Long-acting slow-release lyotropic liquid crystal gel preparation and preparation method thereof

Abstract

The invention discloses a long-acting slow-release lyotropic liquid crystal gel preparation and a preparation method and application thereof, the preparation comprises a matrix material, a cosolvent and a raw material medicine, the preparation has a hexagonal phase microstructure, shows a slow-release effect of more than 72 h and even up to 170 h, can prolong the half-life period of the medicine by nearly 10 times, and can realize analgesia or analgesia and anti-inflammatory dual curative effects.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to the preparation of a long-acting sustained-release lyotropic liquid crystal gel preparation and a preparation method and application thereof. Background Art

[0002] Postoperative pain is a common phenomenon and problem that needs to be solved after clinical surgery. It not only affects the patient's quality of life, but also increases the possibility of postoperative complications. The degree and duration of postoperative pain are closely related to the size of the incision, the duration of the operation, and the intensity of the invasion of internal organs. Ideal local anesthetics usually meet the following conditions: (1) fast onset and long duration; (2) only block sensory nerves but not motor nerves; (3) reversible nerve block or the intensity of the block is concentration-dependent; (4) low local irritation and no toxic side effects on the spinal cord, nerves, surrounding tissues, or even organs or the whole body. At present, the half-life of most local anesthetics used in clinical treatment is only a few hours, while the duration of postoperative pain in patients is generally several days, which is far from achieving the expected clinical effect. Although long-term analgesia can be achieved by regular multiple administration, the special nature of local anesthetics themselves may require special administration methods or expensive instruments to monitor the drug concentration in the body in real time. In addition, some local anesthetics (such as opioid analgesics) are prone to adverse reactions such as tolerance, dependence or central nervous system toxicity when used multiple times or in large doses. Therefore, the development of long-acting sustained-release preparations of local anesthetics has become an important research direction that is highly favored in this field.

[0003] In recent years, a variety of new sustained-release matrix materials have been widely used to transport various APIs and shine in different disease treatment fields, such as liposomes, microspheres, gels, microemulsions, submicroemulsions, microcrystals, etc. Among them, lyotropic liquid crystal (LLC) gel is a material state system between liquid and solid composed of one or more amphiphilic compounds that meet structural requirements and solvents. Under the induction of solvent action, amphiphilic molecules of a certain concentration form micelles through self-assembly. As the concentration increases further, they associate to form liquid crystals, and their phase change or degree of phase change can be triggered and enhanced by the increase of water. In view of its unique structural characteristics, it not only provides a wide range of carrier transport platforms for hydrophilic, lipophilic and amphiphilic drugs, but also has permeability similar to biological membranes to improve bioavailability. According to relevant research, liquid crystal structures can be roughly divided into lamellar, cubic and hexagonal phases. Compared with lamellar liquid crystals and cubic phase liquid crystals, hexagonal phase liquid crystals have better sustained-release effects and have been developed as drug carriers for injection, skin or mucosal administration. Compared with other ordered assemblies (microemulsions, liposomes), it has higher viscoelasticity and is not easily destroyed by external forces, thus better protecting drugs (especially peptides, proteins, nucleic acids). In addition, its preparation process is relatively simple, so it can be used as a good drug carrier.

[0004] At present, the long-acting amide local anesthetics of "dynamic separation" reversibly block the impulse conduction of nerve fibers by blocking the influx of sodium ions in nerve fiber cells, ultimately relieving pain. The use of this local anesthetic alone or only targeting a certain link in the analgesic process usually cannot achieve the best therapeutic effect. Relevant clinical studies have shown that the combined use of non-steroidal anti-inflammatory drugs can selectively accumulate in the injured or inflamed area, not only reducing the inflammatory response and tissue edema associated with surgical trauma, but also promoting the drug to penetrate the cell membrane and exert a stronger analgesic effect. At the same time, it can also effectively inhibit the expression of interleukin-1, interleukin-6 and tumor necrosis factor-α, thereby improving the patient's future long-term efficacy.

