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CN-122005455-A - Levobupivacaine liposome long-acting injection and preparation process and application thereof

CN122005455ACN 122005455 ACN122005455 ACN 122005455ACN-122005455-A

Abstract

The invention belongs to the field of analgesic drugs, and relates to a levobupivacaine liposome long-acting injection, a preparation process and application thereof. The injection comprises levobupivacaine, neutral phospholipid, charged phospholipid, cholesterol, tricaprylin, lysine, glucose and physiological saline. The invention prefers components, and mixes levobupivacaine and lipid component into lipid phase and then mixes with internal water phase in the preparation process, the synergistic improvement of the combined components and process is more beneficial to the stabilization of colostrum, simultaneously, lysine and glucose are added in the external water phase, and the dosage is optimized, thereby forming a stable charge system, leading the generated liposome to be more stable, avoiding aggregation and flocculation of pellets, leading the encapsulation rate of the final product to be more than 90%, leading the D50 to be 25-40um, prolonging the in vivo half-life period by 7 times compared with the common injection, prolonging the MRT by 6 times, realizing the stable release in SD rat, realizing the long-acting slow release for 48 hours, and having wide application prospect in the field of analgesic drugs.

Inventors

  • WANG SHICHENG
  • WEI FURONG
  • ZHANG YA
  • CHEN XIAOYAN
  • QIN XUFENG

Assignees

  • 江苏吉贝尔药业股份有限公司

Dates

Publication Date
20260512
Application Date
20241108

Claims (10)

  1. 1. The levobupivacaine long-acting liposome injection is characterized by comprising the following components of levobupivacaine, neutral phospholipid, charge phospholipid, cholesterol, tricaprylin lysine, glucose and physiological saline.
  2. 2. The levobupivacaine long-acting liposome injection according to claim 1, wherein the levobupivacaine long-acting liposome injection is a liposome suspension injection; Every 1000mL of bupivacaine long-acting liposome injection comprises the following components in parts by weight: 11-16 g of levobupivacaine, 6-10 g of neutral phospholipid, 0.5-3 g of negatively charged phospholipid, 2-6 g of cholesterol, 1-5 g of tricaprylin, 46-60g of lysine, 288-300g of glucose and the balance of normal saline.
  3. 3. The levobupivacaine long-acting liposome injection according to claim 1, wherein the neutral phospholipid is selected from any one or more of tricaprylin, egg yolk lecithin, soybean phosphatidylcholine, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, and dioleoyl phosphatidylcholine, and the negatively charged phospholipid is selected from any one or more of dipalmitoyl phosphatidylglycerol, pessary phosphatidylethanolamine, dimyristoyl phosphatidylglycerol, distearoyl phosphatidylglycerol, and distearoyl phosphatidic acid.
  4. 4. A process for preparing a levobupivacaine long-acting liposome injection according to any one of claims 1 to 3, comprising the steps of: s1, taking an inorganic acid aqueous solution as an internal water phase, wherein the concentration of the inorganic acid aqueous solution is 0.25 mol/L-0.30 mol/L; S2, dissolving levobupivacaine, neutral phospholipid, negatively charged phospholipid, cholesterol and tricaprylin in an organic solvent according to a mass ratio, and carrying out water bath or ultrasonic treatment for dissolution to obtain a lipid phase; s3, adding lysine and glucose into water according to the mass ratio, stirring and dissolving at normal temperature to obtain an external water phase; S4, mixing the inner water phase in S1 and the lipid phase in S2, homogenizing and shearing to form primary emulsion, dividing the outer water phase in S3 into two parts, respectively marking the two parts as outer water phase A and outer water phase B, mixing the primary emulsion and the outer water phase A, performing secondary homogenizing and shearing to form compound emulsion, uniformly mixing the compound emulsion and the outer water phase B, and removing the organic solvent through aeration to obtain a liposome crude product, namely a long-acting liposome intermediate; S5, adding the long-acting liposome intermediate in the S4 into normal saline, and finally, carrying out tangential flow ultrafiltration and concentration to obtain concentrated solution, namely the levobupivacaine long-acting liposome injection.
  5. 5. The preparation process of the levobupivacaine long-acting liposome injection according to claim 4, wherein the inorganic acid aqueous solution in the step S1 is a phosphoric acid solution with the concentration of 0.27 mol/L-0.28 mol/L.
  6. 6. The process for preparing the levobupivacaine long-acting liposome injection according to claim 4, wherein the organic solvent in the step S2 comprises any one or more of absolute ethyl alcohol, chloroform, dichloromethane and methanol, and the temperature during the water bath treatment is 25+/-1 ℃.
  7. 7. The process for preparing the levobupivacaine long-acting liposome injection according to claim 4, wherein in the step S3, the water is water for injection, and the mass fractions of lysine and glucose in the outer water phase are respectively 0.4% -0.8% (w/w) and 3.5% -5.5% (w/w).
  8. 8. The preparation process of the levobupivacaine long-acting liposome injection according to claim 4 is characterized in that in S4, the volume ratio of a lipid phase to an inner water phase to an outer water phase A to an outer water phase B is 1:0.8-1.2:2-6:12-19, in the homogenized and sheared colostrum, the homogenizing and shearing temperature is 20-25 ℃, the linear speed is 6-10m/S and the time is 10-15min, the linear speed of the second homogenizing and shearing is 2-5m/S, the temperature is 20-25 ℃ and the time is 60-300S, and the gas used for removing the organic solvent through aeration is nitrogen.
  9. 9. The preparation process of the levobupivacaine long-acting liposome injection according to claim 4 is characterized in that in S5, the volume ratio of the long-acting liposome intermediate to physiological saline is 1:6-8, an ultrafiltration column used for ultrafiltration concentration is an mPES hollow fiber membrane column, the aperture is 750KD, the particle size D50 of the levobupivacaine long-acting liposome injection is 25-40um, the appearance is white suspension, and the encapsulation rate of the levobupivacaine long-acting liposome injection is more than 90%.
  10. 10. Use of a levobupivacaine long-acting liposome injection according to any one of claims 1 to 3 or prepared by a method according to any one of claims 4 to 9 in the preparation of an analgesic drug.

