Local anesthetic emulsion

Abstract

An emulsion for pain relief comprising a local anesthetic, lecithin, an oil and an aqueous phase, wherein the local anesthetic is non-covalently bound to the emulsion oil droplets, the emulsion is physically and chemically stable, and the emulsion provides better safety, sustained pharmacokinetics and extended duration of action of the local anesthetic.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 169,121, filed March 31, 2021, and U.S. Patent Application No. 17 / 369,369, filed July 7, 2021, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] The present disclosure relates to pharmacologically active, safe, and long-acting local anesthetic-containing emulsions and uses thereof. [Background technology]

[0003] Local anesthetics (LAs), such as lidocaine, bupivacaine, prilocaine, levobupivacaine, and ropivacaine, are chemically related amide local anesthetics that share the same mechanism of action: slowing membrane depolarization and repolarization and resulting in membrane stabilization by inhibiting voltage-gated sodium channels (see Daniel E. Becker and Kenneth L. Reed, Local Anesthetics: Pharmacological Considerations, Anesth Prog 59:90,102 2012).

[0004] Local anesthetics have been shown to be effective and are widely used to prevent or reduce pain from minor surgery, incisions, biopsies, dental and obstetric procedures, and pain from wounds.

[0005] Local anesthetics are usually administered as a single injection at the lesion or incision site, and their anesthetic effect lasts for several hours due to their short half-life (up to about 4 hours). For longer-lasting effects, slow, continuous infusion into the affected tissue can be applied via epidural or wound-delivering catheters for several days. Such long-term infusion is inconvenient for administration, and a single injection of a sustained-release or long-acting formulation is highly desirable to provide a sustained action of the LA.

[0006] To extend the duration of action of LA, use the following: 1. Incorporation of LA into liposome vesicles for delayed release (see U.S. Patent Nos. 8,182,835 and 10,206,876); 2. Incorporation of LA into a polymer matrix for sustained release (see U.S. Pat. No. 10,898,575); 3. Various methods have been developed, including coadministration of LA with vessel restrictor epinephrine (see Lixtraxen Injection (Lidocaine hydrochloride and epinephrine injection, solution) https: / / www.drugs.com / pro / lixtraxen-injection.html).

[0007] Emulsions have historically been used to inactivate LA or as an antidote to LA overdose. It is well documented that drug-free emulsions (such as Intralipid) are commonly used to reduce the cardiovascular effects or toxicity of LA. Various researchers have clearly demonstrated that emulsions inactivate LA, resulting in the abolition of its pharmacological effects or toxicity. (Zausig,York A. et al., Lipid Emulsion Improves Recovery from Bupivacaine-Induced Cardiac Arrest,but Not from Ropivacaine- or Mepivacaine-Induced Cardiac Arrest,Anesthesia&Analgesia:October 2009-Volume109-Issue4-p1323-1326;E.Litonius, et al., Effect of intravenous lipid emulsion on bupivacaine plasma concentration in humans,Anaesthesia 2012,67,600-605;Lotte CG et al., Systematic review of the effect of the intravenous lipid emulsion therapy for local anesthetic toxicity,Clinical Toxicology,2016 Vol. 54, No. 3, 167-193, http: / / dx.doi.org / 10.3109 / 15563650.2015.1121270). The use of emulsions to deliver pharmacologically active LA is contrary to common understanding and medical practice.

[0008] This application relates to the surprising discovery, contrary to current understanding and medical practice, regarding the use of emulsions to inactivate LA. This application discloses the use of emulsions to not only maintain the desired pharmacological effects of LA, but also to prolong its duration of action and reduce toxicity. Because the emulsions of the present disclosure can prolong the desired LA activity for 1 to 5 days after a single injection, thus providing extended pain relief, the emulsions of the present invention are particularly useful for managing pain associated with surgery or trauma. Summary of the Invention

[0009] The present invention relates to the use of the following LA-containing emulsion composition. a. Maintaining and prolonging the pharmacological activity of LA (Ex2), b. It is safer than LA in conventional solution formulations (Ex3). c. To provide a long-term pharmacokinetic (PK) profile compared to the regular solution (Ex1) of the same LA; d. Prolonging the anesthetic effect for approximately 1 to 3 days (Ex. 1 and 2)

[0010] For this reason, the present invention provides the following a) local anesthetics, b) an oil phase, and c) aqueous phase The present invention teaches an emulsion composition comprising, consisting essentially of, or consisting of: 1. The local anesthetic is at a concentration of up to 4% by weight of the emulsion; 2. The oil phase contains lecithin and vegetable oil in a weight ratio of 2:1 to 1:2; 3. The oil phase is at a concentration of about 33% to 99.5% by weight of the emulsion; and 4. The emulsion comprises particles or droplets having a diameter of about 30 to about 2500 nanometers.

[0011] In one embodiment, the emulsion of the present invention contains an LA selected from the group consisting of lidocaine, bupivacaine and ropivacaine (Ex2&21).

[0012] In one embodiment, the emulsion of the present invention contains LA in its free base form (or non-ionized form), LA as a pharmaceutically acceptable salt such as the hydrochloride salt (in its ionized form) (Ex18), or a combination thereof.

[0013] In one embodiment, the emulsion of the present invention is an injectable liquid or a liquid that can be manually expelled through a hypodermic needle using a syringe (Ex11).

[0014] In one embodiment, the emulsions of the present invention have particles or oil droplets sized from about 30 to about 2500 nanometers in diameter. This particle size range is preferred because sizes below 30 nm can result in a shortened action due to the rapid release of LA from the emulsion, and sizes above 2500 nm can result in a very viscous liquid that is difficult to inject (Ex 9, 10).

[0015] In one embodiment, the emulsion of the present invention has particles or oil droplets with an average diameter of about 200 nm to 2500 nm (Ex9).

[0016] In one embodiment, the emulsion of the present invention has particles smaller than 100 nm and particles larger than 100 nm in diameter.

[0017] In one embodiment, the emulsions of the present invention have particles that are polydisperse in size with a polydispersity index (PDI) > 0.7 (Ex17).

[0018] In one embodiment, the emulsion of the present invention has particles with a PDI greater than 0.7, preferably greater than 0.8, most preferably greater than 0.9 (Ex17).

[0019] In one embodiment, the emulsions of the present invention comprise non-liposomal particles with a solid core and a lack of a detectable lipid bilayer membrane surrounding the particle (Ex10).

[0020] In one embodiment, the emulsion of the present invention is formed after being diluted or mixed with water (Ex9).

[0021] In one embodiment, the oil phase is present in the emulsion at a concentration of about 33% to 99.5% by weight of the emulsion (Ex 12 and 13).

[0022] In one embodiment, the oil phase comprises lecithin, oil and LA.

[0023] In one embodiment, the lecithin is present in the oil phase at a concentration of about 55% to about 67% by weight of the oil phase.

[0024] In one embodiment, the oil is present in the oil phase at a concentration of about 33% to 44% by weight of the oil phase.

[0025] In one embodiment, the lecithin and oil are present in the oil phase in a weight ratio of 2:1 to 5:4, which is preferred because too much lecithin makes the emulsion too viscous to be injectable through a syringe needle, whereas too much oil cannot sufficiently solubilize LA or provide long-term release of LA because the oil itself is not a good solvent for LA.

[0026] In one embodiment, the emulsions of the present invention contain no more than 4% LA by weight of the emulsion.

[0027] In one embodiment, greater than 90% by weight of the LA is dispersed in or non-covalently bound to the oil phase of the emulsion.

[0028] In one embodiment, the emulsion of the present invention is a translucent or opaque liquid having a viscosity in the range of about 300-600 cps (Ex8).

[0029] In one embodiment, 90% or more of the LA in the emulsion of the present invention is bound to the emulsion oil phase, regardless of the hydrophobicity of the LA (Ex3).

[0030] In one embodiment, 90% or more of the LA in an emulsion of the present invention is bound to the emulsion oil phase, even if the LA is not hydrophobic or has a logP value of less than 1.5.

[0031] In one embodiment, the emulsions of the present invention are prepared using LA free base (ie, non-ionized form) or LA salt (ie, ionized form, eg, HCl salt) as starting material (Ex3).

[0032] In one embodiment, the emulsions of the present invention comprise a hydrophobic, water-insoluble LA, such as the free base (non-ionized or un-ionized) form of lidocaine, bupivacaine, or ropivacaine.

[0033] In a preferred embodiment, the emulsions of the present invention contain a non-hydrophobic or water-soluble LA in ionized form, such as the hydrochloride salts of ropivacaine, bupivacaine or lidocaine.

[0034] In one embodiment, the emulsion of the present invention contains LA in ionized, non-ionized or both forms (Ex18).

[0035] In one embodiment, the emulsion of the present invention contains about 5% mol to 25% mol of non-ionized LA and about 75% mol to 95% mol of ionized LA (Ex18).

[0036] In one embodiment, the emulsions of the present invention are liquid crystalline, meaning they flow like a liquid but their molecules are crystalline oriented, and can be characterized and distinguished from other liquid formulations by their unique optical or spectroscopic properties, such as small angle X-ray scattering or Fourier transform infrared spectroscopy or FTIR (Ex19 and Ex20).

[0037] In one embodiment, the emulsions of the present invention are lyotropic liquid crystals and exhibit a phase transition as a function of the amount of aqueous phase or water added. In one embodiment, the emulsions of the present invention have a phase transition point at a water level of about 1% (Ex15).

[0038] In one embodiment, the oil droplets of the emulsion of the present invention are substantially free of lipid bilayer membranes, which are an essential structural feature of liposomes (Ex10).

[0039] In one embodiment, the emulsions of the present invention are polymer-free.

[0040] In one embodiment, the emulsions of the present invention slowly release LA, such that the release and availability is over 1, 2, 3 or 4 days (Ex7, 13).

[0041] In one embodiment, the emulsions of the present invention release LA at a different rate than preliposomes or liposome compositions containing the same LA (Ex7).

[0042] In one embodiment, the emulsions of the present invention are structurally distinct from preliposomes or liposome compositions containing the same LA.

[0043] In one embodiment, the emulsion of the present invention does not have any organic solvents, such as alcohols.

[0044] In another embodiment, the emulsions of the present invention may have an organic solvent that is miscible with water.

[0045] In one embodiment, the emulsion of the present invention can be injected using a 10 mL syringe through an 18-27 G needle or a 22 G catheter (Ex11).

[0046] In one embodiment, the emulsion of the present invention comprises an aqueous phase and an oil phase, said oil phase comprising LA, vegetable oil and egg or soybean derived lecithin.

[0047] In another embodiment, the emulsion of the present invention has a pH of from pH 3 to pH 8.

[0048] In one embodiment, the emulsion composition of the present invention does not contain any synthetic surfactants such as polysorbate 80, polymers such as PLGA, or biopolymers such as collagen.

[0049] In one embodiment, the emulsions of the present invention are ready to use or ready to inject.

[0050] In another embodiment, the emulsions of the present invention are mixed with an aqueous solution, such as water or saline, prior to injection.

[0051] In one embodiment, the emulsion is a water-in-oil emulsion. In another embodiment, the emulsion is an oil-in-water emulsion. In another embodiment, the emulsion is converted to an oil-in-water emulsion by diluting the water-in-oil emulsion with a diluent such as water, saline, or the like. In certain other embodiments, the oil-in-water emulsion is converted to a water-in-oil emulsion by removing excess water from the oil-in-water emulsion, for example, by vacuum drying.

[0052] In one embodiment, the emulsion of the present invention is substantially an oil-in-water emulsion at a water level of >10%, a mixture of both oil-in-water and water-in-oil at a water level of 3% to 10%, a predominantly water-in-oil emulsion at a water level of 1% to 3%, and a substantially water-in-oil emulsion at a water level of 1% or less. Any of these emulsion types can be used to provide a long-acting and safe LA drug. Selection of a preferred emulsion type can be achieved at this stage by controlling the water level.

[0053] In one embodiment, the emulsion of the present invention has a liquid crystal structure with a phase transition point in 0.3% (w / w) to 3% (w / w) water, preferably 0.5% (w / w) to 2% (w / w) water, and more preferably about 1% (w / w) water.

[0054] In one embodiment, the emulsions of the present invention are physically stable and do not form LA precipitate, undergo phase separation, or change appearance after being stored at 25° C. for 2 years (Ex8).

