Phospholipid gel as well as preparation method and application thereof

Abstract

The invention relates to the technical field of gel preparations, in particular to phospholipid gel as well as a preparation method and application thereof. The invention provides phospholipid gel. The phospholipid gel comprises a raw material medicine, mixed lipid and a hydration solvent, wherein the mixed lipid comprises neutral phospholipid, negative phospholipid and cholesterol, the neutral phospholipid comprises at least one of phosphatidylcholine and phosphatidylcholine derivatives, and the negative phospholipid is phosphatidic acid or phosphatidylglycerol. According to the invention, the encapsulation effect and the release characteristic of the phospholipid gel are improved by improving the phospholipid raw material and the preparation process.

Description

Technical Field

[0001] This invention relates to the field of gel formulation technology, and in particular to a phospholipid gel, its preparation method, and its application. Background Technology

[0002] Vesicular phospholipid gels (VPGs) are semi-solid phospholipid dispersions. Morphologically similar to vesicles, they differ from traditional liposome gels and ordinary liposome compartment structures. Due to their unique three-dimensional network structure, drug diffusion within VPGs follows a tortuous path, maximizing slow drug release and avoiding the potential toxicity caused by burst release effects. Based on the phospholipid-water interaction mechanism, under certain mechanical strength, typically when the phospholipid content is 1-100 mg / g (150 mmol / L), a common liposome structure spontaneously forms. Within this content range, water is completely absorbed by the phospholipid crystals, forming a single-phase system. Above this range, higher phospholipid contents (100-500 mg / g) are dispersed in a relatively small amount of water, resulting in a supersaturated aqueous phase with a high concentration of phospholipids. The amphoteric phospholipid molecules interact, forming gel-like vesicle morphologies through high-intensity shear forces. This technical approach can regulate the sustained-release behavior of formulations by optimizing phospholipid and drug concentrations, and the range of controllable sustained-release is relatively large.

[0003] The article "Research Progress on Vesicular Phospholipid Gels" (Chinese Journal of Pharmaceutics, Vol. 6, No. 4) describes the preparation method of vesicular phospholipid gels: When the VPG component is a single phospholipid, a "one-step preparation" technique is usually used. The phospholipid is dissolved in an appropriate amount of buffer solution or drug solution, magnetically stirred for 1-2 minutes, and then the viscous mixture is placed in a high-pressure homogenizer or microfluidic jet, and the operation is repeated several times under a certain pressure to obtain the gel. When the VPG component consists of two or more lipid components, the "organic solution freeze-drying" method is usually used. Due to the high concentration of phospholipids, the film dispersion method commonly used in liposome preparation is no longer applicable, and freeze-drying is more ideal. First, the phospholipid mixture is dissolved in an appropriate amount of organic solvent (or a mixture of organic solvents) under slow magnetic stirring, and then the solution is freeze-dried until a loose, spongy solid is formed. Then, it is dissolved and dispersed in a certain amount of aqueous medium to obtain the gel. Here, choosing a suitable organic solvent for freeze-drying is very important. Excellent freeze-drying organic solvents must meet the characteristics of high freezing point, high vapor pressure, high viscosity and low toxicity. Therefore, butanol-based organic solvents are more suitable.

[0004] Currently available marketed formulations for postoperative sustained-release analgesia include:

[0005] (1) Bupivacaine multi-capsule liposome Expallel is a formulation developed by Pacira using its DepoFoam technology. However, the liposomes release insufficient drug in the initial stages after administration, requiring the use of other formulations in clinical practice to achieve initial analgesic effects. Furthermore, its manufacturing process is complex, making it difficult to control batch-to-batch uniformity.

[0006] (2) Bupivacaine gel solution (trade name: Posimir) was developed by Durect Inc. in the United States, and consists of 660 mg bupivacaine and The platform technology is combined. Before injection, Posimir is a flowing liquid. At the end of the procedure, Posimir is placed under arthroscopy to directly observe the subacromial space. Sucrose acetate and benzyl alcohol combine with bupivacaine to form a continuously releasing drug reservoir gel, which continuously releases bupivacaine for more than 72 hours. The main excipients of the formulation are biodegradable sucrose acetate (SAIB) and the organic solvent benzyl alcohol, which poses certain safety risks.

[0007] (3) Bupivacaine / meloxicam sustained-release solution (trade name: Zynrelef) was developed by Heron Therapeutics and uses... The technology uses fourth-generation polyorthoesters (POEs) prepared by the condensation of diols and diketoacetals as sustained-release materials, which can control the diffusion of active ingredients at the surgical site, thereby regulating the release continuously and stably for 72 hours. Zynrelef uses novel excipients and DMSO as a solvent, which poses certain safety risks.

[0008] Chinese patent CN113116823A discloses a liposome and its preparation method, specifically relating to a lipid composition and liposomes obtained therefrom, wherein the liposomes have improved release characteristics. The preparation method includes: (1) providing a lipid composition, comprising: mixing ropivacaine, lipids, and a buffer solution to obtain a mixture, and shearing the mixture, wherein the ratio m / v of the total weight m of the ropivacaine and the lipids to the volume v of the buffer solution is 1:0.5-1:4; (2) diluting the lipid composition with a buffer solution; wherein the buffer solution provided in the lipid composition is a histidine buffer solution; and the buffer solution used for dilution is a histidine buffer solution.

[0009] Patent WO2008039989A2 discloses a composition comprising DNase encapsulated in liposomes, wherein the liposomes further disclose that the liposomes comprise lipids selected from phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), lecithinylcholine (EPC), egg phosphatidylglycerol (EPG), lecithinositol (EPI), lecithinylserine (EPS), methionine phosphatidylethanolamine (EPE), and methionine (EPA). Soybean phosphatidylcholine (SPC), soybean phosphatidylglycerol (SPG), soybean phosphatidylserine (SPS), soybean phosphatidylinositol (SPI), soybean phosphatidylethanolamine (SPE), soybean phosphatidic acid (SPA), HEPC, HSPC, dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), distearate Phosphatidylcholine (DSPC), distearylphosphatidylglycerol (DSPG), dioleoylphosphatidylethanolamine (DOPE), palmitoylstearoylphosphatidylcholine (PSPC), palmitoylstearoylphosphatidylglycerol (PSPG), monooleoylphosphatidylethanolamine (MOPE), cholesterol, cholesterol hemisuccinate, cholesterol bisulfate, cholesterol sulfate, ergosterol, ergosterol hemisuccinate, ergosterol bisulfate, ergosterol sulfate, lanosterol, lanosterol hemisuccinate, lanosterol bisulfate, lanosterol sulfate, fertility Phenols, tocopherol hemisuccinate, tocopherol bisulfate, tocopherol sulfate, myristamide, palmitamide, lauramide, stearamide, dilauroyl ethyl phosphorocholine (DLEP), dimyristoyl ethyl phosphorocholine (DMEP), dipalmitoyl ethyl phosphorocholine (DPEP) and distearyl ethyl phosphorocholine (DSEP), N-(2,3-di-(9-(Z)-octadecenoxy)-propyl-L-yl-N,N,N-trimethylammonium chloride (DOTMA) and 1,2-di(oleoyloxy)-3-(trimethylammonium)propane, or mixtures thereof.