[0005] There are relevant literature (Chountoulesi M, Pispas S, Tseti IK, Demetzos C. Lyotropic Liquid Crystalline Nanostructures as Drug Delivery Systems and Vaccine Platforms. Pharmaceuticals (Basel). 2022 Mar 31; 15 (4): 429.) and patents (CN108309930A, CN 111888475 A) that report on lyotropic liquid crystal sustained-release drug delivery systems in the fields of ophthalmic preparations, anti-tumor, and macromolecular drug delivery. There is almost no coverage of lyotropic liquid crystal systems for local anesthetics. Among the limited information, patent CN108403664A discloses a liquid crystal gel nanoparticle that can encapsulate drugs of different polarities and mentions its application in the field of anesthesia and analgesia. According to the statement of the patent's advantages, the prepared liquid crystal gel nanoparticles have good sustained release effect and high bioavailability, but in the corresponding embodiments, only the cell uptake results prove the improvement of bioavailability, and no in-depth study is conducted on the encapsulated local anesthetic drugs, and there is no in vivo and in vitro release data to support the research, which is not sufficient. Patent CN112955144A discloses a pharmaceutical composition composed of steroidal anti-inflammatory drugs, NK-1 receptor antagonists, local anesthetics and delivery carriers. According to the patent content, the plasma drug concentration of the pharmaceutical composition has a sustained release effect of up to about 10 days after continuous administration. Only the results of pain tests support its sustained release effect, and there is no blood drug concentration data in animals to confirm it; at the same time, there is no specific in vitro release data to prove the sustained release effect. The innovative research on the good sustained release effect is not in-depth enough, and the proof is not sufficient. More importantly, the pharmaceutical composition needs to be administered multiple times under the application conditions, which reduces the compliance of patients in clinical applications.

[0006] Although the FDA has approved four long-acting local anesthetic sustained-release preparations for marketing, one is the implant Xaracoll, one is the liposome suspension Exparel, and two are gel preparations Posimir and Zynrelef. They all have a sustained-release period ranging from 24h to 72h. However, this study surprisingly found that the prepared lyotropic liquid crystal gel showed a sustained-release effect of more than 72h or even up to 170h after a single dose, extending the drug half-life by nearly 10 times, which is a key breakthrough in solving postoperative pain in patients undergoing small and medium-sized surgeries. Moreover, the prepared lyotropic liquid crystal is mainly a hexagonal phase microstructure, and there are currently no similar products on the market. In addition, this gel has the advantages of injectability and simple production process due to its low viscosity. Summary of the invention

[0007] The present invention provides a lyotropic liquid crystal gel preparation with sustained-release long-acting injection performance, wherein the raw drug is dissolved in a system comprising a matrix material and a cosolvent, and is prepared into a liquid with good fluidity and injectability, and the cosolvent diffuses rapidly after being injected into the body, and the drug is wrapped in the matrix material to form a gel, which has a good sustained-release effect. Through a large number of research experiments, a specific matrix material is selected to prepare a hexagonal phase solute lyotropic liquid crystal system, which has an excellent sustained-release effect. When the raw drug is a local anesthetic, the problem of short-term efficacy of postoperative analgesic drugs can be solved, the action time of local anesthetic drugs can be extended, and patient compliance can be improved. At the same time, local anesthetics can also be used in combination with non-steroidal anti-inflammatory drugs to exert analgesic effects and reduce surgical inflammatory reactions.

[0008] The advantages of the present invention are:

[0009] 1) The prepared lyotropic liquid crystal gel has a hexagonal microstructure and exhibits a sustained release effect of more than 72 hours or even up to 170 hours, extending the drug half-life by nearly 10 times. When the API is a local anesthetic, it is a key breakthrough in solving the moderate to severe pain of surgical patients after surgery.

[0010] 2) The prepared lyotropic liquid crystal gel has good safety and can effectively relieve movement pain and achieve "dynamic separation".

[0011] 3) The prepared lyotropic liquid crystal gel only requires a single dose and has good patient compliance; the preparation process is simple and easy to scale up; and the viscosity is easy to inject.

[0012] In order to achieve the above object, the present invention adopts the following technical solution:

[0013] A long-acting sustained-release lyotropic liquid crystal gel preparation comprises a matrix material, a cosolvent and a raw material drug.

[0014] Wherein, the matrix material includes amphiphilic substance and oil phase.

[0015] The amphiphilic substance is selected from phospholipids, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, preferably soybean phosphatidylcholine; the oil phase is selected from monoolein, castor oil, medium chain triglyceride, tocopherol, oleic acid, preferably tocopherol and oleic acid.

[0016] The cosolvent is selected from ethanol, N-methylpyrrolidone, dimethyl sulfoxide, dimethylformamide, preferably ethanol.

[0017] The raw material medicine comprises a local anesthetic, a non-steroidal anti-inflammatory drug or a combination thereof.

[0018] The local anesthetic is selected from ropivacaine, bupivacaine, lidocaine, and pharmaceutically acceptable salts thereof. Preferably, the pharmaceutically acceptable salt is selected from hydrochloride and methanesulfonate, more preferably ropivacaine hydrochloride, ropivacaine mesylate, bupivacaine hydrochloride, bupivacaine mesylate, lidocaine hydrochloride, and lidocaine mesylate.

[0019] The non-steroidal anti-inflammatory drug is selected from meloxicam, ibuprofen, acetaminophen, flurbiprofen, flurbiprofen axetil, celecoxib, preferably meloxicam.

