A liposome-encapsulated long-acting ropivacaine sustained-release system

Abstract

The present disclosure relates to a liposome-encapsulated long-acting ropivacaine sustained-release system. Specifically, the present disclosure provides a ropivacaine liposome wrapped with a polymer material for prolonging the release of ropivacaine and enhancing the analgesic effect, wherein the liposome contains ropivacaine and lipid components; and the polymer material contains gelatin and sodium hyaluronate.

Description

Technical Field

[0001] The present disclosure relates to a liposome-encapsulated long-acting ropivacaine sustained-release system, belonging to the field of medical analgesia. Background Art

[0002] Since surgical intervention has been popularized as an effective clinical treatment method, postoperative pain has always been an inevitable problem to be solved. Although opioid drugs have shown powerful and reliable analgesic effects, the related side effects and the prevalence of the opioid crisis have made it urgent to reduce the use of opioid drugs. In this regard, local anesthetics have become a popular choice for treating postoperative pain due to their rapid onset, low toxicity, and non-addictive properties. However, the analgesic effects of traditional local anesthetic preparations such as ropivacaine hydrochloride and bupivacaine hydrochloride can only last for several hours, far from being able to fully inhibit postoperative pain.

[0003] Ropivacaine, as a kind of amide local anesthetic, has been widely used clinically. It can be used for infiltration anesthesia, intravenous regional anesthesia, peripheral nerve block, and intraspinal anesthesia. Compared with lidocaine, its onset is relatively slower, but its action duration is longer. It can prolong sensory block and analgesia, especially when continuously infused at a low concentration, usually more persistent than the duration and intensity of its motor block. Compared with bupivacaine, its potency is reduced, so its clinical manifestations in peripheral nerve block are similar to those of bupivacaine. These two characteristics result in lower sensory and motor block efficacy and reduced cardiac toxicity compared with bupivacaine. Animal studies have shown that the smaller molecule of ropivacaine may be a more important factor in reducing the risk of cardiac toxicity compared with the relative spatial selectivity of bupivacaine. It also has an intrinsic vasoconstrictive effect, which helps to reduce its cardiac toxicity and may increase the duration of its action. There is evidence that ropivacaine can produce a more favorable sensory and motor dissociation block compared with bupivacaine.

[0004] Gelatin is a macromolecular hydrophilic colloid, which is the product of partial hydrolysis of collagen. Gelatin is widely used in the medical field due to its biodegradability, good biocompatibility, and film-forming property. And it does not produce other by-products after degradation in vivo, has no immunogenicity and blood compatibility, and has the same components and biological properties as collagen, and is widely used in tissue engineering and drug delivery systems.

[0005] Hyaluronic acid, also known as hyaluronic acid, is an acidic mucopolysaccharide. Hyaluronic acid shows a variety of important physiological functions in the body due to its unique molecular structure and physical and chemical properties, such as lubricating joints, regulating the permeability of blood vessel walls, regulating proteins, electrolytes diffusion and transport, and promoting wound healing. Hyaluronic acid is the main component of connective tissues such as human cell interstitial fluid, vitreous humor, and joint synovial fluid, and plays important physiological functions of retaining water, maintaining the extracellular space, regulating osmotic pressure, lubricating, and promoting cell repair in the body. The compound formed by the reaction of hyaluronic acid with other drugs has a sustained-release effect on the drug, and can achieve the purpose of directional and timed release.

[0006] Liposomes are artificial membranes. In water, the hydrophilic heads of phospholipid molecules insert into the water, and the hydrophobic tails of liposomes extend into the air. After agitation, spherical liposomes with a bilayer lipid molecule are formed, with diameters ranging from 25 to 1000 nm. Liposomes can be used for gene transfer or drug preparation. Utilizing the characteristic that liposomes can fuse with cell membranes, drugs can be delivered into the interior of cells. As a drug delivery system, liposomes have developed to the point where they can load chemotherapeutic drugs, anti-microbial and antiviral (SARS, HIV, AIV, RV, etc.) drugs, anti-parasitic drugs, genetic materials, vaccines, therapeutic proteins, anti-inflammatory drugs, hormones, and natural drugs. Drug-loaded liposomes have passive targeting and active targeting (surface-modified liposomes), and sustained-release properties. The drug is protected by liposome encapsulation, which can improve the stability of the drug, reduce the exposure of sensitive tissues to highly toxic drugs, and reduce drug toxicity. The research on liposomes has developed from early, ordinary liposomes to multifunctional liposomes, and has shown its potential application value in many aspects.

[0007] In order to extend the analgesic duration of traditional local anesthetics, various sustained-release local anesthetic preparations based on various types of materials have been developed, including polymers, microspheres, liposomes, hydrogels, peptides, and their hybrid systems. For example, the ropivacaine liposomes provided by CN113116823B and CN114948877A. Summary of the Invention

[0008] The inventors of the present invention unexpectedly found through long-term research that gelatin and hyaluronic acid can significantly enhance the sustained-release effect of ropivacaine or its liposomes. On this basis, the inventors of the present invention conducted a series of studies and thus provided the following technical solutions.

[0009] The present invention provides a polymer material for drug sustained release, which comprises gelatin and hyaluronic acid.

[0010] The present invention provides the use of the combination of gelatin and hyaluronic acid in the preparation of a drug for enhancing the sustained release of ropivacaine or its liposomes.

[0011] The present invention provides a method for enhancing the sustained release of ropivacaine or its liposomes, which includes combining ropivacaine or its liposomes with the polymer material of the present invention.

[0012] The present invention provides a liposome, which comprises:

[0013] ropivacaine (ROP) and a lipid component, wherein the lipid component includes lecithin, cholesterol, DPPC (dipalmitoylphosphatidylcholine), and PEG-DSPE.

[0014] The present invention provides a polymer material-coated ropivacaine liposome for enhancing the sustained release of ropivacaine, wherein the liposome contains ropivacaine and a lipid component, and the lipid component contains lecithin, cholesterol, DPPC, and PEG-DSPE; the polymer material contains gelatin and hyaluronic acid.

[0015] The present invention provides a method for preparing a polymer material-coated ropivacaine liposome, which includes the following steps:

[0016] a. Mix ropivacaine with a lipid component to prepare liposomes;

[0017] b. Mix the prepared liposomes with a polymer material containing gelatin and sodium hyaluronate.

[0018] In the present disclosure, the method for preparing the liposomes may specifically include:

[0019] a. Mix ropivacaine with lecithin, cholesterol, DPPC, and PEG-DSPE in an organic solvent to form a mixture;

[0020] b. Evaporate the organic solvent in the mixture to form liposomes;

[0021] c. Optionally, add an aqueous solvent to the liposomes to form a ropivacaine liposome solution.

[0022] The present disclosure also provides the application of the polymer material-coated ropivacaine liposome, which is applied to prolong the release of ropivacaine and enhance its analgesic effect in the treatment of postoperative pain. Exemplarily, the present disclosure provides the use of the polymer material-coated ropivacaine liposome in the preparation of a drug for prolonging the release of ropivacaine and / or enhancing its analgesic effect.