[0055] In one embodiment, the emulsions of the present invention are chemically stable, retaining 95% or more of intact LA after 2 years of storage at 25° C. (Ex8).

[0056] In one embodiment, the emulsion of the present invention contains less than 0.2% N-oxide of LA after 2 years of storage at 25° C. (Ex8).

[0057] In another embodiment, the emulsions of the present invention may optionally contain an antioxidant selected from the group including methionine, cysteine, dextrose, fructose, lactose, and edetate (EDTA).

[0058] In one embodiment, the emulsion of the present invention contains a combination of sodium EDTA and cysteine ​​(Ex16).

[0059] In one embodiment, the emulsions of the present invention are for administration via infiltration or injection into a wound surface, surgical incision or soft tissue.

[0060] In one embodiment, the emulsions of the present invention provide a prolonged PK profile for LA following injection into soft tissue compared to a solution formulation of the same LA (Ex1).

[0061] In one embodiment, the emulsion of the present invention provides long-lasting pain control (Ex2).

[0062] In one embodiment, the emulsion of the present invention is safer than a solution formulation of the same LA (Ex4).

[0063] In one embodiment, the present invention provides a method for preventing or treating pain comprising administering to a subject an emulsion of the present invention.

[0064] In some embodiments, the emulsions of the present invention are administered in a single dose, ie, only once in the entire treatment.

[0065] In some embodiments, the emulsions of the present invention are administered multiple times, ie, more than once during treatment of the underlying cause.

[0066] In some embodiments, the emulsions of the present invention are administered neat, i.e., undiluted.

[0067] In some embodiments, the emulsions of the present invention are administered after dilution with water or another liquid that is safe for human administration.

[0068] In some embodiments, the emulsions of the present invention are administered to tissues near the site of pain, such as a surgical incision or a traumatic wound.

[0069] In some embodiments, the emulsions of the present invention are used in open or laparoscopic procedures; abdominal surgeries, including but not limited to gastrectomy, proctocolectomy, appendectomy, pancreatectomy, cholecystectomy, herniorrhaphy; colorectal surgeries, such as colectomy, ileostomy, APR, and hemorrhoidectomy; thoracic surgeries, such as pneumonectomy, esophagectomy; hepatic surgeries, such as liver cancer surgery; plastic surgeries, such as abdominoplasty, breast augmentation, or mastopexy; urologic surgeries, such as prostatectomy or cystectomy; obstetrics and gynecology surgeries, including myomectomy, sterilization, hysterectomy, and total hysterectomy with bilateral salpingo-oophorectomy (TAHBSO). into an incision of a surgery, including, but not limited to, an incision of a soft-tissue surgery, including, but not limited to, general surgery performed via ENT surgeries; and ear-nose-throat surgeries.In some embodiments, the emulsions of the present invention are also administered into incisions in bony-tissue surgery, including, but not limited to, orthopedic surgeries such as hop and knee arthroplasty, open reduction and fixation of fractures and joints, laminectomy and spinal fusion; thoracic surgeries such as sternal incision and pectus excavatum repair; podiatric surgery, including bunionectomy; and general bony surgeries, including iliac crest grafts.

[0070] In some embodiments, the emulsions of the present invention are administered to trauma wounds, including but not limited to abrasions, lacerations, skin lacerations, bites, burns, and penetrating trauma wounds.

[0071] In some embodiments, the emulsions of the present invention are administered to a surgical incision or trauma wound at a LA concentration of 0.5% to 4%, preferably 1% to 3%, and most preferably 1.5% to 2.5%.

[0072] In some embodiments, the emulsions of the present invention are administered by infiltration or injection into soft tissue at or near the site of surgery, pain, or nerve.

[0073] In some embodiments, the emulsions of the present invention are administered by infiltration or injection into an incision site during soft tissue or bony surgery.

[0074] In some embodiments, the emulsions of the present invention are administered by infusion or topical application to the surgical incision or wound site.

[0075] In some embodiments, the emulsions of the present invention are administered by infusion or topical application to soft or bony tissue.

[0076] In some embodiments, the emulsions of the present invention are administered by both infiltration and infusion.

[0077] In some embodiments, the emulsions of the present invention are administered by infusion in a volume of up to 5, 10, 15, 20, 25, 30, 40, or 50 mL per surgical incision or wound site.

[0078] In some embodiments, the emulsions of the present invention are administered by infusion in a volume of up to 30 mL, preferably 25 mL, or more preferably 20 mL per surgical incision or wound site.

[0079] In some embodiments, the emulsions of the present invention are administered by infiltration in volumes of up to 5, 10, 15, 20, 25, 30, 40, or 50 mL per surgical incision or wound site.

[0080] In some embodiments, the emulsions of the present invention are administered by infiltration in volumes of up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, and 50 mL per surgical incision or wound site.

[0081] In some embodiments, the emulsions of the present invention are administered by both infusion and infiltration, up to a total of 10, 15, 20, 25, 30, 40, and 50 mL per surgical incision or wound site.

[0082] In some embodiments, the emulsions of the present invention are administered by infusion and infiltration at a volume ratio of 1:20 to 20:1.

[0083] In some embodiments, the emulsions of the present invention are administered by infusion and infiltration into the surgical incision before, during, and after surgery.

[0084] In some embodiments, the emulsions of the present invention are administered by instillation and infiltration into the surgical incision prior to closure of the incision with sutures.

[0085] In some embodiments, the emulsions of the present invention are administered by injection or infiltration into, on, or around soft or bony tissue, including but not limited to bone, joint, fascia, muscle, fat, subcutaneous tissue, and skin tissue at the incision site prior to closure of the incision with sutures.

[0086] In some embodiments, the emulsions of the present invention are administered by instillation into, on, or around soft or bony tissue, including but not limited to bone, joint, fascia, muscle, fat, subcutaneous tissue, and skin tissue at the incision site prior to closure of the incision with sutures.

[0087] In some embodiments, the emulsions of the present invention are administered by intramuscular, intra-articular, peri-articular, subcutaneous or transdermal injection into, on or around soft or bony tissue, including but not limited to bone, joint, fascia, muscle, fat, subcutaneous tissue, and skin tissue, after suturing the incision.

[0088] In some embodiments, the emulsions of the present invention are administered by topical application to a sutured incision or wound.

[0089] In some embodiments, emulsions of the present invention are administered by infiltration using a syringe equipped with a needle.

[0090] In some embodiments, emulsions of the present invention are administered by infusion using a syringe with or without an attached needle.

[0091] In some embodiments, the emulsions of the present invention are administered to block nerves by administering them to tissues close to nerves that transmit pain signals from the site of associated pain, such as a surgical incision or traumatic wound.

[0092] In some embodiments, the emulsions of the present invention are administered to nerves for both field and peripheral nerve blocks, including, but not limited to, TAP blocks, PEC blocks, paravertebral blocks, para-spinal blocks, brachial plexus blocks, cervical plexus blocks, celiac plexus blocks, facet joint blocks, or specific peripheral nerve blocks (e.g., trigeminal nerve blocks, ophthalmic nerve blocks, maxillary nerve blocks, interscalene blocks, subclavian nerve blocks, axillary nerve blocks, iliac nerve blocks, penile nerve blocks, femoral nerve blocks, sciatic nerve blocks, popliteal nerve blocks, saphenous nerve blocks).

[0093] In some embodiments, emulsions of the present invention are administered to block nerves in volumes of up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, and 50 mL.

[0094] In some embodiments, the emulsions of the present invention are administered to block nerves at LA concentrations of 0.1% to 3%, preferably 0.2% to 2%, and most preferably 0.4% to 2%.

[0095] In some embodiments, the emulsions of the present invention are administered to block nerves after being diluted in sodium chloride solution, dextrose solution, water, or any liquid that is safe for use in nerve blocks.

[0096] In a preferred embodiment, the emulsions of the present invention are administered to block nerves after dilution with normal saline to a LA concentration of 0.1% to 2%, preferably 0.2% to 2%, and most preferably 0.4% to 2%. The reason for this preferred range is to achieve a desirable viscosity, injectability, and sustained-release profile for the emulsion after dilution. Too low a dilution rate results in high viscosity and makes injection difficult, while too high a dilution rate reduces or impairs the sustained-release profile (Ex. 11, 12, 13).

[0097] In some embodiments, the emulsions of the present invention are administered to block nerves after being diluted in sodium chloride solution, dextrose solution, or other liquids that are safe for use in nerve blocks to a viscosity of about 40K, preferably 400, and most preferably 4 centipoise or less (Ex. 11, 12).

[0098] In some embodiments, emulsions of the present invention are administered to soft tissues providing a higher concentration of LA in the soft tissue than in the blood.

[0099] In some embodiments, emulsions of the present invention are administered to soft tissues where the concentration of LA in the soft tissue is 1, 2, 3, 5, and 10 times greater than in the blood.

[0100] In some embodiments, the emulsions of the present invention are administered to soft tissue to provide sustained release of LA such that after 1, 2, 3, 4, 5, 6, or 7 days, LA plasma concentrations exceed 5 ng / mL (Ex1).

[0101] In some embodiments, the emulsions of the present invention are peakless or low C max pharmacokinetic profile of LA or C compared to the same dose of LA in solution formulation max is administered to soft tissue to provide a significantly reduced plasma concentration profile (Ex1).

[0102] In some embodiments, the emulsions of the present invention provide a composition that is effective in preventing cardiotoxic or CNS toxic concentrations of LA, i.e., C of less than 3300 ng / mL. max The compound is administered to the soft tissue to provide a plasma concentration profile having a

[0103] In some embodiments, the emulsions of the present invention have a C of 3300 ng / mL or less. max Ropivacaine is administered to the soft tissue in doses of 2 to 800 mg to provide a higher C (Ex1). maxlikely causes cardiovascular or CNS toxicity, max The upper limit is preferred.

[0104] In some embodiments, the emulsions of the present invention have a T of 0.5 to 48 hours. max Ropivacaine is administered into the soft tissues at a dose of 2–800 mg to provide relief (Ex1).

[0105] In some embodiments, the emulsions of the present invention are administered to the soft tissue of a human subject at a dose of 2-800 mg of ropivacaine to provide an AUC of 200-251,000 ng / mL*hr (Ex 1). A lower AUC results in less therapeutic efficacy, while a higher AUC results in toxicity, so this AUC range is preferred.

[0106] In some embodiments, the emulsions of the present invention do not affect the wound healing process of soft tissue after administration to the soft tissue (Ex2, 5).

[0107] In some embodiments, the emulsions of the present invention do not affect the physical integrity of the suture (Ex6).

[0108] In some embodiments, the emulsions of the present invention do not affect the physical integrity of the surgical mesh (Ex6).

[0109] In some embodiments, the emulsions of the present invention provide pain relief for at least about 24 hours.

[0110] In some embodiments, the emulsions of the present invention provide pain relief for 24 to 48 hours.

[0111] In some embodiments, the emulsions of the present invention provide pain relief for at least 48 hours.

[0112] In some embodiments, the emulsions of the present invention provide pain relief for 48 to 72 hours.

[0113] In some embodiments, the emulsions of the present invention provide pain relief for at least 72 hours.

[0114] In preferred embodiments, the emulsions of the present invention provide long-lasting pain relief or nerve block.

[0115] In a preferred embodiment, the emulsions of the present invention are for post-surgical pain management.

[0116] In another embodiment, the emulsions of the present invention are used for perioperative nerve blocks, including but not limited to pre-operative, intra-operative, and post-operative nerve blocks, to achieve long-term pain control before, during, and after surgery.

[0117] These and other aspects, objects and embodiments will become more apparent when read in conjunction with the detailed description and drawings that follow. [Brief explanation of the drawings]

[0118] [Figure 1] FIG. 1 shows the schematic structure of amide-type local anesthetics.

[0119] [Figure 2] FIG. 2 shows the structure of ropivacaine N-oxide.

[0120] [Figure 3] FIG. 3 shows a schematic representation of a liposome bilayer.

[0121] [Figure 4]4A-C show electron micrographs depicting TEM images of particles or droplets of undiluted (top panel, FIG. 4A) and diluted (bottom panel, FIG. 4B) emulsions of the present invention, as well as typical liposomal particles of a well-characterized, FDA-approved liposomal drug (Ambisom™, FIG. 4C). Emulsion droplets have a solid core (i.e., no empty internal void) and particles lack a characteristic membrane, whereas the liposomal vesicles have an empty core surrounded by a characteristic lipid bilayer membrane.

