Compound phospholipid gel sustained release preparation for postoperative analgesia

Abstract

The invention provides a compound phospholipid gel sustained release preparation and a preparation method thereof. The preparation mainly comprises a local anesthetic, a non-steroidal anti-inflammatory drug, phospholipid and water for injection. The preparation can be injected around a surgical incision or directly instilled or coated at the surgical incision to achieve the purpose of long-acting analgesia, and is used for postoperative analgesia.

Description

Technical Field

[0001] The invention relates to a highly stable compound phospholipid gel sustained-release preparation for postoperative analgesia which can be widely used in industrial production, and a preparation method and application thereof, belonging to the technical field of medicine. Background Art

[0002] Postoperative pain is generally caused by inflammation or pain caused by nerve damage caused by tissue damage during surgery. Postoperative pain often causes patients to have various emotional abnormalities, such as depression, anxiety, irritability, sleep disorders, etc. In severe cases, it can cause disorders of gastrointestinal function, cardiopulmonary function, coagulation function, and endocrine and metabolic functions. If not properly managed, postoperative pain may lead to impaired physical function and quality of life, increased morbidity, prolonged recovery time, and increased risk of complications. In addition, it will lead to increased hospital stays, readmission rates, and outpatient time, all of which lead to higher healthcare costs. Although with the advancement of modern medicine, academic research on the physiology and psychology of postoperative pain has made great progress, and the management of postoperative pain has also made significant achievements in the past, how to better control postoperative pain and reduce side effects and complications is still a considerable challenge.

[0003] Opioids have long played an important role in postoperative pain management. Despite their good analgesic effects, they are also accompanied by very significant side effects, including respiratory depression, cognitive impairment, nausea and vomiting, itching, urinary retention, constipation, and other side effects. In addition, they also cause the risk of abuse and addiction. Therefore, the role of opioid analgesics in accelerated recovery after surgery (ERAS) and multimodal analgesia (MMA) has gradually developed into an auxiliary drug, and people have regained interest in non-opioid alternatives that can effectively control postoperative pain, including local anesthetics, nonsteroidal anti-inflammatory drugs (NSAIDs), α-2 adrenergic receptor agonists, magnesium ions, ketamine, etc.

[0004] Local anesthetics are a class of drugs that can reversibly block the generation and conduction of sensory nerve impulses at the site of administration, and are an important alternative to opioid analgesics. However, the local anesthetics commonly used in clinical practice have the characteristics of short duration of action and cannot provide long-term analgesia. Among them, levobupivacaine hydrochloride is a long-acting local anesthetic, and the analgesic time can only be maintained for about 6 hours. As a relatively small molecule, local anesthetics can easily pass through the blood vessel wall and be removed from the injection site. This rapid redistribution from the administration site limits the duration of effective analgesia and the usefulness of this method for pain control. An effective method is to develop a delivery system that can release local anesthetics for a long time.

[0005] The analgesic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) for both acute and chronic pain are well established but are often associated with adverse effects secondary to systemic distribution, including upper gastrointestinal bleeding and renal side effects. One way to overcome these treatment limitations is to maximize drug levels at the site of action and minimize systemic exposure by administering the drug directly to the site of tissue injury. Some studies have shown that placing the nonsteroidal anti-inflammatory drug ketoprofen gel directly on the surgical wound has better analgesic effect than oral medication (RADionne, D. Haynes, JS Brahim, JS Rowan, PH Guivarc'h, Analgesic effect of sustained-release flurbiprofen administered at the site of tissue injury in the oral surgery model, J Clin Pharmacol 44 (12) (2004) 1418-24). However, nonsteroidal anti-inflammatory drugs have a "ceiling effect", that is, after reaching a certain dose, the efficacy does not increase but the side effects increase. The simultaneous use of multiple nonsteroidal anti-inflammatory drugs will lead to the superposition of adverse reactions. Therefore, nonsteroidal anti-inflammatory drugs can be used for postoperative analgesia but can only be used as auxiliary analgesics and cannot completely replace the effects of opioids.

[0006] Sustained-release delivery system refers to a drug delivery system that releases drugs slowly from preparations in vivo at a non-constant rate, thereby prolonging the drug's effect. Currently available bupivacaine long-acting sustained-release preparations include Exparel, a bupivacaine liposome prepared using DepoFoam multivesicular liposome technology; The above-mentioned sustained-release preparations all have complicated production processes, and the overall production line needs to be customized and enlarged, which places high demands on enterprises, and their materials are all synthetic polymer materials or use organic solvents.

[0007] Patent CN 108379269 B discloses a sustained-release preparation that can be used for postoperative analgesia, which contains phospholipids, glycerides, poloxamers, ethanol and three different local anesthetics. The invention can be directly injected into the painful area and can slowly release the drug in situ to achieve the purpose of long-term analgesia. However, the invention contains ethanol, which is irritating to the skin and wound tissues and may produce certain side effects. In addition, although the invention uses a combination of three drugs, they are all local anesthetics and cannot play an enhanced analgesic effect.

[0008] In summary, it is necessary to provide a new preparation with high efficiency and low toxicity, good drug stability, low production cost, simple preparation method, suitable for large-scale industrial production and clinical use, which can make non-opioid analgesics have long-acting sustained release and good analgesic effect, thereby reducing patients' need for opioid analgesics and overcoming the side effects that may be caused by the use of opioid analgesics. Summary of the invention

[0009] One of the purposes of the present invention is to overcome the existing technical defects and provide a safe and effective analgesic preparation with a long-acting sustained-release effect for postoperative analgesia for clinical use.