[0010] Currently, for phospholipid gels, the selection of phospholipid raw materials and the degree of binding with the active pharmaceutical ingredient have a crucial impact on the performance of the resulting gel formulation. Therefore, it is still necessary to combine the effects of sustained release and release rate, and improve the phospholipid raw materials and preparation process to meet more complex clinical needs. Summary of the Invention

[0011] In view of this, this invention refers to traditional liposome formulations and combines vesicle-type phospholipid gel preparation technology to develop a phospholipid gel and its preparation method and application. By improving the phospholipid raw materials and preparation process, the encapsulation effect of the phospholipid gel is improved, the release characteristics of the active pharmaceutical ingredient are optimized, and the organic solvent, as a process solvent, can be removed during the freeze-drying stage, resulting in good in vivo safety.

[0012] To achieve the above-mentioned objectives, the technical solution of this invention is as follows:

[0013] On one hand, the present invention provides a phospholipid gel comprising a pharmaceutical ingredient, mixed lipids, and a hydration solvent;

[0014] The mixed lipids include negatively charged phospholipids, neutral phospholipids, and cholesterol. The negatively charged phospholipids are phosphatidic acid or phosphatidylglycerol, and the neutral phospholipids include at least one of phosphatidylcholine and phosphatidylcholine derivatives.

[0015] The term "phospholipid" refers to a hydrophobic molecule containing at least one phosphorus group, which may be natural or synthetic. For example, phospholipids may contain a phosphorus-containing group and saturated or unsaturated alkyl groups optionally substituted with OH, COOH, oxo, amine, or substituted or unsubstituted aryl groups. Phospholipids differ from each other in the length and degree of unsaturation of their acyclic chains. Negatively charged phospholipids and neutral phospholipids refer to phospholipids that are negatively charged or completely neutral, respectively.

[0016] The term "phospholipid gel" refers to a lipid matrix-based sustained-release drug reservoir-type drug delivery system. During hydration, phospholipids spontaneously recombine, encapsulating the active ingredient within the "reservoir" to form multilayered drug-loaded vesicles with a unique structure.

[0017] The term "active pharmaceutical ingredient" refers to a drug for treating diseases that requires sustained release.

[0018] In some embodiments, the active pharmaceutical ingredient includes at least one of the following: anesthetic, analgesic, antitumor, antifungal, antiallergic, anticoagulant, metabolism enhancer, antituberculosis, antiviral, antianginal, antibiotic, anti-inflammatory, antirheumatic, cardiac glycoside, neuromuscular blocking agent, sedative, and glucocorticoid.

[0019] Furthermore, the anesthetic drugs include general anesthetic drugs and local anesthetic drugs.

[0020] Furthermore, the general anesthetic includes at least one of the following: droperidol, etomidate, fentanyl citrate, droperidol, ketamine hydrochloride, mesobarbital sodium, and thiopental sodium.

[0021] Furthermore, the local anesthetic includes at least one of lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, eticaine, procaine, chloroprocaine, tetracaine, and benzocaine.

[0022] In some embodiments, the analgesics include: alfentanil, allirodine, afarotin, aniridine, benzylmorphine, bezimidoxetine, buprenorphine, butorphanol, chlorpheniramine, codeine, cyclozocine, dimethomorphine, dextromethorphan, dextropropoxyphene, dezocine, dienprofen, dihydrocodeine, dihydromorphine, demetadine, demetonol, dimethylthiamethoxam, butyl methacrylate, dipitipterone, ethazoline, ethacrylamide, ethacrylamide, ethylmorphine, etonidin, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketomidone. Allyl levomuron, hydroxymethyl levomuron, levonorgestrel, lofentanil, meperidine, mepitafen, metazoxine, methadone, metodone, morphine, merophenone, nalbuphine, propionic morphine, nicomorphine, norlevonorgestrel, normethadone, normorphine, nopiperidine, opioid, oxycodone, hydroxymorphone, total opioid, pentazocine, phenoxamone, phenazocine, phenoridone, phenoridone, phenperidine, piminodine, piperonitrile, propoxuridine, dimethperidine, propiril, propoxybenzene, sufentanil, tiridine, tramadol.

[0023] In some embodiments, antitumor drugs include platinum compounds (e.g., spiroplatin, cisplatin, and carboplatin), methotrexate, fluorouracil, doxorubicin, mitomycin, amimimycin, bleomycin, cytarabine, vidarabine, thiol polylysine, vincristine, busulfan, chlorambucil, melphalan, mercaptopurine, mitotane, procarbazine hydrochloride, actinomycin (actinomycin D), daunorubicin hydrochloride, doxorubicin hydrochloride, paclitaxel, mitomycin, procainoxam (scintillan), aminoglutethimide, estradiol sodium phosphate, flutamide, leuprolide acetate, megestrol acetate, tamoxifen citrate, testrolide, and tramostan.

[0024] Antifungal drugs include ketoconazole, nystatin, griseofulvin, flucytosine (5-fc), miconazole, amphotericin B, ricin, cyclosporine, and lactam antibiotics (e.g., sulfadiazine).