[0122] [Figure 5] FIG. 5 shows the in vitro release of a ropivacaine emulsion of the present invention compared to a ropivacaine liposomal composition prepared according to Examples 1 and 2 of US Pat. No. 10,206,876 B2.

[0123] [Figure 6] FIG. 6 shows the sustained local anesthetic effect of ropivacaine emulsion compared to ropivacaine solution (NAROPIN®) or bupivacaine liposomal drug (Exparel®).

[0124] [Figure 7] FIG. 7 shows small angle X-ray scattering (SAXS) results demonstrating the structural differences between the ropivacaine emulsion formulation of the present invention and the preliposomal formulation ("proliposome").

[0125] [Figure 8] 8A-B show the spectroscopic differences between the ropivacaine emulsion of the present invention and a pre-liposomal formulation ("proliposome") by FTIR. DETAILED DESCRIPTION OF THE INVENTION

[0126] Detailed Description of the Invention I. Definition As used herein, various terms shall have the following definitions.

[0127] As used herein, "about" refers to an amount that includes a range covering a 10% expansion on either side of the target value. For example, "about 100" means any value between 90 and 110, inclusive.

[0128] As used herein, "acid" refers to pharmaceutically acceptable acids such as hydrochloric acid, acetic acid, citric acid, methanesulfonic acid, sulfuric acid, and the like, with hydrochloric acid being the preferred acid.

[0129] As used herein, "alkaline" or "base" refers to pharmaceutically acceptable bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, lysine, arginine, and the like, with sodium hydroxide and potassium hydroxide being preferred bases.

[0130] An "antioxidant" is a pharmaceutical additive that can be added to a composition to prevent oxidation of an active agent or inactive ingredient. Antioxidants include reducing agents, metal ion chelating agents, and inert gases. Preferred antioxidants for the emulsions of the present invention are sodium EDTA, cysteine, CO2 gas, ascorbyl palmitate, ascorbic acid, methionine, and glutathione.

[0131] The term "aqueous phase" refers to the aqueous solution that suspends the oil droplets in the emulsion. In the emulsions of the present invention, the aqueous phase can be separated from the oil phase by ultrafiltration, allowing the components in the aqueous and oil phases to be quantified separately. In addition to water, the aqueous phase may contain other water-soluble or hydrophilic components. The aqueous phase of the emulsions of the present invention may contain a pH buffer, a preservative, an antioxidant, a metal ion chelator or chelating agent, and a small portion of the active agent (LA). In one embodiment, the aqueous phase is a biological fluid, such as blood or bodily fluids. In one embodiment, the aqueous phase of the emulsions of the present invention contains a reducing agent, a chelating agent, and 10% wt or less of added LA. In one embodiment, the aqueous phase of the emulsions of the present invention is present in a concentration of 0.1% to 90% by weight of the emulsion, preferably 0.2% to 80% by weight, more preferably 0.2% to 70% by weight, and most preferably 0.2% to 66% by weight.

[0132] As used herein, "chemical stability" or "chemically stable" refers to a formulation state that can maintain the active ingredient at 90% or more of the initial amount and certain impurities below acceptable limits. With respect to the emulsions of the present invention, they are considered chemically stable if they can maintain 90% or more of the initial LA amount and 0.2% or less of LA N-oxide by weight of LA. In one embodiment, the emulsions of the present invention are chemically stable. In a preferred embodiment, the emulsions of the present invention maintain 90% or more of the initial LA amount and 0.2% or less of LA N-oxide by weight of LA after storage at 25°C for 1.5 years or preferably 2 years.

[0133] As used herein, an "emulsion" is a mixture of immiscible oil and water phases. Emulsions can be oil-in-water or water-in-oil and are typically optically opaque and have limited physical stability. In certain embodiments, the compositions of the present invention are optically semi-transparent or translucent, physically stable water-in-oil emulsions having a discrete water or aqueous phase suspended in a continuous oil phase. In one embodiment, the emulsions of the present invention are water-in-oil, with the oil phase composed of discrete oil droplets suspended in a continuous aqueous phase. In certain other embodiments, the emulsions of the present invention are oil-in-water emulsions but can be converted to water-in-oil emulsions after removal of water. In another embodiment, the emulsions of the present invention are water-in-oil emulsions but can be converted to oil-in-water emulsions after addition of water or dilution in a biological fluid such as blood. In another embodiment, the emulsions of the present invention are oil-in-water emulsions and remain oil-in-water emulsions after dilution with water or a biological fluid. In one embodiment, the emulsions of the present invention are mixtures of both water-in-oil and oil-in-water emulsions. In another embodiment, the emulsions of the present invention are optically semi-transparent or translucent and physically stable. In another embodiment, the emulsions of the present invention are white and opaque.

[0134] As used herein, the term "oil droplets" refers to the oil phase of the emulsion of the present invention, which exists as discrete particles surrounded by the aqueous phase. Oil droplets consist of water-insoluble components in the emulsion, including lecithin and oil. Oil droplets are not liposomal particles because they lack the lipid bilayer that defines the liposome structure. Oil droplets are also distinct from micelles or micellar particles. Micelles exist in surfactant solutions in water and are much smaller in size (<100 nm, compared to the 200-2500 nm of the oil droplets of the present invention). Surfactants that can form micelles are water-soluble surfactants, such as polysorbates and cremophors, but are not preferred due to their toxicity and are therefore excluded from the emulsions of the present invention. Due to the high level of oil (30-70% by weight of the oil phase), oil droplets are also distinct from solid lipid nanoparticles (SLNs), which generally contain much less oil than those used in the emulsions of the present invention. Physically, oil droplets are liquid, soft, flexible, and easily filterable through membranes with small pores (0.2-0.45 microns) or injectable through a fine needle, whereas liposomes and SLNs are solid, inflexible, hard particles that are difficult to extrude through a fine needle or filter.

[0135] As used herein, the term "pain relief" means the use of drugs or other methods to prevent, reduce, or eliminate pain; the act of preventing, reducing, or eliminating pain.

[0136] As used herein, "particle size" refers to the diameter of the particles or oil droplets in the emulsions of the present invention or after dilution with water or biological fluids. The size of the oil droplets can significantly affect the in vitro release of LA, the pharmacokinetic profile, and the injectability of the emulsions of the present invention. Very small emulsion droplets (<100 nm), as taught in US 9,517,202, are more difficult to prepare, less stable, and tend to release LA rapidly, resulting in a short pharmacokinetic profile or a short duration of action. On the other hand, large emulsion droplets (>2500 nm) can result in a very viscous emulsion that is difficult to expel through a needle or is not injectable. In certain embodiments, the oil phase in the emulsions of the present invention is present in a particle size greater than 100 nm. In another embodiment, the particle size of the emulsions of the present invention is 200 nm to 2500 nm, preferably 200 nm to 500 nm, and most preferably 300 nm to 400 nm.

[0137] As used herein, the term "drug incorporation capacity" defines the maximum amount of drug that can be loaded into a formulation while maintaining all of the formulation's desirable properties. In the emulsions of the present invention, the drug incorporation capacity of LA is about 4% by weight of the emulsion. If more than 4% LA is added, the emulsion will become cloudy, form a precipitate, and / or lose the desired in vitro release profile. In one embodiment, the emulsions of the present invention contain 4% wt or less LA, preferably 3.5% wt or less LA, and most preferably 0.5%, 1%, 1.5%, 2%, 2.5%, or 3% wt LA.

[0138] As used herein, "filterable" refers to the ability of the emulsions of the present invention to pass through a filter membrane of a certain pore size, such as 0.2 to 5 microns, without significant (>10%) loss of LA adsorbed to the membrane. In one embodiment, the emulsions of the present invention are filterable through a filter having a pore size of 0.2 to 5 microns. In another embodiment, the emulsions of the present invention are filterable through a filter having a pore size of 5 microns, 1.2 microns, 0.8 microns, 0.45 microns, or 0.2 microns. In one embodiment, the emulsions of the present invention are filterable without the use of organic solvents. In a preferred embodiment, the emulsions of the present invention are filterable using either an organic solvent, an aqueous phase, or a mixture thereof.

[0139] As used herein, the term "fine needle" or "needle" includes a thin, hollow hypodermic needle attached to a syringe or catheter for injection and infiltration. The outer diameter of a needle is indicated by a needle gauge system. According to the Stubs Needle Gauge system, hypodermic needles in general medical use range from 7 (largest) to 33 gauge (smallest). In one embodiment, the emulsion of the present invention is extrudable or injectable through a needle or catheter using a syringe. In a preferred embodiment, the emulsion of the present invention is extrudable through a needle ranging from 18 to 27 G, preferably 18 G to 25 G, and most preferably 18 G to 22 G, using a syringe ranging from 1 mL to 50 mL, preferably 10 mL. In another preferred embodiment, the emulsion of the present invention is extrudable through a catheter (6" to 24" long) attached to a needle (16 to 25 G) using a syringe ranging from 1 mL to 50 mL. This needle-catheter-syringe combination is particularly useful for nerve blocks using the LA emulsion of the present invention.

[0140] As used herein, the terms "hydrophobicity" or "hydrophobicity" refer to a LA molecule of interest having a log P of 1.5 or greater, where P is the octanol / water partition coefficient. LA in its free base or non-ionized form is generally insoluble in water and has a high log P, or is hydrophobic. In contrast, the ionized or salt form of the same LA is generally soluble in water and has a log P of less than 1.5, or is non-hydrophobic. For example, ropivacaine as a free base has a log P of 2.9 (P = octanol:water partition coefficient = 794) and is insoluble in water, whereas ropivacaine hydrochloride salt is non-hydrophobic and has a log P of 1.1 (P = 14). In one embodiment, the emulsions of the present invention can incorporate LA in either its free base or salt form, i.e., regardless of the hydrophobicity of the LA. In another embodiment, the emulsion of the present invention provides similar pharmacological activity to LA free base or a salt thereof (Ex3).

[0141] As used herein, the term "infiltration" refers to injection into tissue at one or more sites. For example, LA may be injected into more than one point of surgical wound tissue to soak the site and provide analgesic or pain relief throughout the site.

[0142] As used herein, the term "injectable" means that 10 mL of liquid can be expelled through a fine needle using a 10 mL syringe with a force of 25 Newtons in less than 10 minutes (Ex8).

[0143] As used herein, the term "instillation" refers to the direct or topical administration or application (not injection) of a formulation onto tissue. For example, LA may be administered locally as an instillation to a surgical wound to provide analgesic or pain relief throughout the wound.

[0144] As used herein, the term "in vitro release" refers to the rate and extent to which LA dissociates from a formulation (e.g., an emulsion of the present invention) and becomes unbound or free in water or a target aqueous solution (e.g., physiological saline or a biological fluid) as studied in a test tube or container. In this way, in vitro release studies reveal the onset, rate, and duration of LA release from an emulsion. Under a set of in vitro release study conditions, onset is quantified by the time to reach 20% of the maximum LA concentration, rate by the time to reach 50% of the maximum LA concentration, and duration by the time to reach the maximum LA concentration. If two LA formulations do not have the same in vitro release profile, their biological activity is not considered equivalent, i.e., they are not bioequivalent. Differences in in vitro release profiles also indicate that two formulations are structurally different, even if they are made from the same or similar materials (Ex. 7). Furthermore, the process conditions for preparing the emulsions of the present invention can significantly affect in vitro release. The type and amount of LA added, the materials used in the aqueous and oil phases, their net and relative qualities, the order of their addition, the droplet size, and optionally, the organic solvent in the emulsions of the present invention can all alter the in vitro release profile. Thus, in one embodiment, the emulsions of the present invention provide a different in vitro release profile from liposome-based LA formulations, which is slower and longer than a solution of the same LA (Ex7).

