Intra-articular posteromedial landmark injection for lower limb pain relief

Abstract

Provided herein is a method for alleviating knee pain in a subject, the method comprising the steps of: selecting a needle entry site in the subject's leg; inserting the needle into the needle entry site; advancing the tip of the needle to an injection site; and administering a pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, and the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, causing the needle to advance 1 to 2 inches, thereby alleviating knee pain in the subject.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 470,231, filed on June 1, 2023, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Background The adductor canal block (ACB) has replaced the conventional femoral nerve block by targeting the terminal branches of the femoral nerve (i.e., the saphenous nerve and the nerve to the vastus medialis), in order to facilitate early postoperative walking without using quadriceps muscle strength. In total knee arthroplasty, the ACB is often combined with an additional block in the posterior capsule to provide posterior analgesia as well. These blocks are typically performed via ultrasound guidance by a regional anesthesiologist prior to surgery. However, the ultrasound - based technique may not be an achievable modality for all orthopedic practices. Therefore, additional block techniques are needed to better serve patients who require postoperative pain management of the lower extremities.

Summary of the Invention

Means for Solving the Problems

[0003] Summary Provided herein is a method for reducing knee pain in a subject, the method comprising: selecting an insertion site of an injection needle on the leg of the subject; inserting the injection needle into the needle insertion site; advancing the tip of the injection needle to an injection site; and administering a pharmaceutical composition at the injection site, wherein the needle insertion site is proximal to the adductor tubercle, the step of advancing the tip of the injection needle utilizes an angle of approximately 10 degrees to approximately 20 degrees medial to the axis of the femur and approximately 40 degrees to 75 degrees posterior to the femur, and the needle advances 1 inch to 2 inches, thereby reducing knee pain in the subject.

[0004] In some embodiments, the pharmaceutical composition comprises a polyvesicular liposome. In some embodiments, the polyvesicular liposome comprises bupivacaine or a salt thereof; phosphate; 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 plant sterols, wherein the polyvesicular liposome is prepared by a process comprising: a) preparing a first aqueous component comprising phosphate; 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 spheres; and e) removing the organic solvent from the solvent spheres to form a polyvesicular liposome encapsulating bupivacaine phosphate. In some embodiments, the injection needle is 1.5 inches long. In some embodiments, the tip of the injection needle advances a distance of about 1.5 inches along the angle. In some embodiments, the injection needle is an 18-gauge bevel needle. In some embodiments, the step of selecting the entry point includes palpating the adductor tubercle. In some embodiments, the entry point is about 1 cm from the adductor tubercle on the proximal edge of a nearby femoral condyle. In some embodiments, the administration step includes administering about 20 mL of the pharmaceutical composition in a single bolus. In some embodiments, the administration step includes administering about 20 mL of the pharmaceutical composition in a split bolus. In some embodiments, the split bolus comprises two boluses, each bolus administered without changing the position of the injection needle. In some embodiments, the split bolus includes administering about 10 mL of the pharmaceutical composition, followed by a rest period, followed by administering about 10 mL of the pharmaceutical composition. In some embodiments, the method further includes the step of performing a knee arthrotomy to expose the knee joint capsule prior to the step of selecting the insertion site for the injection needle.In some embodiments, the pharmaceutical composition spreads to affect two or more of the saphenous nerve, the superficial branch of the saphenous nerve, the nerve to the vastus medialis muscle, and the deep geniculate nerve. In some embodiments, the pharmaceutical composition spreads to affect three or more of the saphenous nerve, the superficial branch of the saphenous nerve, the nerve to the vastus medialis muscle, and the deep geniculate nerve. In some embodiments, the pharmaceutical composition spreads to affect the saphenous nerve, the superficial branch of the saphenous nerve, the nerve to the vastus medialis muscle, and the deep geniculate nerve. In some embodiments, less than 10% of the pharmaceutical composition is detectable in the adductor canal. In some embodiments, less than 10% of the pharmaceutical composition is detectable around the anterior femoral cutaneous nerve or the lateral femoral cutaneous nerve.

[0005] Provided herein is a method for treating postoperative knee pain in a subject, the method comprising the steps of: selecting a needle entry site in the subject's leg; inserting the needle into the needle entry site; advancing the tip of the needle to an injection site; and administering a pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, and the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advancing a distance of 1 to 2 inches along the angle, thereby treating postoperative knee pain in the subject.

[0006] Provided herein is a method for alleviating knee pain in a subject, the method comprising: selecting a needle entry site in the subject's leg; inserting the needle into the needle entry site; advancing the tip of the needle to an injection site; and administering a pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances a distance of approximately 1 to 2 inches along the angle, and the pharmaceutical composition comprises a) a polyvesicular liposome containing at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase containing bupivacaine phosphate, the aqueous phase being encapsulated within the polyvesicular liposome.

[0007] Provided herein is a method for treating postoperative knee pain in a subject, the method comprising: selecting a needle entry site in the subject's leg; inserting the needle into the needle entry site; advancing the tip of the needle to an injection site; and administering a pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances a distance of approximately 1 to 2 inches along the angle, and the pharmaceutical composition comprises a) a polyvesicular liposome containing at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase containing bupivacaine phosphate, the aqueous phase being encapsulated within the polyvesicular liposome.

[0008] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains. Methods and materials described herein for use in this invention may also be used, as may other suitable methods and materials known in the art. Materials, methods, and examples are illustrative and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references referenced herein are incorporated by reference in their entirety. In case of any conflict, including definitions, this specification shall prevail.

[0009] Other features and advantages of the present invention will become apparent from the following detailed description and figures, as well as from the claims. [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1 shows C-arm radiographic images and AP images illustrating needle insertion in the proximal adductor tubercle and posteromedial femur.

[0011] [Figure 2] Figure 2 is a lateral view of the C-arm radiograph showing needle insertion proximal to the adductor tubercle and posterior to the femur, needle angle, and spread of 20 mL of contrast agent.

[0012] [Figure 3] Figure 3 is a medial anatomical image of a cadaveric leg demonstrating the spread of the dye of the intra-articular posteromedial landmark injection described herein, with the sartorius muscle, vastus medialis muscle, infrapatellar saphenous nerve, and adductor magnus tendon labeled.

[0013] [Figure 4] Figure 4 is a posteromedial anatomical image of a cadaveric leg demonstrating the spread of the dye of the intra-articular posteromedial landmark injection described herein, with the semitendinosus tendon labeled. [Modes for carrying out the invention]

[0014] Detailed explanation Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. Methods and materials similar to those described herein may be used in the implementation or testing of this disclosure, but preferred methods and materials are described below. All publications, patent applications, patents, and other references referenced herein are incorporated in their entirety by reference. Furthermore, materials, methods, and examples are illustrative and not intended to be limiting.

[0015] As used herein, the terms “subject” and “patient” are interchangeable in relation to human subjects.

[0016] As used herein, the term “pain” means a physiological and / or psychological response or reaction to a stimulus that may result in tissue damage, injury, disease, or other condition. Types of pain include, but are not limited to, acute pain, chronic pain, heat pain, traumatic pain, chemical pain, inflammatory pain, ischemic pain, dull pain, sharp pain, tingling pain, visceral pain, and neuropathic pain.

[0017] As used herein, the term “knee pain” means any pain in the knee region associated with injury, procedure, or disease process. Examples of knee pain include pain associated with disease processes and inflammatory conditions, and pain associated with injury or trauma, such as fractures, dislocations, tears, and sprains, such as, but not limited to, anterior cruciate ligament (ACL) tears and meniscal tears, pain associated with structural abnormalities including osteophytes, cartilage damage, and bone marrow lesions, pain associated with degenerative knee conditions including osteoarthritis, and pain associated with surgery.