[0025] Antihistamines such as Ambroxol;

[0026] Anticoagulants such as phenylpropanol and heparin;

[0027] Metabolic enhancers, such as glutathione;

[0028] Anti-tuberculosis drugs, such as para-aminosalicylic acid, isoniazid ethambutol hydrochloride ethionamide, pyrazinamide, rifampin, and streptomycin sulfate;

[0029] Antiviral drugs, such as acyclovir, amantadine zidovudine (AZT, DDI, phosphonate or zidovudine), ribavirin and vidarabine monohydrate (vidarabine, 25ara-A);

[0030] Antianginal drugs, such as diltiazem, nifedipine, verapamil, erythritol tetranitrate, isosorbide dinitrate, nitroglycerin (trinitroglycerin), and pentaerythritol tetranitrate;

[0031] Anticoagulants, such as phenylcoumarin and heparin;

[0032] Antibiotics, such as dapsone, chloramphenicol, neomycin, cefaclor, cefadroxil, cefadroxil, erythromycin, clindamycin, lincomycin, amoxicillin, ampicillin, bamopicillin, carbenicillin, dicloxacillin, cyclohexidine, picocloxacillin, hetacillin, methicillin, nafcillin, oxacillin, penicillin, ticarcillin, rifampin, tetracycline;

[0033] Anti-inflammatory drugs, such as meloxicam, diflunisal, ibuprofen, indomethacin, meclofenamic acid, naproxen, oxybutazone, phenylbutazone, sulindac, tometine, aspirin, and salicylates;

[0034] Antirheumatic drugs, such as penicillamine;

[0035] Cardiac glycosides, such as deslanoside, digitoxin, digoxin, digitoxin, and digitalis;

[0036] Neuromuscular blocking agents, such as atracurium mesylate, galenamine triethyliodide, hexafluorene bromide, metocorline iodide, pancuronium bromide, succinylcholine chloride (sucetyl chloride), tubocurarine chloride, and vecuronium bromide;

[0037] Sedative drugs (hypnotics), such as amobarbital, sodium amobarbital, alprabarbital, sodium butabarbital, chloral hydrate, ethynolone acetonide, flurazepam hydrochloride, lutet, methoxypromethazine hydrochloride, methylpropane, midazolam hydrochloride, metaldehyde, pentobarbital, sodium pentobarbital, sodium phenobarbital, secobarbital sodium, tabarbital, temazepam, and triazolam.

[0038] Glucocorticoids, such as dexamethasone, betamethasone, hydrocortisone, prednisone, prednisolone, methylprednisolone, and triamcinolone.

[0039] Preferably, the active pharmaceutical ingredient includes at least one of an anti-inflammatory drug, analgesic, and glucocorticoid.

[0040] More preferably, the active pharmaceutical ingredient includes at least one of a nonsteroidal anti-inflammatory drug, an analgesic, and a glucocorticoid.

[0041] This invention introduces a specific combination of negatively charged phospholipids into the phospholipid gel preparation technology, enabling the active pharmaceutical ingredient and the negatively charged phospholipids to form a complex, which can significantly improve the drug encapsulation efficiency and reduce the in vitro drug release rate.

[0042] The active pharmaceutical ingredient may be in the form of a compound salt and / or free base of the listed drugs, such as at least one of hydrochloride, sulfate, phosphate, citrate, hydrobromide, acetate, benzoate, benzenesulfonate, tartrate, carbonate, citrate, gluconate, lactate, malate, methanesulfonate, stearate, valerate, and nitrate.

[0043] Preferably, the neutral phospholipid is at least one of dipalmitoylphosphatidylcholine (DPPC), distearylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), 1-palmitoyl-2-linoleoyl-sn-glycerol-3-phosphatidylcholine (PLPC), dioleoylphosphatidylcholine (DOPC), disqualylphosphatidylcholine (DEPC), egg yolk phosphatidylcholine (EPC), soybean phosphatidylcholine (SPC), and hydrogenated soybean phosphatidylcholine (HSPC).

[0044] More preferably, it is at least one of distearylphosphatidylcholine, soybean phosphatidylcholine, and hydrogenated soybean phosphatidylcholine. Even more preferably, it is at least one of soybean phosphatidylcholine and hydrogenated soybean phosphatidylcholine.

[0045] Preferably, the phosphatidic acid is selected from at least one of dipalmitoyl phosphatidic acid (DPPA), 1,2-dioleoyl-sn-glycerol-3-phosphatidic acid (DOPA), dimyristoyl phosphatidic acid (DMPA), distearate phosphatidic acid (DSPA), and soybean phosphatidic acid (SPA). More preferably, soybean phosphatidic acid is used.

[0046] Preferably, the phosphatidylglycerol is selected from at least one of dioleoylphosphatidylglycerol (DOPG) or its sodium salt, dimyristoylphosphatidylglycerol (DMPG) or its sodium salt, distearate phosphatidylglycerol (DSPG) or its sodium salt, and dipalmitoylglycerol phosphate (DPPG) or its sodium salt.

[0047] More preferably, it is distearylphosphatidylglycerol or its sodium salt.

[0048] In some embodiments, soybean phosphatidic acid (SPA) is prepared by enzymatic hydrolysis, using soybean phosphatidylcholine (SPC) and phospholipase D in an ethyl acetate system followed by purification.

[0049] Preferably, the hydration solvent is selected from at least one of glucose solution, sucrose solution, physiological saline (0.9% NaCl solution), and water for injection.

[0050] More preferably, it is at least one of 1-10% glucose solution, 2-20% sucrose solution, physiological saline, and water for injection; more preferably, it is 1-10% glucose solution or 2-20% sucrose solution; and even more preferably, it is 5% glucose solution or 10% sucrose solution.

[0051] Preferably, the mass ratio (volume mass ratio, etc.) of the hydration solvent and the active pharmaceutical ingredient is 0.02-1:1, ml:mg.

[0052] Preferably, for example, 0.1-0.5:1 (ml:mg), 0.5-1:1 (ml:mg), 20-30:1 (ml:g), 30-40:1 (ml:g), or 40-50:1 (ml:g).

[0053] Further preferably, for example, 0.1-0.2:1 (ml:mg), 0.2-0.3:1 (ml:mg), 0.3-0.4:1 (ml:mg), 0.4-0.5:1 (ml:mg), 0.5-0.6:1 (ml:mg), 0.6-0.7:1 (ml:mg), 0.7-0.8:1 (ml )

[0054] Further preferably, for example, 0.1:1 (ml:mg), 0.2:31 (ml:mg), 0.3:1 (ml:mg), 0.4:1 (ml:mg), 0.5:1 (ml:mg), 0.6:1 (ml:mg), 0.7:1 (ml:mg), 0.8:1 ( ml:mg), 0.9:1(ml:mg), 1:1(ml:mg), 20:1(ml:g), 25:1(ml:g), 30:1(ml:g), 35:1(ml:g), 40:1(ml:g), 45:1(ml:g), 50:1(ml:g).