[0145] As used herein, "ionized" refers to a molecule, such as an LA molecule, that becomes positively charged by losing an electron, as follows: LA - electrons = LA + The aforementioned LA +is referred to as the "ionized" form or "LA ion," and LA is referred to as the "nonionized" or "unionized" form of the LA molecule. Either the ionized or nonionized form of LA can be used as the raw material or starting material for preparing the emulsions of the present invention. For example, ropivacaine salts, such as ropivacaine HCl, are ionized LA, while ropivacaine or ropivacaine free base are nonionized LA. However, the final emulsions of the present invention may contain a different LA form than the starting LA form used. For example, an emulsion composition of the present invention containing both ionized and nonionized ropivacaine molecules was prepared using ropivacaine HCl (100% ionized) as the starting material (Ex. 18), demonstrating that a portion of the ionized ropivacaine was converted to the nonionized form during the emulsion preparation process. It has been discovered that such a mixture of ionized and nonionized LA is preferable compared to 100% ionized or 100% nonionized LA. For example, emulsions containing 100% ionized ropivacaine tend to have less ropivacaine bound to oil droplets, resulting in faster drug release and a shorter duration of action, whereas emulsions containing 100% non-ionized ropivacaine are physically unstable and may form precipitates over time. Therefore, it is desirable to mix both ionized and non-ionized LA to create emulsions of the present invention with unique liquid crystallinity, solubility, stability, release, and other physical properties.

[0146] In one embodiment, the emulsions of the present invention are prepared with 100% ionized LA, such as ropivacaine HCl, as the starting material, and the final emulsion is prepared to contain about 5-25 mol % (or 5% mol to 25% mol) of the non-ionized LA form, preferably 10-20 mol % of the non-ionized LA form, and more preferably 12-18 mol % of the non-ionized LA form.

[0147] This mixture of ionized and non-ionized LA can be obtained by adding a mixture of ionized and non-ionized LA starting materials, by ionizing the non-ionized LA starting material by adding a calculated amount of acid such as hydrochloric acid, or by deionizing the ionized LA starting material by adding a calculated amount of alkali or base such as sodium hydroxide and potassium hydroxide during emulsion preparation (Ex 18).

[0148] As used herein, "local anesthetic" refers to an amide-type local anesthetic molecule having one of the chemical structures as shown in FIG.

[0149] As used herein, "LA-oil droplet binding" refers to non-covalent binding between LA and oil droplets in the emulsions of the present invention. Non-covalent binding is measured by separating unbound or free LA molecules from LA bound to oil droplets in the water or aqueous medium of interest, such as blood or biological fluids, and then measuring their respective concentrations. Separation of free LA from bound LA can be achieved by ultrafiltration, and the LA concentration can be measured by HPLC. The degree of LA-oil droplet binding ratio is expressed as the concentration ratio (LA-oil droplet binding (%) = concentration of bound LA / concentration of total LA × 100). In one embodiment, the emulsions of the present invention have LA-oil droplet binding (%) of 90% or more of LA. In a preferred embodiment, the emulsions of the present invention have LA-oil droplet binding (%) of 90% or more of LA, regardless of hydrophobicity or logP (i.e., greater than or less than 1.5).

[0150] As used herein, "lecithin" refers to a mixture of phospholipids derived from natural sources. Injectable lecithins include those derived from egg or soybean, which are purified and substantially free of irritating, allergenic, inflammatory, or other adverse biological reactions. For the present invention, preferred lecithins include those containing greater than 75% w / w phosphatidylcholine (PC), insoluble in water, and essentially free of lysolecithin (i.e., containing 1-4% or less by weight of lysolecithin). High PC content makes the lecithin relatively soft, providing a smoother, more easily injectable emulsion. Lysolecithin is hemolytic and is therefore undesirable for safety reasons. Examples of preferred lecithins include, but are not limited to, lecithin products under the trade names LIPOID S75, LIPOID S100, LIPOID E80, and Phospholipon 90G. Some fats on the lecithin molecule are unsaturated and can oxidize to form peroxides, which in turn oxidize LA to form N-oxides of LA. Therefore, in one embodiment, the emulsions of the present invention contain antioxidants and / or metal ion chelators, or a combination thereof, to inhibit lecithin oxidation. Some of the lecithin is hydrogenated to contain only saturated fatty acids. These hydrogenated lecithins are less susceptible to oxidation, but have a higher melting point and produce emulsions that are hard (like creams) and difficult to inject. In the emulsions of the present invention, lecithin is required to form oil droplets, bind LA, and provide sustained release of LA. If lecithin is used in an amount less than 20% by weight of the emulsion, the emulsion loses its ability to provide a sustained-release or sustained-action profile of LA. On the other hand, if lecithin is used in an amount greater than 70% by weight of the emulsion, the emulsion becomes hard and difficult to inject. Therefore, the preferred amount of lecithin used in the emulsions of the present invention is 20% to 70% by weight of the emulsion. In one embodiment, preferred lecithins for the emulsions of the present invention have a PC content of 75% wt or less, hi another embodiment, preferred lecithins for the emulsions of the present invention have a lysolecithin content of 1-4% wt or less.In another embodiment, preferred lecithin is derived from soybeans or egg yolk. In another embodiment, preferred lecithin is selected from the group consisting of LIPOID S75, LIPOID S100, LIPOID E80, and Phospholipon 90G, or mixtures thereof. In another embodiment, the lecithin used in the emulsions of the present invention comprises a lecithin having 25% or less by weight of fully saturated fatty acid side chains or a hydrogenated lecithin. In one embodiment, the amount of lecithin used in the emulsions of the present invention is 20% to 70% by weight (w / w) of the emulsion, preferably 40% to 60% by weight (w / w), and most preferably 50% to 60% by weight (w / w).

[0151] As used herein, "lipid bilayer" refers to the characteristic membrane structure surrounding liposome particles or vesicles. Liposomes are spherical vesicles composed of one or more phospholipid bilayers, closely resembling the bilayer structure of cell membranes. The ability of liposomes to encapsulate hydrophilic or lipophilic drugs has enabled these vesicles to become useful drug delivery systems (e.g., Exparel®). Other lipid-based particles or vesicles used in drug formulations, such as emulsions, micelles, and solid lipid nanoparticles (SLNs), do not contain a lipid bilayer (see https: / / em.wikipedia.org / wiki / solid_lipid_nanpartice). While these lipid-based formulations may share the same ingredients, such as phospholipids, oil, and water, they differ significantly from each other in their structure as well as in drug delivery properties, such as in vitro release, drug uptake capacity, stability, and pharmacokinetics. Therefore, liposome and emulsion LA formulations are not considered bioequivalent and are not interchangeable in use. The presence of a lipid bilayer can be determined by visualization with an electron microscope, thereby revealing the structural distinction between liposomal and nonliposomal particles. Figure 4C shows an electron micrograph (EM) image of a known liposomal drug formulation (Ambisome®), in which the lipid bilayer is clearly visible, and an EM image of an emulsion droplet of the present invention, in which the lipid bilayer is clearly absent in Figures 4A and 4B.

[0152] As used herein, "liposome" refers to a spherical vesicle composed of one or more phospholipid bilayers (Figure 3), which closely resemble the structure of a cell membrane. The ability of liposomes to encapsulate hydrophilic or lipophilic drugs and make them injectable has enabled these vesicles to become useful drug delivery systems.

[0153] As used herein, "liquid crystal" refers to a state of matter with properties between traditional liquids and solid crystals. For example, liquid crystals flow like liquids, but the molecules can orient themselves in a crystalline fashion. Many different liquid crystal phases exist and can be distinguished by differences in optical properties (e.g., small-angle X-ray scattering) or spectroscopic properties (e.g., FTIR). Liquid crystal structures are often referred to as domains, where the liquid crystal molecules are oriented in different directions. However, within the domains, the molecules are well-ordered. Small-angle X-ray scattering can measure the average spacing between domains ("lattice spacing"). Meanwhile, FTIR can detect changes in the infrared absorption bands of molecules in liquid crystals as a result of their ordered structure or intermolecular interactions. In one embodiment, the emulsions of the present invention are liquid crystals with unique optical and spectroscopic properties. In one embodiment, the emulsions of the present invention have a lattice spacing greater than 2.8 nm, preferably between 3 nm and 5 nm, and more preferably about 3.8 nm.

[0154] As used herein, "lyotropic" refers to a type of liquid crystal composed mostly of organic molecules (such as those contained in the emulsions of the present invention) and solvent (e.g., water). Lyotropic liquid crystals exhibit a phase transition as a function of solvent volume or concentration. In one embodiment, the emulsions of the present invention are of the lyotropic liquid crystal type, which have a pronounced phase transition from water-in-oil to oil-in-water as the water concentration increases from less than 1% to greater than about 1%. In one embodiment, the emulsions of the present invention have a phase transition point at about 1% water.

[0155] The term "metal ion chelating agent or chelator" includes metal ion chelators that are safe for use in injectable formulations. Metal ion chelators act by binding to metal ions, thereby reducing their catalytic effect on oxidation, hydrolysis, or other decomposition reactions. Metal chelators useful in the present invention include ethylenediaminetetraacetic acid (EDTA, edetate), glycine, and citric acid, as well as their respective salts or mixtures thereof. In one embodiment, the emulsions of the present invention contain an antioxidant and / or a metal ion chelator, or a combination thereof.

[0156] As used herein, the term "nerve block" refers to a procedure in which an anesthetic or analgesic is injected into a site surrounding or directly adjacent to a nerve to block pain, sensation, and movement in a specific part of the body. A nerve block can be a regional or peripheral nerve block and is a form of local anesthesia or pain relief.

[0157] As used herein, "N-oxide" refers to an oxidation product of LA in which oxygen is covalently bonded to a nitrogen atom (N) on the LA structure. For example, ropivacaine N-oxide is shown in Figure 2. Because oxidation of the nitrogen atom is the major degradation product of LA in formulations containing lecithin or oil, it must be kept below 0.2% (based on the weight of LA). The 0.2% upper limit is the Identification and Qualification Thresholds for Impurities in FDA's Guidance for Industry Q3B(R2) Impurity in New Drug Products. In one embodiment, the emulsions of the present invention contain an antioxidant and / or a metal ion chelator, or a combination thereof, to inhibit the formation of N-oxides. In a preferred embodiment, the emulsions of the present invention contain 0.2% wt or less N-oxides (based on the weight of LA).

[0158] As used herein, "neutral pH" is in the range of 4 to 8, preferably 5.2 to 7.2.

[0159] As used herein, an "oil-in-water emulsion" is an emulsion in which the oil phase is in the form of small droplets (dispersed phase) suspended or dispersed in an aqueous phase (continuous phase), and a "water-in-oil emulsion" refers to a form in which small aqueous droplets are suspended or dispersed in an oil phase. In a preferred embodiment, the emulsion of the present invention is a water-in-oil emulsion. In another preferred embodiment, the emulsion of the present invention is a water-in-oil emulsion that converts to an oil-in-water emulsion after dilution in water or a biological fluid such as blood. In another embodiment, the emulsion of the present invention is a mixture of an oil-in-water emulsion and a water-in-oil emulsion.

[0160] As used herein, "oil phase" refers to the water-immiscible phase of an emulsion (o / w) containing oil and phospholipids. The oil phase may also contain other lipophilic additives, including antioxidants and antimicrobial preservatives, as well as LA, as in the emulsions of the present invention. In one embodiment, the emulsions of the present invention contain an oil phase at a concentration of about 20% to 99.5% by weight of the emulsion. If the oil phase is less than 20% wt, the emulsion loses its ability to provide the desired sustained-release and sustained action of LA. On the other hand, the oil phase can reach 99.8%, preferably 99.7%, and more preferably 99.5% by weight of the emulsion. It can be difficult to prepare emulsions with an oil phase greater than 99.8% by weight due to the difficulty of removing residual water (<0.2%) using the current emulsion preparation procedure (Ex. 18) for the emulsions of the present invention. An emulsion is predominantly oil-in-water if the water content is greater than about 50% by weight of the emulsion, and predominantly water-in-oil if the water content is less than about 5% by weight of the emulsion. If the water content is between about 5% and about 50% by weight of the emulsion, the emulsion comprises both oil-in-water and water-in-oil. When injected or infused into the human body, the emulsion exists as both oil-in-water and water-in-oil.

[0161] As used herein, the term "organic solvent" refers to a water-immiscible solvent that is safe for injection into humans. Examples of organic solvents include, but are not limited to, glycerin, ethanol, alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, or a combination thereof. The primary purpose of adding an organic solvent to the emulsion of the present invention is to reduce the viscosity of the emulsion. The organic solvent can also function as an antimicrobial preservative, allowing the emulsion to be used for a long period of time. However, the amount of organic solvent must be controlled within a range of approximately 2% to 12% by weight of the emulsion. If less than 4% of the organic solvent is added, the viscosity-reducing effect may not be achieved. However, if the organic solvent exceeds 12% of the emulsion weight, the emulsion of the present invention will be destroyed by a significant increase in oil droplet size (e.g., >1 to 5 microns, due to droplet aggregation), and the emulsion will turn into a thick paste, making it difficult to inject. In one embodiment, the emulsion of the present invention contains 0% organic solvent. In another embodiment, the emulsion of the present invention contains 2% to 12% by weight, preferably 4% to 10% by weight, more preferably 6% to 8% by weight of the emulsion of organic solvent.

