Treatment of pain associated with total knee arthroplasty using sustained release liposome anesthetic compositions

Abstract

In some embodiments, provided herein is a method of administering an adductor tube block in a patient wherein the method comprises: (a) selecting an entry point of an injection needle in a leg of the patient; (b) inserting an injection needle into the entry point of the patient's leg; (c) identifying a first nerve of the patient's leg; (d) administering normal saline and a pharmaceutical composition to the first nerve; (e) identifying a second nerve of the patient's leg; (f) administering normal saline and the pharmaceutical composition to the second nerve; wherein the first nerve and the second nerve are selected from the group consisting of a medial femoral muscular nerve (NVM) and an implicit nerve, and wherein the first nerve is not the second nerve; and wherein the pharmaceutical composition comprises a multivesicular liposome.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 422,146, filed November 3, 2022, which is incorporated herein by reference in its entirety. Background Art

[0002] Postoperative pain is one of the most common forms of acute pain. It is a normal physiological response to tissue damage or trauma and has therapeutic value, serving as an early warning of danger or injury. Most acute pain is treatable or avoidable, especially in a clinical setting. However, if acute pain is not properly managed or treated in an inappropriate manner, it may develop into chronic pain. Therefore, effective postoperative pain control is a key factor in the patient's postoperative recovery, as most patients may experience severe pain, especially in the first few days after surgery. Improved postoperative pain management can help promote wound healing, accelerate patient activity, shorten hospital stays, and reduce medical costs.

[0003] Knee surgery, including knee replacement, is commonly used to treat knee pain and disability. However, total knee arthroplasty (TKA) is considered a painful orthopedic procedure, with more than half of patients undergoing TKA experiencing severe postoperative pain. Opioids are commonly used to treat postoperative orthopedic pain. Opioid use carries the risk of developing tolerance and dependence. Therefore, an important goal of postoperative treatment is to improve analgesia while reducing opioid consumption.

[0004] Professional societies recommend a multimodal pain management approach to improve analgesia, reduce opioid use, and decrease opioid-related adverse events (AEs) after knee surgery. Recommended regimens include long-acting neuraxial opioids along with scheduled acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). However, the majority of patients with orthopedic pain after cesarean delivery still require opioids for pain relief. Therefore, there remains a need for methods to treat pain associated with surgery, including knee surgery. Summary of the Invention

[0005] Provided herein is a method for administering a pharmaceutical composition for postoperative analgesia to the adductor canal of a patient, comprising: (a) selecting an entry point for an injection needle in the patient's leg using an ultrasonic transducer; (b) inserting an injection needle into the entry point in the patient; (c) identifying a first nerve in the patient's leg; (d) administering saline and a pharmaceutical composition to the first nerve; (e) identifying a second nerve in the patient's leg; (f) administering saline and a pharmaceutical composition to the second nerve; wherein the first nerve and the second nerve are selected from the group consisting of the nerve to the vastus medialis (NVM) and the saphenous nerve, and wherein the first nerve is not the second nerve; and wherein the pharmaceutical composition comprises multivesicular liposomes comprising: at least one amphiphilic lipid, at least one neutral lipid, and bupivacaine phosphate, wherein the bupivacaine phosphate is encapsulated in the multivesicular liposomes, thereby administering the pharmaceutical composition for postoperative analgesia to the patient's adductor canal.

[0006] Provided herein is a method for administering a pharmaceutical composition for postoperative analgesia to the adductor canal of a human patient, comprising: (a) selecting an entry point for an injection needle in the patient's leg using an ultrasonic transducer; (b) advancing the tip of the injection needle into an area between the vastus medialis and sartorius muscles of the patient along a trajectory extending from the entry point to the superficial femoral artery; (c) identifying a first nerve in the patient's leg; (d) administering saline and approximately 10 mL of the pharmaceutical composition to the first nerve through the injection needle; (e) identifying a second nerve in the patient's leg; (f) administering saline and approximately 10 mL of the pharmaceutical composition to the second nerve through the injection needle; wherein the first nerve and the second nerve are selected from the group consisting of the nerve to the vastus medialis (NVM) and the saphenous nerve, and wherein the first nerve is not the second nerve; and wherein the pharmaceutical composition comprises multivesicular liposomes comprising: at least one amphiphilic lipid, at least one neutral lipid, and bupivacaine phosphate, wherein the bupivacaine phosphate is encapsulated in the multivesicular liposomes, thereby administering the pharmaceutical composition for postoperative analgesia to the patient's adductor canal.

[0007] Provided herein is a method for treating postoperative knee pain in a patient, the method comprising: (a) selecting an entry point for an injection needle in the patient's leg; (b) inserting the injection needle into the entry point in the patient's leg; (c) identifying a first nerve in the patient's leg; (d) injecting saline and a pharmaceutical composition into the first nerve; (e) identifying a second nerve in the patient's leg; (f) injecting saline and the pharmaceutical composition into the second nerve; wherein the first nerve and the second nerve are selected from the group consisting of the nerve of the vastus medialis (NVM) and the saphenous nerve, and wherein the first nerve is not the second nerve; and wherein the pharmaceutical composition comprises multivesicular liposomes, the multivesicular liposomes comprising: at least one amphiphilic lipid, at least one neutral lipid, and bupivacaine phosphate, wherein the bupivacaine phosphate is encapsulated in the multivesicular liposomes, thereby treating the patient's postoperative knee pain.

[0008] Provided herein is a method for administering adductor canal block to a patient, comprising: (a) selecting an entry point for an injection needle in the patient's leg using an ultrasonic transducer, wherein the entry point includes a point on the superficial femoral artery located in the middle of the sartorius muscle; (b) advancing the tip of the injection needle along a trajectory extending from the entry point to the superficial femoral artery into the area between the vastus medialis and sartorius muscles of the patient; (c) identifying the patient's vastus medialis nerve (NVM); and (d) administering physiological saline and approximately 10 mL of a multivesicular liposome pharmaceutical composition to the vastus medialis nerve through the injection needle. (e) identifying the saphenous nerve, wherein identifying the saphenous nerve of the patient comprises penetrating the adductor femoris muscle membrane with a needle tip and advancing the needle tip to a position anterior to the superficial femoral artery; (f) administering physiological saline and about 10 mL of a multivesicular liposome pharmaceutical composition to the saphenous nerve through the injection needle; wherein the multivesicular liposome pharmaceutical composition comprises: bupivacaine or a salt thereof; phosphoric acid; a lipid component comprising at least one amphiphilic lipid and at least one neutral lipid lacking a hydrophilic head group; and, optionally, cholesterol and / or phytosterols, thereby administering adductor canal blockade to the patient.

[0009] In addition, in some embodiments, the injection needle is connected to a peripheral nerve stimulator (PNS). In some embodiments, the PNS is adjusted to 2 Hz and 0.5 to 1.0 mA. In some embodiments, the PNS is used to identify the first nerve and / or the second nerve. In some embodiments, the PNS is used to identify the first nerve and the second nerve. In some embodiments, the first nerve is the nerve of the vastus medialis (NVM) and the second nerve is the saphenous nerve. In some embodiments, identifying the entry point for the injection needle includes a point on the superficial femoral artery located in the middle of the sartorius muscle. In some embodiments, the injection needle is a 100 mm, 21 gauge needle. In some embodiments, the injection needle is insulated. In some embodiments, inserting the injection needle into the patient's leg includes advancing the needle tip into the area between the patient's vastus medialis and sartorius muscles along a trajectory extending from the entry point to the superficial femoral artery. In some embodiments, inserting the injection needle into the patient's leg does not include penetrating the adductor vastus membrane. In some embodiments, inserting the injection needle into the patient's leg includes penetrating the adductor vastus membrane with the needle tip and advancing the needle tip to a position in front of the superficial femoral artery. In some embodiments, the saline injection comprises no more than 1 to 2 mL of saline. In some embodiments, the syringe used for the saline injection is different from the syringe used for drug administration. In some embodiments, administering the pharmaceutical composition comprises administering about 10 mL of the pharmaceutical composition to each of the first and second nerves. In some embodiments, the method comprises administering a total of about 20 mL of the pharmaceutical composition. In some embodiments, the multivesicular liposomes comprise: bupivacaine or a salt thereof; phosphoric acid; a lipid component comprising at least one amphiphilic lipid and at least one neutral lipid lacking a hydrophilic head group; and, optionally, cholesterol and / or phytosterols, wherein the multivesicular liposomes are prepared by a process comprising: (a) preparing a first aqueous component comprising phosphoric acid; (b) preparing a lipid component comprising at least one organic solvent, at least one amphiphilic lipid, and at least one neutral lipid lacking a hydrophilic head group; (c) mixing the first aqueous component and the lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof; (d) mixing the water-in-oil emulsion with a second aqueous component to form solvent globules; and (e) removing the organic solvent from the solvent globules to form multivesicular liposomes encapsulating bupivacaine phosphate. In some embodiments, the method further comprises administering a local anesthetic in the space between the popliteal artery and the retropopliteal capsule. In some embodiments, the local anesthetic comprises bupivacaine hydrochloride. In some embodiments, the local anesthetic comprises 15 mL of 0.25% bupivacaine hydrochloride. In some embodiments, the local anesthetic is administered using a 100 mm insulated needle. In some embodiments, the space between the popliteal artery and the retropopliteal capsule is determined by ultrasound. In some embodiments, the administration of the local anesthetic comprises administering the local anesthetic anterior to the popliteal artery. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 Schematic diagram showing exemplary injection locations for femoral nerve block. Figure 2 Schematic diagram showing exemplary injection locations for adductor canal block. Figure 3 Table 1 is shown, summarizing the demographics of the participants in Clinical Trial #1. Figure 4 Table 2 is shown, summarizing the baseline characteristics of the participants in Clinical Trial #1. Figure 5 The timing and events of the study procedures (screening until POD 14) are shown. Figure 6 Table 3 is shown, summarizing the area under the curve for the numeric rating scale (NRS) pain intensity scores for participants in Clinical Trial #1 at 0-96 hours post-surgery. Figure 7 Table 4 is shown, summarizing the area under the curve for Numeric Rating Scale (NRS) pain intensity scores by time interval for participants in Clinical Trial #1. Figure 8 Table 5 is shown, summarizing total opioid consumption by time interval for participants in Clinical Trial #1. Figure 9 Table 6 is shown, summarizing the time to first postoperative opioid intake for participants in Clinical Trial #1. Figure 10 Table 7 is shown, summarizing the worst and average numeric rating scale pain intensity scores over the past 24 hours from postoperative days 1 to 14 for participants in Clinical Trial #1. Figure 11 Shown are pain intensity from hours 0 to 96 for participants treated with EXPAREL mixed with bupivacaine hydrochloride (HCl; circles) compared to bupivacaine HCl alone (plus signs) in Clinical Trial #1. Patients receiving EXPAREL reported pain relief starting approximately 18 hours after surgery. Figure 12 The mean bupivacaine concentrations over time are shown. In Clinical Trial #1, subjects receiving EXPAREL combined with bupivacaine hydrochloride showed early and late C 最大 , while the pharmacokinetic (PK) values of subjects receiving bupivacaine hydrochloride alone were only unimodal. Figure 13 Table 8 is shown, summarizing the pharmacokinetic (PK) parameters for EXPAREL Cocktail patients and bupivacaine HCl alone patients among the participants in Clinical Trial #1. Figure 14 Table 9 is shown, summarizing the onset and duration of motor and sensory blockade in patients treated with the EXPAREL mixture and patients treated with bupivacaine hydrochloride alone in Clinical Trial #1. Figure 15 Table 10 is shown, which is a summary of treatment-emergent adverse events in patients treated with EXPAREL mixture compared to patients treated with bupivacaine hydrochloride alone among participants in Clinical Trial #1. Figure 16 Table 11 is shown, summarizing treatment-emergent adverse events occurring in ≥5% of any cohort among participants in Clinical Trial #1. DETAILED DESCRIPTION