[0018] As used herein, the terms “about” or “approximately” in the context of numbers or ranges mean ±10% of the enumerated or claimed numbers or ranges, unless the context requires a more specific scope. Anatomical form of the knee

[0019] Currently, adductor canal block is replacing conventional femoral nerve block by targeting the terminal branches of the femoral nerve to facilitate early postoperative ambulation without using quadriceps muscle strength. The adductor canal (subsartorius canal or Hunter's canal) is a narrow fascial tunnel in the thigh, approximately 15 cm long. It is located in the deep to middle third of the sartorius muscle. The adductor canal provides an intermuscular passage through which the femoral blood vessels reach the popliteal fossa, where these vessels become the popliteal blood vessels. The adductor canal begins about 15 cm (about 6 inches) below the inguinal ligament, where the sartorius muscle crosses the adductor longus muscle. The adductor canal terminates in the adductor hiatus of the adductor magnus tendon. The saphenous nerve, and partially the obturator nerve, crosses the adductor canal. Adductor canal block should typically be performed under ultrasound guidance.

[0020] The intra-articular posteromedial landmark injection technique described herein is performed after medial parapatellar arthroplasty, where the adductor tubercle serves as a landmark to identify the needle entry point used in the intra-articular posteromedial landmark injection technique. The intra-articular posteromedial landmark injection technique described herein can be performed simply using consistent anatomical landmarks without ultrasound guidance. Therefore, in some implementations, the intra-articular posteromedial landmark injection technique described herein can be performed by a surgeon without the assistance of an anesthesiologist. Needle entry point

[0021] Provided herein are methods for selecting a needle entry point in a patient's leg to treat postoperative pain in the lower extremity. In some embodiments, the needle entry point is superior to the medial condyle of the medial femoral condyle in the flare, near the level of the adductor tubercle or most of the proximal part of the posterior femoral condyle. In some embodiments, the needle entry point is approximately fingertip-proximal to the adductor tubercle, for example, 1-2 cm proximal to the adductor tubercle. In some embodiments, the needle is slightly angled laterally but generally parallel to the medial edge of the femur. Characteristics of the needle

[0022] Provided herein is a method of administering an injectate to a patient using a needle. In some embodiments, the needle can be a Tuohy needle or a hypodermic needle. In some embodiments, the needle can be a 14-gauge, 15-gauge, 16-gauge, 17-gauge, 18-gauge, 19-gauge, 20-gauge, 21-gauge, 22-gauge, 23-gauge, or 24-gauge needle, for example, the needle can be an 18-gauge needle. In some embodiments, the needle can be 4 inches in length, 3.5 inches in length, 3 inches in length, 2.5 inches in length, 2 inches in length, 1.5 inches in length, or 1 inch in length, for example, 1.5 inches in length. Needle trajectory and injectate administration site

[0023] In some embodiments, the tip of the needle for an intra-articular posteromedial landmark injection advances from the needle entry point to the injectate administration site. The tip of the needle may be inserted at approximately 10 degrees to approximately 20 degrees medial to the axis of the femur, which includes, but is not limited to, approximately 11 degrees to approximately 19 degrees, approximately 12 degrees to approximately 18 degrees, approximately 13 degrees to approximately 17 degrees, or approximately 14 degrees to approximately 16 degrees medial to the axis of the femur, and also includes any angle therebetween. For example, the tip of the needle may be inserted at approximately 10 degrees, approximately 11 degrees, approximately 12 degrees, approximately 13 degrees, approximately 14 degrees, approximately 15 degrees, approximately 16 degrees, approximately 17 degrees, approximately 18 degrees, approximately 19 degrees, or approximately 20 degrees medial to the axis of the femur.

[0024] Furthermore, the tip of the needle may be inserted posteriorly to the femur at an angle of approximately 40 to 75 degrees, which includes, but is not limited to, any angle in between, approximately 40 to 70 degrees, approximately 40 to 65 degrees, approximately 40 to 60 degrees, approximately 40 to 55 degrees, approximately 40 to 50 degrees, approximately 45 to 75 degrees, approximately 50 to 75 degrees, approximately 55 to 75 degrees, approximately 60 to 75 degrees, approximately 65 to 75 degrees, approximately 70 to 75 degrees, approximately 45 to 70 degrees, approximately 45 to 65 degrees, approximately 50 to 60 degrees, and approximately 55 to 60 degrees. For example, the tip of the needle may be inserted posterior to the femur at an angle of approximately 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 degrees.

[0025] The injection depth can be approximately 1 inch to approximately 2.5 inches. For example, the injection depth can be approximately 1 inch, 1.1 inches, 1.2 inches, 1.3 inches, 1.4 inches, 1.5 inches, 1.6 inches, 1.7 inches, 1.8 inches, 1.9 inches, 2.0 inches, 2.1 inches, 2.2 inches, 2.3 inches, 2.4 inches, or 2.5 inches. In some implementations, the injection depth can be approximately 1.5 inches. Different combinations of the medial angle of the femoral axis, the posterior angle of the femoral axis, and the injection depth can be used in accordance with the disclosures herein. For example, the tip of the needle may be inserted at a relative angle of 20 degrees medial to the femoral axis and 45 degrees posterior to the femoral axis, and the needle advances to a depth of approximately 1.4 inches. As another example, the tip of the needle may be inserted at a relative angle of 10 degrees medial to the axis of the femur and 55 degrees posterior to the femur, and the needle will advance to a depth of approximately 1.5 inches. As yet another example, the tip of the needle may be inserted at a relative angle of 10 degrees medial to the axis of the femur and 70 degrees posterior to the femur, and the needle will advance to a depth of approximately 1.6 inches. Other combinations of the medial angle of the axis of the femur, the posterior angle of the femur, and the inch depth can be readily determined by those skilled in the art within the range of parameters provided above.

[0026] In some embodiments, during drug administration, the tip of the needle for the intra-articular posteromedial landmark injection is positioned in the subcutaneous space on the surface of the vastus medialis muscle. In some embodiments, during drug administration, the tip of the needle for the intra-articular posteromedial landmark injection is positioned proximal to the adductor tubercle within the joint and directed posteriorly and medially. In some embodiments, during drug administration, the tip of the needle for the intra-articular posteromedial landmark injection is approximately 1 centimeter posterior to the posterior femoral cortex, approximately 1 centimeter medial to the medial femoral cortex, and 1 centimeter proximal to the adductor tubercle. In some embodiments, during drug administration, the tip of the needle for the intra-articular posteromedial landmark injection is positioned at the uppermost part of the adductor tendon. In some embodiments, during drug administration, the tip of the needle for the intra-articular posteromedial landmark injection is positioned anterior to the adductor tendon.

[0027] In some embodiments, during drug administration, the tip of the needle for intra-articular posteromedial landmark injection is directed away from the blood vessels closely attached to the femur. During drug administration, the tip of the needle for intra-articular posteromedial landmark injection is not located within the muscle. Spread of injection using the method described herein

[0028] Provided herein is a method of intra-articular posteromedial landmark injection. The intra-articular posteromedial landmark injection described herein differs from adductor canal block in at least the following respects: The extent of the injection in an adductor canal block includes the adductor canal and reaches its distal end. The extent of the injection in an adductor canal block includes the saphenous nerve and the nerves to the vastus medialis muscle. The extent of the injection in an adductor canal block does not reach the infrapatellar branch of the saphenous nerve.

[0029] As determined by comparison with adductor canal block and by the cadaver studies described in the following examples, the intra-articular posteromedial landmark injection described herein has the spread described below. In some cases, the injection of the intra-articular posteromedial landmark injection spreads approximately 9.5 cm to approximately 15 cm proximal to the joint line, for example, approximately 11.5 or 12.5 cm. The spread of the dye of the intra-articular posteromedial landmark injection method described herein is considered to correspond to the spread of the medicinal anesthetic injection, and therefore, the nerves and structures identified as stained in the cadaver studies described herein are considered to be under anesthesia in living patients. Accordingly, when describing specific nerves and / or structures, technical terms such as “affect,” “affect,” or “anesthetize” describe the anesthetic effect of the method described herein. Those skilled in the art can measure whether a particular nerve is “affected” or “affected” by a physical examination or by using devices and / or techniques known in the art, such as peripheral nerve stimulators, to determine whether a particular nerve is affected by the method described herein.