[0162] As used herein, the terms "pain intensity scale" or "pain intensity score" or "pain scale" or "pain score" refer to a tool useful for assessing a person's pain level. People typically self-report their pain using specially designed scales, sometimes with the assistance of a doctor, parent, or guardian. Commonly used pain scales include, but are not limited to, the Numerical Rating Scale (NRS), the Visual Analog Scale (VAS), the Categorical Scale, and the Wong-Baker Faces Pain Scale. "Rest Pain Score, or NRS-R, and Pain Score with Activity (NRS-A)" refers to a Numerical Rating Scale (NRS) for pain relief, requiring patients to rate their pain on a prescribed scale. For example, 0 to 10, with 0 being no pain and 10 being the worst pain imaginable. Commonly used NRSs are 11 points (0 to 10), 21 points (0 to 20), and 101 points (0 to 100). The NRS-R is a pain score reported while the subject is at rest. The NRS-A is a pain score reported by subjects during or after performing a specific activity or movement.

[0163] As used herein, the term "pH buffer agent" or "pH buffer salt" includes ionizable pH buffer salts such as phosphate, acetate, citrate, bicarbonate, etc., and having counterions such as ammonium, sodium, or potassium.

[0164] In a preferred embodiment, the emulsion of the present invention has a pH of about 4 to about 8, more preferably about 4 to about 7, such as about 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, or 7.2. The pH of the emulsion is achieved by combining all ingredients according to the emulsion composition of the present invention and adjusting to the target pH by adding an acid (e.g., HCl, acetic acid, phosphoric acid) and / or a base (e.g., NaOH, KOH, arginine, lysine). If the pH is lower than pH 4, the emulsion may be irritating and cause injection site reactions. If the pH is higher than pH 7, the degradation of LA is accelerated, making the emulsion more susceptible to precipitate formation.

[0165] As used herein, "pharmacologically active" or "pharmacological activity" of LA refers to in vivo or in vitro measurements of the intended biological activity of LA. The pharmacological activity of LA formulated in the emulsions of the present invention is not impaired compared to free or unbound LA (Ex. 2). This is in stark contrast to the common belief that emulsions reduce the biological activity of LA, demonstrating that the emulsions of the present invention are functionally distinct from other emulsions, such as Intralipid, which are commonly used to inactivate or as an antidote to LA. In one embodiment, the emulsions of the present invention maintain the pharmacological activity of LA within 50% to 150% of the activity of free LA at the same dose.

[0166] As used herein, the term "pharmacokinetic profile" or "PK profile" refers to the blood concentration profile of a drug over time after administration to an animal or human subject. For the emulsions of the present invention, the PK profile is expressed as the LA plasma concentration over time using the following four key parameters: C max :Maximum plasma LA concentration T max :C maxTime to reach AUC: Area under the curve measuring the bioavailability of LA T 1 / 2 :Excretion half-life

[0167] In one embodiment, the emulsion of the present invention exhibits PK parameters as set forth in Ex 1. In another embodiment, the emulsion of the present invention exhibits a Cmax of 224 to 1280 μg / mL, a Tmax of 2.18 to 30.1 hours, and a PK parameter of 10,200 to 35,100 μg / mL after injection and infiltration into a surgical incision in humans of a 2% wt ropivacaine emulsion of the present invention at a dose of 200 mg. * AUC in h / mL 0-inf and T of 16.3 to 33.7 hours. 1 / 2 The human PK profile is shown.

[0168] As used herein, "phospholipid" refers to any triester of glycerol with two fatty acids and one phosphate ion, either covalently bound to a small organic molecule (such as choline, ethanolamine, glycerol, or serine) or uncovalently bound to anything. Thus, typical phospholipids include phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylserine (PS), and phosphatidic acid (PA). The fatty acids generally have about 10 to about 18 carbon atoms with varying degrees of saturation. These phospholipids can be obtained from natural sources or synthesized. Naturally derived phospholipids are called lecithins. Examples of synthetic phospholipids are 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol, sodium salt (DMPG, Na), and 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine, sodium salt (DPPS, Na). Synthetically produced phospholipids are generally difficult to incorporate into the oil phase, have limited safety profiles, and are expensive. In certain embodiments, the emulsions of the present invention are substantially free of synthetic phospholipids. In another embodiment, lecithin is a preferred phospholipid for the emulsions of the present invention.

[0169] As used herein, "physical stability" or "physically stable" refers to the ability of the emulsions of the present invention to maintain certain desirable physical properties, such as droplet size, visual uniformity, absence of LA precipitate, viscosity, and in vitro release profile, after 2 years at 25°C. In certain embodiments, the emulsions of the present invention remain visually uniform, substantially free of LA precipitate, and have the same viscosity (about 90% to about 110% of the initial value) after about 2 years at 25°C. In another embodiment, the emulsions of the present invention retain the same in vitro release profile by maintaining onset, rate, and duration all at about 50% to about 150% of their initial values.

[0170] As used herein, "reducing agents" useful in the present invention include, but are not limited to, ascorbic acid, ascorbate, ascorbyl palmitate, metabisulfite, propyl gallate, butylhydroxyanisole, butylhydroxytoluene, tocopherol, cysteine, methionine, citric acid, citrate, glucose, fructose, glyceraldehyde, galactose, lactose, maltose, and other reducing sugars, salts, or mixtures thereof. In certain embodiments, the emulsions of the present invention contain a reducing agent. In a preferred embodiment, the emulsions of the present invention contain a reducing agent selected from the group consisting of ascorbic acid, ascorbyl palmitate, tocopherol, cysteine, and methionine. In another embodiment, the reducing agent used is 0.1% to 3% by weight of the emulsion.

[0171] As used herein, the terms "semi-transparent" or "translucent" refer to the partial transparency or clarity of a liquid. A semi-transparent or translucent liquid allows visual inspection for foreign matter or microbial contamination. Therefore, being semi-transparent or translucent is far preferable to being opaque (such as milk). The transparency of a liquid can be quantified by measuring the light transmittance (T,%) using a UV-Visible spectrophotometer at a fixed wavelength (e.g., 700 nm). Emulsions of the present invention typically have a T value of 50% or greater at 700 nm using a 10 mm pathlength quartz cuvette. Under the same conditions, water has a T value of approximately 100%, and regular milk has a T value of less than 10%. In one embodiment, the emulsions of the present invention are semi-transparent or translucent (water-in-oil emulsions). In another embodiment, the emulsions of the present invention have a T value (measured at 700 nm using a 10 mm path length quartz cuvette) of greater than 25%, preferably greater than 40%, more preferably greater than 50% (a mixture of water-in-oil and oil-in-water emulsions or an oil-in-water emulsion).

[0172] As used herein, the term "small-angle X-ray scattering" or "SAXS" refers to an analytical technique that measures the intensity of X-rays scattered by a sample as a function of scattering angle. Measurements are made at very small angles, typically in the range of 0.1 to 5 degrees. Bragg's law dictates that as the scattering angle decreases, structural features become increasingly prominent. SAXS signals are observed whenever a material contains structural features on the nanometer length scale, typically in the range of 1 to 100 nm. The SAXS method is one of the most versatile techniques for characterizing the structure of nanomaterials, such as liquid crystals. SAXS probes structural features such as nanoparticle size distribution, particle shape, particle structure, and liquid crystal phases.

[0173] As used herein, the term "soft tissue" means all tissues in the body that are not hardened by the processes of ossification or calcification, such as bones and teeth. Soft tissues connect, surround, and support internal organs and bones, including, but not limited to, muscle, tendons, ligaments, fat, fibrous tissue, lymphatic and blood vessels, fascia, synovial membrane, or skin.

[0174] As used herein, the term "substantially free" means less than 1% by total weight of the composition.

[0175] As used herein, "solution" refers to a clear, homogeneous mixture composed of only one phase. The emulsions of the present invention are not solutions because they have oil droplets (phase 1) suspended in an aqueous phase (phase 2).

[0176] As used herein, "surfactant" refers to a water-soluble component that reduces the surface tension of a liquid or the interfacial tension between oil and water. Examples of surfactants include polysorbates, spans, cremophor, vitamin E TPGS, sodium lauryl sulfate, poloxamer, and tyloxapol. The emulsions of the present invention are substantially free of surfactants, and preferably substantially free of ionized cationic lipids, PEGylated lipids, or cholesterol, which are commonly used in solid lipid nanoparticles (SLNs).

[0177] As used herein, the term "surgical mesh" refers to a type of mesh sheet of plastic, organic, or biological material that can be implanted to support various tissues or organs during surgery. Surgical mesh can be made from inorganic, organic, polymeric, and biological materials.

[0178] As used herein, the term "suture" refers to a medical device used to fasten body tissue together after injury or surgery. The suture generally uses a needle with a thread.

[0179] As used herein, "ultrafiltration" (UF) refers to various membrane filtration techniques in which hydrostatic pressure forces a liquid through a semipermeable membrane. Suspended solids, oil droplets, or solutes of high molecular weight or size are retained, while water and low molecular weight solutes, such as free drugs, pass through the membrane. Ultrafiltration (e.g., using a 30K Dalton MW cutoff membrane) is used to separate the oil phase (oil droplets are retained on the membrane) and the aqueous phase (passes through the membrane) of the emulsion. The separated oil and aqueous phases can then be analyzed for LA concentration in each phase.

[0180] As used herein, "vegetable oil" refers to oil derived from the seeds or nuts of plants. Exemplary vegetable oils include, but are not limited to, almond oil, borage oil, blackcurrant seed oil, corn oil, safflower oil, soybean oil, sesame oil, cottonseed oil, peanut oil, olive oil, rapeseed oil, coconut oil, palm oil, canola oil, castor oil, and the like. Vegetable oils typically contain long-chain triglycerides, which are formed when three fatty acids (usually about 14 to about 22 carbon atoms in length, with chains varying in number and position of unsaturated bonds depending on the oil source) form ester bonds with three hydroxyl groups on glycerol. In certain embodiments, highly refined grades (also called "super refined") of vegetable oils are commonly used to ensure the safety and stability of pharmaceutical-grade oil-in-water emulsions. Preferred oils for the present invention are soybean oil, corn oil, and sesame oil. Compared to other oils, castor oil is more hydrophilic due to the presence of hydroxy groups in the fatty acid side chains. In one embodiment, castor oil is not used due to the physical instability of the emulsion. This is because some of the fatty acid chains on the oil molecule are unsaturated and can undergo oxidation to form peroxides, which in turn can oxidize LA in the same formulation. Therefore, in one embodiment, the emulsions of the present invention contain an antioxidant and / or a metal ion chelator, or a combination thereof, to inhibit oil oxidation. In one embodiment, the emulsions of the present invention contain about 10% to about 50%, preferably about 20% to about 40%, and more preferably about 30% to about 40% vegetable oil by weight of the emulsion. If the oil content is less than 10%, the emulsion will be very hard and difficult to filter and inject. However, if the oil content is more than 50%, the resulting emulsion will be white, opaque, creamy, and viscous, making it difficult to filter and inject. In another embodiment, the weight ratio of lecithin to oil in the emulsion of the present invention is from 7:1 to 2:5, preferably from 3:1 to 1:1, more preferably from 2:1 to 5:4.

[0181] As used herein, "water soluble" refers to a solid or liquid solute that can be dissolved in water to form a homogeneous solution to the extent of 1 part by weight or more of solute for every 10 parts by weight of water.

[0182] As used herein, a "water-soluble surfactant" is a compound that helps solubilize compounds to form a clear, one-phase aqueous solution by lowering the interface between water and other liquids or between water and solids. Water-soluble surfactants include any surfactant or surface-active agent with a hydrophilic-lipophilic balance (HLB) greater than 7. Examples of water-soluble surfactants include, but are not limited to, polysorbates, spans, lysolecithin, labrasol, cremophor, solutol, gelucire, SDS, and TPGS. Lecithin, on the other hand, is not a water-soluble surfactant because it is insoluble in water. While water-soluble surfactants are commonly used in emulsions, most of them are not preferred for the emulsions of the present invention because they can cause hemolysis (destruction of red blood cell membranes) and inflammation or pain at the injection site. In certain embodiments, the emulsions of the present invention are substantially free of water-soluble surfactants. In a preferred embodiment, the emulsions of the present invention are substantially free of lysolecithin.