[0020] The weight percentage of the matrix material is 80% to 90%, further, the weight percentage of the amphiphilic substance is 25% to 60%, preferably 30%-55%, more preferably 40% to 45%, and the weight percentage of the oil phase is 25% to 60%, preferably 30% to 55%, more preferably 40% to 45%. Furthermore, the weight percentages of amphiphilic substances are 43.64%, 44.13%, 43.58%, 44.09%, 41.07%, 43.34%, 40.98%, 43.30%, 56.65%, 28.69%, and 28.75%; the weight percentages of oil phase are 43.64%, 44.13%, 43.58%, 44.09%, 41.07%, 43.34%, 40.98%, 43.30%, 30.51%, 53.27%, and 53.39%.

[0021] The weight percentage of the cosolvent is 6% to 15%, and further, preferably 8% to 11%. Further, the weight percentage of the cosolvent is 8.72%, 8.82%, 9.86%, 10.40%, 9.84%, 10.39%, 8.71%.

[0022] The weight percentage of the raw material medicine is 0.01% to 25%, preferably 0.09% to 20%; further, the weight percentage of the local anesthetic is 2% to 25%, preferably 2% to 20%, more preferably 4% to 20%, more preferably 4% to 15%; the weight percentage of the non-steroidal anti-inflammatory drug is 0.01% to 0.80%, preferably 0.09% to 0.50%, more preferably 0.09% to 0.45%. Further, the weight percentage of the local anesthetic is 2.92%, 4%, 7%, 8%, 10%, 12%, 15%, 18%, and the weight percentage of the non-steroidal anti-inflammatory drug is 0.09%, 0.12%, 0.13%, 0.2%, 0.3%, 0.45%.

[0023] Preferably, the preparation comprises the following components (by mass):

[0024] Soy phosphatidylcholine 25%-60%, tocopherol 25%-60%, anhydrous ethanol 6%-15%, ropivacaine hydrochloride / ropivacaine mesylate / bupivacaine 2%-25%, meloxicam 0.01%-0.80%.

[0025] More preferably, the preparation comprises the following components (by mass):

[0026] Soy phosphatidylcholine 40%-45%, tocopherol 40%-45%, anhydrous ethanol 8%-11%, ropivacaine hydrochloride / ropivacaine mesylate / bupivacaine 2%-18%, meloxicam 0.09%-0.45%.

[0027] The preparation method of the preparation is as follows:

[0028] Method 1 comprises the following steps: weighing appropriate amounts of amphiphilic substances, oil phase, and cosolvents, and heating and stirring under closed conditions until the auxiliary materials are dissolved to obtain a blank gel precursor; weighing appropriate amounts of drugs and adding them to the blank gel precursor, and stirring under closed conditions at room temperature until the drugs are dissolved to obtain a drug-loaded lyotropic liquid crystal gel precursor.

[0029] Method 2 comprises the following steps: weighing an appropriate amount of amphiphilic substance, oil phase, and excess cosolvent, stirring at room temperature under closed conditions until the auxiliary materials are dissolved, thereby obtaining a blank gel precursor; weighing an appropriate amount of drug and adding it to the blank gel precursor, stirring at room temperature under closed conditions until the drug is dissolved, and rotary evaporating ethanol at a certain temperature to the prescribed amount to obtain a drug-loaded lyotropic liquid crystal gel precursor. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The in vitro release curve of the hexagonal liquid crystal gel of ropivacaine hydrochloride prepared in Example 1 is shown;

[0031] Figure 2 The in vitro release curve of the hexagonal liquid crystal gel of ropivacaine hydrochloride prepared in Example 2 is shown;

[0032] Figure 3 The in vitro release curve of the ropivacaine hydrochloride / meloxicam hexagonal liquid crystal gel prepared in Example 3 is shown;

[0033] Figure 4 The in vitro release curve of the ropivacaine hydrochloride / meloxicam hexagonal liquid crystal gel prepared in Example 4 is shown;

[0034] Figure 5 The in vitro release curve of the hexagonal liquid crystal gel of ropivacaine mesylate prepared in Example 5 is shown;

[0035] Figure 6 The in vitro release curve of the hexagonal liquid crystal gel of ropivacaine mesylate prepared in Example 6 is shown;

[0036] Figure 7 The in vitro release curve of the ropivacaine mesylate / meloxicam hexagonal liquid crystal gel prepared in Example 7 is shown;

[0037] Figure 8 The in vitro release curve of the ropivacaine mesylate / meloxicam hexagonal liquid crystal gel prepared in Example 8 is shown;

[0038] Fig. 9 The in vitro release curve of the bupivacaine hexagonal liquid crystal gel prepared in Example 9 is shown;