[0030] The spread of the intra-articular posteromedial landmark injection may include the subcutaneous tissue surrounding the vastus medialis and sartorius muscles, including the space between the vastus medialis and the subcutaneous tissue, and the space between the vastus medialis and the adductor tendons. The spread of the intra-articular posteromedial landmark injection may include the adductor tendons and the hamstring tendons of the adductor magnus. The spread of the injection may include the adductor magnus tendon and the anterior part of the adductor magnus tendon. The spread of the injection may include the distal part of the infrapatellar branch of the saphenous nerve, including the superficial branch and posterior capsule of the saphenous nerve. The spread of the injection may include the nerve to the vastus medialis muscle. The spread of the injection may include from the posterior capsule of the knee to the lateral condyle of the femur (including the lateral condyle of the femur). The extent of the intra-articular posteromedial landmark injection may include the posterior region of the intermuscular fascial septum separating the anterior compartment from the medial compartment, and the extent may be located in the medial and posterior compartments of the knee, including the deep geniculate nerve. The extent of the intra-articular posteromedial landmark injection may include the space between the pes anserinus and bursa of Gerdy's tubercle of the tibia, and the extent may include the superior medial geniculate branch. The extent of the intra-articular posteromedial landmark injection may include the deep region of the semimembranosus tendon.

[0031] In some embodiments, the spread of the intra-articular posteromedial landmark injection may include spaces distal to the adductor canal, but not within the adductor canal. In some embodiments, the spread of the intra-articular posteromedial landmark injection is detectable in less than 30%, less than 20%, or less than 10% of the adductor canal. In some embodiments, the spread of the intra-articular posteromedial landmark injection does not reach between the vastus medialis and sartorius muscles; in alternative embodiments, the spread of the intra-articular posteromedial landmark injection is detectable in less than 30%, less than 20%, or less than 10% of the region between the vastus medialis and sartorius muscles. In some embodiments, the spread of the intra-articular posteromedial landmark injection does not reach the infrapatellar saphenous nerve, which may be located on the surface of the sartorius muscle; in alternative embodiments, the spread of the intra-articular posteromedial landmark injection is detectable in less than 30%, less than 20%, or less than 10% of the region of the infrapatellar saphenous nerve. In some embodiments, the spread of the injection does not reach the intermuscular walls and sartorius space; in alternative embodiments, the spread of the intra-articular posteromedial landmark injection is detectable in less than 30%, less than 20%, or less than 10% of the area of ​​the intermuscular walls and sartorius space. In some embodiments, the spread of the injection does not reach the semimembranosus tendon or the sciatic nerve in the popliteal region; in alternative embodiments, the spread of the intra-articular posteromedial landmark injection is detectable in less than 30%, less than 20%, or less than 10% of the semimembranosus tendon or the sciatic nerve in the popliteal region. In some embodiments, the spread of the injection does not reach the anterior femoral cutaneous nerve or the lateral femoral cutaneous nerve; in alternative embodiments, the spread of the intra-articular posteromedial landmark injection is detectable in less than 30%, less than 20%, or less than 10% of the anterior femoral cutaneous nerve or the lateral femoral cutaneous nerve. Pharmaceutical composition

[0032] Provided herein are analgesic pharmaceutical compositions. In some embodiments, the pharmaceutical compositions can be used for postoperative analgesia.

[0033] In some embodiments, the pharmaceutical composition comprises polyvesicular liposomes. A polyvesicular liposome (or "MVL," as used herein to refer to one or more polyvesicular liposomes) is a lipid vesicle having multiple non-concentric internal aqueous chambers, each having an internal membrane distributed as a network throughout the MVL. The chambers may contain an acid effective in enabling the encapsulation of bupivacaine or a salt thereof and modulating its release rate. Preparation of MVLs is described, for example, in Kim et al., Biochim. Biophys. Acta 728, 339-348, 1983. In some embodiments, the MVL is prepared according to the process described in U.S. Patent No. 9,192,575, which is incorporated herein by reference in its entirety. In some embodiments, the MVL is prepared according to the process described in U.S. Patent No. 8,182,835, which is incorporated herein by reference in its entirety. In some embodiments, the MVL is prepared according to the process described in U.S. Patent No. 8,834,921, which is incorporated herein by reference in its entirety. In some embodiments, the MVL is prepared according to the process described in U.S. Patent No. 9,205,052, which is incorporated herein by reference in its entirety.

[0034] In some embodiments, multivesicular liposomes ("MVLs") are prepared by the following process: A "water in oil" emulsion containing a non-hydrohalogenated bupivacaine, such as bupivacaine phosphate, is formed from two immiscible phases: a lipid phase and a first aqueous phase. The lipid phase consists 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 with a net negative charge, those with a net positive charge, and zwitterionic lipids (which have no net charge at their isoelectric point). The term "neutral lipid" refers to an oil or fat that does not have vesicle-forming ability by itself and does not have a charged or hydrophilic "head" group. Examples of neutral lipids include, but are not limited to, glycerol esters, glycol esters, tocopherol esters, sterol esters, alkanes, and squalenes, which lack charged or hydrophilic "head" groups.

[0035] Amphiphilic lipids are selected from a broad range of lipids that have both hydrophobic and hydrophilic regions within the same molecule. Suitable amphiphilic lipids are zwitterionic phospholipids, including phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, lysophosphatidylcholine, and lysophosphatidylethanolamine. Anionic amphiphilic phospholipids, such as phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, phosphatidic acid, and cardiolipin, are also suitable. Cationic amphiphilic lipids, such as acyltrimethylammoniumpropane, diacyldimethylammoniumpropane, and stearylamine, are also suitable.

[0036] Suitable neutral lipids are triglycerides, propylene glycol esters, ethylene glycol esters, and squalene. Examples of useful triglycerides in this disclosure are triolein, tripalmitrain, trimylistrein, trilinolein, triptyline, tricaproin, tricapryline, and tricaprin. The fatty acid chains in the useful triglycerides in this disclosure may be all identical, all different, or not all identical (mixed chain triglycerides). Both saturated and unsaturated fatty acid chains are useful in this disclosure. Propylene glycol esters may be mixed diesters of caprylic and capric acid.

[0037] Many types of volatile organic solvents, including ethers, esters, halogenated ethers, hydrocarbons, halohydrocarbons, or Freon, can be used in this disclosure. For example, diethyl ether, chloroform, tetrahydrofuran, ethyl acetate, follene, and any combination thereof are suitable for use in preparing the compositions of this disclosure.

[0038] If necessary, other components may be included in the lipid phase. These may include cholesterol or plant sterols.

[0039] The first aqueous phase comprises bupivacaine or a salt thereof, e.g., bupivacaine phosphate, at least one polyhydroxycarboxylic acid, and at least one diprotic or triprotic mineral acid. In some embodiments, hydrochloric acid is also included. The diprotic or triprotic mineral acid includes sulfuric acid and phosphoric acid. Polyhydroxycarboxylic acids such as glucuronic acid, gluconic acid, and tartaric acid are also included in the first aqueous phase. The diprotic and triprotic mineral acids, as well as the polyhydroxy organic acids, are present in the first aqueous phase at concentrations 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 smaller amounts at concentrations of about 0.1 mM to about 50 mM, or preferably about 0.5 mM to about 25 mM.

[0040] The lipid phase and the first aqueous phase are mixed by mechanical turbulence, for example by using rotary or vibrating blades, shaking, baffled structures or extrusion through porous pipes, by ultrasound, or by nozzle spraying 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 production.