[0183] As used herein, the term "wound healing process" or "wound healing" refers to the body's replacement of destroyed or damaged tissue with newly generated tissue. It typically involves four stages: hemostasis, inflammation, proliferation, and maturation. A successful wound healing process does not form a scar or weaken the physical strength of the closed tissue.

[0184] II. Embodiments The present invention provides the following: a) local anesthetics, b) an oil phase, and c) aqueous phase an emulsion composition comprising, consisting essentially of, or consisting of: The aforementioned i. the local anesthetic is at a concentration of up to 4% by weight of the emulsion; ii. the oil phase is at a concentration of about 20% to 99.8% by weight of the emulsion; iii. the oil phase comprises lecithin and vegetable oil in a weight ratio of 7:1 to 2:5; and iv. The emulsion contains particles or droplets having an average diameter of about 200 to 2500 nanometers.

[0185] The present invention provides the following: a) Ropivacaine, its salts or mixtures thereof b) an oil phase, and c) aqueous phase providing an emulsion such as an oil-in-water composition comprising, consisting essentially of, or consisting of The aforementioned i. Ropivacaine is at a concentration of 0.5% to 4% by weight of the emulsion; ii. the oil phase is at a concentration of about 20% to 99.8% by weight of the emulsion; iii. the oil phase comprises lecithin and vegetable oil in a weight ratio of 2:1 to 5:4; and iv. the emulsion comprises particles or droplets having an average diameter of about 200 to 2500 nanometers; v. the emulsion comprises a reducing agent and a metal ion chelating agent; and vi. The pH of the emulsion is 4-7.

[0186] The present invention provides the following: a) ropivacaine hydrochloride, b) an oil phase consisting of soybean lecithin and sesame oil, and c) an aqueous phase consisting of sodium EDTA, cysteine, and water providing an emulsion such as an oil-in-water composition comprising, consisting essentially of, or consisting of The aforementioned i. Ropivacaine is at a concentration of 0.5% to 4% by weight of the emulsion; ii. a sufficient amount of alkali or base to convert about 5-25 mole percent of the added ropivacaine hydrochloride to the non-ionized form, and a sufficient amount of alkali or base to adjust the pH of the emulsion to the target pH; iii. soybean lecithin and vegetable oil are in a weight ratio of 2:1 to 5:4; iv. the emulsion comprises particles or droplets having an average diameter of about 200 to 2500 nanometers; v. The oil droplets have a concentration of about 33% to 99.5% by weight of the emulsion; and vi. The pH of the emulsion is 4-7.

[0187] The present invention provides the following: d) ropivacaine free base; e) an oil phase consisting of soybean lecithin and sesame oil, and f) an aqueous phase consisting of sodium EDTA, cysteine, and water providing an emulsion such as an oil-in-water composition comprising, consisting essentially of, or consisting of The aforementioned vii. Ropivacaine is at a concentration of 0.5% to 4% by weight of the emulsion; viii. a sufficient amount of acid to convert about 75-95 mole percent of the added ropivacaine free base to the ionized form, and a sufficient amount of acid to adjust the pH of the emulsion to the target pH; ix. soybean lecithin and vegetable oil are in a weight ratio of 2:1 to 5:4; x. the emulsion comprises particles or droplets having an average diameter of about 200 to 2500 nanometers; xi. The oil droplets have a concentration of about 33% to 99.5% by weight of the emulsion; and xii. The pH of the emulsion is 4-7.

[0188] III. Method for producing emulsion In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Step 1. Combining oil phase ingredients including lecithin and vegetable oil; Step 2. Homogenizing to form a smooth semi-solid paste ("oil phase"); Step 3. Combining LA, reducing agent, metal chelating agent, and water. Mixing to dissolve all solids and form an aqueous solution ("aqueous phase"); Step 4. Combining the water phase and the oil phase and mixing by homogenization to form an oil-in-water emulsion; Step 5. Adding a sufficient amount of base to convert 5-25 mol % of the LA (salt form) added in step 3 to the non-ionized form, or adding a sufficient amount of acid to convert 75-95 mol % of the LA (free base form) added in step 3 to the ionized form, and then adjusting the pH of the emulsion to 4-7; Step 6. Homogenizing the oil-in-water emulsion so that the average diameter of the oil droplets reaches 200-2500 nm; Step 7. If necessary, adjust the moisture content to 20% to 99.8% by adding more water or removing the water by vacuum drying; Step 8. Optionally, adding a miscible organic solvent (such as ethanol); Step 9. Filtering and sterilizing the emulsion; The present invention provides a method for preparing the emulsion composition of the present invention, comprising, consisting essentially of, or consisting of:

[0189] IV. How to use Pain amenable to management with local anesthetics Administration of the LA emulsion of the present invention can be used to provide pain relief associated with any of a wide variety of disorders, conditions, or diseases. The cause of the pain may be identifiable or unidentifiable. If identifiable, the origin of the pain may be, for example, malignant, non-malignant, infectious, non-infectious, or autoimmune in origin.

[0190] Subjects who are not currently suffering from a disease or condition, but who are susceptible to such a disease or condition, may also benefit from the prophylactic pain relief methods of the present invention, for example, prior to traumatic surgical procedures. Pain suitable for treatment in accordance with the present invention may include long periods of repeated attacks of pain alternating with pain-free periods, or substantially constant pain of varying severity.

[0191] In general, pain can be somatic, neurogenic, or psychogenic. Somatic pain can be muscular or skeletal (i.e., osteoarthritis, lumbosacral back pain, post-traumatic, myofascial), visceral (i.e., chronic pancreatitis, ulcers, irritable bowel), ischemic (i.e., arteriosclerosis obliterans), or associated with the progression of cancer (e.g., malignant or non-malignant). Neurogenic pain can result from post-traumatic and post-operative neuralgia, be associated with neuropathy (i.e., diabetes, toxicity, etc.), nerve entrapment, facial neuralgia, perineal neuralgia, post-amputation, thalamic, causalgia, and reflex sympathetic dystrophy. Each possibility is a separate embodiment of the present invention.

[0192] Specific examples of conditions, diseases, disorders, and origins of pain suitable for management include post-operative pain (also called post-surgical pain), cancer pain (e.g., metastatic cancer, non-metastatic cancer), chronic inflammatory disease pain, neuropathic pain, ectopic pain (e.g., pain after invasive procedures or high-dose radiation therapy, involving scar tissue formation resulting in debilitating freedom of movement and substantial chronic pain), complex regional pain syndrome, low back pain (lower back pain), soft tissue pain, joint and bone pain, central pain, injury (e.g., debilitating pain), and Pain conditions include, but are not limited to, debilitating injuries (e.g., paralysis, quadriplegia, etc.), non-debilitating injuries (e.g., back, neck, spine, joints, legs, arms, hands, feet, etc.), joint pain (e.g., rheumatoid arthritis, osteoarthritis, joint conditions of unknown cause, etc.), genetic diseases (e.g., sickle cell anemia, etc.), infectious diseases and resulting syndromes (e.g., Lyme disease, AIDS, etc.), chronic headaches (e.g., migraine), causalgia, hyperesthesia, sympathetic dystrophy, phantom limb syndrome, denervation, etc. The pain can be associated with any part(s) of the body, e.g., the musculoskeletal system, internal organs, skin, nervous system, etc. Each possibility is a separate embodiment of the present invention.

[0193] Cancer pain is one example of a broad category of pain that may be alleviated using a local anesthetic emulsion. One underlying cause of cancer pain is the intense local stretching of tissues by neoplastic lesions. For example, when cancer cells rapidly proliferate in an uncontrolled manner, tissues in the local area of ​​cancer cell growth are subjected to mechanical stresses required to displace the tissue and accommodate the increased volume occupied by the tumor mass. When the tumor mass is confined to a small, enclosed compartment, such as the marrow of a bone, the resulting pressure can result in severe pain. Another source of pain can result from aggressive treatments used to combat a patient's cancer, such as radiation therapy, chemotherapy, etc. Such cancer treatments can involve local or widespread tissue damage, resulting in pain.

[0194] Pain associated with any type of malignant or non-malignant cancer is suitable for alleviation according to the methods described herein. Specific examples of cancers that may be associated with pain (due to the nature of the cancer itself or therapies used to treat the cancer) include, but are not necessarily limited to, lung cancer, bladder cancer, melanoma, bone cancer, multiple myeloma, brain cancer, non-Hodgkin's lymphoma, breast cancer, oral cancer, cervical cancer, ovarian cancer, colon cancer, rectal cancer, pancreatic cancer, dysplastic nevi, endocrine cancer, prostate cancer, head and neck cancer, sarcoma, Hodgkin's disease, skin cancer, kidney cancer, stomach cancer, leukemia, testicular cancer, liver cancer, endometrial cancer, and aplastic anemia. Certain neuropathic pains may also be suitable for treatment according to the present invention.

[0195] Chronic low back pain is another broad category of pain that may be suitable for management using the methods described herein. Chronic low back pain generally results from one or more of the following six causes: (i) pressure on the facet joints caused by slippage, arthritis, wedging, or scoliosis; (ii) mechanical compression of the nerve roots by radiculopathy, bulging discs, or tumors; (iii) tendonitis or tendon sprain; (iv) muscle spasm or strain; (v) ischemia, localized insufficiency of circulatory flow; and (vi) neuropathy, damage to nerve tissue of metabolic etiology, or resulting from tumors of the cord-like tissue or central nervous system disease.

[0196] The emulsions described herein can be used for a variety of therapeutic purposes requiring a long-acting or sustained-release formulation of LA.

[0197] In common medical practice, emulsions have always been used to inactivate LA or as an antidote to LA overdose. It is well documented that emulsions (drug-free) are commonly used to reduce the cardiovascular effects or toxicity of LA. Various researchers have clearly demonstrated that emulsions inactivate LA, resulting in the disappearance of its pharmacological action or toxicity (Zausig, York A. et al., Lipid Emulsion Improves Recovery from Bupivacaine-Induced Cardiac Arrest, but Not from Ropivacaine- or Mepivacaine-Induced Cardiac Arrest, Anesthesia & Analgesia: October 2009-Volume 109-Issue 4-pp. 1323-1326; E. Litonius et al., Effect of intravenous lipid emulsion on bupivacaine plasma concentration in humans, Anaesthesia 2012, 67, 600-605; Lotte CG et al., Systematic review of the effect of intravenous lipid emulsion therapy for local anesthetic toxicity, Clinical Toxicology, 2016, VOL. 54, NO. 3, 167-193, http: / / dx.doi.org / 10.3109 / 15563650.2015.1121270).

[0198] Therefore, the use of emulsions to deliver pharmacologically active LA is contrary to common understanding and medical practice. The present invention relates to the surprising discovery that, contrary to common understanding and medical practice of using emulsions to inactivate LA, the present application discloses the use of emulsions to not only maintain the pharmacological effect of LA, but also to extend its duration of action and reduce its toxicity.

[0199] The sustained action of the emulsions of the present invention is made possible by the one-time application of relatively high doses of LA by injection, infiltration and / or infusion, providing a high concentration of LA in the local tissue to which it is applied.

[0200] Subjects suffering from or susceptible to pain can benefit from pain relief by the methods described herein for 12 to 24 hours, 24 to 48 hours, 48 ​​to 72 hours, or longer. If longer-term pain relief is desired, administration of the local anesthetic emulsion can be repeated. Typically, administration of the emulsion can be repeated two, three, or more times within about one week or several months.

[0201] The methods of the present invention for treating or preventing pain can further include co-administering another prophylactic or therapeutic agent, including, but not limited to, anti-infective agents, anti-inflammatory agents, anti-renal failure agents and anti-cardiovascular agents, antiemetics, anti-anxiety agents, and analgesics or antidotes, to mitigate any potential side effects of the local anesthetic, including, but not limited to, nausea, vomiting, headache, decreased white blood cell count, decreased red blood cell count, decreased platelet count, headache, fever, fatigue, muscle pain, general pain, bone pain, pain at the injection site, diarrhea, neuropathy, pruritus, stomatitis, alopecia, anxiety, or depression.