[0023] In the present disclosure, preferably, before mixing ropivacaine (ROP) with lipid components to prepare liposomes, ropivacaine is first converted into ropivacaine base (RB). Correspondingly, the ropivacaine contained in the liposomes encapsulated by the polymer material is preferably RB (ropivacaine base). It should be noted that this is only a preferred scheme. It can be obviously understood that when ropivacaine is mentioned in the present disclosure, it is also equivalent to ropivacaine base or its analogs, unless otherwise specified or obviously not understood in this way. Vice versa, when ropivacaine base is mentioned in the present disclosure, it is also equivalent to ropivacaine or its analogs, unless otherwise specified or obviously not understood in this way.

[0024] In addition, in the present disclosure, hyaluronic acid (HA) and sodium hyaluronate (SH) can be used interchangeably because they are essentially the same molecule, except for the different salt forms.

[0025] In the polymer material of the present disclosure, the weight ratio of gelatin to sodium hyaluronate can be exemplarily (1 - 10):(10 - 1), such as (1 - 5):(5 - 1), (1 - 3):(3 - 1), (1 - 2):(2 - 1), or 1:1.

[0026] In the liposomes of the present disclosure, the weight ratio of lecithin:cholesterol:DPPC:PEG - DSPE can be exemplarily (20 - 50):(1 - 10):(0.2 - 2):(0.2 - 2), and further (30 - 40):(3 - 7):(0.5 - 1.5):(0.5 - 1.5), such as 35:5:1:1.

[0027] Exemplarily, the weight ratio of the said ROP (or RB):lecithin:cholesterol:DPPC:PEG - DSPE is (10 - 40):(20 - 50):(1 - 10):(0.2 - 2):(0.2 - 2), and further (20 - 30):(30 - 40):(3 - 7):(0.5 - 1.5):(0.5 - 1.5), such as 25:35:5:1:1.

[0028] The present disclosure also provides a liposome encapsulated by a polymer material containing ropivacaine, which comprises liposomes and a polymer material, wherein the weight ratio between the ropivacaine contained in the liposomes and the polymer material is (1 - 10):(10 - 1), such as (1 - 5):(5 - 1), (1 - 3):(3 - 1), (1 - 2):(2 - 1), or 1:1.

[0029] In the present disclosure, liposomes of ropivacaine encapsulated with a polymer material can protect ropivacaine and control its release in the body, thereby prolonging the duration of its analgesic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] To more clearly illustrate the technical solutions in the embodiments of the present disclosure, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the following drawings are only some embodiments of the present disclosure. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0031] Figure 1 : Results of the hot plate experiment of the long-acting ropivacaine sustained-release system;

[0032] Figure 2 : Results of the acupuncture experiment of the long-acting ropivacaine sustained-release system;

[0033] Figure 3 : Results of the weight-bearing experiment of the long-acting ropivacaine sustained-release system;

[0034] Figure 4 : Results of the numerical rating of weight-bearing of the long-acting ropivacaine sustained-release system;

[0035] Figure 5 : Results of the analgesic efficacy experiment of the porcine incision pain model;

[0036] Figure 6 : Schematic diagram of the structure of liposomes of ropivacaine encapsulated with a polymer material. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0037] In some specific embodiments of the present invention, the present disclosure provides liposomes of ropivacaine encapsulated with a polymer material, which are used to prolong the release of ropivacaine and enhance its analgesic effect, for example, in preoperative, intraoperative, or postoperative pain treatment. These liposomes of ropivacaine contain ropivacaine, lipid components, and a polymer material.

[0038] In the process of preparing liposomes, first, optionally, ropivacaine is converted into ropivacaine base (RB), and then ropivacaine or RB is mixed with lecithin, cholesterol, DPPC, and PEG-DSPE in a volatile organic solvent to form a mixture. Subsequently, the organic solvent is evaporated to form liposomes containing ropivacaine. Optionally, an aqueous solvent is added to the liposomes to dissolve the liposomes of ropivacaine, forming a solution of liposomes of ropivacaine.

[0039] In the present disclosure, the aqueous solvent added to the liposomes can be, for example, a buffer solution, physiological saline, or a glucose solution, such as a phosphate buffer solution, etc.

[0040] In the present disclosure, examples of the volatile organic solvent include, but are not limited to, ethanol, dichloromethane, chloroform, methanol, etc., or combinations thereof.

[0041] It should be noted that in the present disclosure, lecithin can be natural medicinal lecithin from sources such as egg yolk, soybean, sunflower, rapeseed, peanut, or cottonseed, or can be selected from semi-synthetic lecithins, such as hydrogenated lecithin, etc., or combinations thereof. As a specific example, egg yolk lecithin is used in the present disclosure. Obviously, in the present disclosure, egg yolk lecithin can be replaced by other lecithins, such as lecithin from soybean, sunflower, rapeseed, peanut, or cottonseed, such as soybean lecithin, sunflower lecithin, rapeseed lecithin, peanut lecithin, cottonseed lecithin, etc., as long as it meets the standards of medicinal lecithin.

[0042] The full name of PEG-DSPE is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[poly(ethylene glycol)] (1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[poly(ethylene glycol)]). For PEG-DSPE, the degree of polymerization of PEG can be 1000 - 8000, and any value within this range can be selected, such as 1000, 2000, 4000, 6000, 8000. It should be noted that in the present disclosure, PEG2000 can be replaced by PEG1000, 4000, 6000, or 8000, as well as PEG with any degree of polymerization therebetween.

[0043] The full name of DPPC is dipalmitoylphosphatidylcholine (Dipalmitoylphosphatidylcholine), which is a phospholipid.

[0044] The polymeric material comprises or consists of gelatin and sodium hyaluronate. During the preparation of the polymeric material-coated ropivacaine liposomes, the prepared liposomes are mixed with the polymeric material containing gelatin and sodium hyaluronate.

[0045] In terms of the ratio of liposomes to polymer materials, the weight ratio of lecithin, cholesterol, DPPC, and PEG-DSPE can be in the range of (20 - 50):(1 - 10):(0.2 - 2):(0.2 - 2), or more specifically in the range of (30 - 40):(3 - 7):(0.5 - 1.5):(0.5 - 1.5). Exemplarily, these ratios can be 35:5:1:1. The weight ratio of ropivacaine or RB to these lipid components can be in the range of (10 - 40):(20 - 50):(1 - 10):(0.2 - 2):(0.2 - 2), or more specifically in the range of (20 - 30):(30 - 40):(3 - 7):(0.5 - 1.5):(0.5 - 1.5). Exemplarily, these ratios can be 25:35:5:1:1.