[0041] Then, the entire water-in-oil emulsion is dispersed in a second aqueous phase by the means described above, forming solvent spheres suspended in the second aqueous phase. The term "solvent spheres" refers to fine spherical droplets of the organic solvent, in which multiple smaller droplets of aqueous solution are suspended. The resulting solvent spheres thus contain multiple aqueous droplets in which bupivacaine or a salt thereof, such as bupivacaine phosphate, is dissolved. The second aqueous phase may contain additional components such as glucose and / or lysine.

[0042] Then, the volatile organic solvent is removed from the microspheres, for example, by surface evaporation from the suspension. When the solvent evaporates substantially or completely, the microspheres (MVLs) are 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 sparging, rotational evaporation, or the use of solvent-selective membranes.

[0043] In some embodiments, the MVL is prepared according to the process described in U.S. Patent No. 10,398,648, which is incorporated herein by reference in its entirety. In some embodiments, the MVL is prepared according to the process described in U.S. Patent No. 9,585,838, which is incorporated herein by reference in its entirety.

[0044] In some embodiments, the MVL is U.S. Patent Application Publication Nos. 2011-0250264, 2013-0306759, 2013-0177634, 2013-0177633, 2013-0177635, 2013-0195965, 2013-0177636, 2013-0183373, and These U.S. patent applications were prepared in accordance with the process described in U.S. Patent Nos. 2013-0177638, 2013-0177637, 2013-0183372, 2013-0183375, 2016-0361260, or 2018-0092847, and each of these U.S. patent application publications is incorporated herein by reference in its entirety.

[0045] In some embodiments, the MVL is prepared according to the process described in U.S. Patents No. 11,033,495; No. 11,179,336; No. 11,278,494; No. 11,304,904; No. 11,311,486; No. 11,357,727; No. 11,426,348; and No. 11,452,691, each of which is incorporated herein by reference in its entirety.

[0046] In some embodiments, the polyvesicular liposomes described herein may be used in combination with, in conjunction with, or together with other anesthetics or analgesics in an anesthetic or analgesic plan.

[0047] Examples of anesthetics that can be administered according to the methods described herein include, but are not limited to, propofol, etomidate, methhexital and thiopental sodium, midazolam, diazepam, as well as ketamine, benzocaine, chloroprocaine, cocaine, cyclomethicaine, dimethocaine, propoxycaine, procaine, propalacaine, tetracaine, alticaine, bupivacaine, calticaine, dibucaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, pipelocaine, prilocaine, ropivacaine, trimecaine, saxitoxin, and tetrodotoxin. Examples of amide anesthetics that can be administered according to the methods described herein include, but are not limited to, articaine, bupivacaine, calticaine, dibucaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, pipelocaine, prilocaine, ropivacaine, and trimecaine. In some embodiments, the polyvesicular liposomes contain bupivacaine, morphine, cytarabine, or pharmaceutically acceptable salts thereof as therapeutic agents. In some embodiments, the polyvesicular liposomes contain bupivacaine phosphate, morphine sulfate, or cytarabine HCl.

[0048] The term "therapeutably effective" relating to anesthetics or salts thereof present in the pharmaceutical compositions described herein means that the anesthetic present in the first aqueous phase within the polyvesicular liposome is released in a manner sufficient to achieve a specific level of anesthesia. The precise dosage will vary depending on the specific anesthetic and patient factors, such as age, sex, general condition, and patient size. Those skilled in the art can easily consider these factors and use them to establish an effective therapeutic concentration without relying on excessive experimentation.

[0049] 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 in multi-locular liposomes. The term “non-liposomal bupivacaine” encompasses compositions containing bupivacaine or a salt thereof that is not in liposomal form.

[0050] Examples of analgesics may include opioid and non-opioid analgesics. Non-limiting examples of opioid analgesics include hydrocodone, oxycodone, propoxyfen, or fentanyl, thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime, semicarbazone, or bis(methylcarbamate), oxycodone, pharmaceutically acceptable salts thereof, or thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime, semicarbazone, or bis-methylcarbamate. Non-limiting examples of non-opioid analgesics useful in the present invention include aspirin; acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs), aryl alkanates, profens, fenamic acid, oxicam, pyrazolidine derivatives; Cox-2 inhibitors, topical analgesics, antidepressants, atypical analgesics, psychotropic agents, NMDA receptor antagonists, α2-adrenergic receptor agonists, and synthetic drugs having narcotic properties.

[0051] Embodiments of the present disclosure also include compositions prepared for storage or administration, comprising 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 field of pharmaceuticals and are described, for example, in Remington's Pharmaceutical Sciences, Academic Press, (Adeboye Adejare, edit., 2020), which are incorporated herein by reference in their entirety.

[0052] A pharmaceutically effective dose is the dose required to prevent or inhibit the onset of a disease or to treat pain (alleviating symptoms to some extent, preferably all symptoms). Those skilled in the art will understand that the compositions and methods of this disclosure may be used to treat multiple types of pain, and that the effective dose may vary depending on the different types of pain. Types of pain include, but are not limited to, thermal pain, chemical pain, inflammatory pain, ischemic pain, traumatic pain, dull pain, sharp pain, tingling pain, 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 particular mammal under consideration (including, but not limited to, age, physical condition, surgical or other medical procedure being performed, circulatory capacity, cardiovascular function, pain tolerance, neurological function, and hepatic function), concomitant medications, and other factors recognized by those skilled in the art in the medical field.

[0053] In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of bupivacaine phosphate. In some embodiments, the pharmaceutical composition contains bupivacaine phosphate in an amount equivalent to about 20 mg to about 300 mg of bupivacaine. In some embodiments, the pharmaceutical composition contains an amount equivalent to about 133 mg to about 266 mg of bupivacaine.

[0054] In some embodiments, the pharmaceutical composition contains an amount equivalent to about 10 mg to about 300 mg of bupivacaine. In some embodiments, the pharmaceutical composition contains an amount equivalent to about 133 mg to about 266 mg of bupivacaine. In some embodiments, the pharmaceutical composition contains an amount equivalent to about 10 mg to about 70 mg of bupivacaine. In some embodiments, the pharmaceutical composition contains an amount equivalent to about 20 mg to about 60 mg of bupivacaine. In some embodiments, the pharmaceutical composition contains an amount equivalent to about 20 mg to about 50 mg of bupivacaine. In some embodiments, the pharmaceutical composition contains an amount equivalent to about 20 mg to about 40 mg of bupivacaine. In some embodiments, the pharmaceutical composition contains an amount equivalent to about 20 mg to about 30 mg of bupivacaine. In some embodiments, the pharmaceutical composition contains an amount equivalent to about 30 mg to about 60 mg of bupivacaine. In some embodiments, the pharmaceutical composition contains an amount equivalent to about 30 mg to about 50 mg of bupivacaine. In some embodiments, the pharmaceutical composition contains an amount equivalent to about 30 mg to about 40 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to about 10 mg to about 70 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to about 10 mg to about 60 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to about 20 mg to about 60 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to about 20 mg to about 50 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to about 20 mg to about 40 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to about 20 mg to about 30 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to about 30 mg to about 60 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to about 30 mg to about 50 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to about 30 mg to about 40 mg of bupivacaine.

[0055] In some embodiments, the amount of the pharmaceutical composition described herein corresponds to 13.3 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to 26.6 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to 39.9 mg of bupivacaine. In some embodiments, the amount of the pharmaceutical composition described herein corresponds to 53.2 mg of bupivacaine. A method of administering an injectable substance to a patient's lower limbs.

[0056] The anesthetics of this disclosure may be delivered locally or regionally. “Local” or “regional” anesthesia, as used herein, is distinguished from general anesthesia and refers to an anesthetic procedure that allows for preferential delivery of an anesthetic to a specific area of ​​the body, such as near a nerve or nerve bundle. In contrast, general anesthesia allows for systemic administration of an anesthetic, for example, by intravenous administration. Local or regional anesthesia typically allows for a lower overall body concentration (although the local concentration increases) of the anesthetic administered to the subject for analgesia or reduction of pain sensation in at least a portion of the subject's body. Examples of local or regional anesthesia include intrathecal anesthesia, epidural anesthesia, and nerve blocks.