[0202] One therapeutic benefit of pain relief using the emulsions of the present invention is expected to be a reduction in the use of general anesthetics or patient-controlled analgesia, particularly opiates or opioid drugs.

[0203] Despite the relatively high doses given in a one-time application, the emulsions of the present invention do not provide a burst release of LA or a high C of LA that exceeds the cardiovascular or CNS toxicity levels of the drug. max The release profile of LA from the emulsion is smooth, flat and peak-free.

[0204] The LA dose, emulsion volume, or application frequency (single or multiple) can be determined by efficacy as measured by pain scores such as the NRS-R or NRS-A, and reduced use of general anesthetics (which may lead to reduced cardiovascular and CNS toxicity) can be determined by studying local and systemic pharmacokinetic and / or in vitro release profiles.

[0205] Similarly, the method of application (injection, infiltration, or infusion, or a combination thereof) may be determined by efficacy as measured by pain scores such as NRS-R or NRS-A, or reduced use of general anesthetics (which may result in reduced cardiovascular and CNS toxicity) may be determined by studying local and systemic pharmacokinetic profiles and / or in vitro release profiles.

[0206] LA C max Administering a high volume of the emulsion of the present invention is the preferred method for better efficacy, as long as the dose remains below cardiovascular and CNS toxic levels, the local tissue (e.g., surgical incision site) can accept and accommodate a high volume of the emulsion of the present invention, and wound healing is not impaired.

[0207] The dose of LA in the emulsion of the present invention also depends on the type of surgery or wound, the severity of the pain and the co-administration of other anesthetic agents.

[0208] Duration of action also depends on the route of administration, but generally a single injection of a large volume of emulsion into soft tissue is expected to provide a longer duration of action than multiple injections of smaller volumes (e.g., infiltration). Similarly, injection or infiltration into deep tissue generally provides a longer analgesic effect than topical application or infusion. Furthermore, undiluted emulsions tend to provide a longer duration of action than diluted emulsions.

[0209] For surgical incisions or wounds, a combination of infiltration and infusion is a common method of administration. For a given incision / wound, it is generally desirable to apply the maximum amount of emulsion by infiltration to fill the maximum tissue area. It is also desirable to infiltrate the incision / wound with emulsion and inject the remaining amount that the wound can hold. For nerve blocks, injection or infiltration is the preferred route of administration.

[0210] Since all amide-type LAs share similar physical, chemical, and pharmacological properties, it is expected that pain relief by the emulsions of the present invention can be delivered by amide-type LAs, such as, but not limited to, ropivacaine.

[0211] Once the dosage of the emulsion is determined, it can be administered over a variety of time periods, including, but not limited to, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every 2 weeks, about every 3 weeks, about every month, and about every 2 months.

[0212] The dosage and frequency of administration of the emulsion can be adjusted according to various factors, including the type, age, weight, sex, and condition of the subject; the severity of the disease being treated; the route of administration; the subject's renal or hepatic function; and the specific local anesthetic used. Those skilled in the art can easily determine the effective amount of local anesthetic useful for treating pain, including the specific type of pain to be treated.

[0213] The in vivo release characteristics of a given emulsion of the present invention can be evaluated by conducting an in vitro release test, which is particularly useful for ensuring that the emulsion of the present invention retains its sustained release characteristics after being modified. For example, an in vitro release test can be used to determine the degree of dilution that can be used to dilute the emulsion without losing the sustained release characteristics.

[0214] The viscosity of the emulsions of the present invention is also a consideration when selecting the route of administration or dilution. For infusion or topical application, the emulsion can be easily administered by extrusion using a needleless syringe, so the viscosity of the emulsion can be relatively high. For infiltration or injection, the emulsion must be injected through a needle using a syringe, so a lower viscosity is required. Furthermore, for nerve block applications, the emulsion must have an even lower viscosity because longer needles or catheters are usually required for such applications. The viscosity of the emulsions of the present invention varies with the water content or dilution ratio. A low dilution ratio (too little water) may result in a viscosity that is too high to inject. On the other hand, a very high dilution ratio (too much water) will result in the loss of the sustained-release properties of the emulsion. Therefore, a balance between the viscosity and in vitro release properties of the emulsion can be achieved to define acceptable diluents and dilution methods for the emulsions of the present invention.

[0215] The emulsions of the present invention may be administered before, simultaneously with, or after an opioid or non-opioid analgesic, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 ​​hours, or 72 hours of each other.

[0216] In one embodiment, the emulsion of the present invention is a translucent homogeneous liquid filled in a glass or plastic container such as a vial, bottle, ampoule, syringe, or bag. The typical volume per container is 5 mL to 50 mL, preferably 10 mL to 25 mL. The liquid is drawn into a syringe before use.

[0217] In a preferred embodiment, the emulsions of the present invention are provided in a pre-filled syringe with an attached hypodermic needle, ready for injection, a feature particularly preferred for intraoperative applications.

[0218] In one embodiment, the pre-filled syringe may also include a needle suitable for injection, instillation and infiltration and topical application of the emulsion.

[0219] In one embodiment, the needle used for the emulsion is an 18 to 25 G needle, preferably a 21 G needle.

[0220] In certain embodiments, the emulsions of the present invention are administered via injection or infiltration into soft tissue or near a nerve using a needle attached to a syringe or a needle attached to a catheter and then a syringe.

[0221] In certain embodiments, the emulsions of the present invention are infiltrated or applied to an open surgical wound, topically or injected with a syringe. In some embodiments, the formulations are administered by subcutaneous, intradermal, intramuscular, or transdermal injection.

[0222] In one embodiment, the emulsion will be administered via wound infiltration to the surgical site.

[0223] In one embodiment, the emulsion will be administered via wound injection to the surgical site.

[0224] In one embodiment, the emulsion will be administered via a combination of wound infiltration and injection into the surgical site. The dosage range will depend on the size and location of the surgical incision. Typical volumes are 5 mL to 50 mL. Preferred dosage volumes are 10 mL to 40 mL. Typical volume ratios between infiltration and injection are 1:20 to 20:1. A typical syringe and needle combination is used to perform the wound infiltration. Typical syringe sizes are 1 mL to 50 mL. Preferred syringe sizes are 10 mL to 30 mL. Typical needle sizes are 18 to 30 Gauge, 3 / 8 to 3.5 inches. Preferred needle sizes are 19 to 22 Gauge, 1 to 1.5 inches.

[0225] In another embodiment, the emulsion will be administered via a peripheral nerve block, a local nerve block, field block, or plain block near a specific nerve or bundle of nerves, blocking the sensation of pain from that specific area to the body.

[0226] In one preferred embodiment, the emulsion will be administered via ultrasound-guided regional nerve block. Typical volumes are 5 mL to 50 mL. Preferred doses are 10 mL to 40 mL. In another preferred embodiment, the emulsion will be administered using a nerve block needle, with or without tubing and an extension set. Typical nerve block needles are 20 to 22 Gauge, 1-3 / 8 to 6 inches. In one embodiment, the emulsion will be administered via an epidural needle. Typical epidural needles are 17 to 22 Gauge.

[0227] Because surgeries vary in terms of incision size and pain severity, dilution is always preferable for drugs used to control postoperative pain, allowing for adjustment of dosage, concentration, and release profile. Furthermore, the application of nerve blocks generally requires a low LA concentration. It is known that some polymer-based sustained-release formulations cannot be diluted, thereby limiting their applicability in surgery. As an oil-in-water emulsion, the composition of the present invention is miscible with water and can therefore be diluted. In a preferred embodiment, the emulsion of the present invention is diluted with water, saline, dextrose solution, or other safe injectable diluents before administration to a subject.

[0228] Dilution of the emulsions of the present invention may change their viscosity and drug release profile. Therefore, dilution can only be performed within a specified range. High viscosities (e.g., >400 centipoise) make injection through a syringe difficult. The viscosity of the emulsions of the present invention is sensitive to the diluent and dilution ratio. The diluent for the emulsions of the present invention may be an IV infusion fluid such as water, saline, dextrose solution, lactated Ringer's solution, or other safe injectable diluents such as ethanol or propylene glycol, or a combination thereof. The dilution ratio is defined as the volume of diluent relative to the volume of emulsion. Surprisingly, dilution with water initially increases the viscosity of the emulsions of the present invention, and then decreases the viscosity after excessive dilution. For example, 1:1 dilution with saline and 2:1 dilution with water increase the viscosity of the emulsion to about 500 to 17,000-28,000 centipoise and about 500 to about 40,000 centipoise, respectively. On the other hand, excessive dilution (e.g., a dilution ratio >10:1) can alter the emulsion's sustained-release characteristics and impair its pain relief efficacy or duration of action. To balance viscosity and release characteristics, the emulsions of the present invention are diluted with diluents at dilution ratios of 10:1 to 1:1. A preferred dilution ratio for the emulsions of the present invention is 4:1 to 2:1 with normal saline or water. For example, a 2:1 dilution with normal saline resulted in an emulsion viscosity of approximately 21 centipoise while maintaining an acceptable in vitro release profile (EX12, 13). Different diluents also likely affect viscosity differently, necessitating adjustment of the dilution ratio. Therefore, the preferred dilution ratio for new diluents is one that will result in an emulsion viscosity of 400 centipoise or less and an acceptable in vitro release profile for LA.

[0229] In one embodiment, the emulsion is diluted with saline and then mixed to a uniform concentration by physical mixing, including, but not limited to, repeated withdrawal and expulsion using a syringe in an open container and shaking the emulsion and diluent in a closed container, such as a bottle, vial, bag, or syringe. Preferred containers for mixing are open sterile containers and sterile syringes for surgical bedside admixes. 3 to 20 withdrawal / expulsion cycles will produce a uniform mixture. 8 to 12 preferred cycles have also produced a uniform mixture.

[0230] In one embodiment, the emulsion and its diluted emulsion have different in vitro release profiles. For example, the undiluted emulsion has a LA release range of 19-46% at 12 hours, 30-60% at 24 hours, 45-77% at 48 hours, and 56-84% at 72 hours. The emulsion diluted with 2:1 saline has a LA release range of 49-90% at 12 hours, 67-100% at 24 hours, 83-100% at 48 hours, and 89-100% at 72 hours, using the in vitro release method described in Example 13. In one embodiment, the emulsion of the present invention has an LA release range of 19-90% in 12 hours, 30-100% in 24 hours, 45-100% in 48 hours, and 56-100% in 72 hours, preferably 19-49% in 12 hours, 30-67% in 24 hours, 45-83% in 48 hours, and 56-89% in 72 hours.

[0231] Some liquid injectables or implants are incompatible with other surgical instruments, such as sutures or mesh, and therefore cannot be used in surgeries requiring sutures or mesh. In one embodiment, the emulsion of the present invention is compatible with surgical instruments such as mesh and sutures, and can be safely used in surgeries where mesh and sutures are used. Typical mesh materials include polypropylene (PP), expanded polytetrafluoroethylene (e-PTFE), and PP / PCG-25 (polyglucaprone 25). Typical suture materials include nylon, polydioxanone, polypropylene, polyglyconate, and polyglactin 910.

[0232] In one embodiment, a surgical mesh will retain 90-110% of its original tensile strength after being immersed in an emulsion of the present invention at 37 deg C for at least 7 days (Ex6).

[0233] In one embodiment, surgical sutures will retain 90-110% of their original tensile strength after being immersed in an emulsion of the present invention at 37 deg C for at least 7 days (Ex6).

[0234] Drugs suitable for administration to surgical or wound sites do not affect the healing process of the incision or wound. Some drugs are known to alter the wound healing process, resulting in changes in the healing rate or scar formation after application. The emulsions of the present invention have been shown to have no adverse effect on the wound healing process, as evidenced by unchanged tensile strength and scar-free appearance of tissues healed from surgical wounds (Ex. 2, 5). In one embodiment, the emulsions of the present invention do not adversely affect soft tissue wound healing. In another embodiment, the emulsions of the present invention do not adversely affect bone healing. In another embodiment, the emulsions of the present invention do not adversely affect nerve tissues, including, but not limited to, the sciatic nerve, ventral spinal roots / branches, and peripheral nerves in tissues near the wound site.