[0046] Among the polymer materials, the weight ratio of gelatin to sodium hyaluronate can be in the range of (1 - 10):(10 - 1), or more specifically in the ranges of (1 - 5):(5 - 1), (1 - 3):(3 - 1), (1 - 2):(2 - 1), or 1:1. When the weight ratio of gelatin to sodium hyaluronate is within the range of 1:1, the material has obvious fluidity and can be injected through a 23G syringe needle in a continuous filamentous structure. No solid jelly-like substances are seen in the system, and it still maintains stable physical and chemical properties within 1 week of storage at room temperature, without gelation, adhesion, or deterioration. Of course, if it is administered in the form of, for example, a gel patch, there is no need to specifically consider its fluidity, so the weight ratio of gelatin to sodium hyaluronate does not need to be limited to the range of 1:1. The present disclosure provides a method for preparing ropivacaine liposomes encapsulated with polymer materials for prolonging the release of ropivacaine and enhancing the analgesic effect, as well as the application of these ropivacaine liposomes, which can prolong the analgesic effect of ropivacaine in pain treatment before, during, and after surgery.

[0047] In the present invention, gelatin and sodium hyaluronate are used as polymer materials to encapsulate ropivacaine liposomes to improve the stability of liposomes and the controllability of drug release. It has been found that these two polymer materials can synergistically enhance the analgesic effect of ropivacaine liposomes. Gelatin has good biocompatibility and biodegradability and can provide mechanical strength and structural support; sodium hyaluronate has high viscosity and moisturizing properties, can prolong the drug release time, and enhance the lubricity and comfort of local tissues. When these two materials are combined in the above ratios, they can form a stable network structure to effectively encapsulate ropivacaine liposomes and prevent the rapid release of drugs, thereby prolonging the analgesic effect.

[0048] If the polymer material contains only gelatin or only sodium hyaluronate, it will affect the analgesic effect. If gelatin is used alone, the polymer material will lack viscoelasticity. Although gelatin has good structural support, its viscoelasticity is low, and it cannot effectively control the drug release rate, which may lead to rapid drug release and an unsustained analgesic effect. Moreover, the degradation rate of gelatin in the body is relatively fast, resulting in a weakened protective effect of the liposome and uneven drug release.

[0049] If sodium hyaluronate is used alone, the polymer material will lack mechanical strength. This is because, although sodium hyaluronate has high viscosity and moisture retention, its mechanical strength is low and it cannot provide sufficient structural support, and the liposome is prone to rupture or deformation. In addition, due to the high viscosity of sodium hyaluronate, drug release may be too slow to provide a sufficient concentration of analgesic drugs when needed, affecting the analgesic effect.

[0050] Therefore, the present invention provides the use of both gelatin and sodium hyaluronate or a method for prolonging drug sustained release thereof.

[0051] To understand this invention more deeply, the characteristics, ratios, preparation methods, and applications of related components will be discussed in detail below.

[0052] Ropivacaine is a local anesthetic drug commonly used for local anesthesia during surgery and the treatment of postoperative pain. Its mechanism of action is to block the potential changes of neurons, thereby preventing the conduction of nerve impulses and achieving the effect of anesthesia. Ropivacaine is selected as the drug active ingredient for analgesia in the present disclosure for the preparation of liposomes encapsulated by a polymer material. It can be obviously understood that in the present disclosure, ropivacaine can be equivalently replaced by any active variant of ropivacaine, such as ropivacaine or its salts, such as hydrochloride.

[0053] The lipid component is an important part of ropivacaine liposomes, and its main function is to provide a carrier for ropivacaine and regulate its release rate. In the present invention, the lipid component mainly includes lecithin, cholesterol, DPPC, and PEG-DSPE.

[0054] As a lipid component, lecithin has good biocompatibility and biodegradability in drug delivery. Its presence in liposomes helps to enhance the stability of liposomes and the drug encapsulation rate.

[0055] Cholesterol is an important component of cell membranes and can increase the stability of liposomes and regulate their fluidity. In the present invention, the addition of cholesterol helps to improve the structural stability of ropivacaine liposomes and the drug release rate.

[0056] DPPC (Dipalmitoylphosphatidylcholine) is a phospholipid with good biocompatibility and biodegradability. Its presence in liposomes helps enhance the structural stability of liposomes and regulate the release rate of ropivacaine.

[0057] PEG-DSPE: is a surfactant with good hydrophilicity and biocompatibility. Its addition to liposomes helps enhance the stability of liposomes and regulate the release rate of ropivacaine.

[0058] The polymer material is an external carrier used to encapsulate ropivacaine liposomes. Its main function may be to enhance the stability of ropivacaine liposomes and improve their bioavailability. In the present invention, the polymer material comprises or consists mainly of gelatin and sodium hyaluronate.

[0059] Gelatin is a natural colloidal material with good biocompatibility and biodegradability. Its addition to the polymer material helps enhance the stability of the material and improve the sustained release of ropivacaine liposomes.

[0060] Sodium hyaluronate is a water-soluble polysaccharide with good biocompatibility and biodegradability. Its presence in the polymer material helps enhance the fluidity of the material and improve the bioavailability of ropivacaine liposomes.

[0061] The present invention provides a simple and effective method for preparing polymer material-encapsulated ropivacaine liposomes. The specific steps are as follows:

[0062] a. Mix ropivacaine with lipid components to prepare liposomes: Mix ropivacaine with lecithin, cholesterol, DPPC and PEG-DSPE in an organic volatile solvent to form a mixture, and then evaporate the organic solvent to form liposomes. Optionally, add the solvent to the liposomes to form a ropivacaine liposome solution.

[0063] b. Mix the prepared liposomes with a polymer material containing gelatin and sodium hyaluronate: Mix the prepared ropivacaine liposomes with a polymer material containing gelatin and sodium hyaluronate evenly to form polymer material-encapsulated ropivacaine liposomes.

[0064] In the present disclosure, the buffer solvent solution can be, for example, a buffer solution, a glucose solution or a physiological saline solution. Specifically, the buffer solution can include, but is not limited to, phosphate buffer, Tris buffer, HEPES buffer, etc. These buffer solutions provide a stable environment within various pH ranges, which helps maintain the stability and activity of the drug. The glucose solution can be a 5% or 10% glucose solution, which is used to provide an isotonic environment. The physiological saline solution is usually a 0.9% sodium chloride solution, which is used to maintain isotonicity and ionic balance.

[0065] In the present disclosure, the mixing process of the liposomes and the polymeric material comprising gelatin and sodium hyaluronate can be carried out, for example, within a temperature range of 25 - 75°C. Operating within this temperature range can ensure the uniform mixing of the materials while avoiding material degradation or drug inactivation caused by excessive temperature.

[0066] This mixing process can be carried out in a solution state or in a solid state. When mixing in a solution state, the liposomes and the polymeric material are usually dissolved in a suitable solvent and thoroughly mixed by methods such as stirring or sonication. This method helps to form a uniform mixture and is simple to operate and easy to control. When mixing in a solid state, the liposomes and the polymeric material can be mixed in proportion and then evenly distributed by physical methods such as mechanical stirring.

