precursor solution promotes the penetration of the drug. Under the same dose of single injection, the lipid liquid crystal precursor solution can extend the local analgesic effect of bupivacaine hydrochloride from less than 48h to 168h, significantly improving the analgesic duration, among which prescription D has the strongest long-term local analgesic effect.

[0054] Example 13 Evaluation of the local analgesic effect of bupivacaine hydrochloride lipid liquid crystal microspheres In this example, on the basis of Examples 5 and 9, 48 C57BL / 6 male mice were prepared and randomly divided into 6 groups, with 8 mice in each group. Groups I, II, III, IV and V were the drug-administered groups, and group VI was the control group. By subcutaneous injection of the hind limbs and lower legs, groups I and II were injected with 1% bupivacaine hydrochloride lipid liquid crystal microspheres of prescriptions A and C, respectively (0.7 mg / mouse in terms of bupivacaine hydrochloride), recorded as LLC-A and LLC-C; groups III and IV were injected with 1% bupivacaine hydrochloride saline solution (0.1 and 0.35 mg / mouse in terms of bupivacaine hydrochloride, respectively), recorded as Free1 / 7 and Free1 / 2; group V was injected with commercially available bupivacaine hydrochloride multivesicular liposome solution (0.7 mg / mouse in terms of bupivacaine hydrochloride), recorded as MVL. The control mice in group VI were injected with an equal volume of saline. The Von Frey method described in Example 9 was used to determine the rapid and long-acting local analgesic effects of each group ( Fig.16 , 17 ).

[0055] The results showed that increasing the dose of free drug can enhance the rapid local analgesia, but cannot prolong the analgesia time. Under the same dose of single injection, bupivacaine hydrochloride lipid liquid crystal microspheres showed stronger rapid local analgesia and long-term local analgesia than commercial bupivacaine hydrochloride multivesicular liposomes.

Claims

1. A long-acting analgesic composition based on lipid liquid crystal technology, characterized in that: The composition consists of analgesics, fat-soluble vitamins, phospholipids and non-aqueous solvents, wherein the mass percentage of the analgesics is 0.5% to 15%, the mass percentage of the fat-soluble vitamins is in the range of 21% to 75%, the mass percentage of the phospholipids is in the range of 21% to 75%, and the mass percentage of the non-aqueous solvent is up to 100%.

2. The composition according to claim 1, characterized in that The analgesic drug is lidocaine, bupivacaine, ropivacaine or mepivacaine and pharmaceutically acceptable salts thereof.

3. The composition according to claim 1, characterized in that The fat-soluble vitamins are one or more of vitamin A, vitamin D, vitamin E or vitamin K and their derivatives.

4. The composition according to claim 1, characterized in that The phospholipid is one or more of phosphatidylglycerol, phosphatidylinositol, phosphatidylcholine and phosphatidylserine.

5. The composition according to claim 1, characterized in that The non-aqueous solvent is one or more of polyethylene glycol, ethanol, propylene glycol, glycerol, glycerol, benzyl alcohol, dimethyl sulfoxide, 2-pyrrolidone, and N-methylpyrrolidone.

6. Use of the composition according to claim 1 in the preparation of long-acting local analgesic injection.

7. The use according to claim 6, characterized in that: The long-acting local analgesic injection is prepared by the following steps: (1) completely dissolving the phospholipids and fat-soluble vitamins in a non-aqueous solvent, adding an analgesic drug, and mixing them uniformly to obtain a lipid liquid crystal precursor solution; (2) adding the obtained lipid liquid crystal precursor solution to the aqueous phase for emulsification, removing the aqueous phase after emulsification, and collecting the obtained microspheres to obtain the long-acting analgesic injection.

8. The use according to claim 7, characterized in that: The dissolving and mixing method in step (1) is one or more of vortexing, stirring and ultrasound.

9. The use according to claim 7, characterized in that: The aqueous phase described in step (2) is a mixture of water and a non-aqueous solvent, wherein the mass percentage of the non-aqueous solvent ranges from 0% to 50%. An O / W type emulsifier or an auxiliary emulsifier is added to the aqueous phase, and sodium dodecyl sulfate or Tween 80 is selected.

10. The use according to claim 7, characterized in that: The emulsification method in step (2) is stirring, shearing, homogenization and microfluidics, and the size of the obtained lipid liquid crystal microspheres is controlled by the emulsification step; the method for removing the aqueous phase is dialysis, ultrafiltration or freeze-drying.

Images