[0039] Fig.10 The in vitro release curve of the bupivacaine / meloxicam hexagonal liquid crystal gel prepared in Example 10 is shown;

[0040] Fig.11 The in vitro release results of ropivacaine mesylate liquid crystal gel formulations 1, 2, and 3 prepared in Example 11 are shown;

[0041] Fig.12 The in vitro release results of bupivacaine / meloxicam liquid crystal gel formulations 1 and 2 prepared in Example 12 are shown;

[0042] Fig.13 The in vitro release results of ropivacaine mesylate / meloxicam liquid crystal gel formulations 1 and 2 prepared in Example 13 are shown;

[0043] Fig.14 The in vitro release results of ropivacaine mesylate liquid crystal gel formulations 1 and 2 prepared in Example 14 are shown;

[0044] Fig.15 Polarized light microscopy of different samples is shown: AD: (left side) is the gel precursor of implementation cases 1, 4, 5, and 7; (right side) is the gel precursor of implementation cases 1, 4, 5, and 7 after being fully mixed with PBS (scale bar: 100 μm);

[0045] Fig.16 The intra-dose curve of ropivacaine mesylate injection liquid is shown;

[0046] Fig.17 The in vivo drug-time curve of the preparation of Example 5 is shown;

[0047] Fig.18 The in vivo drug-dose curve of bupivacaine prepared in Example 10 is shown;

[0048] Fig.19 The in vivo drug-dose curve of meloxicam prepared in Example 10 is shown. DETAILED DESCRIPTION

[0049] Before describing the present invention in detail below, it should be understood that the present invention is not limited to the specific methodology, scheme and reagent described herein, because these can change. It should also be understood that the terms used in this article are only for describing specific embodiments, and are not intended to limit the scope of the present invention. Unless otherwise defined, all technical and scientific terms used in this article have the same meaning as those of ordinary skill in the art to which the present invention belongs. Below in conjunction with specific examples, the present invention is further described. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0050] Example 1

[0051] The present embodiment provides a ropivacaine hydrochloride liquid crystal gel precursor, which is prepared from the following raw materials in percentage by weight: 43.64% soybean phosphatidylcholine, 43.64% DL-α-tocopherol, 8.72% anhydrous ethanol, and 4.00% ropivacaine hydrochloride.

[0052] This example adopts method 1 to prepare the product, and the appearance of the obtained product is a light yellow clear liquid, indicating that the raw materials are evenly mixed and have good compatibility; there is no stratification phenomenon when placed in the dark at room temperature for 3 months, indicating that the product has good storage stability. The lyotropic liquid crystal gel preparation precursor prepared in this example can undergo a phase change to form a liquid crystal gel when it encounters moisture.

[0053] The membraneless release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt % Tween 80 as the in vitro release medium. The cumulative release data within two weeks of Example 1 are shown in FIG. Figure 1 shown.

[0054] Example 2

[0055] The present embodiment provides a ropivacaine hydrochloride liquid crystal gel precursor, which is prepared from the following raw materials in percentage by weight: 44.13% soybean phosphatidylcholine, 44.13% DL-α-tocopherol, 8.82% anhydrous ethanol, and 2.92% ropivacaine hydrochloride.

[0056] This example adopts method 1 to prepare the product, and the appearance of the obtained product is a light yellow clear liquid, indicating that the raw materials are evenly mixed and have good compatibility; there is no stratification phenomenon when placed in the dark at room temperature for 3 months, indicating that the product has good storage stability. The lyotropic liquid crystal gel preparation precursor prepared in this example can undergo a phase change to form a liquid crystal gel when it encounters moisture.

[0057] The membraneless release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt % Tween 80 as the in vitro release medium. The cumulative release data within two weeks of Example 2 are shown in FIG. Figure 2 shown.

[0058] Example 3

[0059] The present embodiment provides a ropivacaine hydrochloride and meloxicam liquid crystal gel precursor, which is prepared from the following raw materials in weight percentage: 43.58% soybean phosphatidylcholine, 43.58% DL-α-tocopherol, 8.72% anhydrous ethanol, 4.00% ropivacaine hydrochloride, and 0.12% meloxicam.

[0060] This example adopts method 1 to prepare the product, and the appearance of the obtained product is a light yellow clear liquid, indicating that the raw materials are evenly mixed and have good compatibility; there is no stratification phenomenon when placed in the dark at room temperature for 3 months, indicating that the product has good storage stability. The lyotropic liquid crystal gel preparation precursor prepared in this example can undergo a phase change to form a liquid crystal gel when it encounters moisture.

[0061] The membraneless release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt% Tween 80 as the in vitro release medium. The cumulative release data within two weeks of Example 3 are shown in FIG. Figure 3 shown.