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Although methods and materials similar to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0011] As used herein, the term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that is to be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein to refer to a human subject.

[0012] As used herein, the term "pain" refers to the physiological and / or psychological reaction or response to a potential or actual stimulus that may result in tissue damage, trauma, disease, or other one or more conditions. Types of pain include, but are not limited to, acute pain, chronic pain, thermal pain, traumatic pain, chemical pain, inflammatory pain, ischemic pain, dull pain, sharp pain, stabbing pain, visceral pain, and neuropathic pain. Adductor canal / adductor canal block

[0013] In some embodiments, the method includes administering a pharmaceutical composition to the adductor canal. In some embodiments, the adductor canal can be described as a tapered musculoaponeurotic channel that passes through the distal portion of the mid-third of the thigh. In some embodiments, the adductor canal has three boundaries: the vastus medialis muscle constitutes the anterolateral boundary, the adductor longus and adductor magnus muscles constitute the posterolateral boundary, and the sartorius muscle constitutes the medial wall. The main structures passing through the adductor canal include the superficial femoral artery, femoral vein, and saphenous nerve. The adductor canal (also known as the subsartorial canal or Hunter's canal) is approximately 15 cm long and is a narrow fascial channel in the thigh. The adductor canal is located deep in the mid-third of the sartorius muscle. The adductor canal provides an intermuscular channel through which the femoral blood vessels pass through the popliteal fossa and merge into the popliteal vessels here. The adductor canal begins approximately 15 cm (approximately 6 inches) below the inguinal ligament, where the sartorius muscle crosses with the adductor longus muscle. The adductor canal terminates at the adductor hiatus within the tendon of the adductor magnus. The saphenous nerve and part of the obturator nerve pass through the adductor canal.

[0014] In some embodiments, administering the pharmaceutical composition to the adductor canal comprises administering an adductor canal block. In some embodiments, administering the pharmaceutical composition to the adductor canal can be an injection into the femoral triangle. In some embodiments, administering the pharmaceutical composition to the adductor canal comprises administering a "femoral triangle block." In some embodiments, the adductor canal block can be used to deliver sensory anesthesia for surgeries involving the distal thigh, femur, knee, and inner calf. In some embodiments, the adductor canal block can be used to deliver sensory anesthesia to the distal branches of the femoral nerve (including the saphenous nerve), as well as mixed sensory and motor nerve branches of the quadriceps femoris and branches of the obturator nerve. In some embodiments, administering the pharmaceutical composition to the adductor canal can be administering only a sensory nerve block, rather than a motor nerve block. In some embodiments, the adductor canal is located in the mid-third of the thigh. In some embodiments, the adductor canal is located below the location of the femoral nerve block. In some embodiments, the location of the adductor canal block is below the location of the femoral nerve block. In some embodiments, the location of the adductor canal block is distal to the location of the femoral nerve block. In some embodiments, the location of the adductor canal block is medial to the location of the femoral nerve block.

[0015] In some embodiments, the adductor canal can be located using body landmarks. In some embodiments, the adductor canal can be located using ultrasound guidance. In some embodiments, the adductor canal can be located using a combination of body landmarks and ultrasound guidance. In some embodiments, an adductor canal block preserves quadriceps strength better than a femoral nerve block. In some embodiments, an adductor canal block preserves mobility better than a femoral nerve block. In some embodiments, an adductor canal block reduces falls compared to a femoral nerve block. In some embodiments, an adductor canal block facilitates better postoperative recovery than a femoral nerve block. Femoral nerve / femoral nerve block

[0016] In some embodiments, administering a pharmaceutical composition to the adductor canal is not equivalent to administering a pharmaceutical composition to a femoral nerve block. In some embodiments, the methods of administering a pharmaceutical composition described herein (including those that administer a pharmaceutical composition to the adductor canal) do not administer a femoral nerve block. In some embodiments, the methods of administering a pharmaceutical composition described herein (including methods that administer a pharmaceutical composition to the adductor canal) do not include administering a femoral nerve block.

[0017] The anatomical location of the femoral nerve block can include identifying the inguinal ligament by drawing a line between the anterior superior iliac spine and the pubic symphysis. The femoral nerve passes through the center of this line and is most superficial at the level of the inguinal crease. In some embodiments, the location of the femoral nerve block is near the buttocks. In some embodiments, the location of the femoral nerve block is higher in the leg than the location of the adductor canal block. In some embodiments, the location of the femoral nerve block is higher than the location of the adductor canal block. In some embodiments, the location of the femoral nerve block is proximal to the location of the adductor canal block. In some embodiments, the location of the femoral nerve block is lateral to the location of the adductor canal block.

[0018] In some embodiments, the location of the femoral nerve block can be located using body landmarks. In some embodiments, the location of the femoral nerve block can be located using ultrasound guidance. In some embodiments, the location of the femoral nerve block can be located using a combination of body landmarks and ultrasound guidance. In some embodiments, the femoral nerve block causes a greater decrease in quadriceps muscle strength than the adductor canal block. In some embodiments, the femoral nerve block causes a greater degree of walking dysfunction than the adductor canal block. In some embodiments, the femoral nerve block causes more postoperative falls than the adductor canal block. In some embodiments, the femoral nerve block requires more rigorous postoperative rehabilitation than the adductor canal block. Pharmaceutical composition

[0019] Provided herein are analgesic pharmaceutical compositions. In some embodiments, the pharmaceutical compositions can be used for postoperative analgesia.

[0020] In some embodiments, the pharmaceutical composition comprises multivesicular liposomes. Multivesicular liposomes (or "MVLs," as used herein to refer to multivesicular liposomes or multiple multivesicular liposomes) are lipid vesicles with multiple non-concentric internal aqueous cavities having an inner membrane distributed throughout the MVL in a network. The chambers may contain acids that effectively encapsulate bupivacaine or a salt thereof and regulate its release rate. The preparation of MVL is described in, for example, Kim et al., Biochim.Biophys.Acta 728, 339-348, 1983. In some embodiments, MVL is prepared according to the method described in US9,192,575, which is incorporated herein by reference in its entirety. In some embodiments, MVL is prepared according to the method described in US8,182,835, which is incorporated herein by reference in its entirety. In some embodiments, MVL is prepared according to the method described in US8,834,921, which is incorporated herein by reference in its entirety. In some embodiments, MVL is prepared according to the method described in US 9,205,052, which is incorporated herein by reference in its entirety.

[0021] In some embodiments, multivesicular liposomes ("MVL") are prepared by the following method. A "water-in-oil" emulsion containing a non-hydrohalide salt of bupivacaine, such as bupivacaine phosphate, is formed by two immiscible phases: a lipid phase and a first aqueous phase. The lipid phase is made of at least one amphiphilic lipid and at least one neutral lipid in a volatile organic solvent. The term "amphiphilic lipid" refers to a molecule having a hydrophilic "head" group and a hydrophobic "tail" group, and may have membrane-forming ability. As used herein, amphiphilic lipids include those having a net negative charge, a net positive charge, and zwitterionic lipids (having no net charge at their isoelectric point). The term "neutral lipid" refers to an oil or fat that does not itself have vesicle-forming ability and lacks a charged or hydrophilic "head" group. Examples of neutral lipids include, but are not limited to, glycerides, glycol esters, tocopherol esters, sterol esters lacking a charged or hydrophilic "head" group, and alkanes and squalene.

[0022] Amphipathic lipids are selected from various lipids having a hydrophobic region and a hydrophilic region in the same molecule. Suitable amphipathic lipids are zwitterionic phospholipids, including phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, lysophosphatidylcholine, and lysophosphatidylethanolamine. Also suitable are anionic amphipathic phospholipids, such as phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, phosphatidic acid, and cardiolipin. Also suitable are cationic amphipathic lipids, such as acyltrimethylammonium propane, diacyldimethylammonium propane, and stearylamine.