[0057] Provided herein is a method for administering an injectable substance, such as a pharmaceutical composition, to a patient's lower extremity. The injectable substance can be used in subjects who require it to treat pain, such as postoperative pain.

[0058] In some embodiments, an arthrotomy is performed to expose the knee joint capsule, the medial surface of the knee joint capsule is retracted, the adductor tubercle is palpated, and the injection needle is inserted immediately proximal to the adductor tubercle, for example, 1 cm proximal. The tip of the needle advances from the point of needle entry to the injection site. The advancement of the needle tip is typically along a plane 10 to 20 degrees medial to the axis of the femur and along a plane 40 to 70 degrees posterior to the femur, and the advancement of the needle tip is typically to a depth of 1 to 2 inches. In some embodiments, the needle advances until the hub of the needle touches or nearly touches the subject. Once the injection site is reached, the position of the needle tip can be confirmed as necessary by fluoroscopy, for example, live fluoroscopy. Once the needle tip has reached the injection site, the injection can be performed, which may be saline solution, sterile water, a pharmaceutical composition, or a combination thereof. The injection may include a single bolus injection or a divided bolus injection. The volume of the injection may be approximately 1 ml to approximately 40 ml, and this includes, but is not limited to, approximately 1 ml to approximately 35 ml, approximately 5 ml to approximately 35 ml, approximately 10 ml to approximately 40 ml, approximately 10 ml to approximately 35 ml, approximately 10 ml to approximately 30 ml, approximately 15 ml to approximately 40 ml, approximately 15 ml to approximately 35 ml, approximately 15 ml to approximately 30 ml, approximately 15 ml to approximately 25 ml, or approximately 15 ml to approximately 20 ml. The volume of the injection may be any specific amount between approximately 1 ml and approximately 40 ml, including approximately 1 ml, approximately 2 ml, approximately 3 ml, approximately 4 ml, approximately 5 ml, approximately 6 ml, approximately 7 ml, approximately 8 ml, approximately 9 ml, approximately 11 ml, approximately 12 ml, approximately 13 ml, approximately 14 ml, approximately 15 ml, approximately 16 ml, approximately 17 ml, approximately 18 ml, approximately 19 ml, approximately 20 ml, approximately 21 ml, approximately 22 ml, approximately 23 ml, approximately 24 ml, approximately 25 ml, approximately 26 ml, approximately 27 ml, approximately 28 ml, approximately 29 ml, approximately 30 ml, approximately 31 ml, approximately 32 ml, approximately 33 ml, approximately 34 ml, approximately 35 ml, approximately 36 ml, approximately 37 ml, approximately 38 ml, approximately 39 ml, or approximately 40 ml, or any partial volume therein.In some embodiments, the volume of the injection is 20 ml, and the injection can be administered as a single bolus or two boluses. In some embodiments, the volume of the delivered injection is expected to remain within the area described for intra-articular posteromedial landmark injection techniques.

[0059] The bolus spreads and affects the saphenous nerve, superficial saphenous nerve, nerve to the vastus medialis muscle, and deep geniculate nerve. The method described herein is not an adductor canal block and does not involve the adductor canal, but rather distal to the terminal adductor canal. The intra-articular posteromedial landmark injection technique described herein has several advantages. The intra-articular posteromedial landmark injection method described herein may be an efficient landmark that can serve as an alternative to ultrasound-guided adductor canal block, and surgeons may be able to deliver the intra-articular posteromedial landmark injection without the additional assistance of an anesthesiologist. Firstly, surgeon-guided intra-articular posteromedial landmark injections can be performed without ultrasound guidance, simplifying the implementation of the method. Furthermore, anesthesiologists often perform nerve blocks in a different room from where the surgery is performed, and with different hospital staff than those performing the surgery. Therefore, the intra-articular posteromedial landmark injection described herein can offer efficiency in that the hospital does not need to coordinate a location or staff for the intra-articular posteromedial landmark injection, as the intra-articular posteromedial landmark injection can be performed by surgical staff in the surgical operating room. The advantage of the novel intra-articular posteromedial landmark injection method described herein is that the surgeon can anesthetize both the nerves typically involved in adductor canal block (e.g., the saphenous nerve, the nerve to the vastus medialis, and the superficial saphenous nerve) and the posterior joint capsular nerves of the genu genu (e.g., the geniculate nerve) with a single injection (i.e., at one needle entry point, without the surgeon changing the needle angle or injection site during the injection). Thus, intra-articular posteromedial landmark injection is more efficient than other existing techniques because the person administering the injection does not need to place the needle at multiple needle entry points, nor does the person administering the injection need to change the needle position to deliver the injection to multiple injection sites.In some embodiments, the intra-articular posteromedial landmark injection method described herein can achieve sufficient analgesia without performing an "interspace between the popliteal artery and capsule of the posterior knee" (IPACK) procedure or other posterior capsule block. Furthermore, an additional advantage of the novel intra-articular posteromedial landmark injection technique described herein is that patients receiving the intra-articular posteromedial landmark injection method described herein do not experience quadriceps weakness. While we do not wish to be bound by theory, it is believed that the intra-articular posteromedial landmark injection described herein does not contribute to quadriceps weakness because the injectable (e.g., any of the anesthetic injectables described herein) does not enter and / or travel proximal through the adductor canal. An additional advantage of the intra-articular posteromedial landmark injection method disclosed herein is that this method / technique is reproducible across patients with different body mass index (BMI) and / or different leg circumferences.

[0060] The present disclosure relates to a pharmaceutical composition for use in a method of administering a pharmaceutical composition to a patient's leg for postoperative analgesia, the method comprising the steps of: selecting a needle entry site in the patient's leg; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, and the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the sagittal plane of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advancing a distance of 1 to 2 inches, and the pharmaceutical composition comprises a) a polyvesicular liposome comprising at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the polyvesicular liposome.This disclosure relates to a pharmaceutical composition for use in a method of administering the pharmaceutical composition to a patient's leg for postoperative analgesia, the method comprising the steps of: selecting a needle entry site in the patient's leg; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, and the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the sagittal plane of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances 1 to 2 inches, and the 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, The pharmaceutical composition also includes a multi-lobed liposome containing cholesterol and / or plant sterols, wherein the multi-lobed liposome is prepared by a process comprising: a) preparing a first aqueous component containing phosphate; b) preparing a lipid component containing 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 contains bupivacaine or a salt thereof; d) mixing the water-in-oil emulsion with a second aqueous component to form solvent spheres; and e) removing the organic solvent from the solvent spheres to form a multi-lobed liposome encapsulating bupivacaine phosphate.

[0061] Furthermore, the present disclosure relates to a pharmaceutical composition for use in a method for treating postoperative knee pain in a patient, the method comprising the steps of: selecting a needle entry site in the patient's leg; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the sagittal plane of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances a distance of 1 to 2 inches, and the pharmaceutical composition comprises a) a polyvesicular liposome containing at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase containing bupivacaine phosphate, the aqueous phase being encapsulated within the polyvesicular liposome.Furthermore, the present disclosure relates to a pharmaceutical composition for use in a method for treating postoperative knee pain in a patient, the method comprising the steps of: selecting an entry site for a needle in the patient's leg; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, and the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances a distance of 1 to 2 inches, and the 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, A pharmaceutical composition comprising a multi-lobed liposome containing resterol and / or plant sterol, wherein the multi-lobed liposome is prepared by a process comprising: a) preparing a first aqueous component containing phosphate; 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 spheres; and e) removing the organic solvent from the solvent spheres to form a multi-lobed liposome encapsulating bupivacaine phosphate.