[0062] Example 4

[0063] The present embodiment provides a ropivacaine hydrochloride and meloxicam lyotropic liquid crystal gel preparation precursor, which is prepared from the following raw materials in weight percentage: 44.09% soybean phosphatidylcholine, 44.09% DL-α-tocopherol, 8.82% anhydrous ethanol, 2.92% ropivacaine hydrochloride, and 0.09% meloxicam.

[0064] This example adopts method 1 to prepare the product, and the appearance of the obtained product is a light yellow clear liquid, indicating that the raw materials are evenly mixed and have good compatibility; there is no stratification phenomenon when placed in the dark at room temperature for 3 months, indicating that the product has good storage stability. The lyotropic liquid crystal gel preparation precursor prepared in this example can undergo a phase change to form a liquid crystal gel when it encounters moisture.

[0065] The membraneless release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt % Tween 80 as the in vitro release medium. The cumulative release data within two weeks of Example 4 are shown in FIG. Figure 4 shown.

[0066] Example 5

[0067] The present embodiment provides a ropivacaine mesylate lyotropic liquid crystal gel preparation precursor, which is prepared from the following raw materials in percentage by weight: 41.07% soybean phosphatidylcholine, 41.07% DL-α-tocopherol, 9.86% anhydrous ethanol, and 8.00% ropivacaine mesylate.

[0068] This example adopts method 1 to prepare the product, and the appearance of the obtained product is a light yellow clear liquid, indicating that the raw materials are evenly mixed and have good compatibility; there is no stratification phenomenon when placed in the dark at room temperature for 3 months, indicating that the product has good storage stability. The lyotropic liquid crystal gel preparation precursor prepared in this example can undergo a phase change to form a liquid crystal gel when it encounters moisture.

[0069] The membraneless release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt % Tween 80 as the in vitro release medium. The cumulative release data within two weeks of Example 5 are shown in FIG. Figure 5 shown.

[0070] Example 6

[0071] The present embodiment provides a ropivacaine mesylate lyotropic liquid crystal gel preparation precursor, which is prepared from the following raw materials in percentage by weight: 43.34% soybean phosphatidylcholine, 43.34% DL-α-tocopherol, 10.40% anhydrous ethanol, and 2.92% ropivacaine mesylate.

[0072] This example adopts method 1 to prepare the product, and the appearance of the obtained product is a light yellow clear liquid, indicating that the raw materials are evenly mixed and have good compatibility; there is no stratification phenomenon when placed in the dark at room temperature for 3 months, indicating that the product has good storage stability. The lyotropic liquid crystal gel preparation precursor prepared in this example can undergo a phase change to form a liquid crystal gel when it encounters moisture.

[0073] The membraneless release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt % Tween 80 as the in vitro release medium. The cumulative release data within two weeks of Example 6 are shown in FIG. Figure 6 shown.

[0074] Example 7

[0075] The present embodiment provides a ropivacaine mesylate and meloxicam lyotropic liquid crystal gel preparation precursor, which is prepared from the following raw materials in weight percentage: 40.98% soybean phosphatidylcholine, 40.98% DL-α-tocopherol, 9.84% anhydrous ethanol, 8.00% ropivacaine mesylate, and 0.20% meloxicam.

[0076] This example adopts method 1 to prepare the product, and the appearance of the obtained product is a light yellow clear liquid, indicating that the raw materials are evenly mixed and have good compatibility; there is no stratification phenomenon when placed in the dark at room temperature for 3 months, indicating that the product has good storage stability. The lyotropic liquid crystal gel preparation precursor prepared in this example can undergo a phase change to form a liquid crystal gel when it encounters moisture.

[0077] The membraneless release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt % Tween 80 as the in vitro release medium. The cumulative release data within two weeks of Example 7 are shown in FIG. Figure 7 shown.

[0078] Example 8

[0079] The present embodiment provides a ropivacaine mesylate-meloxicam lyotropic liquid crystal gel preparation precursor, which is prepared from the following raw materials in weight percentage: 43.30% soybean phosphatidylcholine, 43.30% DL-α-tocopherol, 10.39% anhydrous ethanol, 2.92% ropivacaine mesylate, and 0.09% meloxicam.

[0080] This example adopts method 1 to prepare the product, and the appearance of the obtained product is a light yellow clear liquid, indicating that the raw materials are evenly mixed and have good compatibility; there is no stratification phenomenon when placed in the dark at room temperature for 3 months, indicating that the product has good storage stability. The lyotropic liquid crystal gel preparation precursor prepared in this example can undergo a phase change to form a liquid crystal gel when it encounters moisture.

[0081] The membraneless release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt % Tween 80 as the in vitro release medium. The cumulative release data of Example 8 within two weeks are shown in FIG. Figure 8 shown.