[0010] Local anesthetics and nonsteroidal anti-inflammatory drugs are two types of drugs with different properties and mechanisms of action. Clinical studies have shown that the postoperative analgesic effect of bupivacaine / meloxicam PR preparations is significantly better than the two drugs used alone (see "Current Status of Clinical Application Research of Meloxicam", Li Xinyu, Chinese Journal of Clinical Pharmacology and Therapeutics, Vol. 28, No. 2, 2023). However, local anesthetics are usually very easy to pass through the blood vessel wall and be removed from the injection site, and they have the characteristics of a short half-life; compared with local anesthetics, nonsteroidal anti-inflammatory drug injections generally have a longer half-life in the body. The significant difference in the metabolic behavior of the two drugs in combination prevents the synergistic effect of the two drugs from being fully exerted.

[0011] The present invention creatively provides a phospholipid gel sustained-release preparation, which on the one hand simultaneously encapsulates a local anesthetic and a nonsteroidal anti-inflammatory drug in the preparation, so that the two drugs are slowly released at the same time at the same site, playing a synergistic analgesic effect, and the analgesic time can be up to 120 hours. The analgesic effect of the preparation that simultaneously encapsulates the local anesthetic and the nonsteroidal anti-inflammatory drug after dripping or coating on the postoperative incision site is significantly better than that of the preparation that only encapsulates one of the drugs. On the other hand, it can successfully overcome the above-mentioned defects existing in the application process of the two drugs, and can obtain the technical effect of fully utilizing the two drugs. The above-mentioned preparation can make the pharmacokinetic curves of the two drugs relatively consistent within 120 hours after administration, which is close to synchronous release.

[0012] One of the purposes of the present invention is to provide a phospholipid gel long-acting sustained-release preparation which can be injected or dripped or coated on the administration site, thereby releasing the drug in situ to achieve a long-acting analgesic effect.

[0013] The study also found that the viscosity of the preparation increases with the increase of phospholipid content, thereby prolonging the sustained release time of the drug. However, a semi-solid dispersion system with too high viscosity is not suitable for use as an injection preparation. If the semi-solid preparation is covered on the surgical incision wound surface by dripping or coating, and then sutured after surgery, the injection difficulty caused by the high viscosity of the dispersion system can be avoided. Therefore, preferably, the administration method of the preparation is dripping or coating on the surgical incision wound surface.

[0014] One of the purposes of the present invention is to provide a compound phospholipid gel sustained-release preparation, which comprises a composition of a local anesthetic, a nonsteroidal anti-inflammatory drug, a phospholipid, and water for injection or a saline solution.

[0015] The study also found that compared with other phospholipid gel dispersion systems, the gel sustained-release preparation provided in the present application does not require the use of any organic solvents to aid dissolution, is more gentle and friendly to the fragile and sensitive incision environment after surgery, and will not cause irritation to the tissues and skin at the surgical incision site.

[0016] The study also found that the dosage ratio and drug concentration of local anesthetics and non-steroidal anti-inflammatory drugs will not affect the sustained-release curve of the drugs in the body. Therefore, the gel sustained-release preparation can select different drugs or different proportions of drugs for combination use according to different clinical purposes.

[0017] Furthermore, other pharmaceutically acceptable excipients may be added to the gel sustained-release preparation.

[0018] Furthermore, the gel sustained-release preparation comprises, by weight, 0.25 to 40 parts of local anesthetic, 0.0015 to 20 parts of nonsteroidal anti-inflammatory drugs, 20 to 70 parts of phospholipids, and 30 to 80 parts of water for injection or saline solution.

[0019] Furthermore, the gel sustained-release preparation preferably contains, by weight, 0.5 to 20 parts of local anesthetic, 0.0015 to 10 parts of nonsteroidal anti-inflammatory drugs, 25 to 65 parts of phospholipids, and 35 to 75 parts of water for injection or saline solution.

[0020] Furthermore, the local anesthetic is selected from one or more of lidocaine, tetracaine, procaine, bupivacaine, levobupivacaine, ropivacaine or pharmaceutically acceptable salts thereof, preferably bupivacaine, levobupivacaine, ropivacaine or pharmaceutically acceptable salts thereof.

[0021] Furthermore, the weight percentage of the local anesthetic is in the range of 0.25%-40%, preferably 1%-15%.

[0022] Further, the nonsteroidal anti-inflammatory drug is selected from acetylsalicylic acid, sodium salicylate, disalsalate, benolate, diflunisal, acetaminophen, phenacetin, ibuprofen, flurbiprofen, ketoprofen, naproxen, indoprofen, fenoprofen, pirprofen, suprofen, butibufen, oxaprozin, tiaprofenic acid, ketorolac, indomethacin, benzydamine, acemetacin, sulindac, zidometacin, tolmetin sodium , diclofenac sodium, etodolac, nabumetone, fenbufen, meloxicam, piroxicam, sudoxicam, isoxicam, tenoxicam, phenylbutazone, hydroxybutazone, sulfinpyrazone, γ-ketophenylbutazone, flufenamic acid, clofenamic acid, clonixin, celecoxib, rofecoxib, etoricoxib, nimesulide, etc., preferably one or more of meloxicam, piroxicam, sudoxicam, isoxicam, and tenoxicam. Preferably one or more of meloxicam, piroxicam, sudoxicam, isoxicam, and tenoxicam, more preferably meloxicam.

[0023] Furthermore, the weight percentage of the non-steroidal anti-inflammatory drug ranges from 0.0015% to 20%, preferably from 0.0015% to 10%, and more preferably from 0.01% to 4.5%.

[0024] Furthermore, the weight ratio of the local anesthetic to the non-steroidal anti-inflammatory drug is 1:0.01-60, preferably 1:0.025-1.0, and more preferably 1:0.03-0.3.