[0023] Suitable neutral lipids are triglycerides, propylene glycol esters, ethylene glycol esters and squalene. Examples of triglycerides that can be used for the present disclosure are triolein, tripalmitolein, trimyristin, trilinolein, tributyrin, tricaproin, tricaprylin and tricaprin. The fatty chains that can be used for the triglycerides of the present disclosure can all be the same, or not completely the same (mixed chain triglycerides), including all different. Both saturated and unsaturated fatty chains can be used for the present disclosure. Propylene glycol ester can be a mixed diester of caprylic and capric acid.

[0024] Many types of volatile organic solvents can be used in the present disclosure, including ethers, esters, halogenated ethers, hydrocarbons, halogenated hydrocarbons or freons. For example, diethyl ether, chloroform, tetrahydrofuran, ethyl acetate, forane and any combination thereof are suitable for preparing the compositions of the present disclosure.

[0025] Optionally, other components are included in the lipid phase, including cholesterol or phytosterols.

[0026] The first aqueous phase includes bupivacaine or a salt thereof, such as bupivacaine phosphate, at least one polyhydroxy carboxylic acid, and at least one diprotic or triprotic inorganic acid. In some embodiments, hydrochloric acid is also included. Diprotic or triprotic inorganic acids include sulfuric acid and phosphoric acid. Polyhydroxy carboxylic acids, such as glucuronic acid, gluconic acid, and tartaric acid, are also included in the first aqueous phase. The diprotic and triprotic inorganic acids and polyhydroxy organic acids are present in the first aqueous phase at a concentration of 0.01 mM to about 0.5 M, or preferably about 5 mM to about 300 mM. When hydrochloric acid is used, it is present in lower amounts, about 0.1 mM to about 50 mM, or preferably about 0.5 mM to about 25 mM.

[0027] The lipid phase and the first aqueous phase are mixed by mechanical turbulence, such as by using rotating or vibrating blades, shaking, extrusion through a baffled structure or porous tube, by ultrasound, or by atomization through a nozzle, to produce a water-in-oil emulsion. Thus, bupivacaine or a salt thereof, such as bupivacaine phosphate, is directly encapsulated in the first step of MVL manufacturing.

[0028] The entire water-in-oil emulsion is then dispersed into a second aqueous phase using the method described above, forming solvent globules suspended in the second aqueous phase. The term "solvent globules" refers to microscopic, spherical droplets of organic solvent within which multiple smaller droplets of aqueous solution are suspended. Thus, the resulting solvent globules contain multiple droplets of aqueous phase in which bupivacaine or a salt thereof, such as bupivacaine phosphate, is dissolved. The second aqueous phase may contain other components, such as glucose and / or lysine.

[0029] The volatile organic solvent is then removed from the pellet, for example by surface evaporation from the suspension: when the solvent is substantially or completely evaporated, an MVL is formed. Gases that can be used for evaporation include nitrogen, argon, helium, oxygen, hydrogen, and carbon dioxide. Alternatively, the volatile solvent can be removed by spraying, rotary evaporation, or using a solvent-selective membrane.

[0030] In some embodiments, MVL is prepared according to the method described in US 10,398,648, which is incorporated herein by reference in its entirety. In some embodiments, MVL is prepared according to the method described in US 9,585,838, which is incorporated herein by reference in its entirety.

[0031] In some embodiments, MVL is prepared according to the methods described in U.S. published patent applications US2011-0250264, US2013-0306759, US2013-0177634, US2013-0177633, US2013-0177635, US2013-0195965, US2013-0177636, US2013-0183373, US2013-0177638, US2013-0177637, US2013-0183372, US2013-0183375, US2016-0361260, or US2018-0092847, each of which is incorporated herein by reference in its entirety.

[0032] In some embodiments, the pharmaceutical compositions described herein can be combined with, used in conjunction with, or used within an anesthetic or analgesic regimen with other anesthetics or analgesics.

[0033] Examples of anesthetics include, but are not limited to, propofol, etomidate, methohexital and thiopental sodium, midazolam, diazepam and ketamine, benzocaine, chloroprocaine, cocaine, cyclomethicaine, dimethocaine, propoxycaine, procaine, proparacaine, tetracaine, articaine, bupivacaine, carticaine, dibucaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimecaine, saxitoxin, and tetrodotoxin. Examples of amide anesthetics include, but are not limited to, articaine, bupivacaine, carticaine, dibucaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, piperocaine, prilocaine, ropivacaine, and trimecaine. In some embodiments, the multivesicular liposomes further comprise bupivacaine, morphine, cytarabine, or a pharmaceutically acceptable salt thereof as a therapeutic agent. In some embodiments, the multivesicular liposomes further comprise bupivacaine phosphate, morphine sulfate, or cytarabine hydrochloride.

[0034] The term "therapeutically effective," when referring to bupivacaine or a salt thereof, such as bupivacaine phosphate, present in the pharmaceutical compositions described herein, means that the anesthetic present in the first aqueous phase of the multivesicular liposomes is released in a manner sufficient to achieve a specific level of anesthesia. The exact dosage will vary depending on factors such as the specific anesthetic, as well as patient factors such as age, sex, general condition, and size. Those skilled in the art can readily take these factors into account and use them to establish effective therapeutic concentrations without undue experimentation.

[0035] As used herein, "non-liposomal bupivacaine" refers to bupivacaine or a salt thereof that is not in liposomal form. For example, "non-liposomal bupivacaine" refers to bupivacaine or a salt thereof that is not contained within multivesicular liposomes. The term "non-liposomal bupivacaine" encompasses compositions comprising bupivacaine or a salt thereof that is not in liposomal form.

[0036] Examples of analgesics include opioid analgesics and non-opioid analgesics. Non-limiting examples of opioid analgesics include hydrocodone, oxycodone, propoxyphene or fentanyl, thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime, thiosemicarbazone or bis(methylcarbamate), oxycodone, a pharmaceutically acceptable salt thereof, or thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime, thiosemicarbazone or bis(methylcarbamate). Non-limiting examples of non-opioid analgesics useful in the present invention include aspirin; acetaminophen; non-steroidal anti-inflammatory drugs (NSAIDs), arylalkanoic acids, profen, fenamic acid, oxicams, pyrazolidine derivatives; Cox-2 inhibitors, local analgesics, antidepressants, atypical analgesics, psychotropic drugs, NMDA receptor antagonists, α2-adrenergic receptor agonists, and synthetic drugs with anesthetic properties.

[0037] Embodiments of the present disclosure also include compositions prepared for storage or administration, which include a pharmaceutically effective amount of the desired compound in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, for example, as described in Remington's Pharmaceutical Sciences, Academic Press, (Adeboye Adejare edit, 2020), which are incorporated herein by reference in their entirety.

[0038] The pharmaceutically effective dose refers to the dose required for preventing, suppressing the occurrence of pain or treating / processing (relieving symptoms to a certain extent, preferably all symptoms) pain. It will be appreciated by those skilled in the art that the compositions and methods of the present invention can be used to treat various types of pain, and the effective doses of different types of pain may be different. The types of pain include, but are not limited to, thermal pain, chemical pain, inflammatory pain, ischemic pain, traumatic pain, dull pain, sharp pain, tingling and visceral pain. The pharmaceutically effective dose depends on the type of condition (e.g., pain), the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal being considered (including but not limited to age, physical condition, ongoing surgery or other medical procedures, circulatory capacity, cardiovascular function, pain tolerance, neurological function, liver function), the drugs taken simultaneously, and other factors that can be recognized by those skilled in the art of medicine. Giving Method

[0039] Provided herein are methods for administering adductor canal blockade. In some embodiments, the method comprises administering a pharmaceutical composition for postoperative analgesia to the adductor canal of a patient, comprising: (a) selecting an entry point for an injection needle in the patient's leg using an ultrasonic transducer; (b) inserting an injection needle into the entry point in the patient; (c) identifying a first nerve in the patient's leg; (d) administering saline and a pharmaceutical composition to the first nerve; (e) identifying a second nerve in the patient's leg; (f) administering saline and a pharmaceutical composition to the second nerve; wherein the first nerve and the second nerve are selected from the group consisting of the nerve to the vastus medialis (NVM) and the saphenous nerve, and wherein the first nerve is not the second nerve; and wherein the pharmaceutical composition comprises multivesicular liposomes comprising: at least one amphiphilic lipid, at least one neutral lipid, and bupivacaine phosphate, wherein the bupivacaine phosphate is encapsulated in the multivesicular liposomes, thereby administering the pharmaceutical composition for postoperative analgesia to the adductor canal of the patient.

[0040] In some embodiments, the method includes administering a pharmaceutical composition for postoperative analgesia to the adductor canal of a human patient, comprising: (a) selecting an entry point for an injection needle in the patient's leg using an ultrasonic transducer; (b) advancing the tip of the injection needle into an area between the vastus medialis and sartorius muscles of the patient along a trajectory extending from the entry point to the superficial femoral artery; (c) identifying a first nerve in the patient's leg; (d) administering saline and approximately 10 mL of the pharmaceutical composition to the first nerve through the injection needle; (e) identifying a second nerve in the patient's leg; (f) administering saline and approximately 10 mL of the pharmaceutical composition to the second nerve through the injection needle; wherein the first nerve and the second nerve are selected from the group consisting of the nerve of the vastus medialis (NVM) and the saphenous nerve, and wherein the first nerve is not the second nerve; and wherein the pharmaceutical composition comprises multivesicular liposomes, the multivesicular liposomes comprising: at least one amphiphilic lipid, at least one neutral lipid, and bupivacaine phosphate, wherein the bupivacaine phosphate is encapsulated in the multivesicular liposomes, thereby administering the pharmaceutical composition for postoperative analgesia to the patient's adductor canal.