[0082] Example 9

[0083] The present embodiment provides a bupivacaine lyotropic liquid crystal gel preparation precursor, which is prepared from the following raw materials in percentage by weight: 43.64% soybean phosphatidylcholine, 43.64% DL-α-tocopherol, 8.72% anhydrous ethanol, and 4.00% bupivacaine.

[0084] This example adopts method 1 to prepare the product, and the appearance of the obtained product is a light yellow clear liquid, indicating that the raw materials are evenly mixed and have good compatibility; there is no stratification phenomenon when placed in the dark at room temperature for 3 months, indicating that the product has good storage stability. The lyotropic liquid crystal gel preparation precursor prepared in this example can undergo a phase change to form a liquid crystal gel when it encounters moisture.

[0085] The membraneless release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt % Tween 80 as the in vitro release medium. The cumulative release data of Example 9 within two weeks are shown in FIG. Fig. 9 shown.

[0086] Example 10

[0087] The present embodiment provides a bupivacaine-meloxicam lyotropic liquid crystal gel preparation precursor, which is prepared from the following raw materials in weight percentage: 43.58% soybean phosphatidylcholine, 43.58% DL-α-tocopherol, 8.71% anhydrous ethanol, 4.00% bupivacaine, and 0.13% meloxicam.

[0088] This example adopts method 1 to prepare the product, and the appearance of the obtained product is a light yellow clear liquid, indicating that the raw materials are evenly mixed and have good compatibility; there is no stratification phenomenon when placed in the dark at room temperature for 3 months, indicating that the product has good storage stability. The lyotropic liquid crystal gel preparation precursor prepared in this example can undergo a phase change to form a liquid crystal gel when it encounters moisture.

[0089] The membraneless release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt % Tween 80 as the in vitro release medium. The cumulative release data of Example 10 within two weeks are shown in FIG. Fig.10 shown.

[0090] Embodiment 11

[0091] This embodiment provides an 8% ropivacaine mesylate lyotropic liquid crystal gel preparation precursor containing different oil phases, using equal amounts of oleic acid (for injection), medium chain triglycerides (for injection), and mixed oil phases (oleic acid + DL-α-tocopherol, medium chain triglycerides + DL-α-tocopherol) to replace DL-α-tocopherol, and the ratio of soybean phosphatidylcholine to DL-α-tocopherol, oleic acid + DL-α-tocopherol, oleic acid, medium chain triglycerides, or medium chain triglycerides + DL-α-tocopherol is 40.98%:40.98%, and they are named prescriptions 1, 2, 3, 4, and 5, respectively.

[0092] The example was prepared by method 1, and the results are shown in Table 1. It can be seen that soybean phosphatidylcholine can be mixed evenly with DL-α-tocopherol or oleic acid or medium chain triglyceride or mixed oil phase to obtain a light yellow or yellow clear transparent liquid.

[0093] Use a 1mL syringe to draw 100-150μL of the above sample, inject it into a certain volume of injection water, and observe its gelation. The results are shown in Table 1. It can be seen that the mixed oil phase of soybean phosphatidylcholine and oleic acid or DL-α-tocopherol or the two can form a relatively regular spherical gel at a ratio of 40.98%:40.98%, and the mixed oil phase of soybean phosphatidylcholine and medium-chain triglycerides or medium-chain triglycerides and DL-α-tocopherol cannot form a gel at a ratio of 40.98%:40.98%.

[0094] Table 1 Appearance and gel formation of different prescriptions in Example 11

[0095]

[0096] The membrane-free release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt% Tween 80 as the in vitro release medium. The cumulative release data are shown in Fig.11As shown in the figure, the soybean phosphatidylcholine and DL-α-tocopherol preparation has a significant sustained release effect on drugs, and the in vitro sustained release period exceeds 170h; the soybean phosphatidylcholine and mixed oil phase (DL-α-tocopherol + oleic acid) preparation has a poor sustained release effect on drugs, and the release is completed within 24-48 hours; although the soybean phosphatidylcholine and oleic acid preparation also has a certain sustained release effect on drugs, and the in vitro sustained release period can reach 140h, it is significantly inferior to the sustained release effect of the soybean phosphatidylcholine and DL-α-tocopherol preparation.

[0097] Example 12

[0098] This embodiment provides two bupivacaine / meloxicam liquid crystal gel precursor prescriptions, wherein the ratios of soybean phosphatidylcholine to DL-α-tocopherol are 43.58%:43.58% and 56.65%:30.51%, respectively, and the ratios of the other components remain unchanged, namely, 8.72% anhydrous ethanol, 4.0% bupivacaine, and 0.13% meloxicam, and are named prescriptions 1 and 2.

[0099] The example was prepared by method 1, and the results are shown in Table 2. It can be seen that soybean phosphatidylcholine and DL-α-tocopherol in different proportions can be mixed evenly to obtain a yellow clear liquid.