[0025] Further, the phospholipids include but are not limited to a combination of one or more of natural phospholipids, semi-synthetic phospholipids, and synthetic phospholipids; wherein the natural lecithin includes but is not limited to egg yolk lecithin, soybean lecithin, etc.; the semi-synthetic phospholipids include but are not limited to hydrogenated soybean lecithin; the synthetic phospholipids include but are not limited to a combination of one or more of dipalmitoyl phosphatidylethanolamine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, oleoyl phosphatidylethanolamine, dipalmitoyl phosphatidylglycerol, and dipalmitoyl phosphatidic acid, etc. Preferably, the phospholipids are preferably egg yolk lecithin and soybean lecithin, and the weight percentage of the phospholipids is preferably 20%-70%, more preferably 25%-65%. Further, the other pharmaceutically acceptable excipients include cholesterol, and its weight percentage is 0%-40%, preferably 4%-30%.

[0026] One of the purposes of the present invention is to provide a method for preparing a compound phospholipid gel sustained-release preparation for postoperative analgesia, which is characterized by comprising the following steps:

[0027] ⑴ Dissolve or suspend the drug in an appropriate amount of water for injection or saline solution to form a drug solution or drug suspension;

[0028] (2) adding phospholipids to the drug solution or drug suspension;

[0029] ⑶ Stir for an appropriate amount of time until the preparation is a uniform milky white cream. Preferably, the stirring condition is stirring under sterile conditions at room temperature for 0.5-4h, preferably 1.5-2h.

[0030] The salt solution in step (1) is selected from one or more of physiological saline, phosphate buffer and carbonate buffer.

[0031] One of the purposes of the present invention is to provide a use of a phospholipid gel long-acting sustained-release preparation for in situ sustained release, which can be injected around a surgical incision or directly coated on the surgical incision site to achieve the purpose of long-acting analgesia and is used for postoperative analgesia.

[0032] Advantages of the present invention

[0033] ⑴The preparation method is simple and easier to mass produce;

[0034] ⑵The carrier material is safe and non-toxic, has good biocompatibility, is biodegradable, and is relatively safer;

[0035] ⑶The prescription ingredients are simple, no organic solvents are used, and it is non-toxic and non-irritating;

[0036] ⑷ It can encapsulate hydrophilic drugs and lipophilic drugs at the same time;

[0037] ⑸ The drug concentration and the ratio of combined drugs will not affect the drug release curve in the body, and can be more widely used in combination of multiple different drugs or different ratios;

[0038] (6) The preparation of the present invention makes the pharmacokinetic curves of two drugs with greatly different release curves in vivo tend to be consistent, which is conducive to the synergistic effect of the two drugs;

[0039] ⑺ Both hydrophilic drugs and lipophilic drugs are released at a relatively stable rate in the preparation without obvious burst release, which greatly enhances drug safety and reduces possible drug toxicity, especially the toxicity caused by the burst release of local anesthetics;

[0040] ⑻ The analgesic effect of the combination of the two drugs is significantly stronger than that of using either drug alone. In this system, the combination of the two drugs has a significant synergistic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 : In vivo sustained release curves of two drugs in compound phospholipid gel.

[0042] Figure 2 : In vivo sustained release curves of two drugs in phospholipid gels with different formulations.

[0043] Figure 3 : In vivo sustained release curves of two drugs in compound phospholipid gels with different drug ratios.

[0044] Figure 4 : In vivo sustained release curves of bupivacaine from compound phospholipid gels with different bupivacaine concentrations.

[0045] Figure 5 : Sustained release curves of compound phospholipid gel and commercially available bupivacaine multivesicular liposomes in vivo.

[0046] Figure 6 : Comparison of the efficacy of compound phospholipid gel (bupivacaine) and normal saline (PWT).

[0047] Figure 7 :Comparison of the efficacy of phospholipid gels with different prescriptions (PWT).

[0048] Figure 8 : Comparison of the efficacy of compound phospholipid gel and commercially available bupivacaine multivesicular liposomes (PWT).

[0049] Fig. 9 : Comparison of the efficacy of compound phospholipid gel and single drug phospholipid gel (PWT).

[0050] Fig.10 : Comparison of the efficacy of compound phospholipid gel (ropivacaine) and normal saline (PWT). DETAILED DESCRIPTION

[0051] The following examples are further explanations of the present invention, but are by no means limitations of the scope of the present invention. The present invention is further described in detail below with reference to the examples, but it should be understood by those skilled in the art that the present invention is not limited to these examples and the preparation methods used. Moreover, those skilled in the art can carry out equivalent replacement, combination, improvement or modification to the present invention based on the description of the present invention, but these will all be included in the scope of the present invention.

[0052] Example 1

[0053] Take 350 mg of bupivacaine hydrochloride and 10.5 mg of meloxicam, add 3325 mg of water for injection, and perform water bath ultrasound until the bupivacaine hydrochloride is completely dissolved, and shake to fully disperse the meloxicam; take 3325 mg of egg yolk lecithin E80 and add it to the aqueous phase, and stir magnetically for 1.5 h-2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound phospholipid gel sustained-release preparation.

[0054] Example 2

[0055] Take 300 mg of bupivacaine hydrochloride and 9 mg of meloxicam, add 5335 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully dissolve the bupivacaine hydrochloride, and shake to fully disperse the meloxicam; take 365 mg of egg yolk lecithin E804, add it to the aqueous phase, and stir magnetically for 4 hours until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound phospholipid gel sustained-release preparation.

[0056] Example 3

[0057] Take 6.6g of egg yolk lecithin E80 and 3.3g of cholesterol, add an appropriate amount of anhydrous ethanol, heat to dissolve them into a yellow clear solution, use rotary evaporation to completely evaporate the ethanol, and take the light yellow residue for later use.