[0055] Preferably, when the active pharmaceutical ingredient is an analgesic, the ratio of the hydration solvent to the active pharmaceutical ingredient is 20-50:1, ml:g; when the active pharmaceutical ingredient is a nonsteroidal anti-inflammatory drug or glucocorticoid, the ratio is 0.1-1:1, ml:mg.

[0056] The type and amount of hydration solvent have a significant impact on the encapsulation efficiency of the resulting product. By selecting a suitable hydration solvent, a higher encapsulation efficiency can be ensured.

[0057] Preferably, in the mixed lipids, the mass ratio of negatively charged phospholipids, cholesterol, and neutral phospholipids is 1-10:1-7:2-13, more preferably 2-10:1-7:2-9, and even more preferably 2-10:1-7:2-7. Specific examples include 2:1:2, 9:4:7, 10:7:3, 9:6:5, 10:3:7, 10:5:5, and 8:5:7, 8:3:9, 7:4:9, 2:3:5, etc.

[0058] The mass ratio (drug-lipid ratio) of the active pharmaceutical ingredient and the mixed lipids is 1:2-500;

[0059] More preferably, when the active pharmaceutical ingredient is an analgesic, the ratio is 1:2-10; when the active pharmaceutical ingredient is a nonsteroidal anti-inflammatory drug, the ratio is 1:20-500; and when the active pharmaceutical ingredient is a glucocorticoid, the ratio is 1:30-500.

[0060] More preferably, when the active pharmaceutical ingredient is an analgesic, the ratio is 1:5-10; when the active pharmaceutical ingredient is a nonsteroidal anti-inflammatory drug, the ratio is 1:25-300; and when the active pharmaceutical ingredient is a glucocorticoid, the ratio is 1:50-300.

[0061] More preferably, when the active pharmaceutical ingredient is ropivacaine, the ratio is 1:7-10; when the active pharmaceutical ingredient is meloxicam, the ratio is 1:50-300; and when the active pharmaceutical ingredient is dexamethasone, the ratio is 1:100-300.

[0062] This invention discovers that, under specific combinations of negatively charged phospholipids, cholesterol, and neutral phospholipids, and by combining the corresponding ratios of these compounds with the drug-lipid ratio, the drug encapsulation efficiency can be significantly improved, and release characteristics optimized. Some specific embodiments of this invention include:

[0063] The negatively charged phospholipids are selected from distearylphosphatidylglycerol or its sodium salt, or soybean phosphatidyl acid; the neutral phospholipids are selected from at least one of distearylphosphatidylcholine, soybean phosphatidylcholine, and hydrogenated soybean phosphatidylcholine; the mass ratio of negatively charged phospholipids, cholesterol, and neutral phospholipids is 2-10:1-7:2-9; when the active pharmaceutical ingredient is ropivacaine, the ratio is 1:7-10; when the active pharmaceutical ingredient is meloxicam, the ratio is 1:50-300; when the active pharmaceutical ingredient is dexamethasone, the ratio is 1:100-300.

[0064] or,

[0065] The negatively charged phospholipids are selected from distearylphosphatidylglycerol or its sodium salt, or soybean phosphatidyl acid; the neutral phospholipids are selected from at least one of soybean phosphatidylcholine and hydrogenated soybean phosphatidylcholine; the mass ratio of negatively charged phospholipids, cholesterol, and neutral phospholipids is 2-10:1-7:2-7; when the active pharmaceutical ingredient is ropivacaine, the ratio is 1:7-10; when the active pharmaceutical ingredient is meloxicam, the ratio is 1:50-300; when the active pharmaceutical ingredient is dexamethasone, the ratio is 1:100-300.

[0066] Preferably, the phospholipid gel composition, after dispersion, has a median diameter (Dv50) of not less than 1 μm, for example greater than 5 μm, for example greater than 10 μm, for example greater than 15 μm, for example greater than 20 μm.

[0067] Preferably, the phospholipid gel composition further includes other pharmaceutically acceptable excipients.

[0068] More preferably, the other pharmaceutically acceptable excipients are present in the phospholipid gel composition at a concentration of 0.5%-5%.

[0069] Preferred amounts include, for example, 0.5-2%, 1-4%, and 2-5%.

[0070] Preferred values ​​are, for example, 0.5%-1%, 1%-2%, 2%-3%, 3%-4%, and 4%-5%.

[0071] Preferred values, for example, are 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, and 5%.

[0072] The term "pharmaceutically acceptable excipient" is well-known in the art and includes pharmaceutically acceptable materials, components, or carriers suitable for administration of the compounds of this invention to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that participate in carrying or delivering the principal substance from one part of an organ or body to another. Each carrier must be "acceptable" in terms of compatibility with other components of the formulation or inconvenience to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium methylcellulose, ethylcellulose, and cellulose acetate; saffron gum, malt, gelatin, and talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; and polyols, such as glycerol and sorbitol. Mannitol, polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogens, isotonic saline, ethanol, phosphate buffer and other non-toxic compatibility substances used in pharmaceutical formulations, wetting agents, emulsifiers and lubricants such as sodium dodecyl sulfate and stearates, as well as colorants, separating agents, coating agents, sweeteners, flavoring and aroma agents, preservatives, lyophilization protectants and antioxidants may also be present in the composition.

[0073] Examples of pharmaceutically usable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as palmitic acid ascorbate, butylated benzoic acid (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal compounds such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0074] Examples of freeze-drying protectants include: trehalose, sucrose, maltose, mannitol, sorbitol, polyethylene glycol, serum albumin, hydroxyethyl starch, and amino acids (glycine, histidine, etc.).

[0075] Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (e.g., NaCl), alcohols, gum arabic, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, sugars (e.g., lactose, amylose, or starch), polyethylene glycol, magnesium stearate, talc, silica, viscous paraffin, aromatic oils, fatty acid esters, methylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical composition may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, humectants, emulsifiers, salt buffers affecting osmotic pressure, colorants, flavorings, and / or aromatic substances, which react harmlessly with the active compound.

[0076] Pharmaceutically acceptable excipients can also mean the following: containing minor amounts of wetting agents, emulsifiers, or pH buffers.

[0077] According to conventional methods, the composition may also include stabilizers and local anesthetics to reduce pain at the injection site.

[0078] Generally, the ingredients are supplied individually or mixed together in unit dosage forms, such as in sealed containers like ampoules or small capsules indicating the amount of active agent, as a dry lyophilized powder or anhydrous concentrate. When the composition is administered by injection, a single ampoule of sterile water or saline for injection may be provided, allowing the ingredients to be mixed before administration.