[0041] In some embodiments, the method includes treating postoperative knee pain in a patient, comprising: (a) selecting an entry point for an injection needle in the patient's leg; (b) inserting the injection needle into the entry point in the patient's leg; (c) identifying a first nerve in the patient's leg; (d) injecting saline and a pharmaceutical composition into the first nerve; (e) identifying a second nerve in the patient's leg; (f) injecting saline and the pharmaceutical composition into the second nerve; wherein the first nerve and the second nerve are selected from the group consisting of the nerve to the vastus medialis (NVM) and the saphenous nerve, and wherein the first nerve is not the second nerve; and wherein the pharmaceutical composition comprises multivesicular liposomes, the multivesicular liposomes comprising: at least one amphiphilic lipid, at least one neutral lipid, and bupivacaine phosphate, wherein the bupivacaine phosphate is encapsulated in the multivesicular liposomes, thereby treating the patient's postoperative knee pain.

[0042] In some embodiments, the method comprises administering an adductor canal block to a patient, comprising: (a) selecting an entry point for an injection needle in the patient's leg using an ultrasonic transducer, wherein the entry point comprises a point on the superficial femoral artery located in the middle of the sartorius muscle; (b) advancing the tip of the injection needle along a trajectory extending from the entry point to the superficial femoral artery into an area between the vastus medialis and sartorius muscles of the patient; (c) identifying the patient's nerve to the vastus medialis (NVM); and (d) administering saline and approximately 10 mL of a multivesicular liposome drug to the vastus medialis nerve through the injection needle. (e) identifying the saphenous nerve of the patient, wherein identifying the saphenous nerve of the patient comprises penetrating the adductor femoris muscle membrane with a needle tip and advancing the needle tip to a position anterior to the superficial femoral artery; (f) administering physiological saline and about 10 mL of a multivesicular liposome pharmaceutical composition to the saphenous nerve through the injection needle; wherein the multivesicular liposome pharmaceutical composition comprises: bupivacaine or a salt thereof; phosphoric acid; a lipid component comprising at least one amphiphilic lipid and at least one neutral lipid lacking a hydrophilic head group; and, optionally, cholesterol and / or phytosterols, thereby administering adductor canal blockade to the patient.

[0043] Additionally, these methods can be used to treat knee pain associated with total knee replacement surgery, reduce postoperative pain in patients undergoing total knee replacement surgery, reduce the dose of opioid analgesics used by patients undergoing total knee replacement surgery, administer a pharmaceutical composition to the adductor canal of a patient, or administer a pharmaceutical composition to the adductor canal of a patient to manage postoperative pain associated with total knee replacement surgery. In some embodiments, the methods described herein for administering adductor canal block are described in In some embodiments, about 30 mg to 300 mg of the pharmaceutical composition is administered to the adductor canal, for example, about 133 mg or about 266 mg of the pharmaceutical composition is administered. Route of administration

[0044] Anesthetics of the present disclosure can be delivered regionally or locally. As used herein, "regional" or "local" anesthesia is different from general anesthesia and refers to an anesthetic procedure that allows anesthetics to be preferentially delivered to specific areas of the body (such as near a nerve or nerve bundle). The difference is that general anesthesia allows anesthetics to be administered systemically, for example, by intravenous administration. Regional or local anesthesia generally allows lower systemic concentrations (although the local concentration is higher) of anesthetics to be administered to the subject to achieve the purpose of analgesia or alleviating pain sensation in at least part of the subject's body. For example, intrathecal anesthesia, epidural anesthesia, and nerve blocks are all examples of regional or local anesthesia.

[0045] Pharmacological compositions can refer to compositions in a form suitable for administration (e.g., perineural administration) to a subject or proximal to at least one nerve in a subject (including, for example, wherein the subject is a human). Suitable form depends in part on the purpose or route of entry. Examples of routes of entry include, but are not limited to, injection (including, but not limited to, subcutaneous injection), single injection, continuous injection, indwelling catheter, and continuous infusion. Such routes of entry should not prevent the composition from reaching the target cells (i.e., neurons). For example, an injectable pharmacological composition should be soluble. Other factors are known in the art and include considerations such as toxicity and forms that prevent the composition or formulation from exerting its effect. Example Example 1 - Clinical Trial #1

[0046] A multicenter, randomized, double-blind clinical trial was conducted as follows to investigate the efficacy and safety of a pharmaceutical composition comprising: a) multivesicular liposomes disclosed herein and b) an aqueous phase disclosed herein, wherein the aqueous phase is encapsulated within the multivesicular liposomes. This pharmaceutical composition is hereinafter referred to as a "multivesicular liposome" pharmaceutical composition or "MVL."

[0047] This trial compared the postoperative analgesic effect of a single dose of MVL mixed with bupivacaine hydrochloride versus bupivacaine hydrochloride administered via adductor canal block in subjects undergoing primary unilateral total knee arthroplasty (TKA). Furthermore, the trial compared postoperative opioid consumption after a single dose of MVL mixed with bupivacaine hydrochloride versus bupivacaine hydrochloride. Furthermore, the trial compared the time to first postoperative opioid intake after a single dose of MVL mixed with bupivacaine hydrochloride versus bupivacaine hydrochloride. Furthermore, the trial characterized and compared the duration of sensory and motor blockade after a single dose of MVL mixed with bupivacaine hydrochloride versus bupivacaine hydrochloride. Furthermore, the trial evaluated the safety and PK profiles of MVL mixed with bupivacaine hydrochloride versus bupivacaine hydrochloride. Inclusion criteria

[0048] Subjects must meet the following criteria to be included in this study: 1. Male or female, 18 years of age or older at the time of screening. 2. Suitable for primary unilateral TKA under spinal anesthesia. 3. The main indication for TKA is degenerative osteoarthritis of the knee. 4. American Society of Anesthesiologists (ASA) physical status class 1, 2, or 3 (see protocol section 18.5 [section 16.1.1]). 5. Able to provide informed consent, adhere to the study plan, and complete all study assessments. 6. Body mass index ≥18 and <40 kg / m 2 . Exclusion criteria

[0049] Subjects meeting any of the following criteria will be excluded from the study: 1. Allergy, hypersensitivity, intolerance or contraindications to the study drug, and no alternative drugs are listed in the study protocol (e.g., amide local anesthetics, opioids, bupivacaine hydrochloride, nonsteroidal anti-inflammatory drugs [NSAIDs]). 2. Planned simultaneous surgeries (e.g., bilateral TKA). 3. Underwent unicompartmental TKA or revision TKA. 4. Concurrent painful medical conditions (e.g., arthritis, fibromyalgia, and cancer) that may require post-dose analgesia with NSAIDs or opioids, but such pain is not strictly related to knee surgery and, in the opinion of the investigators, may interfere with post-dose assessments. 5. Investigator-assessed sensory deficit below the knee. 6. History of contralateral TKA within 1 year. 7. Patients who have undergone open knee surgery and are being considered for TKA. Arthroscopy is permitted. 8. Have, be suspected of, or be known to be addicted to or abuse one or more illicit drugs, one or more prescription drugs, or alcohol in the past two years. 9. During the subject's participation in this study, the study drug has been administered within 30 days prior to administration of the study drug or within 5 elimination half-lives of the study drug (whichever is longer), or another investigational product or procedure is planned. 10. Previous participation in the EXPAREL study. 11. The investigator believes that the patient has uncontrollable anxiety, schizophrenia, or other psychiatric disorders that may interfere with study assessment or compliance. 12. Currently pregnant, breastfeeding, or planning to become pregnant during the study. 13. The researcher believes that the patient has a clinically significant medical disease that makes him or her unsuitable for participation in the clinical study, including diabetic neuropathy, coagulation or bleeding disorders, severe peripheral vascular disease, renal insufficiency, liver dysfunction, or other diseases that constitute contraindications to participation in the study. 14. Currently taking neuromodulators (e.g. gabapentin, pregabalin Duloxetine wait)]. 15. Systemic glucocorticoids are currently being used within 30 days before randomization in this study. 16. Use of dexmedetomidine hydrochloride within 3 days before taking study drugs Or clonidine. 17. Use of cannabis (including tetrahydrocannabinol and cannabidiol) within 30 days before randomization, or plan to use cannabis during the study. 18. Long-term use of opioids (average ≥30 OMED / day) within 30 days before randomization. method

[0050] This phase III, multicenter, randomized, double-blind, active-controlled study enrolled 167 subjects undergoing primary unilateral TKA under spinal anesthesia. The study was divided into two cohorts, which were enrolled simultaneously. Cohort 1 enrolled 46 subjects to obtain pharmacokinetic (PK) characteristics, pharmacodynamics (PD), efficacy, and safety information. Cohort 2 enrolled 121 subjects to obtain efficacy and safety information. This study used an adaptive study design, and an interim analysis was performed by an unblinded independent review committee to assess sample size assumptions and futility.

[0051] Participants began participating in the study after obtaining informed consent, which was obtained within 45 days before the administration of study medication. The screening process included an assessment of eligibility; recording of medical / surgical history, previous and concomitant medications (where relevant), demographic and baseline characteristics, and height and weight for calculation of body mass index (BMI); assessment of chronic opioid and any cannabis use (average ≥30 OMED per day) in the past 30 days; urine pregnancy test for women of childbearing potential (WOCBP); 12-lead electrocardiogram (EKG); and monitoring for adverse events (AEs) and serious adverse events (SAEs).

[0052] On the day of surgery, preoperatively, subjects in Cohorts 1 and 2 were randomly assigned in a 1:1 ratio to receive adductor canal blockade with a single dose of either 10 mL of EXPAREL (133 mg) mixed with 10 mL of 0.5% bupivacaine hydrochloride (50 mg; hereafter referred to as the EXP133-ADMIX group) or 10 mL of 0.5% bupivacaine hydrochloride (50 mg) mixed with 10 mL of normal saline (hereafter referred to as the BUP50 group). The total dose volume for all subjects was 20 mL.