[0100] Use a 1mL syringe to draw 100-150μL of the above sample, inject it into a certain volume of injection water, and observe its gelation. The results are shown in Table 2. It can be seen that soybean phosphatidylcholine and DL-α-tocopherol can form relatively regular spherical gels in different proportions.

[0101] Table 2 Appearance and gel formation of different prescriptions in Example 12

[0102]

[0103] The membrane-free release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt% Tween 80 as the in vitro release medium. The cumulative release data are shown in Fig.12 shown.

[0104] Embodiment 13

[0105] This embodiment provides two ropivacaine mesylate / meloxicam liquid crystal gel precursors, wherein the ratios of soybean phosphatidylcholine to DL-α-tocopherol are 28.69%:53.27% and 40.98%:40.98%, respectively, and the feed ratios of the other components remain unchanged, namely, 9.84% anhydrous ethanol, 8.0% ropivacaine mesylate, and 0.2% meloxicam, and are named as Prescriptions 1 and 2.

[0106] The example was prepared by method 1, and the results are shown in Table 3. It can be seen that soybean phosphatidylcholine and DL-α-tocopherol in different proportions can be mixed evenly to obtain a yellow clear liquid.

[0107] Use a 1mL syringe to draw 100-150μL of the above sample, inject it into a certain volume of injection water, and observe its gelation. The results are shown in Table 3. It can be seen that soybean phosphatidylcholine and DL-α-tocopherol can form relatively regular spherical gels in different proportions.

[0108] Table 3 Appearance and gel formation of different prescriptions in Example 13

[0109]

[0110] The membrane-free release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt% Tween 80 as the in vitro release medium. The cumulative release data are shown in Fig.13 shown.

[0111] Embodiment 14

[0112] This embodiment provides two ropivacaine mesylate liquid crystal gel precursors, wherein the weight ratios of soybean phosphatidylcholine and DL-α-tocopherol are 28.75%:53.39% and 40.98%:40.98% respectively, and the weight ratios of the other components remain unchanged, namely, 9.86% anhydrous ethanol and 8.0% ropivacaine mesylate, and they are named as prescriptions 1 and 2 respectively.

[0113] The example was prepared by method 1, and the results are shown in Table 4. It can be seen that soybean phosphatidylcholine and DL-α-tocopherol in different proportions can be mixed evenly to obtain a yellow clear liquid.

[0114] Use a 1mL syringe to draw 100-150μL of the sample and inject it into a certain volume of injection water to observe its gelation. The results are shown in Table 4. It can be seen that when the soybean phosphatidylcholine accounts for 28.75% and 40.98%, a relatively regular spherical gel can be formed, and when the proportion is 45.18% and 53.39%, no gel can be formed.

[0115] Table 4 Appearance and gel formation of different prescriptions in Example 14

[0116]

[0117] The membrane-free release method was used, with phosphate buffer at pH 7.4 containing 0.2 wt% Tween 80 as the in vitro release medium. The cumulative release data are shown in Fig.14 shown.

[0118] Embodiment 15

[0119] The lyotropic liquid crystal precursors prepared in Example 1, Example 4, Example 5, and Example 7 were selected, and the release medium was added dropwise and observed under a polarizing microscope. The results are as follows: Fig.15 From the polarizing microscope results, it can be observed that after the release medium is dropped, the sample after stabilization mainly presents polygonal textures and cone-like fan-shaped patterns, indicating that the sample is a lyotropic liquid crystal system mainly dominated by hexagonal phase.

[0120] Example 16

[0121] The prescription preparation in Example 5 was selected to conduct a pharmacokinetic test. SD rats were selected and a single subcutaneous injection was administered at the back of the neck, with a dosage of 40 mg / kg. Blood was collected from the jugular vein at a predetermined time point, and the blood drug concentration results were observed and compared with the blood drug concentration results of ropivacaine mesylate injection.

[0122] Depend on Fig.16 and 17 It can be seen that after the ropivacaine mesylate gel prepared by the present invention is injected into the back of the neck of SD rats, the drug quickly accumulates to the blood drug peak in a short time (about 1.5 hours). Compared with the ropivacaine mesylate injection, the present preparation extends the release time from <10 hours to more than 72 hours or even up to about 170 hours, so it has a good sustained release effect. In addition, the Cmax value of the present preparation in rats is lower than that of the ordinary injection, which can ensure that the present preparation maintains low cardiac and neurotoxicity and has higher safety.

[0123] Embodiment 17

[0124] The prescription preparation in Example 10 was selected to conduct a pharmacokinetic test. SD rats were selected and administered with a single subcutaneous injection at the back of the neck, wherein the bupivacaine dosage was 40 mg / kg and the meloxicam dosage was 1.2 mg / kg. Blood was collected from the jugular vein at a predetermined time point to observe the blood drug concentration results of bupivacaine and meloxicam.