[0058] Take 300 mg of bupivacaine hydrochloride and 9 mg of meloxicam, add 4850 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully dissolve the bupivacaine hydrochloride, and shake to fully disperse the meloxicam; take 4.85 g of the above light yellow solid and add it to the aqueous phase, and stir magnetically for 1.5 h-2 h until the preparation becomes a uniform off-white creamy semisolid, i.e., the compound phospholipid gel sustained-release preparation.

[0059] Example 4

[0060] Take 300 mg of bupivacaine hydrochloride and 27 mg of meloxicam, add 5200 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully dissolve the bupivacaine hydrochloride, and shake to fully disperse the meloxicam; take 500 mg of egg yolk lecithin E804, add it to the aqueous phase, and stir magnetically for 1.5 h-2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound phospholipid gel sustained-release preparation.

[0061] Example 5

[0062] Take 300 mg of bupivacaine hydrochloride and 90 mg of meloxicam, add 5100 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully dissolve the bupivacaine hydrochloride, and shake to fully disperse the meloxicam; take 500 mg of egg yolk lecithin E804, add it to the aqueous phase, and stir magnetically for 1.5 h to 2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound phospholipid gel sustained-release preparation.

[0063] Example 6

[0064] Take 270 mg of bupivacaine hydrochloride and 8.1 mg of meloxicam, add 1650 mg of water for injection, heat in a water bath until the bupivacaine hydrochloride is completely dissolved, and shake to fully disperse the meloxicam; take 1350 mg of egg yolk lecithin E80 and add it to the aqueous phase, stir magnetically for 1.5 h-2 h, until the preparation becomes a uniform milky white creamy semisolid, that is, the compound phospholipid gel sustained-release preparation.

[0065] Example 7

[0066] Take 360 ​​mg of bupivacaine hydrochloride and 11 mg of meloxicam, add 1820 mg of water for injection, heat in a water bath and ultrasonicate until the bupivacaine hydrochloride is completely dissolved, and shake to fully disperse the meloxicam; take 1820 mg of egg yolk lecithin E80 and add it to the aqueous phase, stir magnetically for 1.5h-2h, until the preparation becomes a uniform milky white creamy semisolid, that is, the compound phospholipid gel sustained-release preparation.

[0067] Example 8

[0068] Take 270 mg of levobupivacaine hydrochloride and 8.1 mg of meloxicam, add 1500 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully dissolve the levobupivacaine hydrochloride, and shake to fully disperse the meloxicam; take 1500 mg of egg yolk lecithin E80 and add it to the aqueous phase, and stir magnetically for 1.5 h to 2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound phospholipid gel sustained-release preparation.

[0069] Example 9

[0070] Take 200 mg of ropivacaine hydrochloride and 4.5 mg of meloxicam, add 2400 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully dissolve the ropivacaine hydrochloride, and shake to fully disperse the meloxicam; take 400 mg of egg yolk lecithin E802, add it to the aqueous phase, and stir mechanically for 1.5 h to 2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound phospholipid gel preparation.

[0071] Example 10

[0072] Take 80 mg of ropivacaine hydrochloride and 48 mg of flurbiprofen, add 2130 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully dissolve the ropivacaine hydrochloride, and shake to fully disperse the flurbiprofen; take 1742 mg of soybean lecithin S100 and add it to the aqueous phase, and stir magnetically for 1.5 h to 2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound lecithin gel sustained-release preparation.

[0073] Embodiment 11

[0074] Take 120 mg of bupivacaine and 36 mg of flurbiprofen, add 2114 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully disperse the bupivacaine and flurbiprofen; take 1730 mg of soybean lecithin S100 and add it to the aqueous phase, and stir magnetically for 1.5 h-2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound lecithin gel preparation.

[0075] Example 12

[0076] Take 200 mg of tetracaine hydrochloride and 120 mg of flurbiprofen, add 2024 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully dissolve the tetracaine hydrochloride, and shake to fully disperse the flurbiprofen; take 1656 mg of hydrogenated soybean lecithin and add it to the aqueous phase, and stir magnetically for 1.5 h-2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound lecithin gel sustained-release preparation.

[0077] Embodiment 13

[0078] Take 120 mg of tetracaine hydrochloride and 96 mg of acetaminophen, add 2081 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully dissolve the tetracaine hydrochloride, and shake to fully disperse the acetaminophen; take 1900 mg of dipalmitoylphosphatidylethanolamine, add it to the aqueous phase, and stir magnetically for 1.5 h to 2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound phospholipid gel preparation.

[0079] Embodiment 14

[0080] Take 80 mg of ropivacaine hydrochloride and 62.4 mg of celecoxib, add 2122 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully dissolve the ropivacaine hydrochloride and fully disperse the celecoxib; take 1736 mg of soybean lecithin S100 and add it to the aqueous phase, and stir magnetically for 1.5 h-2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound lecithin gel sustained-release preparation.

[0081] Embodiment 15

[0082] Take 200 mg of lidocaine hydrochloride and 60 mg of diclofenac sodium, add 2057 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully dissolve the lidocaine hydrochloride, and shake to fully disperse the diclofenac sodium; take 1683 mg of egg yolk lecithin E80 and add it to the aqueous phase, and stir magnetically for 1.5 h-2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound phospholipid gel sustained-release preparation.

[0083] Example 16

[0084] Take 40 mg of procaine and 4 mg of diclofenac sodium, add 2178 mg of water for injection, and perform water bath ultrasound for 5 minutes to fully disperse lidocaine and diclofenac sodium; take 1782 mg of egg yolk lecithin E80 and add it to the aqueous phase, and stir magnetically for 1.5 h-2 h until the preparation becomes a uniform milky white creamy semisolid, i.e., the compound phospholipid gel sustained-release preparation.