[0067] In addition, a method of first mixing in a solid state and then further mixing in a solvent can also be adopted. The specific operation is to first mix the liposomes and the polymeric material evenly in proportion, and then dissolve or disperse the mixture in a suitable solvent and further mix it by methods such as stirring or sonication. This method combines the advantages of solid mixing and solution mixing, can improve the mixing uniformity, and at the same time ensure the dispersion effect of the materials.

[0068] In actual operation, the choice of solution state, solid state, or first solid mixing followed by solution mixing depends on specific application requirements. For example, for applications that require a high degree of dispersion uniformity, mixing in a solution state may be more suitable; while for applications that require rapid preparation or avoid the use of solvents, mixing in a solid state or first solid mixing followed by solution mixing can be selected.

[0069] The liposomal ropivacaine encapsulated by the polymeric material provided by the present invention can be applied to a variety of medical fields, especially suitable for postoperative pain treatment. It can prolong the release of ropivacaine and enhance its analgesic effect in pain treatment before, during, and after surgery, thereby improving the quality of life and treatment effect of patients.

[0070] In actual application, the dose and administration route of liposomal ropivacaine can be adjusted according to the specific conditions and severity of the patient's condition to achieve the best treatment effect. At the same time, the present invention can also be used in combination with other drugs or treatment methods to further improve the treatment effect and reduce side effects.

[0071] Furthermore, in the present disclosure, the ropivacaine liposomes encapsulated with a polymer material are preferably processed as follows: placed at a low temperature (such as 2 - 8 °C, preferably 4 °C) for a period of time (such as 0.5 - 6 hours, e.g., 1, 2, 3, 4, 5 h), after restoring to room temperature, 2-hydroxy-2-methyl-1-phenyl-1-propanone (0.5 - 10 mM) is added and irradiated with ultraviolet light for a period of time (such as 5 - 30 min, e.g., 10, 15 or 20 min). The benefit of placing at a low temperature is to break the system balance, which helps to control the structure and morphology of the liposomes, allowing the liposome components to slowly aggregate to form a steady state, and then consolidating this steady state under subsequent light irradiation to form a more stable structure of ropivacaine liposomes encapsulated with a polymer material.

[0072] The present invention provides ropivacaine liposomes encapsulated with a polymer material for prolonging the release of ropivacaine and enhancing the analgesic effect, which has the advantages of simple preparation, low cost, remarkable therapeutic effect, etc., and has broad application prospects and market potential.

[0073] In the present disclosure, encapsulation refers to a porous structure composed of gelatin and sodium hyaluronate, which is used to encapsulate and slowly release ropivacaine liposomes. The formation and mechanism of action of this porous structure are as follows:

[0074] 1. Formation of the porous structure: Both gelatin and sodium hyaluronate are polymer materials. When they are dissolved in water, they can form a cross-linked network. Under ultraviolet light irradiation, gelatin and sodium hyaluronate can undergo a cross-linking reaction induced by a photoinitiator to further form a stable three-dimensional porous structure. This porous structure has the characteristics of high hydrophilicity and porosity. Among them, due to the high hydrophilicity of sodium hyaluronate and gelatin itself, the porous structure has strong water retention ability; during the cross-linking process, the formed porous structure is conducive to capturing and encapsulating liposomes, increasing the drug loading capacity.

[0075] 2. Encapsulation of liposomes: Ropivacaine liposomes are evenly distributed and encapsulated in the porous network during the formation of the porous structure. Liposomes are tiny vesicles that can carry drugs such as ropivacaine. The liposomes encapsulated in the porous structure can exist stably under the protection of the porous network.

[0076] 3. Achievement of the slow-release effect: The combination of the porous structure and liposomes achieves the slow-release effect of the drug through the following mechanism: The porous structure forms a physical barrier that hinders the rapid release of ropivacaine from the liposomes. The drug needs to gradually diffuse through the porous network to achieve the effect of slow release; the degradation rate of sodium hyaluronate and gelatin can be controlled by adjusting the cross-linking density, thereby affecting the release rate of the drug. Over time, sodium hyaluronate and gelatin gradually degrade, and the ropivacaine in the liposomes is gradually released; the porous structure provides protection for the liposomes to prevent the premature release of drugs due to the influence of the external environment (such as pH, enzymatic hydrolysis, etc.).

[0077] The encapsulation of the polymer material in the present disclosure can improve the drug stability. Since the encapsulation of the porous structure for liposomes protects ropivacaine and prevents it from being damaged during storage and transportation. Additionally, this encapsulation structure can extend the drug release time. Meanwhile, through the physical barrier and controllable degradation of the porous structure, the slow and sustained release of ropivacaine is achieved, prolonging the action time of the drug. Moreover, the release rate can be controlled because by adjusting the ratio of gelatin and sodium hyaluronate and the cross-linking density, the release rate of the drug can be precisely controlled to meet different treatment requirements.

[0078] The porous structure formed by gelatin and sodium hyaluronate realizes the sustained-release effect by encapsulating liposomes containing ropivacaine. This structure not only improves the drug stability but also effectively extends the drug release time and action effect through the physical barrier and controllable degradation mechanism. In the fields of biomedicine and drug delivery, the application of this porous structure provides new ideas and solutions for long-acting drug formulations.

[0079] The following only describes the most specific embodiments of the present disclosure and is not intended to limit the present disclosure. Any modifications, equivalent replacements, improvements, etc. made within the principles of the present disclosure shall be included within the protection scope of the present disclosure.

[0080] Preparation Example 1: Alkalization of Ropivacaine Hydrochloride

[0081] Add 3 grams of crystalline ropivacaine hydrochloride to 75 milliliters of deionized water and mix until completely dissolved. Subsequently, slowly add 6.52 milliliters of ammonium hydroxide with a concentration of 14N (10 times the molar equivalent) to the ropivacaine hydrochloride solution to induce the precipitation of ropivacaine base. Subsequently, remove the residual ammonium hydroxide by filtration with deionized water and thorough washing. Finally, lyophilize the obtained precipitated powder and store it under a desiccant for further use.

[0082]

[0083] Preparation Example 2: Preparation of Ropivacaine Base Liposomes

[0084] First, dissolve ropivacaine base (RB), egg yolk lecithin, cholesterol, DPPC, and PEG2000-DSPE in a solvent of chloroform and ethanol (1:1) according to the ratio of 25:35:5:1:1. Then, rotary evaporate to remove the organic volatile solvent to form liposomes. Next, add PBS (phosphate buffer solution) to the liposome film and perform ultrasonic dispersion and dissolution to finally obtain a ropivacaine base liposome solution.

[0085] Exemplarily, 5 mg of ropivacaine base (RB), 7 mg of egg yolk lecithin, 1 mg of cholesterol, 0.2 mg of DPPC (dipalmitoyl phosphatidylcholine), and 0.2 mg of PEG2000-DSPE were dissolved in 2 mL of a solvent of chloroform and ethanol (1:1). Then, rotary evaporation was carried out at a speed of 30 rpm in a water bath at 50 °C to form a liposome film. Subsequently, 0.5 mL of PBS (phosphate buffered saline) was added to the liposome film, and ultrasonic dispersion and dissolution were performed to finally obtain a ropivacaine base liposome solution with a concentration of 10 mg / mL. The concentration of ropivacaine in the ropivacaine base liposome solution can be adjusted by the amount of PBS added, and the volume of the prepared ropivacaine base liposome solution can be adjusted by magnification or reduction operations.