[0053] Subjects may have received mild sedation with 1 to 2 mg of midazolam intravenously before the nerve block. Study medication was administered under ultrasound guidance 90 (±30) minutes before the procedure. A peripheral nerve stimulator was used to confirm nerve location within the adductor canal before study medication administration. During the nerve block (hydrodissection with saline injection and study medication administration), confirmatory ultrasound videos were obtained and needle placement was performed to ensure accurate block placement. Immediately after study medication administration, all subjects in Cohorts 1 and 2 underwent an infiltration injection (IPACK technique) of 15 mL of 0.25% bupivacaine hydrochloride (37.5 mg) between the popliteal artery and the posterior popliteal capsule under ultrasound guidance.

[0054] Treatment prior to study drug administration may include 200 mg of celecoxib orally within 4 hours before surgery. Other permitted prior medications and therapies include 1 to 2 mg of midazolam and / or ondansetron. Prior to study drug administration, restricted medications and therapies include systemic glucocorticoids and neuromodulators (e.g., gabapentin, pregabalin, and steroids). Duloxetine Long-acting or sustained-release opioids and NSAIDs (except low-dose acetylsalicylic acid for cardiovascular protection) should not be used within 3 days before the study drug is administered; dexmedetomidine hydrochloride should not be used within 3 days before the study drug is administered. or clonidine; scopolamine patches must not be used; opioids must not be used within 24 hours before study drug administration; no investigational product should be used within 30 days before study drug administration or within 5 elimination half-lives of the study drug (whichever is longer), and no planned administration of another investigational product or other procedures are allowed during the subject's participation in this study; no medication (except the bupivacaine hydrochloride mixture described) should be mixed with study drugs (e.g., epinephrine, dexamethasone, clonidine); lidocaine or other local anesthetics should not be administered topically to the area where nerve blocks are to be administered, except for needle insertion in superficial skin wheals.

[0055] Perioperative care may include an IPACK infusion (using the same settings as for nerve blocks) with 15 mL (37.5 mg) of 0.25% bupivacaine hydrochloride under ultrasound guidance immediately after study drug administration; spinal anesthesia with 0.5% bupivacaine hydrochloride (≥15 mg) immediately before surgery. If spinal anesthesia fails or cannot be completed, subjects may receive total intravenous anesthesia; 1000 mg of intravenous acetaminophen at the time of surgical incision; and propofol for induction and intraoperative sedation. Other permitted medications may include tranexamic acid. Restrictions include not mixing any other medications (including opioids) with bupivacaine for spinal anesthesia; not using dexamethasone, acetaminophen / paracetamol, ketorolac, or other nonsteroidal anti-inflammatory drugs preoperatively or intraoperatively except for emergency management of adverse events; and not using opioids (intravenous fentanyl, not exceeding 1 μg / kg, unless medically necessary) or ketamine intraoperatively.

[0056] Postoperative care may include a single postoperative dose of 1000 mg intravenous acetaminophen, given approximately 8 hours after the first dose (approximately 8 hours after incision), with a maximum total dose of 2000 mg; no further acetaminophen is allowed after the second intravenous acetaminophen. Other permitted medications may include ondansetron or metoclopramide, which can be used for postoperative nausea and vomiting. Restrictions on medication include not using any other analgesics, including fentanyl, within 96 hours after surgery; not using scopolamine patches; not using patient-controlled analgesia; and not using dexmedetomidine hydrochloride. Do not use lidocaine (unless used as a local anesthetic at the IV site) or other local anesthetics administered locally in the area of nerve block administration by POD 7; systemic corticosteroids and neuromodulators (e.g., gabapentin, pregabalin) should not be used. Duloxetine wait).

[0057] Before administering any medication for breakthrough pain within the first 96 hours after surgery, an unplanned pain intensity assessment using the NRS (measured as "On a scale of 0 to 10, where 0 represents no pain and 10 represents the worst possible pain, how severe is your pain in the operated knee right now?") should be performed immediately. Medication should be administered as needed; opioids should not be administered on a predetermined schedule. Immediate-release PO oxycodone may be administered in steps as follows: an initial dose of 5 mg oxycodone; if the initial opioid dose is insufficient for pain relief, an additional 5 mg of oxycodone may be provided, for a maximum total dose of 10 mg; if the patient cannot tolerate oral medications or oral oxycodone is inadequate for analgesia, intravenous morphine (starting dose of 2 mg) or hydromorphone (starting dose of 0.2 mg) may be administered. NSAIDs or other opioids, including tramadol, should not be used for breakthrough pain management. Acetaminophen (other than prescribed IV acetaminophen) should not be used for breakthrough pain management. Pain management during the first 96 hours after surgery is standardized. After 96 hours, the physician in charge of postoperative care can adjust the analgesia regimen for each subject as needed.

[0058] All postoperative analgesic use should be recorded until discharge.

[0059] Efficacy assessments included pain intensity scores focused on the operated knee using a numeric rating scale (NRS), total postoperative opioid consumption (OMED), time to first postoperative opioid intake, and subject satisfaction assessed using the International Pain Outcomes (IPO) In addition, blood samples were collected from subjects in Cohort 1 for PK analysis (area under the curve [AUC], maximum plasma concentration [Cmax], time to maximum plasma concentration [Tmax], including early and late Cmax and Tmax (EXP133-ADMIX group only), apparent terminal elimination half-life [t1 / 2el], apparent clearance [CL / F], and apparent volume of distribution [Vd / F]) as well as PD assessment data (sensory and motor block).

[0060] Safety assessments included monitoring of AEs (including SAEs and adverse events of special interest [AESIs]), vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation, and blood pressure), 12-lead EKG, and recording of concomitant medications.

[0061] The screening visit was conducted within 45 days before study drug administration, and the duration from study drug administration to the end of the study was 14 days after surgery (±3 days), at which time the last telephone follow-up was conducted. Therefore, the total duration of study participation for the subjects was up to 62 days. end

[0062] The primary endpoint was the AUC of the NRS pain intensity score from 0 to 96 hours after surgery.

[0063] Secondary efficacy end points included total postoperative opioid consumption in the OMED from 0 to 96 hours after surgery; time to first postoperative opioid ingestion; and worst and mean NRS pain intensity scores at 24, 48, 72, and 96 hours after surgery.

[0064] Exploratory efficacy endpoints included opioid-free status from 0 to 24, 48, 72, and 96 hours postoperatively; subject satisfaction measured by IPO at 96 hours postoperatively; the area under the curve (AUC) of the “average” pain score from POD1 to POD4; the area under the curve (AUC) of the “worst” pain score from POD1 to POD4; and the current pain intensity score from 0 to 96 hours postoperatively.

[0065] Safety endpoints included the incidence of treatment-emergent adverse events and SAEs from the start of the nerve block procedure to POD 14; changes in vital signs from baseline over time; and abnormal post-baseline EKG results.

[0066] Pharmacokinetic endpoints included the area under the plasma concentration versus time curve, specifically the time from the time of dosing to the last quantifiable concentration (AUC0-final) and the AUC from the time of dosing to infinity (AUC0-∞); maximum plasma concentration (Cmax) and time of maximum plasma concentration (Tmax) in subjects receiving bupivacaine hydrochloride; and determination of early and late Cmax and Tmax for subjects receiving EXPAREL mixed with bupivacaine hydrochloride (EXP133-ADMIX group); t1 / 2el; CL / F; and Vd / F.

[0067] Pharmacodynamic endpoints included: duration of sensory and motor blockade; onset of sensory and motor blockade; and resolution of sensory and motor blockade. Pharmacokinetic parameters Pharmacokinetic parameters Abbreviations: HCL = hydrochloric acid (salt); IPACK = instillation injection between the popliteal artery and retropopliteal capsule; LLOQ = lower limit of quantitation. 1 Calculations were performed only for the BUP50 group. 2 Calculations are performed only for the EXP133-ADMIX group. Statistical analysis

[0068] For continuous data, descriptive statistics (number of subjects, mean, standard deviation [SD], median, minimum, and maximum) are provided. For categorical data, tables are provided (number of subjects and percentages) by category. Unless otherwise stated, all confidence intervals (CIs) are two-sided with a 95% confidence level. All hypothesis testing was performed between the selected EXPAREL dose groups and the bupivacaine hydrochloride group. All statistical comparisons were one-sided with an alpha level of 0.025.

[0069] The AUC of the NRS pain intensity score from 0 to 96 hours after surgery was analyzed using an analysis of covariance (ANCOVA) model. The primary comparison indicator for evaluating treatment efficacy was the difference in the least squares mean AUC of the pain score between treatment groups.

[0070] Total opioid consumption (expressed as OMED) between 0 and 96 hours after surgery was analyzed using an ANCOVA model. Time to first postoperative opioid use was analyzed using Kaplan-Meier survival curves. Worst and mean NRS pain intensity scores were summarized by treatment group at 24, 48, 72, and 96 hours after surgery.

[0071] To control the overall type I error rate for multiple comparisons in the power analysis, statistical tests were performed in the following hierarchical order: 1. Primary endpoint (AUC of NRS pain from 0 to 96 hours after surgery). 2. The first secondary endpoint (total opioid dose from 0 to 96 hours after surgery). 3. Secondary endpoint (time to first postoperative opioid use). 4. The third secondary endpoint (the worst and mean NRS pain intensity scores 24, 48, 72 and 96 hours after surgery).

[0072] At any step, if a statistical test becomes nonsignificant, all subsequent tests are considered nonsignificant.

[0073] Adverse events and SAEs were recorded from the date of informed consent until day 14 after study entry. Adverse events were coded using the Medical Dictionary for Regulatory Activities, version 24.1, and summary tables were based on the Safety Analysis Set. All AEs were tabulated with subject data, including the reporting term, preferred term, system organ class, treatment-emergent adverse event marker, date of AE onset, AE start / end date and time, relationship to study drug, frequency of occurrence, severity, action taken for the subject, outcome, and severity criteria.