[0085] Embodiment 17

[0086] Take 2000 mg of bupivacaine hydrochloride and 100 mg of meloxicam, add 3325 mg of water for injection, and use water bath ultrasound to fully disperse the bupivacaine hydrochloride and meloxicam; take 2500 mg of soybean lecithin S100 and add it to the aqueous phase, and stir it magnetically for 1.5h-2h until the preparation becomes a uniform milky white creamy semisolid, that is, the compound lecithin gel sustained-release preparation.

[0087] Effect Experiment

[0088] Experiment 1: Sustained release of two drugs in compound phospholipid gel in vivo

[0089] The preparation obtained by the method described in Example 1 and the compound injection group were subjected to in vivo pharmacokinetic experiments at equal doses, wherein the compound injection group used injection water as the solvent and was prepared according to the concentrations in Table 1.

[0090] The specific method is:

[0091] 1.1 In vivo animal experiments

[0092] Ten healthy male SD rats were randomly divided into two groups (n=5): the compound preparation group and the compound injection group. Each group was given the drug at the same time, and blood was collected from the orbital venous plexus at the pre-set time points of 0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 120h, 144h, and 168h using an EP tube moistened with sodium heparin. The blood was immediately centrifuged at 6000rmp and 4℃ for 5min to obtain 100μL of upper plasma, which was refrigerated at -40℃ for later use.

[0093] Table 1:

[0094] Preparation group Injection group Bupivacaine concentration (w / v) 5％ 0.75％ Meloxicam weight (w / v) 0.15％ 0.0225％ Bupivacaine dosage 13mg 13mg Meloxicam dosage 0.39mg 0.39mg

[0095] 1.2 Plasma processing methods

[0096] Add 5 volumes of protein precipitant (methanol:acetonitrile = 1:5, v / v) to 100 μL of plasma sample, vortex for 5 min to mix, centrifuge at 10000 rpm for 10 min, filter the supernatant with a 0.22 μm organic filter membrane and inject.

[0097] 1.3 Preparation of standard curve

[0098] 1.3.1 Preparation of bupivacaine standard curve

[0099] Weigh 20 mg of bupivacaine reference substance, accurately weigh, use a pipette to take 4.0 ml of methanol to make a 5.0 mg / ml solution, use a pipette to take 1.0 ml of the 5.0 mg / ml bupivacaine solution, and then add methanol to dilute it to a 1.0 mg / ml solution as the bupivacaine stock solution, take an appropriate amount and dilute it with methanol to obtain bupivacaine solutions with concentrations of 10 ng / ml, 20 ng / ml, 50 ng / ml, 100 ng / ml, 200 ng / ml, 500 ng / ml, 1000 ng / ml, 2000 ng / ml, 5000 ng / ml, and 10000 ng / ml as the reference substance solution.

[0100] Take 100 μL of blank plasma, add 10.0 μL of the reference solution series, so that the concentration of bupivacaine in the plasma sample is 1 ng / ml, 2 ng / ml, 5 ng / ml, 10 ng / ml, 20 ng / ml, 50 ng / ml, 100 ng / ml, 200 ng / ml, 500 ng / ml, 1000 ng / ml, add five times the volume of protein precipitation agent (methanol: acetonitrile = 1: 5, v / v), vortex for 5 min to mix, centrifuge at 10000 rpm for 10 min, filter the supernatant with a 0.22 μm organic filter membrane, and inject. Linear regression is performed with the plasma concentration to be tested as the horizontal axis and the peak area as the vertical axis to obtain the standard curve equation: y = 32.608x + 2383.4, R 2 =0.9995, linear range is 2ng / ml-1000ng / ml.

[0101] 1.3.2 Preparation of Meloxicam Standard Curve

[0102] Weigh 20 mg of meloxicam reference substance, accurately weigh, use a pipette to take 4.0 ml of solvent (40% methanol, 23 mM sodium hydroxide) and add it to dissolve, ultrasonicate for five minutes to ensure that all the meloxicam is dissolved, and make a 5.0 mg / ml solution, use a pipette to take 1.0 ml of 5.0 mg / ml meloxicam solution, and then add the above methanol solution to dilute it to 1.0 mg / ml solution as meloxicam stock solution, take appropriate amount of stock solution for gradient dilution to obtain meloxicam solutions with concentrations of 20 ng / ml, 50 ng / ml, 100 ng / ml, 200 ng / ml, 500 ng / ml, 1000 ng / ml, 2000 ng / ml, 5000 ng / ml, 10000 ng / ml, 20000 ng / ml, 50000 ng / ml, 100000 ng / ml as reference substance solution.

[0103] Take 100μL of blank plasma, add 10.0μL of series reference solution respectively, make the concentration of meloxicam in plasma sample 2ng / ml, 5ng / ml, 10ng / ml, 20ng / ml, 50ng / ml, 100ng / ml, 200ng / ml, 500ng / ml, 1000ng / ml, 2000ng / ml, 5000ng / ml, 10000ng / ml, add five times volume of protein precipitation agent (methanol: acetonitrile = 1: 5, v / v), vortex for 5min, centrifuge at 10000rpm for 10min, filter the supernatant with 0.22μm organic filter membrane, and inject. Linear regression is performed with the plasma concentration to be tested as the abscissa and the peak area as the ordinate, and the calibration curve equation is obtained: y = 15.234x + 202.21, R2 = 0.9997, and the linear range is 2ng / ml-10000ng / ml.