[0079] On the other hand, the present invention provides a method for preparing the above-mentioned phospholipid gel, comprising the steps of:

[0080] (1) Dissolve the active pharmaceutical ingredient, mixed lipids, and other pharmaceutically acceptable excipients in a solvent, dry them, and obtain a cake;

[0081] (2) Mix the cake obtained in step (1) with the hydration solvent and hydrate to obtain phospholipid gel.

[0082] Preferably, in step (1), the solvent is an organic solvent, more preferably a mixture of alcohol and water, even more preferably a mixture of tert-butanol and water, and even more preferably, the volume percentage of tert-butanol in the mixture is 30%-100%. Examples include 30%, 35%, 40%, 40.1%, 40.5%, 46%, 50%, 60%, 70%, 80%, 90%, and 100%. As specific examples in this invention, 50% and 100% are used.

[0083] At the above ratio, the active pharmaceutical ingredient and phospholipids can form a homogeneous structure in the tert-butanol-water solvent system, and can be completely removed during the freeze-drying stage, thus improving the safety of clinical use.

[0084] Preferably, in step (1), the concentration of lipids in the solvent is 50 mg / mL to 200 mg / mL, for example, 50 mg / mL, 55 mg / mL, 60 mg / mL, 70 mg / mL, 100 mg / mL, 100.1 mg / mL, 110 mg / mL, 111 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, etc.

[0085] In step (1), the drying method includes, but is not limited to, oven drying, natural drying, freeze drying, vacuum drying, air drying, and sun drying. As a preferred technical solution in this invention, freeze drying is selected.

[0086] The freeze-drying process can be a common setup in the art, which allows the active pharmaceutical ingredient, mixed lipids, and other pharmaceutically acceptable excipients to be dissolved in a solvent to obtain a loose, porous freeze-dried cake.

[0087] As a specific implementation plan, the freeze-drying process is as follows:

[0088]

[0089] In step (2), the hydration temperature is set differently depending on the type of lipid in the prescription. Preferably, the hydration temperature is 20-70℃.

[0090] Preferably, in step (2), the hydration is high-speed vortex hydration, including but not limited to manual vortex, automatic vortex, and heated vortex. As a specific example in this invention, a heated vortex integrated device is used for hydration.

[0091] More preferably, the rotational speed of the high-speed vortex hydration is set to be no less than 1000 rpm.

[0092] Preferably, the hydrated phospholipid concentration is not less than 50 mg / mL, and more preferably not less than 100 mg / mL.

[0093] In another aspect, the present invention provides the use of the above-mentioned phospholipid gel in the preparation of nonsteroidal anti-inflammatory drugs, analgesics or glucocorticoids.

[0094] In some embodiments, the analgesia is postoperative analgesia for more than 72 hours.

[0095] Finally, the present invention provides a method of anesthesia and / or analgesia, comprising administering the above-described phospholipid gel to an individual.

[0096] In some embodiments, the application is parenteral. In some embodiments, the application is local. In some embodiments, the application is both parenteral and local. In some embodiments, parenteral application is selected from subcutaneous injection, tissue injection, wound infiltration, or wound infusion.

[0097] Standard methods and devices, such as pens, syringe systems, needles and syringes, subcutaneous injections, catheters, etc., can be used to apply phospholipid gels.

[0098] Preferably, the dose administered to an individual is 5-800 mg / day.

[0099] Preferably, for example, 5-100mg / day, 100-200mg / day, 200-300mg / day, 300-400mg / day, 400-500mg / day, 500-600mg / day, 600-700mg / day, or 700-800mg / day.

[0100] More preferably, 5-50mg / dose, 50-100mg / dose, 100-150mg / dose, 150-200mg / dose, 200-250mg / dose, 250-300mg / dose, 300-350mg / dose, 350-400mg / dose, 400-450mg / dose, 450-500mg / dose, 500-550mg / dose, 550-600mg / dose, 600-650mg / dose, 650-700mg / dose, 700-750mg / dose, 750-800mg / dose.

[0101] More preferably, for example, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 2 10mg / day, 220mg / day, 230mg / day, 240mg / day, 250mg / day, 260mg / day, 270mg / day, 280mg / day, 290mg / day, 300mg / day, 310mg / day, 320mg / day, 330mg / day, 340mg / day, 350mg / day, 360mg / day, 370mg / day, 380mg / day, 390mg / day, 400mg / day.

[0102] "Individual" refers to an individual suffering from a disease, symptom, or condition, including both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates (e.g., chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0103] The beneficial effects of this invention are as follows:

[0104] (1) After hydration, the encapsulation rate of formulations prepared with different types and proportions of phospholipids in the formulation varies from approximately 10% to 90%. By introducing specific negatively charged phospholipid combinations into the phospholipid gel preparation technology, the drug encapsulation rate can be significantly improved and the in vitro release rate of the drug can be reduced.

[0105] (2) Experimental data show that, compared with the original formulation of ropivacaine hydrochloride injection, which releases 0.5h-100% in vitro, the phospholipid gel form of ropivacaine hydrochloride can achieve in vitro release of 72h and above.

[0106] (3) In animal experiments, ropivacaine hydrochloride phospholipid gel showed a significant sustained-release effect in vivo compared with ropivacaine hydrochloride injection, which is consistent with the in vivo comparison trend of marketed postoperative analgesic sustained-release preparations.

[0107] (4) In terms of analgesic efficacy, in the Pin-Prick model (the efficacy model in the FDA application for Expare), the analgesic sustained-release effect of ropivacaine hydrochloride phospholipid gel is superior to that of the pre-modified formulation ropivacaine hydrochloride injection and the marketed formulation Expare.

[0108] (5) The phospholipid gel prepared by the present invention can be mixed with different free / encapsulated ratios by different hydration solvents, which is suitable for different clinical needs; different hydration volumes form phospholipid gels with different phospholipid concentrations (different viscosities), and the sustained release can be adjusted in a large range; at the same time, the hydration process is optimized and the manual hydration process is replaced by automated equipment, which is more efficient and convenient.

[0109] (6) The phospholipid gel of the present invention is suitable for use as a carrier for various active pharmaceutical ingredients, such as nonsteroidal anti-inflammatory drugs, analgesics or glucocorticoids. By selecting an appropriate drug-lipid ratio, an excellent sustained-release effect can be achieved. At the same time, the present invention has demonstrated that the composition of lipids has a key influence on the sustained-release effect. Under the specific lipid composition and ratio of the present invention, the encapsulation rate and sustained-release effect of different active pharmaceutical ingredients can be improved simultaneously. Attached Figure Description

[0110] Figure 1 The graph shows the pharmacokinetic (PK) results of subcutaneous administration to rats.