Description

Levobupivacaine liposome long-acting injection and preparation process and application thereof Technical Field The invention belongs to the field of analgesic drugs, and in particular relates to a levobupivacaine liposome long-acting injection and a preparation process and application thereof. Background Postoperative pain often causes stress reaction to a patient, and serious patients can cause dysfunction of gastrointestinal tract functions, cardiopulmonary functions, coagulation functions and endocrine metabolism functions, so that postoperative rehabilitation of the patient is affected, and physical pain and psychological burden are brought to the patient. Clinically, postoperative pain varies from days to 2 months and even longer, depending on the type of surgery performed on the patient, the size of the surgical wound, and the patient's tolerance to pain. Most postoperative pain is intense in 2-3 days, and multiple doses are generally required to relieve postoperative pain of patients, so it is necessary and valuable to develop a long-acting preparation to solve the drawbacks of multiple doses. Bupivacaine as an amide local anesthetic is a clinically widely used surgical local anesthetic and postoperative analgesic. However, the conventional administration concentration of bupivacaine is 0.5%, and a single administration produces a local analgesic effect of less than 7 hours, and an insufficient long-acting drug effect must be continuously administered in other ways to satisfy clinical continuous treatment. The bupivacaine is a levorotatory body of bupivacaine, is mainly used for anesthesia clinically, has the anesthesia efficacy similar to the bupivacaine, but obviously reduces the toxicity of nerves and hearts, and is safer to use. Based on the above, the long-acting sustained release preparation of levobupivacaine for postoperative analgesia is the research direction of important development. The chemical name of the levobupivacaine is S- (-) -1-butyl-N- (2, 6-dimethylphenyl) -2-piperidinecarboxamide, and the structural formula is shown as formula 1: The long-acting liposome is in a non-concentric honeycomb shape, is an approximately spherical preparation formed by extruding a plurality of cells together, and can be accumulated at an injection position, and the cells are gradually ruptured to release the medicine wrapped in the inner cavity, so that the aim of good slow release is achieved, the medicine carrying capacity of the traditional liposome medicine is improved, and the medicine release time is prolonged. The multi-vesicle liposome is prepared by mixing an organic phase containing a drug with an inner water phase to prepare a first phase W/O, dispersing the first phase W/O into an outer water phase to obtain a relatively stable dispersed W/O/W emulsion, forming a multi-vesicle structure by rapidly removing the organic solvent, and gradually increasing the hardness of the multi-vesicles along with the gradual removal of the organic solvent to finally form the stable multi-vesicle liposome. Thus, the ability to form stable W/O/W emulsions is a critical step in the formation of multiple vesicles. The improper process control in the liquid preparation process is extremely easy to cause phospholipid to be broken, agglomerated and floccule to float in the solution, which is a technical problem to be solved at present. Disclosure of Invention In order to solve the technical problems, the invention provides a preparation method of a levobupivacaine long-acting liposome injection, which has the advantages of stable quality, long-acting analgesic effect, 7 times of in-vivo half-life extension, 6.0 times of MRT extension, stable in-vivo drug release and long-acting slow release effect of 48 hours, thereby increasing new indications. In addition, the invention also correspondingly provides a preparation process of the levobupivacaine liposome long-acting injection and application thereof in the postoperative pain relieving aspect, and the levobupivacaine liposome long-acting injection has good stability and long-acting effect, can reduce the injection times, improve the compliance of patients, increase the indication of the levobupivacaine, is more convenient in clinical application, can better serve the patients, and has good application prospect. In order to overcome the defects in the prior art, the invention provides the following technical scheme: The invention provides a long-acting liposome injection of levobupivacaine, which consists of the following components of levobupivacaine, neutral phospholipid, charge phospholipid, cholesterol, tricaprylin lysine, glucose and physiological saline. Further, each 1000mL of bupivacaine long-acting liposome injection comprises the following components in parts by weight: 11-16 g of levobupivacaine, 6-10 g of neutral phospholipid, 0.5-3 g of negatively charged phospholipid, 2-6 g of cholesterol, 1-5 g of tricaprylin, 46-60g of lysine, 288-300g of glucose and