[0104] result:

[0105] Bupivacaine: Test results are as follows Figure 1 A. Figure 1 As shown in B, bupivacaine in the compound injection can only be detected in the blood for 24 hours, while the sustained-release time of bupivacaine in the compound phospholipid gel can reach more than 120 hours, and the control solution group has a significantly excellent sustained-release effect.

[0106] Meloxicam: Test results are as follows Figure 1 As shown in C, the meloxicam in the compound injection can maintain a low blood concentration for 120 hours, and the sustained release time of meloxicam in the compound phospholipid gel can reach 144 hours, reaching the peak concentration at 24h-36h. The overall blood concentration is much higher than that of the injection.

[0107] Experiment 2 Effects of changes in formulation composition on the sustained release profiles of two drugs in phospholipid gel in vivo

[0108] The preparations obtained by the methods described in Example 2 and Example 3 were subjected to in vivo pharmacokinetic experiments at equal doses.

[0109] Specific methods:

[0110] Ten healthy male SD rats were randomly divided into two groups (n=5): prescription group 1 and prescription group 2. Each group was administered with the same time, and blood was collected from the orbital venous plexus at the preset time points of 0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 120h, 144h, and 168h using an EP tube moistened with sodium heparin. The obtained blood was immediately centrifuged at 6000rmp and 4°C for 5min to obtain 100μL of upper plasma. The blood was refrigerated at -40°C for later use.

[0111] Table 2:

[0112] Group 1 Group 2 Bupivacaine concentration (w / v) 3％ 3％ Meloxicam concentration (w / v) 0.09％ 0.09％ <![CDATA[E80:H20(w / w)]]> 45 / 55 / <![CDATA[(E80+CHOL):H20(w / w)]]> / 50 / 50

[0113] The method for detecting drug concentration in plasma is the same as the specific method described in Experimental Example 1.

[0114] result:

[0115] Bupivacaine: Test results are as follows Figure 2 A. After changing the prescription composition, the sustained-release time of bupivacaine did not change significantly, but the blood drug concentration before 24 hours was slightly different. The blood drug concentration of the prescription with added cholesterol was lower in the early stage and the safety was better.

[0116] Meloxicam: Test results are as follows Figure 2 B. After changing the formula composition, the release curve of the formula with added cholesterol is slightly better than that of the formula with only added egg yolk lecithin.

[0117] Experiment 3 Effect of the ratio of two drugs in compound phospholipid gel on its sustained release curve in vivo

[0118] The preparations obtained by the methods described in Example 2, Example 4 and Example 5 were subjected to in vivo pharmacokinetic experiments at equal doses.

[0119] Specific methods:

[0120] Fifteen healthy male SD rats were randomly divided into three groups (n=5): experimental group 1, experimental group 2, and experimental group 3. Each group was given the drug at the same time, and blood was collected from the orbital venous plexus at the pre-set time points of 0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 120h, 144h, and 168h using EP tubes moistened with sodium heparin. The blood was immediately centrifuged at 6000rmp and 4°C for 5min to obtain 100μL of upper plasma. The blood was refrigerated at -40°C for later use.

[0121] Group 1 Group 2 Group 3 Melox:Bup(w / w) 0.03 0.09 0.3

[0122] The method for detecting drug concentration in plasma is the same as the specific method described in Experimental Example 1.

[0123] result:

[0124] Bupivacaine: Test results are as follows Figure 3 A, The experiment was carried out with the ratio of meloxicam to bupivacaine at 0.03, 0.09, and 0.3, respectively, and a comparative experiment was conducted. It was found that when the ratio of the two drugs was different, the sustained-release curve of bupivacaine remained basically unchanged.

[0125] Meloxicam: Test results are as follows Figure 3 B, The trend of meloxicam sustained-release curve in preparations with different ratios remains unchanged.

[0126] In summary, the ratio of the two drugs will not affect the trend of the drug release curve in vivo.

[0127] Experiment 4 Effect of bupivacaine concentration in compound phospholipid gel on its sustained release curve in vivo

[0128] The same doses of the preparations obtained by the methods described in Example 2 and Example 6 were subjected to in vivo pharmacokinetic experiments for comparison; the same doses of the preparations obtained by the methods described in Example 1 and Example 7 were subjected to in vivo pharmacokinetic experiments for comparison.

[0129] Specific methods:

[0130] Twenty healthy male SD rats were randomly divided into 4 groups (n=5): each group was administered with the drug at the same time, and blood was collected from the orbital venous plexus at the preset time points of 0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 120h, 144h, and 168h using EP tubes moistened with sodium heparin. The blood was immediately centrifuged at 6000rmp and 4°C for 5min to obtain 100μL of upper plasma. The blood was refrigerated at -40°C for later use.

[0131] Group 1 Group 2 Group 3 Group 4 Bupivacaine concentration (w / v) 3％ 8.3％ 5％ 9％ Meloxicam concentration (w / v) 0.09％ 0.25％ 0.15％ 0.27％ <![CDATA[E80:H20(w / w)]]> 45 / 55 45 / 55 50 / 50 50 / 50

[0132] The method for detecting drug concentration in plasma is the same as the specific method described in Experimental Example 1.

[0133] result:

[0134] Bupivacaine: Test results are as follows Figure 4 A, 4B; When other factors in the prescription (preparation composition, phospholipid concentration, ratio of the two drugs) are kept unchanged, changes in the bupivacaine concentration in the preparation do not affect its sustained release curve in vivo.

[0135] Experiment 5: Sustained release curves of compound phospholipid gel and commercially available bupivacaine multivesicular liposomes in vivo

[0136] The preparation obtained by the method described in Example 1 and the commercially available multivesicular liposome suspension of bupivacaine were used in an in vivo pharmacokinetic experiment at equal doses.