[0111] Figure 2 A schematic diagram of a guinea pig acupuncture model.

[0112] Figure 3 The figure shows the analgesic efficacy results (Pin-Prick acupuncture model).

[0113] Figure 4 This is a cryo-scanning electron microscope image of the ropivacaine hydrochloride phospholipid gel prepared in this invention. Detailed Implementation

[0114] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention. Those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and these should also fall within the scope of protection claimed by the present invention. Unless otherwise specified, all percentages are by mass; unless otherwise specified, all operating temperatures are at room temperature; unless otherwise specified, all raw materials can be obtained through conventional purchasing channels or conventional methods.

[0115] "Encapsulation percentage" or "encapsulation ratio" refers to the percentage of the molar amount of all drug forms encapsulated within the liposomes relative to the total molar amount of drug in the composition. A preferred encapsulation ratio range is about 1%.

[0116] -99%, more preferably about 60%-85%. Encapsulation efficiency can be determined using conventional encapsulation efficiency determination methods, such as HPLC.

[0117] "Particle size distribution" or "PSD" refers to the particle size distribution in liposomes as measured by dynamic light scattering techniques well known to those skilled in the art, such as using a Malvern Mastersizer™ 2000. "d(0.1)" as used in this disclosure refers to the particle size at which the cumulative particle size distribution percentage of a sample reaches 10%.

[0118] “d(0.5)” refers to the particle size corresponding to a sample when the cumulative particle size distribution percentage reaches 50%. “d(0.9)” refers to the particle size corresponding to a sample when the cumulative particle size distribution percentage reaches 90%.

[0119] Example 1: Preparation of Ropivacaine Compositions with Different Lipid Types and Formulation Ratios

[0120] Ropivacaine lipid compositions were prepared using different types and proportions of lipids and ropivacaine hydrochloride, and different types and proportions of drug lipid compositions were prepared according to drug-lipid ratios of 1:5 / 1:10.

[0121] Ropivacaine hydrochloride and phospholipids were dissolved in tert-butanol-water solvent systems of varying proportions to form a homogeneous structure. The volume-to-mass ratio of the solvent system to ropivacaine hydrochloride was 40-100:1 (ml:g), specifically 10-20 ml:0.2 g. The solutions were filled into vials and lyophilized to obtain the drug-lipid lyophilized formulation.

[0122]

[0123] A 5% glucose solution was used as the hydration solvent, and hydration was carried out at 20-70℃. The volume-to-mass ratio of the hydration solvent to ropivacaine hydrochloride was 20:1-50:1 (ml:g), specifically 10ml:0.2g. The hydration time was 2-10min. This prepared ropivacaine phospholipid gel formulation. After hydration, the phospholipid concentration was 50mg / mL-300mg / mL, and the ropivacaine concentration was 10mg / mL-30mg / mL, forming phospholipid gels of different viscosities.

[0124] Weigh 1g of the hydrated drug phospholipid gel into a 25mL volumetric flask, add 5% glucose solution, shake to disperse evenly, and continue to dilute with 5% glucose solution to the mark, mixing well. Take 5mL of the above solution and place it in an ultrafiltration centrifuge tube (brand: Millipore, 100KD), centrifuge at 2500rpm at 20℃ for 30 minutes, and the filtered clear liquid is the unencapsulated sample solution; separately take the above diluted solution, dissolve it in diluent (chloroform:methanol = 2:1), and use this as the total free and encapsulated sample to determine the encapsulation rate. The encapsulation rate results for different formulations are shown in the table below.

[0125]

[0126]

[0127] The results showed that different phospholipid combinations, phospholipid mass ratios, and drug-lipid ratios had a significant impact on the encapsulation efficiency, with formulations 1-36 exhibiting significant differences.

[0128] Example 2: Preparation of Ropivacaine Compositions with Different Aqueous Solvents

[0129] Ropivacaine lipid lyophilized formulations were prepared according to the preparation method of Formula 13 above. Different hydration solvents were used: water for injection, 0.9% NaCl solution, 5% glucose solution, and 10% sucrose solution. Hydration was carried out at 60℃ and 1500 rpm for 2-10 min. The detection results of the ropivacaine lipid composition after hydration are shown in the table below. Hydration with different solvents yields mixtures with different free / encapsulated ratios, suitable for different clinical needs.

[0130] The encapsulation efficiency test method is as described in Example 1 above. Particle size test method: Take 100 μL of the hydrated sample solution, add 900 μL of 5% glucose solution, vortex mix, and use 5% glucose solution as the dispersant. Use a wet method to determine the particle size by stirring at 2500 rpm and adding the sample dropwise to make the opacity about 10% (between 2% and 20%).

[0131]

[0132] The results showed that different hydration solvents resulted in significant differences in encapsulation efficiency. For ropivacaine, 5% glucose solution and 10% sucrose solution were used as hydration solvents to achieve better encapsulation efficiency.

[0133] Example 3: Preparation of ropivacaine phospholipid gels with different lipid concentrations

[0134] Ropivacaine lipid lyophilized formulations were prepared according to the preparation method of the above-mentioned formulation 30. Different volumes of 5% glucose solution were used for hydration at 60°C and 1500 rpm for 2-5 min. After hydration, ropivacaine hydrochloride phospholipid gels with different lipid concentrations were formed, and their viscosities varied greatly. The results are shown in the table below.

[0135] The encapsulation efficiency / particle size detection method is as described in Examples 1 and 2 above.

[0136] In vitro release assay: Accurately transfer 1 mL of the hydrated sample solution using a syringe and weigh it. Add the sample to a glass slide, place the slide in a dissolution vessel (containing 500 mL of hydrated PBS, equilibrated to 37 ± 0.5 °C), weigh the syringe again, and record the sample volume. Set the rotation speed to 25 rpm and take samples at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, and 48 h for measurement. After each sampling, add release medium (under this release method, ropivacaine hydrochloride solution is 100% released after 0.25 h sampling).

[0137]

[0138] Example 4. Pharmacokinetic Study in Rats

[0139] Ropivacaine hydrochloride phospholipid gel was prepared according to prescription 13; ropivacaine hydrochloride injection was prepared using 5% glucose solution (control group before dosage form modification, API concentration the same as prescription 13); commercially available bupivacaine liposome injection Expareel was used as a positive control group for animal experiments. The experimental animals were SD rats, 5 rats per group. The injection was administered subcutaneously at a dose of 40 mg / kg. Blood samples were collected at 0, 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration for content detection. The pharmacokinetic (PK) results are shown in the table below. Figure 1 As shown.