[0086] Preparation Example 3

[0087] First, hydrochloride of ropivacaine (ropivacaine hydrochloride), soybean lecithin, cholesterol, DPPC, and PEG4000-DSPE were dissolved in a solvent of chloroform and ethanol (1:1) in a ratio of 10:20:1:0.2:0.2. Then, the organic volatile solvent was removed by rotary evaporation to form liposomes. Subsequently, 0.9% normal saline was added to the liposomes, and ultrasonic dispersion and dissolution were performed to finally obtain a ropivacaine base liposome solution.

[0088] Exemplarily, 10 mg of ropivacaine hydrochloride, 20 mg of soybean lecithin, 1 mg of cholesterol, 0.2 mg of DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), and 0.2 mg of PEG4000-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-4000) were dissolved in 2 mL of a solvent of chloroform and ethanol (1:1). Then, rotary evaporation was carried out at a speed of 30 rpm in a water bath at 50 °C to form a liposome film. Subsequently, 1.0 mL of 0.9% normal saline was added to the liposome film, and ultrasonic dispersion and dissolution were performed to finally obtain a ropivacaine hydrochloride liposome solution with a concentration of 10 mg / mL.

[0089] Preparation Example 4

[0090] First, ropivacaine hydrochloride, hydrogenated egg yolk lecithin, cholesterol, DPPC, and PEG6000-DSPE were dissolved in a solvent of chloroform and ethanol (1:1) in a ratio of 20:25:5:1:1. Then, the organic volatile solvent was removed by rotary evaporation to form liposomes. Subsequently, 0.9% normal saline was added to the liposome film, and ultrasonic dispersion and dissolution were performed to finally obtain a ropivacaine base liposome solution.

[0091] Exemplarily, ropivacaine hydrochloride: 10 mg, soy lecithin: 12.5 mg, cholesterol: 2.5 mg, DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine): 0.5 mg, PEG4000-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-4000): 0.5 mg were dissolved in 2 ml of a solvent of chloroform and ethanol (1:1). Then, rotary evaporation was carried out at a speed of 30 rpm in a water bath at 50 °C to form a liposome film. Subsequently, 1.0 ml of 0.9% normal saline was added to the liposome film and ultrasonic dispersion dissolution was performed to finally obtain a ropivacaine hydrochloride liposome solution of 10 mg / ml.

[0092] Preparation Example 5: Ropivacaine Liposome Encapsulated with Polymer Material

[0093] Take 10 ml of the ropivacaine base liposome solution prepared according to Preparation Example 2, and add 100 mg of gelatin and 100 mg of sodium hyaluronate. The mixture was placed in a water bath at 50 °C and stirred and dissolved at a speed of 100 revolutions per minute for 30 minutes to finally obtain a product containing 1% gelatin, 1% sodium hyaluronate and 1% ropivacaine base liposome.

[0094] Preparation Example 6: Ropivacaine Liposome Encapsulated with Polymer Material

[0095] Take 10 ml of the ropivacaine base liposome solution prepared according to Preparation Example 3, and add 20 mg of gelatin and 180 mg of sodium hyaluronate. The mixture was placed in a water bath at 50 °C and stirred and dissolved at a speed of 100 revolutions per minute for 30 minutes to finally obtain a product containing 0.2% gelatin, 1.8% sodium hyaluronate and 1% ropivacaine hydrochloride liposome.

[0096] Preparation Example 7: Ropivacaine Liposome Encapsulated with Polymer Material

[0097] Take 10 ml of the ropivacaine base liposome solution prepared according to Preparation Example 4, and add 50 mg of gelatin and 50 mg of sodium hyaluronate. The mixture was placed in a water bath at 50 °C and stirred and dissolved at a speed of 100 revolutions per minute for 30 minutes to finally obtain a product containing 1% gelatin, 0.5% sodium hyaluronate and 0.5% ropivacaine hydrochloride liposome.

[0098] Preparation Example 8: Optimized Ropivacaine Liposome Encapsulated with Polymer Material

[0099] Take 10 ml of the ropivacaine liposome encapsulated with polymer material prepared according to Preparation Example 5, first place it at low temperature (4 °C) for 1 hour, and after restoring to room temperature, add 2 mM 2-hydroxy-2-methyl-1-phenyl-1-propanone, and irradiate with ultraviolet light (365 nm) for 10 minutes.

[0100] Effect Example 1: Effect Verification

[0101] By observing the lower limb sensation and movement after sciatic nerve block surgery in rats, it was verified that the present invention can prolong the release of ropivacaine and enhance the analgesic effect.

[0102] In the experiment, the rats were randomly divided into the following five groups, with 5 rats in each group, specifically as follows:

[0103] Group A: Control group, liposomes produced with lidocaine hydrochloride as the material instead of ropivacaine base according to Example 2, with a concentration of 40 mg / ml;

[0104] Group B: According to Example 5, liposomes encapsulated with a polymer material produced with lidocaine hydrochloride as the material instead of ropivacaine base (Rop-lipo-gel), with a concentration of 40 mg / ml;

[0105] Group C: Liposomes of ropivacaine encapsulated with a polymer material prepared according to Preparation Example 5, that is, a polymer ropivacaine base system (Rop-base-lipo-gel), with a concentration of 40 mg / ml;

[0106] Group D: Using lidocaine hydrochloride solution (Rop-HCl), with a concentration of 40 mg / ml;

[0107] Group E: Negative control group, using normal saline (Saline).

[0108] The ropivacaine concentration in each group was 40 mg / ml.

[0109] The effect of the present invention on prolonging the release of ropivacaine and the extension of the analgesic effect was demonstrated by the influence on the lower limb sensation and movement after sciatic nerve block in rats.

[0110] Hot plate experiment:

[0111] After injecting different ropivacaine sustained-release preparations, when the rats felt blocked on the hot plate, their toes were in a contracted state and they could not feel pain. When the anesthetic effect was insufficient, obvious licking or jumping behaviors occurred. The time from the start of heat stimulation to the occurrence of licking the paw, retracting the paw or bouncing was recorded as the paw withdrawal latency (PWL) of the rats. Align the center cross of the plantar tester with the sole of the experimental side lower limb of the rats, and the plantar tester will automatically sense and record the time when the rats retract their paws. The rats were placed on the plantar tester platform 30 min before the test to allow them to rest quietly and adapt to the environment. Each rat was subjected to two basic heat latency tests before the operation and 4 heat latency tests after the operation, with an interval of 5 min each time, and the average PWL time of each rat was recorded. To protect the animals, the maximum PWL was set to 20 seconds. The results are shown in Figure 1 .