[0074] Baseline and pre-specified time points will include summary of vital signs and changes from baseline, including means, medians, and standard deviations. Screening and pre-specified time points will include summary of the frequency and percentage of EKG results (normal, abnormal / not clinically significant, abnormal / clinically significant).

[0075] An interim analysis was performed to assess sample-size assumptions and futility after a total of 80 subjects (40 in each group) had been enrolled in Cohort 1 or Cohort 2 and complete data for the primary efficacy outcome were available. result Efficacy

[0076] The mean AUC for NRS pain intensity scores was lower in the EXP133 ADMIX group compared with the BUP50 group from 0 to 96 hours postoperatively, with a LSM difference of -65.8 (95% CI = -118.7, -12.9; p = 0.0074). The mean AUC for NRS pain intensity scores was significantly lower in the EXP133 ADMIX group compared with the BUP50 group, especially within 24 hours postoperatively (LSM difference range = -55.9 to 10.0; p value ≤ 0.0404).

[0077] Total opioid consumption was lower in the EXP133 ADMIX group than in the BUP50 group at all intervals within the first 96 hours postoperatively, with LSM to bupivacaine ratios ranging from 0.72 to 0.83; this was particularly evident within the first 48 hours postoperatively (p ≤ 0.0201).

[0078] All participants received rescue opioids. The median time to first rescue medication use was 4.15 hours (95% CI = 3.80, 4.83) in the EXP133-ADMIX group and 3.63 hours (95% CI = 2.98, 4.05) in the BUP50 group, with a hazard ratio of 0.70 (95% CI = 0.51, 0.96; one-sided p-value = 0.0127; two-sided p-value = 0.0578).

[0079] On day 3, the mean worst pain intensity was significantly lower in the EXP133 ADMIX group than in the BUP50 group (LSM difference [SE] = -0.7 [0.34]; p = 0.0215). On days 2 and 3, the mean worst pain intensity was significantly lower in the EXP133 ADMIX group than in the BUP50 group (LSM difference [SE] 0.6 [0.28] and -0.5 [0.31], respectively; p values ≤ 0.0476).

[0080] From 0 to 24 hours, 1.2% of subjects in the EXP133-ADMIX group were opioid-free. No subjects were opioid-free at all other time intervals (0 to 48 / 72 / 96 hours post-surgery). No subjects in the BUP50 group were opioid-free at any time interval up to 96 hours post-surgery.

[0081] At 96 hours post-surgery, mean subject satisfaction was similar between the EXP133-ADMIX group (mean [SD] = 8.1 [2.47]) and the BUP50 group (mean [SD] = 8.1 [2.16]) (LSM difference [SE] = 0.0 [0.36]; p = 0.4608).

[0082] The mean AUCs for the worst pain and average pain within 24 hours after surgery (from POD 1 to POD 4) were significantly different between the EXP133ADMIX and BUP50 groups (p value ≤ 0.0270), with the values in the EXP133-ADMIX group being 6.09% and 8.97% lower, respectively.

[0083] Mean postoperative current pain intensity peaked at 24 hours postoperatively in both treatment groups and then gradually declined until 96 hours postoperatively. From 24 to 54 hours postoperatively, LSM in the EXP133-ADMIX group was significantly lower than that in the BUP50 group at all time points (p ≤ 0.0269).

[0084] In the EXP133-ADMIX group, mean pharmacokinetic peak concentrations were best described by early and late Cmax. The mean early Cmax was 467.04 ng / mL, occurring at a median of 0.63 hours after dosing; this was consistent with the results in the BUP50 group, which had a Cmax of 333.89 ng / mL and a median of 0.65 hours. The mean late Cmax in the EXP133 ADMIX group was 334.79 ng / mL, occurring at a median of 60.94 hours; in comparison, the mean bupivacaine concentration at 60 hours in the BUP50 group was 43.25 ng / mL.

[0085] The mean exposures, described by AUC0-final and AUC0-∞, were 25038.63 hours × ng / mL and 25109.09 hours × ng / mL in the EXP133-ADMIX group and 7283.31 hours × ng / mL and 7446.40 hours × ng / mL (3510.207), respectively, in the BUP50 group. The mean t1 / 2el, CL / F, and Vd / F values were similar between the two treatment groups.

[0086] • In both treatment groups, the majority of subjects (EXP133 ADMIX: 58.3%; BUP50: 71.4%) first experienced knee extension 8 hours after dosing.

[0087] The median duration of sensory block in the EXP133-ADMIX group (22.90 hours) was approximately twice that in the BUP50 group (11.63 hours). However, the difference in duration of sensory block compared to bupivacaine did not reach statistical significance (p-value ≥ 0.1222). At 30 minutes post-dose, ≥ 50% of subjects in each treatment group experienced sensory block. All subjects in the BUP50 group recovered normal sensory function within 24 hours of dosing, whereas none of the subjects in the EXP133-ADMIX group achieved this level of function within 144 hours of dosing. Security

[0088] No deaths occurred during the study, and the mixture of EXPAREL and bupivacaine hydrochloride was well tolerated by subjects.

[0089] The proportion of subjects experiencing ≥1 TEAE was similar across treatment groups (EXP133-ADMIX: 89.5%; BUP50: 88.8%). Overall, the most common TEAEs were nausea (38.6%), constipation (36.7%), muscle cramps (12.0%), and insomnia (10.8%). All other TEAEs occurred in <10% of subjects.

[0090] Five subjects (3.0%) experienced ≥1 TEAE related to study drug, including 3 in the EXP133ADMIX group and 2 in the BUP50 group. Related TEAEs included hypokalemia, hyponatremia, confusion, tachycardia, and muscle cramps (1 patient each), and procedural pain (2 patients).

[0091] Overall, TEAEs were mostly mild; 102 subjects (61.4%) experienced a mild TEAE of the highest severity, 43 subjects (25.9%) experienced a moderate TEAE, and 3 subjects (1.8%) experienced a severe TEAE. The proportion of subjects experiencing moderate and severe TEAEs was similar across treatment groups. Severe TEAEs included muscle spasms (three subjects) and pulmonary embolism (one subject).

[0092] • Four subjects (2.4%) experienced AESIs, including falls, postoperative hematoma, and dizziness (2 subjects).

[0093] Six (3.6%) subjects experienced ≥1 SAE, 3 in each treatment group. All SAEs were assessed as unrelated or unlikely to be related to study drug and included postoperative hematoma, pneumonia, acute myocardial infarction, atrial fibrillation, pulmonary embolism, and angioedema.

[0094] One subject in the BUP50 group withdrew from the study due to a SAE of acute myocardial infarction and atrial fibrillation.

[0095] Changes in vital signs were minimal, with values similar between the two groups. Systolic and diastolic blood pressures and heart rate all decreased slightly after surgery.

[0096] From screening to POD 7, the majority of subjects had normal or clinically insignificant scheduled EKG results; only three subjects (two in EXP133-ADMIX and one in BUP50) had clinically significant abnormal EKG results at either time point. Summary of Results and Conclusions

[0097] After surgery, subjects in the EXP133 ADMIX group experienced reduced pain intensity and lower total opioid consumption.

[0098] The median time to first rescue medication was significantly longer in the EXP133 ADMIX group compared to the BUP50 group (4.15 hours vs. 3.63 hours).

[0099] In the EXP133-ADMIX group, mean pharmacokinetic peak concentrations occurred at a median time of 0.63 hours and 60.94 hours, supporting longer-term pain control for patients receiving the study drug. In the BUP50 group, a single pharmacokinetic peak concentration occurred at a median time of 0.65 hours.

[0100] Peak bupivacaine concentrations in the EXP133-ADMIX and BUP50 groups correlated well with the recovery of motor and sensory function, suggesting that the combination of EXP133-ADMIX and bupivacaine hydrochloride provides superior analgesic efficacy compared to bupivacaine hydrochloride alone. All motor and sensory functions returned to normal within 168 hours of dosing in both treatment groups.

[0101] No deaths occurred during the study, and EXPAREL mixed with bupivacaine hydrochloride was well tolerated by the subjects.

[0102] The proportion of subjects experiencing ≥1 TEAE was similar across treatment groups (EXP133-ADMIX: 89.5%; BUP50: 88.8%). Five subjects (3.0%) experienced ≥1 TEAE related to study drug, including 3 in the EXP133-ADMIX group and 2 in the BUP50 group. Six subjects (3.6%) experienced ≥1 SAE, including 3 in each treatment group. Adverse events

[0103] An AE can be defined as any untoward medical occurrence associated with a person's use of a drug, regardless of whether it is considered drug-related. An adverse event (also known as an adverse experience) can be any unpleasant and unexpected sign (e.g., laboratory abnormality), symptom, or illness that is temporally associated with drug use and does not require a causal relationship. An AE may arise from any use of a drug (e.g., when used in combination with another drug not in accordance with label instructions) and from any route of administration, dosage form, or dose, including overdose.

[0104] An AE is any unfavorable and unexpected change in body structure or function. An adverse event includes any clinically significant worsening of a subject's medical condition. Adverse events may involve any organ or system and may be the appearance or worsening of a disease, syndrome, symptom, or sign, or the findings and results of instrumental and laboratory tests. After a subject signs the ICF, any medically relevant adverse change, including a change in the frequency or pattern of fluctuating illnesses (e.g., migraines), is considered an adverse event.

[0105] AEs occurring after administration of study treatment were considered treatment-emergent adverse events (TEAEs). Persistent AEs of varying severity were counted as one AE. The highest severity experienced by the subject during a persistent adverse event should be recorded.

[0106] In general, the severity of AEs can be classified according to the following principles:

[0107] Mild: An AE that is easily tolerated by the subject, causes minimal discomfort, and does not interfere with daily activities.