[0140]

[0141] Example 5. Analgesic Efficacy Experiment - Guinea Pig Acupuncture Model

[0142] Ropivacaine hydrochloride phospholipid gel was prepared according to prescriptions 42 and 44; ropivacaine hydrochloride injection was prepared using 5% glucose solution (control group before dosage form improvement, API concentration same as prescription 42); commercially available bupivacaine liposome injection Expareel was used as a positive control group, and a blank liposome gel group (lipid concentrations same as prescriptions 42 and 44) ​​was set up to conduct pharmacodynamic experiments on a guinea pig acupuncture model.

[0143] The experimental animals were guinea pigs (approximately 500g). The fur on the backs of the guinea pigs was shaved before the experiment. Six areas were drawn on the back of each guinea pig, as shown below. Figure 2 As shown, the sensitivity of each area to acupuncture was confirmed through acupuncture.

[0144] Three animals in each experimental group received intradermal injection of medication at a dose of 7 mg / kg. The location of wheals was marked after administration. The response of each area to acupuncture was measured at 0.25 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 30 h, 48 h, 52 h, and 72 h post-administration. The number of positive reactions (the number of times no reaction occurred out of 6 acupuncture needles) was recorded. The experimental results are as follows: Figure 3 As shown.

[0145] Eight hours after administration of ropivacaine hydrochloride injection, the pain threshold decreased by approximately 50%. Ten hours after administration of the positive control bupivacaine liposome injection, the pain threshold decreased by more than 50%. Twenty-four hours after administration of ropivacaine hydrochloride phospholipid gel, the pain threshold decreased by more than 50%. The analgesic and sustained-release effects of ropivacaine hydrochloride phospholipid gel under this pharmacodynamic model were superior to those of the positive control bupivacaine liposome injection.

[0146] The 200 mg / mL lipid concentration (viscous) after hydration was superior to the 150 mg / mL lipid concentration (good fluidity) after hydration in terms of the duration of analgesic effect.

[0147] Example 7. Cryo-scanning electron microscopy observation

[0148] Ropivacaine hydrochloride phospholipid gel was prepared according to prescription 39, hydrated and diluted with 5% glucose injection, and then observed by cryo-scanning electron microscopy. The results are as follows: Figure 4 As shown, the product exhibits a multilayered liposome structure.

[0149] Example 8: Preparation of phospholipid gel compositions with different active ingredients from different phospholipid types

[0150] Following the preparation method of Example 1, phospholipid gel compositions with different active ingredients were prepared using different negatively charged phospholipids SPA and DSPG-Na. After hydration with 5% glucose solution, a phospholipid gel formulation with a lipid concentration of 170 mg / ml was formed. The ratio of hydration solvent to active pharmaceutical ingredient was 0.1-1:1, specifically 0.5:1. The encapsulation efficiency was tested according to the method described in Example 1 and the in vitro release conditions (0.5% Tween 80 added to the release medium) described in Example 3. The results are shown in the table below.

[0151]

[0152]

[0153] No significant differences were observed in the properties and encapsulation efficiency of the hydrated formulations of different negatively charged phospholipids SPA and DSPG-Na. The results of the in vitro release test using the negatively charged phospholipid DSPG-Na formulation are as follows (under this release method, the ropivacaine hydrochloride / meloxicam / dexamethasone sodium phosphate / dexamethasone palmitate solution was 100% released after sampling at 0.5 h). The single and compound formulations of phospholipid gels prepared with different active ingredients all showed significant sustained-release effects in in vitro release.

[0154]

[0155]

[0156] Comparative Examples 1-3

[0157] Encapsulation efficiency test results:

[0158]

[0159] The encapsulation efficiency of Comparative Examples 2 and 3 decreased significantly, indicating that the composition of lipids has a key influence on the encapsulation efficiency. In addition, the lipid formulations of the comparative examples were very difficult to hydrate, which is not conducive to preparation. Therefore, in vitro release tests were further conducted on Comparative Examples 2 and 3 and Formulation 30.

[0160] Results of in vitro release rate test:

[0161]

[0162]

[0163] The results showed that, compared with formulation 30, the sustained-release effect of the products prepared in comparative examples 2-3 was significantly reduced, indicating that the lipid composition has a key influence on the sustained-release effect. Under the specific lipid composition and ratio of the present invention, both the encapsulation efficiency and the sustained-release effect can be improved simultaneously.

[0164] The above description is merely an exemplary illustration of the scope of protection claimed by this invention. Those skilled in the art can make various changes and modifications to this invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by this application.

Claims

1. A phospholipid gel, characterized in that, Including active pharmaceutical ingredients, mixed lipids, and hydration solvents; The mixed lipids include neutral phospholipids, negatively charged phospholipids, and cholesterol. The neutral phospholipids include at least one of phosphatidylcholine and phosphatidylcholine derivatives, and the negatively charged phospholipids are phosphatidic acid or phosphatidylglycerol.

2. The phospholipid gel according to claim 1, characterized in that, The active pharmaceutical ingredient includes at least one of the following: anesthetics, analgesics, antitumor drugs, antifungal drugs, antiallergic drugs, anticoagulants, metabolism enhancers, antituberculosis drugs, antiviral drugs, antianginal drugs, antibiotics, anti-inflammatory drugs, antirheumatic drugs, cardiac glycosides, neuromuscular blocking agents, sedatives, and glucocorticoids. Preferably, it includes at least one of nonsteroidal anti-inflammatory drugs, analgesics, and glucocorticoids. More preferably, the active pharmaceutical ingredient includes at least one of meloxicam, dexamethasone, and ropivacaine. Preferably, the active pharmaceutical ingredient is in the form of a compound salt and / or a free base.

3. The phospholipid gel according to claim 1, characterized in that, The neutral phospholipid is at least one of dipalmitoyl phosphatidylcholine, distearyl phosphatidylcholine, dimyristoyl phosphatidylcholine, 1-palmitoyl-2-linoleoyl-sn-glycerol-3-phosphatidylcholine, dioleoyl phosphatidylcholine, disqualoyl phosphatidylcholine, egg yolk phosphatidylcholine, soybean phosphatidylcholine, and hydrogenated soybean phosphatidylcholine. Preferably, the neutral phospholipid is at least one of distearylphosphatidylcholine, soybean phosphatidylcholine, and hydrogenated soybean phosphatidylcholine; More preferably, the neutral phospholipid is at least one of soybean phosphatidylcholine and hydrogenated soybean phosphatidylcholine.