[0112] In the hot plate test results, it was found that the average PWL of the saline group in group E and each experimental group before surgery was < 10 s, and the effective threshold of PWL was set at 10 s. The sustained-release systems containing liposomal ropivacaine in groups A, B, and C all showed relatively satisfactory sensory block effects within 6 h after surgery, and then the sensory block effects continued to decline over time. Among them, in the liposomal ropivacaine group of group A, the sensory block effect was close to the baseline of 10 s after 48 h, and the effect almost completely disappeared, indicating that the release rate of ropivacaine was relatively fast. In groups B (liposomal ropivacaine + polymer system) and C (polymeric ropivacaine base system), at 144 h (Day 6) after surgery, they still maintained a high sensory block effect, indicating superior analgesic ability, and also indicating the superior ropivacaine sustained-release ability of the polymer system. Even at 168 h, groups B and C still had analgesic effects. The performance of the polymeric ropivacaine base liposome in group C was slightly better than that in group B, showing a more efficient analgesic performance.

[0113] Similar hot plate tests were also conducted on liposomal ropivacaine encapsulated with the polymeric materials prepared in Preparation Examples 6, 7, and 8. The results showed that the analgesic effects of the liposomes in Preparation Examples 6 and 7 were significantly better than those of their corresponding groups A, D, and E, and maintained superior analgesic ability at 120 h after surgery. Notably, the liposomal ropivacaine encapsulated with the further optimized polymeric material in Preparation Example 8 had a significantly longer PWL time (s) at 168 h than the liposomal ropivacaine encapsulated with the polymeric material prepared in Example 5.

[0114] Acupuncture experiment:

[0115] Before the detection, the animals were first placed in the detection box on the wire rack to adapt for 3 days, 30 min each day; each time during the detection, the animals were first placed in the detection box to adapt for 10 min, and then the mechanical withdrawal threshold (MWT) of the hind limb on the experimental side of the animals was detected using a von Frey analgesimeter. The interval between each detection was 5 min. During the detection, hold the stimulation handle of the mechanical analgesimeter, and the tip of the test needle is vertically in contact with the detection site and the force is slowly applied until the animal has a paw withdrawal response, then remove the detection handle, and record the pressure value corresponding to the pain detection rod that causes this response (i.e., the mechanical pain threshold of the animal's detection site). The average pressure of each group of rats was taken for statistics. The results are shown in Figure 2 。

[0116] According to the results of the control group in the acupuncture experiment, MWT < 60 was considered that the sensory block effect almost disappeared. In group A (ropivacaine liposome group), the sensory block effect was lower than the baseline of 60 g after 48 h, and the effect almost completely disappeared, indicating a relatively fast release rate of ropivacaine. In groups B (ropivacaine liposome + polymer system group) and C (polymeric ropivacaine base system), at 144 h after surgery, a high level of sensory block effect was still maintained, significantly superior to groups D and A, indicating the superior ropivacaine sustained-release ability of the combination of polymeric materials and liposomes.

[0117] Weight-bearing test:

[0118] Place one hind paw of the rat on an electronic balance and let it bear its own weight. Record the maximum weight that the rat can bear without the ankle touching the balance. When the bearing weight is greater than half of the rat's body weight, the weight-bearing test is considered successful. Each rat is measured five times at each time point, and the average value of the successful times of each group of rats is recorded for further data analysis. The results are shown in Figure 3 .

[0119] The results of the weight-bearing experiment found that in group D (ropivacaine hydrochloride group), the motor block effect completely disappeared 12 h after injection, indicating the recovery of the motor function of the unilateral lower limb of the rat. The three liposome sustained-release systems in groups A, B, and C all inhibited the lower limb movement of the operative side of the rat within 12 h after surgery. However, the inhibitory effects of the liposome groups wrapped with polymeric materials in groups B and C were both less than that of the ropivacaine liposome group in group A. After 48 h, the inhibitory effects of the three experimental groups almost disappeared. After 6 h, the number of weight-bearing experiments in groups B and C was greater than that in group A, reflecting the excellent ropivacaine sustained-release ability of the polymeric materials and the resulting lower motor block effect.

[0120] Weight-bearing numerical rating test:

[0121] First, a numerical rating system based on the behavior of the animal at different time points was used to evaluate the motor function. The rating system is as follows: normal movement (0 points); weight-bearing activity, unable to fully spread the toes when lifted by the tail (1 point); unable to fully load movement, unable to spread the toes (2 points); leg weakness, completely unable to bear weight, completely unable to open the toes (3 points); and completely unable to bear weight and bend the toes, gait drag (4 points). The results are shown in Figure 4 .

[0122] The results of the weight-bearing numerical scoring showed that the motor block effect in Group D (ropivacaine hydrochloride group) also completely disappeared after 12 h. The performance of the weight-bearing numerical scoring was basically consistent with the results of the weight-bearing test. The average score of Group A (ropivacaine liposome group) at 24 h after surgery was >1, showing a faster sustained-release ability and a stronger motor influence result. The motor scores of the rats in Group B and Group C (ropivacaine liposomes encapsulated with high-molecular materials) were both less than 1 at 24 h after surgery, without affecting the basic activities of the rats, reflecting the excellent ropivacaine sustained-release ability of the high-molecular materials and the resulting lower motor block effect.

[0123] Effect Example 2: Deficiencies of using gelatin or sodium hyaluronate alone:

[0124] Take 10 mL of the ropivacaine base liposome solution prepared according to Preparation Example 2, add 200 mg of gelatin, or add 200 mg of sodium hyaluronate. Place the mixture in a water bath at 50 °C and stir to dissolve at a speed of 100 revolutions per minute for 30 minutes to finally obtain a product (G1) containing 2% gelatin and 1% ropivacaine base liposome; a product (G2) containing 2% sodium hyaluronate and 1% ropivacaine base liposome.

[0125] Take 10 mL of the ropivacaine base liposome solution prepared according to Preparation Example 2, add 100 mg of gelatin and 100 mg of sodium hyaluronate. Place the mixture in a water bath at 50 °C and stir to dissolve at a speed of 100 revolutions per minute for 30 minutes to finally obtain a product (G3) containing 1% gelatin, 1% sodium hyaluronate and 1% ropivacaine base liposome.

[0126] Perform a hot plate experiment on G1 - G3, where the ropivacaine concentration in each group is 40 mg / mL. The results showed that the G3 group still had a PWL greater than 10 s on the 7th day; the sensory block effects of the G1 and G2 groups were close to the baseline of 10 s on the 6th day and the effects disappeared. Thus, it can be seen that the network structure formed by the combination of gelatin and sodium hyaluronate as the high-molecular material has the best stability, can effectively protect the liposomes, and form a stronger uniform sustained-release effect. At the same time, the drug release results showed that the ropivacaine liposomes containing both gelatin and sodium hyaluronate had a continuous drug release ability compared with single gelatin or sodium hyaluronate, significantly prolonging the analgesic effect.