[0108] Moderate: AEs are uncomfortable and interfere with normal daily activities.

[0109] Severe: The AE interferes with normal daily activities.

[0110] The relationship between AEs and study drug is assessed on a case-by-case basis after careful medical consideration. The general principles are as follows:

[0111] Unrelated: A causal relationship between the study drug and the AE can be readily excluded (e.g., based on temporal sequencing, lack of a plausible pathophysiological mechanism, or direct evidence of an actual cause).

[0112] Unlikely: A clinical event with a temporal relationship to study drug administration that makes a causal relationship unlikely and for which other drugs, chemicals, or underlying disease provide a reasonable explanation.

[0113] Possible: A clinical event that is reasonably temporally related to the administration of study drug but could also be explained by concurrent illness or other drugs or chemicals.

[0114] Probable: Clinical events that occur in a reasonable time sequence after study drug administration and are unlikely to be attributable to intercurrent illness or other drugs or chemicals, and that have a clinically reasonable response after drug discontinuation (non-challenge).

[0115] Clear: The pharmacological properties of the study drug(s) or substance class(es), the course of the AE after cessation of challenge and, if applicable, after rechallenge, and / or specific testing indicate that the study drug(s) are related to the occurrence / exacerbation of the AE, and there is no indication of an alternative cause.

[0116] Based on a review of all peripheral nerve blocks, the following were considered adverse events of special interest (AESI) after review of AEs: ·fall Persistent stinging Persistent numbness Persistent weakness Hypersensitivity reactions ·epilepsy Tremor ·Dizziness Hematoma formation Cardiovascular depression Difficulty breathing Cardiovascular arrest Changes in sensory centers Visual impairment Local anesthesia systemic toxicity

[0117] An adverse event of special interest classified as persistent was any condition that lasted >168 hours from the time of onset (e.g., tingling, numbness, or sensory / motor weakness affecting the area of nerve block after study drug administration).

[0118] A serious adverse event (SAE) was defined as an AE or suspected adverse reaction that, in the opinion of the investigator or sponsor, resulted in any of the following:

[0119] Death: Any event resulting in the death of a subject is reported as a serious adverse event (SAE). However, death itself is not an AE; it is the outcome. The cause of death is the AE. Therefore, researchers should make every effort to obtain and record the cause of death for all subjects who die during the study. If, despite all efforts, the cause of death remains unknown, the adverse event should be recorded as "unspecified fatal event."

[0120] Life-threatening: An AE is considered life-threatening if the investigator or sponsor believes that the AE would put the subject at immediate risk of death. This does not include AEs that could result in death if they occurred in a more severe form.

[0121] Hospitalization or prolongation of an existing hospitalization: Hospitalization itself does not constitute an SAE. Only AEs that result in a subject's hospitalization are considered "serious" if they require hospitalization. Therefore, if a subject has a pre-planned hospitalization for a pre-existing condition that does not worsen during the study, an SAE should not be reported. However, any medical condition that delays a subject's discharge (i.e., prolongs their hospital stay) or requires a subject's readmission to the hospital should be reported as an SAE.

[0122] Persistent or severe incapacity: A person's ability to carry out normal life activities is severely disrupted.

[0123] Congenital Malformations / Birth Defects: If exposure to the study drug before or during pregnancy is suspected to cause adverse consequences to the child.

[0124] Medically significant: A significant medical event that does not result in death, is not life-threatening, or does not require hospitalization may be considered a serious event if, based on appropriate medical judgment, it could endanger the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

[0125] Any SAE or death occurring at any time between the time the subject signs the ICF and POD 14, regardless of whether it is related to study drug, should be reported within 24 hours of discovery.

Claims

1. A method for administering a pharmaceutical composition for postoperative analgesia to the adductor canal of a patient, the method comprising: a) Selecting the entry point of the injection needle in the patient's leg using an ultrasound transducer; b) inserting the injection needle into the patient's entry point; c) identifying a first nerve in the patient's leg; d) administering physiological saline and the pharmaceutical composition to the first nerve; e) identifying a second nerve in the patient's leg; (f) administering physiological saline and the pharmaceutical composition to the second nerve; wherein the first nerve and the second nerve are selected from the group consisting of the nerve of the vastus medialis (NVM) and the saphenous nerve, and wherein the first nerve is not the second nerve; and wherein the pharmaceutical composition comprises multivesicular liposomes, wherein the multivesicular liposomes comprise: at least one amphiphilic lipid, at least one neutral lipid, and bupivacaine phosphate, wherein the bupivacaine phosphate is encapsulated in the multivesicular liposomes, The pharmaceutical composition for postoperative analgesia is thereby administered to the adductor canal of the patient.

2. The method of claim 1, wherein the injection needle is connected to a peripheral nerve stimulator (PNS).

3. The method of claim 1, wherein the PNS is adjusted to 2 Hz and 0.5 to 1.0 mA. The method of claim 1 , wherein the PNS is used to identify the first nerve and / or the second nerve. The method of claim 1 , wherein the PNS is used to identify the first nerve and / or the second nerve.

6. The method of claim 1, wherein the first nerve is the nerve of the vastus medialis (NVM) and the second nerve is the saphenous nerve.

7. The method of claim 1, wherein identifying the entry point for the injection needle comprises a point of the superficial femoral artery located midway within the sartorius muscle.

8. The method of claim 1, wherein the injection needle is a 100 mm, 21 gauge needle.

9. The method of claim 1, wherein about 133 mg or about 266 mg of the pharmaceutical composition is administered.

10. The method of claim 1, wherein inserting the injection needle into the patient's leg comprises advancing the tip of the injection needle into the area between the patient's vastus medialis and sartorius muscles along a trajectory extending from the entry point to the superficial femoral artery.

11. The method of claim 1 , wherein inserting the injection needle into the patient's leg does not include penetrating the adductor vastus muscle membrane.

12. The method of claim 1, wherein inserting the injection needle into the patient's leg comprises penetrating the adductor femoris muscle membrane with the needle tip and advancing the needle tip to a position anterior to the superficial femoral artery.

13. The method of claim 1, wherein the saline injection comprises no more than 1 to 2 mL of saline.

14. The method of claim 1, wherein the syringe used for the saline injection is different from the syringe used for drug administration.

15. The method of claim 1, wherein administering the pharmaceutical composition comprises administering about 10 mL of the pharmaceutical composition to each of the first and second nerves.

16. The method of claim 1, wherein the method comprises administering a total of about 20 mL of the pharmaceutical composition.

17. The method of claim 1, wherein the multivesicular liposomes comprise: Bupivacaine or its salts; Phosphoric acid; a lipid component comprising at least one amphiphilic lipid and at least one neutral lipid lacking a hydrophilic head group; and, Optionally, cholesterol and / or phytosterols, The multivesicular liposomes are prepared by a process comprising: a) preparing a first aqueous component comprising phosphoric acid; b) preparing a lipid component comprising at least one organic solvent, at least one amphiphilic lipid, and at least one neutral lipid lacking a hydrophilic head group; c) mixing the first aqueous component and the lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof; d) mixing the water-in-oil emulsion with a second aqueous component to form solvent globules; and e) removing the organic solvent from the solvent beads to form multivesicular liposomes encapsulating bupivacaine phosphate.

18. The method of claim 1, further comprising administering a local anesthetic into the space between the popliteal artery and the retrogenicular capsule.

19. The method of claim 18, wherein the local anesthetic comprises bupivacaine hydrochloride.

20. The method of claim 18, wherein the local anesthetic comprises 15 mL of 0.25% bupivacaine hydrochloride.

21. The method of claim 18, wherein the local anesthetic is administered using a 100 mm insulated needle.

22. The method of claim 18, wherein the space between the popliteal artery and the retropopliteal capsule is determined by ultrasound.

23. The method of claim 18, wherein administering the local anesthetic comprises administering anterior to the popliteal artery.

24. A method of administering a pharmaceutical composition for postoperative analgesia to the adductor canal of a human patient, the method comprising: a) Selecting the entry point of the injection needle in the patient's leg using an ultrasound transducer; b) Advance the tip of the injection needle along a trajectory extending from the entry point to the superficial femoral artery into the area between the patient's vastus medialis and sartorius muscles; c) identifying a first nerve in the patient's leg; d) administering physiological saline and approximately 10 mL of the pharmaceutical composition to the first nerve through the injection needle; e) identifying a second nerve in the patient's leg; f) administering physiological saline and approximately 10 mL of the pharmaceutical composition to the second nerve through the injection needle; wherein the first nerve and the second nerve are selected from the group consisting of the nerve of the vastus medialis (NVM) and the saphenous nerve, and wherein the first nerve is not the second nerve; and wherein the pharmaceutical composition comprises multivesicular liposomes, wherein the multivesicular liposomes comprise: at least one amphiphilic lipid, at least one neutral lipid, and bupivacaine phosphate, wherein the bupivacaine phosphate is encapsulated in the multivesicular liposomes, The pharmaceutical composition for postoperative analgesia is thereby administered to the adductor canal of a human patient.

25. The method of claim 24, wherein the injection needle is connected to a peripheral nerve stimulator (PNS).

26. The method of claim 24, wherein the PNS is adjusted to 2 Hz and 0.5 to 1.0 mA.

27. The method of claim 24, wherein the PNS is used to identify a first nerve and / or a second nerve.

28. The method of claim 24, wherein the PNS is used to identify the first nerve and the second nerve.

29. The method of claim 24, wherein the first nerve is the nerve of the vastus medialis (NVM) and the second nerve is the saphenous nerve.

30. The method of claim 24, wherein the injection needle is a 100 mm, 21 gauge needle.

31. The method of claim 24, wherein about 133 mg or about 266 mg of the pharmaceutical composition is administered.

32. The method of claim 24, wherein advancing the tip of the injection needle into the area between the vastus medialis and sartorius muscles of the patient does not include penetrating the adductor vastus membrane.