4. The phospholipid gel according to claim 1, characterized in that, The phosphatidic acid is selected from at least one of dipalmitoyl phosphatidic acid, 1,2-dioleoyl-sn-glycero-3-phosphatidic acid, dimyristoyl phosphatidic acid, distearyl phosphatidic acid, and soybean phosphatidic acid; The phosphatidylglycerol is selected from at least one of dioleoyl phosphatidylglycerol or its sodium salt, dimyristoyl phosphatidylglycerol or its sodium salt, and dipalmitoyl phosphoglycerol or its sodium salt. More preferably, the phosphatidylglycerol is selected from distearylphosphatidylglycerol or its sodium salt.

5. The phospholipid gel according to claim 1, characterized in that, The hydration solvent is selected from at least one of glucose solution, sucrose solution, physiological saline, and water for injection; Preferably, the hydration solvent is selected from at least one of 1-10% glucose solution, 2-20% sucrose solution, physiological saline, and water for injection; More preferably, the hydration solvent is selected from 1-10% glucose solution or 2-20% sucrose solution; More preferably, the hydration solvent is selected from a 5% glucose solution or a 10% sucrose solution.

6. The phospholipid gel according to claim 1, characterized in that, The ratio of the aqueous solvent to the active pharmaceutical ingredient is 0.02-1:1, ml: mg; Preferably, when the active pharmaceutical ingredient is an analgesic, the ratio of the hydration solvent to the active pharmaceutical ingredient is 20-50:1, ml:g; when the active pharmaceutical ingredient is a nonsteroidal anti-inflammatory drug or glucocorticoid, the ratio is 0.1-1:1, ml:mg.

7. The phospholipid gel according to claim 1, characterized in that, In the mixed lipids, the mass ratio of negatively charged phospholipids, cholesterol, and neutral phospholipids is 1-10:1-7:2-13, preferably 2-10:1-7:2-9, and more preferably 2-10:1-7:2-7; The mass ratio of the active pharmaceutical ingredient to the mixed lipids is 1:2-500; More preferably, when the active pharmaceutical ingredient is an analgesic, the ratio is 1:2-10; when the active pharmaceutical ingredient is a nonsteroidal anti-inflammatory drug, the ratio is 1:20-500; and when the active pharmaceutical ingredient is a glucocorticoid, the ratio is 1:30-500. More preferably, when the active pharmaceutical ingredient is an analgesic, the ratio is 1:5-10; when the active pharmaceutical ingredient is a nonsteroidal anti-inflammatory drug, the ratio is 1:25-300; and when the active pharmaceutical ingredient is a glucocorticoid, the ratio is 1:50-300. More preferably, when the active pharmaceutical ingredient is ropivacaine, the ratio is 1:7-10; when the active pharmaceutical ingredient is meloxicam, the ratio is 1:50-300; and when the active pharmaceutical ingredient is dexamethasone, the ratio is 1:100-300.

8. The phospholipid gel according to any one of claims 1-7, characterized in that, The negatively charged phospholipids are selected from distearylphosphatidylglycerol or its sodium salt, or soybean phosphatidyl acid; the neutral phospholipids are selected from at least one of distearylphosphatidylcholine, soybean phosphatidylcholine, and hydrogenated soybean phosphatidylcholine; the mass ratio of negatively charged phospholipids, cholesterol, and neutral phospholipids is 2-10:1-7:2-9; when the active pharmaceutical ingredient is ropivacaine, the mass ratio of the active pharmaceutical ingredient to the mixed lipids is 1:7-10; when the active pharmaceutical ingredient is meloxicam, the mass ratio of the active pharmaceutical ingredient to the mixed lipids is 1:50-300; when the active pharmaceutical ingredient is dexamethasone, the mass ratio of the active pharmaceutical ingredient to the mixed lipids is 1:100-300. or, The negatively charged phospholipids are selected from distearylphosphatidylglycerol or its sodium salt, or soybean phosphatidyl acid; the neutral phospholipids are selected from at least one of soybean phosphatidylcholine and hydrogenated soybean phosphatidylcholine; the mass ratio of negatively charged phospholipids, cholesterol, and neutral phospholipids is 2-10:1-7:2-7; when the active pharmaceutical ingredient is ropivacaine, the mass ratio of the active pharmaceutical ingredient to the mixed lipids is 1:7-10; when the active pharmaceutical ingredient is meloxicam, the mass ratio of the active pharmaceutical ingredient to the mixed lipids is 1:50-300; when the active pharmaceutical ingredient is dexamethasone, the mass ratio of the active pharmaceutical ingredient to the mixed lipids is 1:100-300.

9. The phospholipid gel according to any one of claims 1-7, characterized in that, The phospholipid gel, after dispersion, has a median diameter of not less than 1 μm.

10. The phospholipid gel according to any one of claims 1-7, characterized in that, The phospholipid gel also includes other pharmaceutically acceptable excipients, which are present in the phospholipid gel composition at a concentration of 0.5%-5%. Preferably, the other pharmaceutically acceptable excipients are pharmaceutically acceptable antioxidants and / or lyophilization protectants.

11. A method for preparing the phospholipid gel according to any one of claims 1-10, characterized in that, Including the following steps: (1) Dissolve the active pharmaceutical ingredient, mixed lipids, and other pharmaceutically acceptable excipients in a solvent, dry them, and obtain a cake; (2) Mix the cake obtained in step (1) with the hydration solvent and hydrate to obtain phospholipid gel.

12. The preparation method according to claim 11, characterized in that, In step (1), the solvent is an organic solvent, preferably a mixture of alcohol and water, and more preferably, the volume percentage of tert-butanol in the mixture is 30%-100%.

13. The preparation method according to claim 11, characterized in that, In step (1), the concentration of lipids in the solvent is 50 mg / ml to 200 mg / ml.

14. The preparation method according to claim 11, characterized in that, In step (1), the drying method is freeze drying, and the phospholipid concentration after hydration is not less than 50 mg / ml.

15. The use of the phospholipid gel according to any one of claims 1-10 in the preparation of nonsteroidal anti-inflammatory drugs, analgesics or glucocorticoids, preferably, the analgesia is postoperative analgesia for more than 72 hours.

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