[0127] Effect Example 3: Compatibility of high-molecular materials

[0128] Remove or not remove any one of cholesterol, DPPC, and PEG2000-DSPE in Preparation Example 2 to prepare corresponding liposomes containing ropivacaine. Take 10 mL of the ropivacaine base liposome solution, add 100 mg of gelatin and 100 mg of sodium hyaluronate. Place the mixture in a water bath at 50 °C and stir to dissolve at a speed of 100 revolutions per minute for 30 minutes to finally obtain products G1 (without cholesterol), G2 (without DPPC), G3 (without PEG2000-DSPE), and G4 (Preparation Example 5) containing 1% gelatin, 1% sodium hyaluronate, and 1% ropivacaine base liposomes. Perform a hot plate experiment on G1-G4, and the results show that the sustained-release effect of G4 is significantly better than that of G1-G3, but G1-G3 is significantly better than their corresponding liposomes.

[0129] Remove (abbreviation: "remove") or not remove (abbreviation: "not remove") any one of cholesterol, DPPC, and PEG2000-DSPE in Preparation Example 3 to prepare corresponding liposomes containing ropivacaine. Then, prepare the corresponding ropivacaine liposomes encapsulated with a polymer material according to Example 6. Remove or not remove any one of cholesterol, DPPC, and PEG2000-DSPE in Preparation Example 4 to prepare corresponding liposomes containing ropivacaine. Then, prepare the corresponding ropivacaine liposomes encapsulated with a polymer material according to Example 7. Perform a hot plate experiment on the above liposomes and the corresponding ropivacaine liposomes encapsulated with a polymer material, and the results are similar. The sustained-release effect of the polymer material-encapsulated liposomes is significantly better than that of the corresponding liposomes, and the sustained-release effect of the ropivacaine liposomes encapsulated with the polymer materials prepared in Examples 6 and 7 is better than that of the corresponding ropivacaine liposomes encapsulated with the polymer material ("remove").

[0130] Thus, it can be seen that gelatin and sodium hyaluronate can significantly enhance the sustained-release ability of ropivacaine liposomes and prolong the analgesic effect. Therefore, the polymer material of the present invention has broad compatibility with liposomes containing ropivacaine and can match different ropivacaine liposomes.

[0131] Effect Example 4: Screening specificity of gelatin and sodium hyaluronate

[0132] In the present disclosure, the combination of gelatin and sodium hyaluronate exhibits unique advantages in the sustained-release application of liposomes containing ropivacaine. To illustrate the specificity and superiority of this combination, the effect differences are reflected by comparing with other analog combinations.

[0133] The combination of gelatin and PEG can form a hydrogel with good biocompatibility and mechanical properties. The hot plate experiment shows that the combination of gelatin and PEG is inferior to gelatin and sodium hyaluronate in the sustained release of liposomes containing ropivacaine.

[0134] Chitosan is a natural polysaccharide with good biocompatibility and antibacterial properties. The combination of gelatin and chitosan can form a biomaterial. However, hot plate experiments have shown that the combination of gelatin and chitosan is inferior to the combination of gelatin and sodium hyaluronate in terms of the sustained release of liposomes containing ropivacaine.

[0135] The combination of sodium hyaluronate and hydroxypropyl methylcellulose (HPMC) can form a hydrogel with good water retention and viscoelasticity. However, compared with gelatin, HPMC lacks biodegradability. At the same time, hot plate experiments have shown that the combination of gelatin and HPMC is inferior to the combination of gelatin and sodium hyaluronate in terms of the sustained release of liposomes containing ropivacaine.

[0136] The combination of sodium hyaluronate and poly(lactic-co-glycolic acid) (PLGA) can be used to prepare nanoparticles or microspheres with good drug controlled release properties. However, PLGA may produce acidic degradation products during degradation, affecting the pH value of the local environment and having an adverse effect on tissues. At the same time, hot plate experiments have shown that the combination of gelatin and PLGA is inferior to the combination of gelatin and sodium hyaluronate in terms of the sustained release of liposomes containing ropivacaine.

[0137] Effect Example 5: Analgesic Pharmacodynamic Experiment on Pig Incision Pain Model

[0138] Experimental Design:

[0139] Group Design of the Model Group: A total of 4 groups were set up;

[0140] Number of Animals: 3 animals / group, a total of 12 animals: Bama mini-pigs;

[0141] Sex Ratio: All males;

[0142] Basis for the Selection of Experimental Animals: In this experiment, Bama mini-pigs were used. Their genetic and biological backgrounds (including the normal ranges of various data such as anatomy, physiology, and clinical pathology) are relatively clear; the epidermal thickness of pigs is very similar to that of humans, and the skin structure, physiological functions, immune functions, and wound healing processes are very similar to those of humans. Due to their large body surface area, it is convenient for experimental operations. The research results of Obreja and DI GIminiani et al. have confirmed that the skin innervation system of pigs is similar to that of humans. By studying the responses of pigs to thermal and mechanical stimuli, their pain sensitivity can be evaluated. In this experiment, Bama mini-pigs were used as experimental animals, and human surgical wounds were simulated by cutting the skin on their posterior backs. After surgery, the mechanical pain threshold was measured to evaluate the postoperative pain sensitivity of the animals and the postoperative analgesic effect of the test article.

[0143] Reasons for the Selection of the Number of Animals: On the premise of meeting the research objectives, scientific standards, and regulatory requirements, as few animals as possible were used. Therefore, in this experiment, there were 4 groups with 3 animals / group, a total of 12 animals.

[0144] The specific grouping information is as follows:

[0145] G1 (Model Group): Normal saline

[0146] G2 A (Drug A): Hengrui ropivacaine liposome 18 mg / ml (from Hengrui Pharmaceutical Co., Ltd.)

[0147] G3 B (Drug B): Hengrui ropivacaine liposome 18 mg / ml (from Hengrui Pharmaceutical Co., Ltd.) + 1% gelatin & 1% hyaluronic acid

[0148] G4 C (Drug C): Hengrui ropivacaine liposome 36 mg / ml (from Hengrui Pharmaceutical Co., Ltd.) + 1% gelatin & 1% hyaluronic acid

[0149] Modeling method: For animals in the anesthetized state, take the prone position, prepare the skin at 3 cm from the mid-dorsal line on the right back, and after disinfection (with iodophor), make a 5-cm-long incision parallel to the mid-dorsal line. The method of making the incision is to separate the fascia downward with forceps after cutting the skin without damaging the muscle.

[0150] Route of administration: Administer the drug by multi-point subcutaneous injection around the wound (near the dermis under the epidermis);

[0151] Administration site: Subcutaneous injection, the injection sites are densely arranged in a circle around the wound, the injection sites are 0.5 cm away from the incision, the number of injection points is 10, and the volume per point is 0.28 mL;

[0152] Detection time: Collect the baseline before the incision surgery, and detect once at 1 h, 3 h, 5 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, and 168 h after drug administration, for a total of 10 detections;

[0153] Animals to be measured: All surviving experimental animals planned to be measured;

[0154] Detection method: Use an electronic Von Frey analgesia meter for detection. Stimulate the animals at both ends of the incision and at 0.5 cm away from the incision (a total of 6 points) using a tactile measurement kit, and record the thresholds of the escape responses of the animals at each point.