[0137] Specific methods:

[0138] Ten healthy male SD rats were randomly divided into two groups (n=5): experimental group 1 and experimental group 2. Each group was given the drug at the same time, and blood was collected from the orbital venous plexus at the preset time points of 0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 120h, 144h, and 168h using EP tubes moistened with sodium heparin. The blood was immediately centrifuged at 6000rmp and 4°C for 5min to obtain 100μL of upper plasma. The blood was refrigerated at -40°C for later use.

[0139] Group 1 Group 2 Bupivacaine concentration (w / v) 5％ 1.33％ Meloxicam concentration (w / v) 0.15％ / <![CDATA[E80:H20(w / w)]]> 50 / 50 / Bupivacaine dosage 13mg 13mg Meloxicam dosage 0.39mg /

[0140] The method for detecting drug concentration in plasma is the same as the specific method described in Experimental Example 1.

[0141] result:

[0142] Bupivacaine: Test results are as follows Figure 5 A, 5B. Compared with the commercially available bupivacaine multivesicular liposomes, the compound phospholipid gel has better sustained-release effect in the later stage, lower blood drug concentration in the initial stage of administration, and better preparation safety.

[0143] Experiment 6: Compound lecithin gel efficacy experiment

[0144] The preparation obtained by the method described in Example 1 was subjected to a comparative experiment on the efficacy with an equal amount of normal saline.

[0145] Specific methods:

[0146] 6.1 Modeling method:

[0147] Male SD rats weighing 250-300 g were anesthetized by intraperitoneal injection of tribromoethanol. The sole of the right foot of the rat was wiped with sterile alcohol or iodine to disinfect it. A 1 cm longitudinal incision was made on the skin and the underlying fascia 0.5 cm from the proximal edge of the heel with a No. 11 surgical blade. The flexor digitorum brevis muscle was gently separated from the surrounding tissue with blunt-tipped forceps, and the flexor digitorum brevis muscle from the heel to the toe was gently lifted with blunt-tipped forceps, and then a 1 cm longitudinal incision was made on it. The wound was sutured.

[0148] 6.2 Administration:

[0149] Due to the high viscosity of the preparation, a No. 21 injection tip was used to inject the preparation directly into the wound, which was then sutured.

[0150] Preparation group Normal saline group Bupivacaine concentration (w / v) 5％ / Meloxicam concentration (w / v) 0.15％ / Bupivacaine dosage 5.4mg / Meloxicam dosage 0.16mg /

[0151] 6.3 Mechanical withdrawal threshold (PWT) test method

[0152] Rats need 3-5 days to adapt to the new environment. When they are fully adapted, the basal value can be measured. If the basal value is stable for three consecutive days, the experiment can be started.

[0153] During the test, the rats were placed in a separate transparent compartment with a metal mesh floor at the bottom, with enough space at the bottom to touch the soles of the rats' feet. The rats were placed in the transparent compartment 30 minutes before the test, and the test began when they were calm and no longer moved around and lifted their feet at will. During the evaluation period, the electronic pain meter probe was used to vertically stimulate the soles of the rats with continuous force. If the rats had a withdrawal reaction within 5 seconds, it was recorded as a positive reaction, and the pain threshold value was recorded. The evaluation was repeated three times for each rat at an interval of 1 minute, and the average value was taken. The final average value was recorded as the mechanical withdrawal threshold (PWT) of the rats. After surgery, this method was used for continuous measurement for 6-7 days.

[0154] Results: Figure 6 As shown, the group that received the compound phospholipid gel in the surgical incision had a significant difference compared with the control group that received only saline.

[0155] Experiment 7: Efficacy of phospholipid gels with different prescriptions

[0156] The preparations obtained by the methods described in Example 2 and Example 3 were compared with normal saline in equal doses for efficacy comparison experiments.

[0157]

[0158]

[0159] Specific method: Same as the specific method described in Experiment 6

[0160] Results: Figure 7 As shown, the two preparation groups of composite phospholipid gel administered to the surgical incision had significant differences three days after surgery compared with the control group administered only with normal saline; there was no significant difference between the two preparation groups.

[0161] Experiment 8 Comparison of the efficacy of compound phospholipid gel and commercially available bupivacaine multivesicular liposomes

[0162] The preparation obtained by the method described in Example 1 was subjected to a comparative experiment on the efficacy of the same dose of commercially available bupivacaine multivesicular liposomes.

[0163] Preparation group Liposome group Normal saline group Bupivacaine concentration (w / v) 5％ 1.33％ / Meloxicam concentration (w / v) 0.15％ / / Bupivacaine dosage 6mg 6mg / Meloxicam dosage 0.18mg / /

[0164] Specific method: Same as that described in Experiment 6. Specific method results: Figure 8 As shown, the group that was administered with the compound phospholipid gel sustained-release preparation at the surgical incision and the control group that was administered with the commercially available preparation of bupivacaine multivesicular liposomes showed significant differences five days after surgery compared with the control group that was administered with normal saline; the compound phospholipid gel group and the bupivacaine multivesicular liposome group also showed significant differences in the first five days after surgery, and the compound phospholipid gel group had a significantly better analgesic effect.

[0165] Experiment 9 Comparison of the efficacy of compound phospholipid gel and single drug phospholipid gel

[0166] The compound phospholipid gel preparation obtained by the method described in Example 1 was subjected to a comparative experiment on the efficacy of the phospholipid gel preparation containing only bupivacaine or meloxicam at equal doses.