[0062] Furthermore, the present disclosure relates to a pharmaceutical composition for use in a method of anesthetizing a subject requiring anesthesia after a knee procedure, the method comprising the steps of: selecting a needle entry site in the patient's leg; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances 1 to 2 inches, and the pharmaceutical composition comprises a) a polyvesicular liposome containing at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase containing bupivacaine phosphate, the aqueous phase being encapsulated within the polyvesicular liposome.This disclosure relates to a pharmaceutical composition for use in a method of anesthetizing a subject requiring anesthesia after a knee procedure, the method comprising the steps of: selecting a needle entry site in the patient's leg; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, and the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances a distance of 1 to 2 inches, and the 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, The pharmaceutical composition also includes a multi-lobed liposome containing cholesterol and / or plant sterols, wherein the multi-lobed liposome is prepared by a process comprising: a) preparing a first aqueous component containing phosphate; b) preparing a lipid component containing 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 contains bupivacaine or a salt thereof; d) mixing the water-in-oil emulsion with a second aqueous component to form solvent spheres; and e) removing the organic solvent from the solvent spheres to form a multi-lobed liposome encapsulating bupivacaine phosphate.

[0063] Furthermore, the present disclosure includes a pharmaceutical composition for use in a method for reducing knee pain in a subject, the method comprising: selecting a needle entry site in the patient's leg; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to an injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances 1 to 2 inches, and the pharmaceutical composition comprises a) a polyvesicular liposome containing at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase containing bupivacaine phosphate, the aqueous phase being encapsulated within the polyvesicular liposome.This disclosure relates to a pharmaceutical composition for use in a method for reducing knee pain in a subject, the method comprising the steps of: selecting an injection needle entry site in the patient's leg; inserting the injection needle into the patient at the needle entry site; advancing the tip of the injection needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, and the step of advancing the tip of the injection needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances 1 to 2 inches, and the 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 The pharmaceutical composition also includes a multi-lobed liposome containing a phosphate and / or plant sterols, wherein the multi-lobed liposome is 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 spheres; and e) removing the organic solvent from the solvent spheres to form a multi-lobed liposome encapsulating bupivacaine phosphate.

[0064] Furthermore, the present disclosure relates to a pharmaceutical composition for use in a method for reducing postoperative knee pain in a subject, the method comprising the steps of: selecting a needle entry site in the patient's leg; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances 1 to 2 inches, and the pharmaceutical composition comprises a) a polyvesicular liposome containing at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase containing bupivacaine phosphate, the aqueous phase being encapsulated within the polyvesicular liposome.This disclosure relates to a pharmaceutical composition for use in a method for reducing postoperative knee pain in a subject, the method comprising the steps of: selecting an insertion site for a needle in the patient's leg; inserting the needle into the patient at the needle insertion site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle insertion site is proximal to the adductor tubercle, and the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances 1 to 2 inches, and the 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 The pharmaceutical composition also includes a multi-lobed liposome containing a phosphate and / or plant sterol, wherein the multi-lobed liposome is prepared by a process comprising: a) preparing a first aqueous component containing phosphate; 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 spheres; and e) removing the organic solvent from the solvent spheres to form a multi-lobed liposome encapsulating bupivacaine phosphate.

[0065] Furthermore, the present disclosure includes a pharmaceutical composition for use in a method of anesthetizing the knee nerve, the method comprising the steps of: selecting a needle entry site in the leg of a patient; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances 1 to 2 inches, and the pharmaceutical composition comprises a) a polyvesicular liposome containing at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase containing bupivacaine phosphate, the aqueous phase being encapsulated within the polyvesicular liposome.This disclosure relates to a pharmaceutical composition for use in a method of anesthetizing the knee nerve, the method comprising the steps of: selecting an entry site for a needle in the leg of a patient; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, and the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances 1 to 2 inches, and the 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. The pharmaceutical composition also includes a multi-lobed liposome containing a and / or plant sterols, wherein the multi-lobed liposome is prepared by a process comprising: a) preparing a first aqueous component containing phosphate; b) preparing a lipid component containing 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 contains bupivacaine or a salt thereof; d) mixing the water-in-oil emulsion with a second aqueous component to form solvent spheres; and e) removing the organic solvent from the solvent spheres to form a multi-lobed liposome encapsulating bupivacaine phosphate.

[0066] Furthermore, the present disclosure relates to a pharmaceutical composition for use in a method of anesthetizing nerves to the saphenous nerve and the vastus medialis muscle, the method comprising the steps of: selecting a needle entry site in the leg of a patient; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, and the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advancing 1 to 2 inches, and the pharmaceutical composition comprises a) a polyvesicular liposome comprising at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the polyvesicular liposome.This disclosure relates to a pharmaceutical composition for use in a method of anesthetizing nerves to the saphenous nerve and vastus medialis muscle, the method comprising the steps of: selecting an entry site for a needle in the leg of a patient; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, and the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, and the needle advances 1 to 2 inches, and the 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 The pharmaceutical composition also includes a multi-lobed liposome containing terol and / or plant sterols, wherein the multi-lobed liposome is prepared by a process comprising: a) preparing a first aqueous component containing phosphate; 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 spheres; and e) removing the organic solvent from the solvent spheres to form a multi-lobed liposome encapsulating bupivacaine phosphate.

[0067] Furthermore, the present disclosure includes a pharmaceutical composition for use in a method of anesthetizing a lower limb, the method comprising the steps of: selecting a needle entry site in the leg of a patient; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to an injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances 1 to 2 inches, and the pharmaceutical composition comprises a) a polyvesicular liposome containing at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase containing bupivacaine phosphate, the aqueous phase being encapsulated within the polyvesicular liposome.This disclosure relates to a pharmaceutical composition for use in a method of anesthetizing a lower limb, the method comprising the steps of: selecting a needle entry site in the patient's leg; inserting the needle into the patient at the needle entry site; advancing the tip of the needle to the injection site; and administering the pharmaceutical composition at the injection site; wherein the needle entry site is proximal to the adductor tubercle, and the step of advancing the tip of the needle utilizes an angle of approximately 10 to 20 degrees medial to the axis of the femur and approximately 40 to 75 degrees posterior to the femur, the needle advances 1 to 2 inches, and the 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. The pharmaceutical composition also includes a multi-lobed liposome containing / or plant sterols, wherein the multi-lobed liposome is prepared by a process comprising: a) preparing a first aqueous component containing phosphate; b) preparing a lipid component containing 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 contains bupivacaine or a salt thereof; d) mixing the water-in-oil emulsion with a second aqueous component to form solvent spheres; and e) removing the organic solvent from the solvent spheres to form a multi-lobed liposome encapsulating bupivacaine phosphate. [Examples]

[0068] The present invention will be further illustrated by the following embodiments, which will not limit the scope of the invention as described in the claims. Example 1 Legs used for human cadaver experiments

[0069] The intra-articular posteromedial landmark injection techniques described herein were performed in April 2023 at the Pacira Innovation & Training Center on five human cadaver legs. The results of the five procedures are detailed below.

[0070] Leg 1: Specimen characteristics: 80-year-old male. Left leg. BMI = 24.37. Thigh circumference = 47.5 cm. An ultrasound-guided adductor canal (AC) block was performed with 20 mL of solution (sterile saline + green dye), targeting the saphenous nerve with 10 mL and the nerve to the vastus medialis (NVM) with 10 mL. After the ultrasound-guided AC block, an arthrotomy was performed to expose the knee joint capsule. After retracting the medial surface of the knee joint capsule, the adductor tubercle was palpated, and a 4-inch, 18-gauge Tuohy needle was inserted immediately proximal to the adductor tubercle at an angle of 20 degrees medial to the femoral axis and 30 degrees posterior to the femur, and the needle was advanced to the 6 cm mark. After confirming the needle position by fluoroscopy, 10 mL of the combined solution (sterile water, Omnipaque, and blue dye) was injected under live fluoroscopy. After inserting the needle and waiting a moment, another 10 mL of the same solution was injected under live fluoroscopy. The fluoroscopic image demonstrated the spread of the injected substance to a point 15 cm proximal to the joint line. Post-injection, blue pigmentation was observed on the medial surface of the thigh through the skin.