[0125] Depend on Fig.18 and 19 It can be seen that after the bupivacaine-meloxicam gel prepared by the present invention is injected into the back of the neck of SD rats, bupivacaine quickly accumulates to a blood drug peak in a short time (about 1.5 hours), while the Tmax of meloxicam is relatively long (8-24 hours). The sustained release time of bupivacaine in the body exceeds 72 hours and even reaches about 170 hours, and the release time of meloxicam in the body can reach hundreds of hours. Therefore, the present preparation has a good sustained release effect on both bupivacaine and meloxicam, thereby ensuring that the two drugs achieve analgesic and anti-inflammatory synergistic effects in the body.

[0126] Although the present invention has been described in detail above by means of general description, specific implementation methods and tests, it is obvious to those skilled in the art that some modifications or improvements may be made to the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. A long-acting sustained-release lyotropic liquid crystal gel preparation, comprising a matrix material, a cosolvent and a raw drug, wherein the matrix material comprises an amphiphilic substance and an oil phase, characterized in that: The amphiphilic substance is selected from phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylglycerol; the oil phase is selected from monoolein, castor oil, medium-chain triglycerides, tocopherol, and oleic acid.

2. The preparation according to claim 1, characterized in that The amphiphilic substance is preferably soybean phosphatidylcholine, preferably tocopherol and oleic acid.

3. A preparation according to any one of the preceding claims, characterized in that The raw material drug comprises one or a combination of local anesthetics and non-steroidal anti-inflammatory drugs; preferably, the local anesthetic is selected from ropivacaine, bupivacaine, lidocaine, and pharmaceutically acceptable salts thereof, more preferably, the pharmaceutically acceptable salt is selected from hydrochloride and methanesulfonate, more preferably, the local anesthetic is selected from ropivacaine hydrochloride, ropivacaine mesylate, bupivacaine hydrochloride, bupivacaine mesylate, lidocaine hydrochloride, and lidocaine mesylate; preferably, the non-steroidal anti-inflammatory drug is selected from meloxicam, ibuprofen, acetaminophen, flurbiprofen, flurbiprofen axetil, celecoxib, more preferably, selected from meloxicam.

4. A preparation according to any one of the preceding claims, characterized in that The cosolvent is selected from ethanol, N-methylpyrrolidone, dimethyl sulfoxide, dimethylformamide, preferably ethanol.

5. A preparation according to any one of the preceding claims, characterized in that The weight percentage of the matrix material is 80% to 90%, further, the weight percentage of the amphiphilic substance is 25% to 60%, preferably 30%-55%, more preferably 40% to 45%, and the weight percentage of the oil phase is 25% to 60%, preferably 30% to 55%, more preferably 40% to 45%.

6. A preparation according to any one of the preceding claims, characterized in that The weight percentage of the co-solvent is 6% to 15%, preferably 8% to 11%.

7. A preparation according to any one of the preceding claims, characterized in that The weight percentage of the raw material medicine is 0.01% to 25%, preferably 0.09% to 20%. Further, the weight percentage of the local anesthetic is 2% to 25%, preferably 2% to 20%, and the weight percentage of the non-steroidal anti-inflammatory drug is 0.01% to 0.80%, preferably 0.09% to 0.50%.

8. A preparation according to any one of the preceding claims, characterized in that The invention comprises the following components (by mass percentage): 25% to 60% of soybean phosphatidylcholine, 25% to 60% of tocopherol, 6% to 15% of anhydrous ethanol, 2% to 25% of ropivacaine hydrochloride / ropivacaine mesylate / bupivacaine, and 0.01% to 0.80% of meloxicam.

9. The method for preparing the preparation according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: weighing appropriate amounts of amphiphilic substances, oil phase and cosolvent, heating and stirring under closed conditions until the auxiliary materials are dissolved to obtain a blank gel precursor; weighing appropriate amounts of drugs, adding them to the blank gel precursor, stirring under closed conditions at room temperature until the drugs are dissolved to obtain a drug-loaded lyotropic liquid crystal gel precursor.

10. The method for preparing the preparation according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: weighing an appropriate amount of amphiphilic substance, oil phase and excess cosolvent, stirring at room temperature under closed conditions until the auxiliary materials are dissolved, thereby obtaining a blank gel precursor; weighing an appropriate amount of drug and adding it to the blank gel precursor, stirring at room temperature under closed conditions until the drug is dissolved, and rotary distilling ethanol at a certain temperature to a prescribed amount, thereby obtaining a drug-loaded lyotropic liquid crystal gel precursor.

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