[0167]

[0168]

[0169] Specific method: Same as the specific method described in Experiment 6

[0170] Results: Fig. 9 As shown, the group that received the composite phospholipid gel preparation at the surgical incision had a significant difference in the first five days after surgery compared with the control group that received normal saline; the group that received the phospholipid gel preparation containing only bupivacaine or only meloxicam had a significant difference in the first two days after surgery compared with the control group that received normal saline; the group that received the phospholipid gel preparation containing only bupivacaine or only meloxicam had a significant difference in the first five days after surgery compared with the composite phospholipid gel preparation group, and the postoperative analgesic effect of the composite phospholipid gel was extremely significantly better than that of the single medication.

[0171] Experiment 10 Pharmacodynamics of compound phospholipid gel (ropivacaine)

[0172] The preparation obtained by the method described in Example 9 was subjected to a comparative experiment on the efficacy with an equal amount of normal saline.

[0173] Preparation group Normal saline group Ropivacaine concentration (w / v) 4％ / Meloxicam concentration (w / v) 0.09％ / Ropivacaine dosage 7.2mg / Meloxicam dosage 0.18mg 0.18ml

[0174] Specific method: Same as the specific method described in Experiment 6

[0175] like Fig.10 As shown, the group that received the compound phospholipid gel at the surgical incision had a significant difference five days after surgery compared with the control group that received only saline.

[0176] In summary, the compound phospholipid gel sustained-release preparation for postoperative analgesia prepared by the present invention not only has a small amount of auxiliary materials, a very simple preparation process, good drug stability, and good auxiliary material biocompatibility; and the preparation prepared by the present invention can significantly prolong the analgesic effect of postoperative pain; and enhance the analgesic intensity of a single analgesic; in addition, the sustained-release preparation prepared by the present invention also greatly increases the safety of medication; therefore, the preparation prepared by the present invention is expected to be used in large-scale industrial production for clinical use.

Claims

1. A compound phospholipid gel sustained-release preparation, characterized in that: Calculated by weight, the invention comprises 0.25 to 40 parts of local anesthetic, 0.0015 to 20 parts of nonsteroidal anti-inflammatory drugs, 20 to 70 parts of phospholipids, and 30 to 80 parts of injection water or saline solution.

2. According to the phospholipid gel sustained-release preparation of claim 1, the local anesthetic is selected from one or more of lidocaine, tetracaine, procaine, bupivacaine, levobupivacaine, ropivacaine or pharmaceutically acceptable salts thereof, preferably levobupivacaine hydrochloride and ropivacaine, and the weight percentage of the local anesthetic is preferably 0.25%-40%, more preferably 1%-15%.

3. The phospholipid gel sustained-release preparation according to claim 1, wherein The nonsteroidal anti-inflammatory drug is selected from acetylsalicylic acid, sodium salicylate, salsalate, benolate, diflunisal, acetaminophen, phenacetin, ibuprofen, flurbiprofen, ketoprofen, naproxen, indoprofen, fenoprofen, pirprofen, suprofen, butibufen, oxaprozin, tiaprofenic acid, ketorolac, indomethacin, benzydamine, acemetacin, sulindac, zidometacin, tolmetin sodium, diclofenac sodium, etodolac, nabumetone, fenbufen, meloxicam, piroxicam, sudoxicam One or more of oxaliplatin, isoxicam, tenoxicam, phenylbutazone, hydroxybutazone, sulfinpyrazone, γ-ketophenylbutazone, flufenamic acid, clofenamic acid, clonixin, celecoxib, rofecoxib, etoricoxib, and nimesulide, preferably meloxicam, piroxicam, sudoxicam, isoxicam, and tenoxicam, more preferably meloxicam, and the weight percentage of the non-steroidal anti-inflammatory drug is preferably 0.0015%-20%, preferably 0.0015%-10%, and more preferably 0.01-4.5%.

4. The phospholipid gel sustained-release preparation according to claim 1, wherein The phospholipids are selected from a combination of one or more of natural phospholipids, semi-synthetic phospholipids, and synthetic phospholipids. The natural lecithin is selected from one or more of egg yolk lecithin and soybean lecithin; the semi-synthetic phospholipids are preferably hydrogenated soybean lecithin; the synthetic phospholipids are selected from one or more of dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dimyristoylphosphatidylcholine, oleoylphosphatidylethanolamine, dipalmitoylphosphatidylglycerol, and dipalmitoylphosphatidic acid. Preferably, the phospholipids are preferably egg yolk lecithin and soybean lecithin, and the weight percentage of the phospholipids is preferably 20%-70%, more preferably 25%-65%.

5. According to any one of claims 1 to 4, the weight ratio of the local anesthetic to the non-steroidal anti-inflammatory drug is 1:0.01-60, preferably 1:0.025-1.0, and more preferably 1:0.03-0.

3.

6. The compound phospholipid gel sustained-release preparation according to any one of claims 1 to 4, characterized in that: The formulation does not contain any organic solvent.

7. The compound phospholipid gel sustained-release preparation according to any one of claims 1 to 4, characterized in that: The preparation also contains cholesterol in an amount of 0%-40% by weight, preferably 4%-30% by weight.

8. The method for preparing the compound phospholipid gel sustained-release preparation according to any one of claims 1 to 7, characterized in that: The following steps are involved: ⑴ Dissolve or suspend the drug in an appropriate amount of water for injection or saline solution to form a drug solution or drug suspension; (2) adding phospholipids to the drug solution or drug suspension; ⑶ Stirring until the preparation is a uniform milky white cream. Preferably, the stirring condition is stirring under sterile conditions at room temperature for 0.5-4h, preferably 1.5-2h; The salt solution in step (1) is selected from one or more of physiological saline, phosphate buffer and carbonate buffer.

9. Use of the composite phospholipid gel sustained-release preparation according to any one of claims 1 to 7 in the preparation of a drug for postoperative analgesia.

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