[0071] Upon dissection, the tip of the needle used for the intra-articular posteromedial landmark injection appeared to be in the subcutaneous space on the surface of the vastus medialis muscle. Blue staining from the intra-articular posteromedial landmark injection was not observed within the adductor canal. There was no blue staining between the vastus medialis and sartorius muscles; rather, staining was observed only in the subcutaneous tissue. Green staining from the ultrasound-guided adductor canal block was present within the adductor canal, staining the saphenous nerve approximately 7.5–9.5 cm below its total length, terminating in the femoral triangle, and also staining the nerve leading to the vastus medialis muscle. The infrapatellar saphenous nerve was found to be located on the surface of the sartorius muscle along its entire pathway and was not stained by either the green (ultrasound-guided adductor canal block) or blue (intra-articular posteromedial landmark injection as described herein) dyes.

[0072] Leg 2: Specimen characteristics: 81-year-old female. Left leg. BMI = 26.45. Thigh circumference = 47.5. An ultrasound-guided block of the anterior femoral cutaneous nerve (AFCN) was performed with 10 mL of solution (sterile water + green dye). After the AFCN block was completed, a left knee arthrotomy was performed to expose the knee joint capsule. The adductor tubercle was palpated from inside the knee joint capsule, and a 1.5-inch, 18-gauge subcutaneous needle was inserted immediately proximal to the adductor tubercle at an angle of 20 degrees medial to the femoral axis and 40 degrees posterior to the femur. The entire 1.5-inch needle was inserted. After confirming the needle position by fluoroscopy, 10 mL of the combined solution (sterile water, Omnipaque, and blue dye) was injected under live fluoroscopy. The needle was left in place, and after a breath, another 10 mL of the same solution was injected under live fluoroscopy. Fluorescent imaging demonstrated the spread of the injected substance 9.5 cm proximal to the joint line.

[0073] Upon dissection, deep blue staining was observed in the space between the vastus medialis muscle and the subcutaneous tissue, originating from an intra-articular posteromedial landmark injection. Blue staining was also observed in the hamstring tendons of the adductor tendons and adductor magnus, with some staining in the space between the vastus medialis and adductor tendons. Significant blue staining was observed in the distal portion of the infrapatellar branch of the saphenous nerve, as well as posteromedial staining of the posterior capsule. The AFCN branch and the infrapatellar saphenous nerve were observed to originate from a common trunk of the anterior segment of the femoral nerve, separate from the posterior segment and the main body of the saphenous nerve.

[0074] The sartorius muscle was dissected and traced to its distal attachment to the Gerdy's tubercle of the tibia in the pes anserinus. Blue staining was sufficiently limited to the space between the foot and the capsule, because the superior medial geniculate branch is covered by this technique. The tendon of the semimembranosus muscle was not stained, but the deep region of the semimembranosus tendon was sufficiently stained. There was no blue staining of the sciatic nerve in the popliteal region. The posterior capsule was stained with blue dye up to the lateral condyle.

[0075] There was no blue staining within the adductor canal, and the staining remained distal to the adductor canal. The green dye stained three branches of the AFCN, which were located deep within the subcutaneous tissue on the surface of the fascia lata.

[0076] Leg 3: Specimen characteristics: 73-year-old male. Right leg. BMI = 24.68. Thigh circumference = 49.5. Right knee arthrotomy was performed to expose the knee joint capsule. From inside the knee joint capsule, the adductor tubercle was palpated, and a 1.5-inch, 18-gauge subcutaneous injection needle was inserted 1 cm proximal to the adductor tubercle at a 10-degree angle medial to the femoral axis and 55-degree angle posteriorly, and the entire 1.5-inch length of the needle was advanced. After confirming the needle position by fluoroscopy, 10 mL of a combined solution (sterile water, Omnipaque, and blue dye) was injected under live fluoroscopy. The needle was left in place, and after a brief pause, another 10 mL of the same solution was injected under live fluoroscopy. Fluorescent imaging demonstrated the spread of the injected substance approximately 12.5 cm proximal to the joint line. Next, an ultrasound-guided adductor canal block was performed using a trans-sartorial technique, with 20 mL of a green dye solution (sterile water + green dye).

[0077] Upon dissection, blue staining from an intra-articular posteromedial landmark injection was observed between the vastus medialis and adductor tendons. Most of the blue staining was located posterior to the intermuscular fascial septum separating the anterior compartment from the medial compartment, and the dye was maintained in the medial and posterior compartments of the knee. Some blue staining was observed on the very distal surface of the adductor canal through a hiatus from the inferior edge of the adductor canal, converging with the diffusion of green staining from an ultrasound-guided adductor canal block maintained in the adductor canal.

[0078] Leg 4: Specimen characteristics: 83-year-old male. Left leg. BMI = 22.24. Thigh circumference = 39.0 cm. Right knee arthrotomy was performed to expose the knee joint capsule. The adductor tubercle was palpated from inside the knee joint capsule, and a 1.5-inch, 18-gauge subcutaneous needle was inserted 1 cm proximal to the adductor tubercle at an angle of 10 degrees medial to the femoral axis and approximately 30 degrees posteriorly, and the entire 1.5-inch length of the needle was advanced. After confirming the needle position by fluoroscopy, 20 mL of a combined solution (sterile water, Omnipaque, and blue dye) was injected under live fluoroscopy. Fluorescent imaging demonstrated the spread of the injected substance approximately 11.5 cm proximal to the joint line. Ultrasound-guided block was not performed in this specimen.

[0079] Dissection revealed that the infrapatellar branch of the saphenous nerve penetrated the sartorius muscle proximal to it and retained its surface. Blue staining from an intra-articular posteromedial landmark injection was observed between the vastus medialis and sartorius muscles. In this specimen, the blue staining did not extend beyond the intermuscular wall. The posterior capsule was not stained.

[0080] Leg 5: Specimen characteristics: 73-year-old male. Left leg. BMI = 24.68. Thigh circumference = 49.5. Left knee arthrotomy was performed to expose the left knee joint capsule. From inside the knee joint capsule, the adductor tubercle was palpated, and a 1.5-inch, 18-gauge subcutaneous injection needle was inserted approximately 10 degrees medial to the femoral axis and 70 degrees posteriorly just proximal to the adductor tubercle, and the entire 1.5-inch length of the needle was advanced. After confirming the needle position by fluoroscopy, 20 mL of a combined solution (sterile water, Omnipaque, and blue dye) was injected under live fluoroscopy. Ultrasound-guided block was not performed in this specimen. Autopsy identified the adductor magnus tendon, and blue dye staining was observed anterior to the adductor magnus tendon. Marked posterior capsule staining was observed. Blue dye staining was not observed in the intermuscular walls or sartorius space. Example 2 Summary of results from human cadaver experiments [Table 1-1] [Table 1-2] Other Embodiments

[0081] While the present invention has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to illustrate, and not to limit, the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. A method for reducing knee pain in a subject, wherein the method is a) The step of selecting the injection site for the needle in the subject's leg; b) The step of inserting the injection needle into the needle entry point; c) The step of advancing the tip of the injection needle to the injection site; d) The step of administering the pharmaceutical composition at the injection site. Including; The aforementioned needle entry point is proximal to the adductor tubercle, The step of advancing the tip of the injection needle utilizes an angle of approximately 10 to 20 degrees inward from the axis of the femur and approximately 40 to 75 degrees posterior to the femur, so that the needle advances 1 to 2 inches. A method to reduce knee pain in the subject.