33. The method of claim 24, wherein advancing the tip of the injection needle into the area between the vastus medialis and sartorius muscles of the patient comprises: The needle tip is passed through the adductor femoris muscle membrane and advanced to a position anterior to the superficial femoral artery.

34. The method of claim 24, wherein the saline injection comprises no more than 1 to 2 mL of saline.

35. The method of claim 24, wherein the syringe used for the saline injection is different from the syringe used for drug administration.

36. The method of claim 24, wherein the multivesicular liposomes comprise: Bupivacaine or its salts; Phosphoric acid; a lipid component comprising at least one amphiphilic lipid and at least one neutral lipid lacking a hydrophilic head group; and, Optionally, cholesterol and / or phytosterols, The multivesicular liposomes are prepared by a process comprising: a) preparing a first aqueous component comprising phosphoric acid; b) preparing a lipid component comprising at least one organic solvent, at least one amphiphilic lipid, and at least one neutral lipid lacking a hydrophilic head group; c) mixing the first aqueous component and the lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof; d) mixing the water-in-oil emulsion with a second aqueous component to form solvent globules; and e) removing the organic solvent from the solvent beads to form multivesicular liposomes encapsulating bupivacaine phosphate.

37. The method of claim 24, further comprising administering a local anesthetic into the space between the popliteal artery and the retropopliteal capsule.

38. The method of claim 37, wherein the local anesthetic comprises bupivacaine hydrochloride.

39. The method of claim 37, wherein the local anesthetic comprises 15 mL of 0.25% bupivacaine hydrochloride.

40. The method according to claim 37, wherein the local anesthetic is administered using a 100 mm insulated needle.

41. The method of claim 37, wherein the space between the popliteal artery and the retropopliteal capsule is determined by ultrasound.

42. The method of claim 37, wherein administering the local anesthetic comprises administering anterior to the popliteal artery.

43. A method for treating postoperative knee pain in a patient, the method comprising: a) Select the entry point for the injection needle in the patient's leg; b) inserting the injection needle into the patient's leg at the entry point; c) identifying a first nerve in the patient's leg; d) administering physiological saline and the pharmaceutical composition to the first nerve; e) identifying a second nerve in the patient's leg; (f) administering physiological saline and the pharmaceutical composition to the second nerve; wherein the first nerve and the second nerve are selected from the group consisting of the nerve of the vastus medialis (NVM) and the saphenous nerve, and wherein the first nerve is not the second nerve; and wherein the pharmaceutical composition comprises multivesicular liposomes, wherein the multivesicular liposomes comprise: at least one amphiphilic lipid, at least one neutral lipid, and bupivacaine phosphate, wherein the bupivacaine phosphate is encapsulated in the multivesicular liposomes, This treats postoperative knee pain in patients.

44. The method of claim 43, wherein the injection needle is connected to a peripheral nerve stimulator (PNS).

45. The method of claim 43, wherein the PNS is adjusted to 2 Hz and 0.5 to 1.0 mA.

46. The method of claim 43, wherein the PNS is used to identify a first nerve and / or a second nerve.

47. The method of claim 43, wherein the PNS is used to identify the first nerve and the second nerve.

48. The method of claim 43, wherein the first nerve is the nerve of the vastus medialis (NVM) and the second nerve is the saphenous nerve.

49. The method of claim 43, wherein identifying the entry point for the injection needle comprises a point of the superficial femoral artery located midway within the sartorius muscle.

50. The method of claim 43, wherein the injection needle is a 100 mm, 21 gauge needle.

51. The method of claim 43, wherein about 133 mg or about 266 mg of the pharmaceutical composition is administered.

52. The method of claim 43, wherein inserting the injection needle into the patient's leg comprises advancing the tip of the injection needle into the area between the patient's vastus medialis and sartorius muscles along a trajectory extending from the entry point to the superficial femoral artery.

53. The method of claim 43, wherein inserting the injection needle into the patient's leg does not include penetrating the adductor vastus muscle membrane.

54. The method of claim 43, wherein inserting the injection needle into the patient's leg comprises penetrating the adductor femoris muscle membrane with the needle tip and advancing the needle tip to a position anterior to the superficial femoral artery.

55. The method of claim 43, wherein the saline injection comprises no more than 1 to 2 mL of saline.

56. The method of claim 43, wherein the syringe used for the saline injection is different from the syringe used for drug administration.

57. The method of claim 43, wherein administering the pharmaceutical composition comprises administering about 10 mL of the pharmaceutical composition to each of the first and second nerves.

58. The method of claim 43, wherein the method comprises administering a total of about 20 mL of the pharmaceutical composition.

59. The method of claim 43, wherein the multivesicular liposomes comprise: Bupivacaine or its salts; Phosphoric acid; a lipid component comprising at least one amphiphilic lipid and at least one neutral lipid lacking a hydrophilic head group; and, Optionally, cholesterol and / or phytosterols, The multivesicular liposomes are prepared by a process comprising: a) preparing a first aqueous component comprising phosphoric acid; b) preparing a lipid component comprising at least one organic solvent, at least one amphiphilic lipid, and at least one neutral lipid lacking a hydrophilic head group; c) mixing the first aqueous component and the lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof; d) mixing the water-in-oil emulsion with a second aqueous component to form solvent globules; and e) removing the organic solvent from the solvent beads to form multivesicular liposomes encapsulating bupivacaine phosphate.

60. The method of claim 43, further comprising administering a local anesthetic into the space between the popliteal artery and the retropopliteal capsule.

61. The method of claim 60, wherein the local anesthetic comprises bupivacaine hydrochloride.

62. The method of claim 60, wherein the local anesthetic comprises 15 mL of 0.25% bupivacaine hydrochloride.

63. The method according to claim 60, wherein the local anesthetic is administered using a 100 mm insulated needle.

64. The method of claim 60, wherein the space between the popliteal artery and the retropopliteal capsule is determined by ultrasound.

65. The method of claim 60, wherein administering the local anesthetic comprises administering anterior to the popliteal artery.

66. A method of administering adductor canal block to a patient, the method comprising: a) selecting an entry point for an injection needle in the patient's leg using an ultrasound transducer, wherein the entry point includes a point on the superficial femoral artery located in the middle of the sartorius muscle; b) Advance the tip of the injection needle along a trajectory extending from the entry point to the superficial femoral artery into the area between the patient's vastus medialis and sartorius muscles; c) Identify the patient's nerve to the medial vastus musculus (NVM); d) administering physiological saline and about 10 mL of the multivesicular liposome pharmaceutical composition to the NVM through the injection needle; e) identifying the saphenous nerve, wherein identifying the patient's saphenous nerve comprises penetrating the adductor femoris muscle membrane with a needle tip and advancing the needle tip to a position anterior to the superficial femoral artery; f) administering physiological saline and about 10 mL of the multivesicular liposome pharmaceutical composition to the saphenous nerve through the injection needle; The multivesicular liposome pharmaceutical composition comprises: Bupivacaine or its salts; Phosphoric acid; a lipid component comprising at least one amphiphilic lipid and at least one neutral lipid lacking a hydrophilic head group; and, Optionally, cholesterol and / or phytosterols, The patient is then given an adductor canal block.

67. The method of claim 66, wherein the injection needle is connected to a peripheral nerve stimulator (PNS).

68. The method of claim 66, wherein the PNS is adjusted to 2 Hz and 0.5 to 1.0 mA.

69. The method of claim 66, wherein the PNS is used to identify a first nerve and / or a second nerve.

70. The method of claim 66, wherein the PNS is used to identify the first nerve and the second nerve.

71. The method of claim 66, wherein the injection needle is a 100 mm, 21 gauge needle.

72. The method of claim 66, wherein about 133 mg or about 266 mg of the pharmaceutical composition is administered.

73. The method of claim 66, wherein advancing the needle tip of the injection needle into the area between the vastus medialis and sartorius muscles of the patient does not include penetrating the adductor vastus membrane.

74. The method of claim 66, wherein advancing the tip of the injection needle into the area between the vastus medialis and sartorius muscles of the patient comprises: The needle tip is passed through the adductor femoris muscle membrane and advanced to a position anterior to the superficial femoral artery.

75. The method of claim 66, wherein the saline injection comprises no more than 1 to 2 mL of saline.

76. The method of claim 66, wherein the syringe used for the saline injection is different from the syringe used for drug administration.

77. The method of claim 66, wherein the multivesicular liposomes comprise: Bupivacaine or its salts; Phosphoric acid; a lipid component comprising at least one amphiphilic lipid and at least one neutral lipid lacking a hydrophilic head group; and, Optionally, cholesterol and / or phytosterols, The multivesicular liposomes are prepared by a process comprising: a) preparing a first aqueous component comprising phosphoric acid; b) preparing a lipid component comprising at least one organic solvent, at least one amphiphilic lipid, and at least one neutral lipid lacking a hydrophilic head group; c) mixing the first aqueous component and the lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof; d) mixing the water-in-oil emulsion with a second aqueous component to form solvent globules; and e) removing the organic solvent from the solvent beads to form multivesicular liposomes encapsulating bupivacaine phosphate.

78. The method of claim 66, further comprising administering a local anesthetic into the space between the popliteal artery and the retropopliteal capsule.

79. The method of claim 78, wherein the local anesthetic comprises bupivacaine hydrochloride.

80. The method of claim 78, wherein the local anesthetic comprises 15 mL of 0.25% bupivacaine hydrochloride.

81. The method of claim 78, wherein the local anesthetic is administered using a 100 mm insulated needle.

82. The method of claim 78, wherein the space between the popliteal artery and the retropopliteal capsule is determined by ultrasound.

83. The method of claim 78, wherein administering the local anesthetic comprises administering anterior to the popliteal artery.

84. The method of claim 78, wherein the local anesthetic comprises bupivacaine hydrochloride.

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