[0155] Experimental results (see Figure 5 ):

[0156] (1) The stimulation baseline collected before surgery was 300 g. Due to the simultaneous presence of postoperative pain (PP) and hyperalgesia (Ha), the mechanical pain threshold in the control group decreased rapidly to about 19.67 g after surgery and remained at a low level (<50 g) within 96 h. Due to the gradual decrease in the influence of Ha over time and the gradual healing of the surgical wound, the mechanical threshold (MT) value began to rise. After 96 h, the rising rate of the MT value accelerated, indicating that the pain gradually decreased. However, due to the persistent PP in the unhealed wound, the mechanical pain threshold on the sixth day was about 83.06 g, far less than the preoperative 300 g.

[0157] (2) In the Drug A group with liposomal ropivacaine, PP and Ha could be effectively controlled within 48 h after surgery, and the MT value always remained above 150 g. After 36 h, the efficacy of group A began to disappear, and the MT value decreased rapidly due to the influence of PP and Ha. After 96 h, it began to rise again, which was consistent with the control group, indicating that the pain gradually decreased.

[0158] (3) The content of ropivacaine in the gel liposome of the Drug B group was the same as that of group A, and the obtained experimental curve was also similar to that of group A. However, it should be noted that the average MT value of group B was always above that of group A, and the lowest MT value of group B was 146.67 g, near 150 g. The lowest MT value of group B appeared at 120 h, which was greater than the MT value (138.78 g) of the liposome of Hengrui in group A at 72 h, indicating that the analgesic effect of group B was better than that of group A.

[0159] (4) The gel liposome of the Drug C group contained twice the dose of ropivacaine as that of group A. It could be clearly seen that group C had excellent control ability for PP and Ha. The MT value was still 190 g at 120 h after surgery. Moreover, during the acute pain outbreak period from 5 to 96 h after surgery, group C could maintain the MT value at about 200 g (the lowest was 199.94 g). The MT value of group C at 144 h was 199.72 g, far greater than the value of 24 h (183.67 g) of Hengrui group A, and was also similar to the effects of the 1st h (216.94 g), 3rd h (220.50 g), and 5th h (216.67 h) of Hengrui group A. The rate of decrease of the MT value in group C was also much smaller than that in groups A and B, indicating its excellent encapsulation ability and sustained-release effect.

[0160] It can be seen that the polymer gel system has excellent encapsulation ability, can safely accommodate more drug content, and ensure the analgesic intensity. During the experiment of group C, the polymer gel system encapsulated more liposomal ropivacaine, and could safely and slowly release ropivacaine near the tissue to maintain the anesthetic effect.

[0161] Meanwhile, the polymer gel system has excellent sustained-release ability, ensuring a longer action time of the drug and achieving better action effects. The B group and the A group had the same content of ropivacaine, but the analgesic effect of the B group was stronger than that of the A group, and there was no obvious burst release phenomenon throughout the experiment, precisely because of the slower and more stable release effect of the gel system.

[0162] Structural embodiment

[0163] Electron microscopy scans of the ropivacaine liposomes encapsulated with the polymer materials prepared in the present disclosure all showed that they had a porous structure, with liposomes filled in the voids. Exemplarily, Figure 6 is a schematic diagram of the electron microscopy scan of the ropivacaine liposomes encapsulated with the polymer materials in Example 5 of the present disclosure.

[0164] Finally, it should be pointed out that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than limiting the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, it should be understood that those of ordinary skill in the art can modify or equivalently replace the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A ropivacaine liposome, wherein the liposome is encapsulated by a polymer material, and the liposome contains ropivacaine and lipid components, and the lipid components include lecithin, cholesterol, DPPC, and PEG-DSPE; the polymer material includes gelatin and sodium hyaluronate, and in the polymer material, the weight ratio of gelatin to sodium hyaluronate is (1 - 10):(10 - 1); the weight ratio of ropivacaine:lecithin:cholesterol:DPPC:PEG-DSPE is (10 - 40):(20 - 50):(1 - 10):(0.2 - 2):(0.2 - 2).

2. The ropivacaine liposome according to claim 1, wherein in the polymer material, the weight ratio of gelatin to sodium hyaluronate is (1 - 3):(3 - 1).

3. The ropivacaine liposome according to claim 1, wherein the weight ratio of ropivacaine:lecithin:cholesterol:DPPC:PEG-DSPE is (20 - 30):(30 - 40):(3 - 7):(0.5 - 1.5):(0.5 - 1.5).

4. The ropivacaine liposome according to claim 1, wherein the weight ratio of ropivacaine:lecithin:cholesterol:DPPC:PEG-DSPE is 25:35:5:1:

1.

5. The ropivacaine liposome according to claim 1, wherein in the polymer material, the weight ratio of gelatin to sodium hyaluronate is (1 - 5):(5 - 1).

6. The ropivacaine liposome according to claim 1, wherein in the polymer material, the weight ratio of gelatin to sodium hyaluronate is (1 - 3):(3 - 1).

7. The ropivacaine liposome according to claim 1, wherein in the polymer material, the weight ratio of gelatin to sodium hyaluronate is (1 - 2):(2 - 1).

8. The ropivacaine liposome according to claim 1, wherein in the polymer material, the weight ratio of gelatin to sodium hyaluronate is 1:

1.

9. The ropivacaine liposome according to any one of claims 1 - 8, wherein the weight ratio between the ropivacaine and the polymer material contained in the liposome is 1:

1.

10. A method for preparing the ropivacaine liposome as defined in any one of claims 1 - 9, which comprises the following steps: a. Dissolve ropivacaine and lipid components in an organic volatile solvent and then remove the solvent to prepare liposomes; b. Mix the prepared liposomes with a polymer material containing gelatin and sodium hyaluronate.

11. The method for preparing the ropivacaine liposome according to claim 10, which includes: a. Mix ropivacaine with lecithin, cholesterol, DPPC, and PEG-DSPE in an organic solvent to form a mixture; b. Evaporate the organic solvent in the mixture to form liposomes; c. Dissolve the liposomes to form a ropivacaine liposome solution; d. Mix the prepared liposome solution with a polymer material containing gelatin and sodium hyaluronate.

12. A drug, which contains the ropivacaine liposome according to any one of claims 1 - 9, or contains the ropivacaine liposome prepared by the preparation method of claim 10 or 11.

13. A method for prolonging the release of ropivacaine, which comprises preparing ropivacaine into the ropivacaine liposomes described in any one of claims 1-9.

14. Use of the ropivacaine liposomes described in any one of claims 1-9 in the preparation of a drug for prolonging the release of ropivacaine and / or enhancing its analgesic effect.

15. Use of the ropivacaine liposomes prepared by the preparation method of claim 10 or 11 in the preparation of a drug for prolonging the release of ropivacaine and / or enhancing its analgesic effect.

16. According to the preparation method of claim 10, wherein the organic volatile solvent is ethanol, chloroform or a mixture thereof.

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