2. The method according to claim 1, wherein the pharmaceutical composition comprises polyvesicular liposomes.

3. The aforementioned multivesicular liposomes Bupivacaine or its salts; Phosphate and; A lipid component comprising at least one amphiphilic lipid and at least one neutral lipid lacking a hydrophilic head group; If necessary, cholesterol and / or plant sterols Includes, The aforementioned multivesicular liposomes a) a step of preparing a first aqueous component containing phosphoric acid; b) The step of 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) A step of 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) The step of mixing the water-in-oil emulsion with a second aqueous component to form solvent spheres; e) The step of removing the organic solvent from the solvent spheres to form a multi-vesicular liposome containing bupivacaine phosphate. The method according to claim 2, manufactured by a process including the following:

4. The method according to claim 1, wherein the injection needle is 1.5 inches in length.

5. The method according to claim 4, wherein the tip of the injection needle advances a distance of about 1.5 inches along the angle.

6. The method according to claim 1, wherein the injection needle is an 18-gauge bevel needle.

7. The method according to claim 1, wherein the step of selecting an entry point includes palpating the adductor tubercle.

8. The method according to claim 7, wherein the point of entry is approximately 1 cm from the adductor tubercle at the proximal edge of a nearby femoral condyle.

9. The method according to claim 1, wherein the administration step includes administering about 20 mL of the pharmaceutical composition as a single bolus.

10. The method according to claim 1, wherein the administration step includes administering about 20 mL of the pharmaceutical composition in a divided bolus.

11. The method according to claim 10, wherein the divided bolus comprises two boluses, and each bolus is administered without changing the position of the injection needle.

12. The method according to claim 10, wherein the divided bolus comprises administering approximately 10 mL of the pharmaceutical composition, followed by a rest period, followed by the administration of approximately 10 mL of the pharmaceutical composition.

13. The method according to claim 1, further comprising the step of performing a knee joint dissection to expose the knee joint capsule prior to the step of selecting the insertion site of the injection needle.

14. The method according to claim 1, wherein the pharmaceutical composition spreads and affects two or more of the saphenous nerve, the superficial branch of the saphenous nerve, the nerve to the vastus medialis muscle, and the deep geniculate nerve.

15. The method according to claim 14, wherein the pharmaceutical composition spreads to affect three or more of the saphenous nerve, the superficial branch of the saphenous nerve, the nerve to the vastus medialis muscle, and the deep geniculate nerve.

16. The method according to claim 15, wherein the pharmaceutical composition spreads and affects the saphenous nerve, the superficial branch of the saphenous nerve, the nerve to the vastus medialis muscle, and the deep geniculate nerve.

17. The method according to claim 1, wherein less than 10% of the pharmaceutical composition is detectable by the adductor canal.

18. The method according to claim 1, wherein less than 10% of the pharmaceutical composition is detectable around the anterior femoral cutaneous nerve or the lateral femoral cutaneous nerve.

19. A method for treating postoperative knee pain in a subject, wherein the method is a) The step of selecting the injection site for the needle in the subject's leg; b) The step of inserting the injection needle into the needle entry point; c) The step of advancing the tip of the injection needle to the injection site; d) The step of administering the pharmaceutical composition at the injection site. Including; The aforementioned needle entry point is proximal to the adductor tubercle, The step of advancing the tip of the injection needle utilizes an angle of approximately 10 to 20 degrees inward from the axis of the femur and approximately 40 to 75 degrees posterior to the femur, so that the needle advances 1 to 2 inches. A method for treating postoperative knee pain in the subject.

20. The method according to claim 19, wherein the pharmaceutical composition comprises polyvesicular liposomes.

21. The aforementioned multivesicular liposomes Bupivacaine or its salts; Phosphate and; A lipid component comprising at least one amphiphilic lipid and at least one neutral lipid lacking a hydrophilic head group; If necessary, cholesterol and / or plant sterols Includes, The aforementioned multivesicular liposomes a) a step of preparing a first aqueous component containing phosphoric acid; b) The step of 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) A step of 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) The step of mixing the water-in-oil emulsion with a second aqueous component to form solvent spheres; e) The step of removing the organic solvent from the solvent spheres to form a multi-vesicular liposome containing bupivacaine phosphate. The method according to claim 20, manufactured by a process including the following:

22. The method according to claim 19, wherein the injection needle is 1.5 inches in length.

23. The method according to claim 22, wherein the tip of the injection needle advances a distance of about 1.5 inches along the angle.

24. The method according to claim 19, wherein the injection needle is an 18-gauge bevel needle.

25. The method according to claim 19, wherein the step of selecting an entry point includes palpating the adductor tubercle.

26. The method according to claim 25, wherein the point of entry is approximately 1 cm from the adductor tubercle at the proximal edge of a nearby femoral condyle.

27. The method according to claim 19, wherein the administration step includes administering about 20 mL of the pharmaceutical composition as a single bolus.

28. The method according to claim 19, wherein the administration step includes administering about 20 mL of the pharmaceutical composition in a divided bolus.

29. The method according to claim 28, wherein the divided bolus comprises two boluses, and each bolus is administered without changing the position of the injection needle.

30. The method according to claim 28, wherein the divided bolus comprises administering approximately 10 mL of the pharmaceutical composition, followed by a rest period, followed by the administration of approximately 10 mL of the pharmaceutical composition.

31. The method according to claim 19, further comprising the step of performing a knee joint dissection to expose the knee joint capsule prior to the step of selecting the insertion site of the injection needle.

32. The method according to claim 19, wherein the pharmaceutical composition spreads to affect two or more of the saphenous nerve, the superficial branch of the saphenous nerve, the nerve to the vastus medialis muscle, and the deep geniculate nerve.

33. The method according to claim 32, wherein the pharmaceutical composition spreads to affect three or more of the saphenous nerve, the superficial branch of the saphenous nerve, the nerve to the vastus medialis muscle, and the deep geniculate nerve.

34. The method according to claim 32, wherein the pharmaceutical composition spreads and affects the saphenous nerve, the superficial branch of the saphenous nerve, the nerve to the vastus medialis muscle, and the deep geniculate nerve.

35. The method according to claim 19, wherein less than 10% of the pharmaceutical composition is detectable in the adductor canal.

36. The method according to claim 19, wherein less than 10% of the pharmaceutical composition is detectable around the anterior femoral cutaneous nerve or the lateral femoral cutaneous nerve.

37. A method for reducing knee pain in a subject, wherein the method is a) The step of selecting the injection site for the needle in the subject's leg; b) The step of inserting the injection needle into the needle entry point; c) The step of advancing the tip of the injection needle to the injection site; d) The step of administering the pharmaceutical composition at the injection site. Including; The aforementioned needle entry point is proximal to the adductor tubercle, The step of advancing the tip of the injection needle utilizes an angle of approximately 10 to 20 degrees inward from the axis of the femur and approximately 40 to 75 degrees posterior to the femur, and the needle advances a distance of 1 to 2 inches along the angle. A method wherein the pharmaceutical composition comprises a) a polyvesicular liposome comprising at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the polyvesicular liposome.

38. A method for treating postoperative knee pain in a subject, wherein the method is a) The step of selecting the injection site for the needle in the subject's leg; b) The step of inserting the injection needle into the needle entry point; c) The step of advancing the tip of the injection needle to the injection site; d) The step of administering the pharmaceutical composition at the injection site. Including; The aforementioned needle entry point is proximal to the adductor tubercle, The step of advancing the tip of the injection needle utilizes an angle of approximately 10 to 20 degrees inward from the axis of the femur and approximately 40 to 75 degrees posterior to the femur, and the needle advances a distance of 1 to 2 inches along the angle. A method wherein the pharmaceutical composition comprises a) a polyvesicular liposome comprising at least one amphiphilic lipid and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the polyvesicular liposome.

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