[0235] Postoperative pain can persist for 3 to 5 days, and therefore it is desirable for the effects of a pain drug to last for 3 to 5 days. The emulsions of the present invention are designed to have a long retention time at the injection site, slowly releasing LA to produce a local anesthetic effect at the incision / wound site or nerve block. The sustained release properties can be demonstrated by an extended pharmacokinetic profile compared to LA in conventional solution formulations (e.g., NAROPIN®). For example, subcutaneous injection of the emulsion in rats resulted in C max 576-4110ng / mL, T max is 0.5 to 6 hours and T 1 / 2 Subcutaneous injection of the emulsion in minipigs provided a sustained release pharmacokinetic profile with a C max 339-1570ng / mL, T max is 4.75 to 16.8 hours and T 1 / 2 Infiltration of the emulsion into wounds in minipigs resulted in a sustained release pharmacokinetic profile with a C of 392 to 1080 ng / mL. max , T 1.08~5.5 hours max and T of 18.6 to 31.7 hours. 1 / 2 In human studies, infiltration of the emulsion into postoperative wounds resulted in the production of 200-3000 ng / mL C max , T of 1 to 40 hours max and T of 10 to 40 hours 1 / 2 This resulted in...

[0236] In one embodiment, the emulsions of the present invention have a longer pharmacokinetic profile, a lower C compared to the same dose of LA in a conventional solution formulation such as NAROPIN®. max , longer T max and T 1 / 2 to provide.

[0237] In one embodiment, the pharmacokinetic profile of the emulsion of the present invention exhibits a lower C than that produced by a solution formulation of the same LA. max , long T max and Big T 1 / 2 It has.

[0238] In one embodiment, the emulsion of the present invention is a C produced by a solution formulation of the same LA. max C, which is about 10 to 100% of max The present invention provides a pharmacokinetic profile having the following structure:

[0239] In one embodiment, the emulsion of the present invention is a T produced by a solution formulation of the same LA. max T max The present invention provides a pharmacokinetic profile having the following structure:

[0240] In one embodiment, the emulsion of the present invention is a T produced by a solution formulation of the same LA. 1 / 2 T, which is about 2 to 5 times 1 / 2 The present invention provides a pharmacokinetic profile having the following structure:

[0241] The emulsions of the present invention also provide a longer duration of analgesic effect in animals and humans compared to solution LA formulations (e.g., NAROPIN®) or liposomal formulations of the LA drug bupivacaine (Exparel®).

[0242] In one embodiment, the emulsions of the present invention provide 3-4 times longer analgesia compared to NAROPIN® or Exparel® as measured by latency to first opioid use in humans or latency to response using a pin-prick model in animals. In another embodiment, the emulsions of the present invention provide longer-lasting analgesia and enhance post-operative recovery (ERAS) as measured by shorter time spent in the PACU (Ex3).

[0243] In one embodiment, the emulsions of the present invention provide superior analgesic efficacy for the management of postoperative pain when administered via wound infiltration or nerve block compared to NAROPIN® (ropivacaine solution), Marcaine (bupivacaine solution), Exparel (liposomal formulation of bupivacaine), saline placebo, or vehicle placebo in humans, as measured by lower pain intensity scores, including, but not limited to, lower mean area under the curve (AUC) of the NRS-A and / or NRS-R through 0-24, 0-48, 0-72, 24-72, 24-48, and 48-72 hours after administration. In another embodiment, the emulsions of the present invention exhibit superior analgesic efficacy as measured by a reduction in total opioid consumption at equivalent doses of oral morphine over the following post-administration periods: 0-6, 0-12, 0-24, 0-48, 0-72, 6-12, 6-24, 6-48, 6-72, 12-24, 12-48, 12-72, 24-48, 24-72, and 48-72. In another embodiment, the emulsions of the present invention provide better efficacy as measured by lower total opioid consumption by Day 7 and through the end of study / treatment. In another embodiment, the emulsions of the present invention exhibit better efficacy as measured by greater subject satisfaction with analgesia at 24, 48, and 72 hours. In yet another embodiment, the emulsions of the present invention exhibit better efficacy as measured by an earlier time to readiness for discharge, including, but not limited to, assessment based on the MPADSS at 12, 24, 48, and 72 hours. (EX2)

[0244] In another embodiment, the emulsions of the invention, when administered via wound infiltration, provide a lower pain score at rest (NRS-R) or pain score with activity (NRS-A) than NAROPIN®, Marcaine, Exparel, saline placebo, or vehicle placebo in humans during the following post-administration windows: 0-24 hours, 0-48 hours, 0-72 hours, 24-48 hours, 48-72 hours, and 24-72 hours (EX2).

[0245] In another embodiment, administration of the emulsion of the present invention via wound infiltration / infusion or nerve block reduces opioid consumption by a patient after surgery. In a preferred embodiment, administration of the emulsion via wound infiltration / infusion or nerve block reduces opioid consumption by a patient by 5%, 10%, 20%, 30%, 40%, or 50% or more. In another preferred embodiment, administration of the emulsion via wound infiltration / infusion or nerve block reduces opioid consumption by a patient compared to administration of NAROPIN®, Marcaine®, or Exparel®.

[0246] In one embodiment, the emulsions of the present invention do not cause local anesthetic toxicity (LAST) when administered via wound infiltration or nerve block. In another preferred embodiment, the emulsions of the present invention do not cause more local anesthetic toxicity (LAST) when administered via wound infiltration or nerve block compared to the same dose of LA in NAROPIN®, Marcaine®, or Exparel®.

[0247] 1. Use of an emulsion composition for pain relief, comprising: a. local anesthetics, b. an oil phase, and c. an aqueous phase i. the local anesthetic is at a concentration of up to 4% by weight of the emulsion; ii. the oil phase is at a concentration of about 20% to 99.8% by weight of the emulsion; iii. the oil phase comprises lecithin and vegetable oil in a weight ratio of 7:1 to 2:5; and iv. The emulsion comprises particles or droplets of about 30 to 2500 nanometers. Includes:

[0248] The present disclosure provides a method for alleviating pain in a subject in need thereof, said method comprising: Administering to a subject an effective amount of an emulsion composition, said emulsion composition comprising: an amide-type local anesthetic, wherein the amide-type local anesthetic is present in an amount of about 4% by weight or less of the emulsion; an oil phase, the oil phase comprising lecithin and vegetable oil in a weight ratio of 2:1 to 5:4, the oil phase being at a concentration of about 20% to 99.8% by weight of the emulsion; and an aqueous phase, the emulsion comprising particles or droplets having a diameter of about 30 nm to about 2500 nm; an emulsion composition comprising: The present invention provides a method comprising:

[0249] In certain embodiments, the pain is a member selected from the group consisting of somatic, neuropathic and psychogenic pain.

[0250] In certain embodiments, the pain is post-operative pain or cancer pain.

[0251] In certain embodiments, administration of the composition provides pain relief in a subject for at least 24 hours.

[0252] In certain embodiments, the composition is administered to the subject by a member selected from the group consisting of wound infiltration, an infusion, and a nerve block.

[0253] In certain embodiments, the amide-type local anesthetic is a member selected from the group consisting of bupivacaine, ropivacaine, and pharmaceutically acceptable salts thereof.

[0254] In certain embodiments, the amide-type local anesthetic is ropivacaine.

[0255] In certain embodiments, administering the ropivacaine composition by wound infiltration or infusion maintains the plasma level of ropivacaine below its cardiotoxic level.

[0256] In certain embodiments, administration of the composition does not cause any detectable local anesthetic toxicity (LAST).

[0257] In certain embodiments, the vegetable oil is a member selected from the group consisting of sesame oil, soybean oil, olive oil, and combinations thereof.

[0258] In a particular embodiment, the vegetable oil is sesame oil.

[0259] In certain embodiments, the composition further comprises a water-miscible organic solvent selected from the group consisting of ethanol, propylene glycol, glycerol, and liquid polyethylene glycol.

[0260] In certain embodiments, the composition has a viscosity of about 2 to 600 centipoise.

[0261] In certain embodiments, the composition has a pH of about 4 to about 7.

[0262] In certain embodiments, the composition is a translucent or white opaque liquid and is filterable through a 0.2 micron filter.

[0263] In certain embodiments, the lecithin contains 75% or more by weight of phosphatidylcholine.

[0264] In certain embodiments, the composition is diluted with saline at a ratio of 2:1 or greater, or with water at a ratio of 4:1 or greater, prior to administration.

[0265] In certain embodiments, greater than 90% by weight of the amide-type local anesthetic is non-covalently bound to the oil droplets.

[0266] In certain embodiments, the composition is administered using a syringe, a syringe with a needle, or a syringe with a catheter.

[0267] In certain embodiments, administration of the composition results in a lower C compared to the same local anesthetic in a solution formulation.max , longer T max and larger T 1 / 2 The present invention provides a long-term pharmacokinetic profile having

[0268] In certain embodiments, the composition provides pain relief by reducing pain intensity as measured by a pain intensity scale by 10% or more for up to 72 hours.

[0269] In certain embodiments, administration of the composition provides rapid onset of relief in at least 60 minutes, which lasts for about 48-72 hours after administration.

[0270] In certain embodiments, the composition provides for the delay of opioid use by the subject.

[0271] In certain embodiments, the composition is provided in a vial or syringe and is ready to be injected or administered.

[0272] In certain embodiments, the composition is administered via a needle syringe or a catheter syringe.

[0273] In certain embodiments, the oil droplets are non-liposomal and substantially free of liposomal bilayer structures. [Example]

[0274] The present invention will be further understood by reference to the following non-limiting examples.

[0275] Example 1 Human pharmacokinetic study of ropivacaine emulsion compared with ropivacaine solution (NAROPIN®)

[0276] In this example, a human pharmacokinetic (PK) study was conducted on a ropivacaine emulsion of the present invention, with a composition coded as F-53. F-53 contains approximately 2.6% ropivacaine HCl, approximately 52% soybean lecithin, approximately 35% sesame oil, approximately 0.02% sodium EDTA, approximately 0.1% cysteine, ethanol, and water. F-53 was injected into 12 human subjects at a dose of 200 mg and infiltrated into the surgical incision site. Blood samples were collected, and blood ropivacaine concentrations were measured by LC-MS analysis. PK results were compared with reported PK data (Pettersson et al.) for a ropivacaine solution (NAROPIN® Injection), an FDA-approved drug that is a sterile isotonic solution containing ropivacaine HCl, sodium chloride, and water. The following table summarizes the human PK data for F-53 and NAROPIN®. [Table 1]

[0277] Conclusion: F-53 significantly improved T max is long, T 1 / 2 is long, C max It has a characteristic human PK profile with a highly sustained release state, as evidenced by a lower T max and T 1 / 2 exhibits long-lasting anesthetic action and has a high C max is associated with cardiotoxicity, so a lower C max exhibits a better safety profile.

[0278] Example 2 Human Efficacy and Safety Studies

[0279] In this example, a human clinical safety and efficacy study of ropivacaine emulsion was conducted in human subjects after mini-abdominoplasty. This was a randomized, double-blind, single-center study to evaluate the safety, PK profile, and duration of analgesic action of F-53 in men and women aged ≥18 years and ≤70 years for the management of postoperative pain after mini-abdominoplasty. Each randomly assigned patient received either F-53 (200 mg of ropivacaine) or placebo (0.9% NaCl) administered by wound infiltration and infusion into the soft tissues prior to suturing after mini-abdominoplasty. This study revealed the following key findings: 1. F-53 effectively reduced patients' pain intensity (NRS-R) by 10-25% every 12-24 hour period for up to 72 hours. 2. The analgesic effect of F-53 appeared quickly (within 60 minutes) and was sustained evenly throughout the period from 0 to 72 hours after drug administration. 3. F-53 delayed patients' time to first opioid use: 16.5 hours for F-53 vs. 12.3 hours for placebo 4. F-53 was well tolerated and showed no evidence of local tissue reactions or impaired wound healing. No subjects were assessed by the investigator as having LAST. No serious adverse events (SAEs) were observed in the study. Clinical laboratory data and vital sign values ​​did not show any abnormalities suggesting adverse effects of F-53. No subjects in the F-53 group experienced clinically significant ECG changes.

[0280] Example 3 Local anesthetic efficacy of ropivacaine emulsion compared to NAROPIN® and Exparel® (1.3% bupivacaine liposomal injectable suspension)

[0281] The purpose of this study was to compare the local anesthetic efficacy of the ropivacaine emulsion of the present invention, NAROPIN® Injection, and a liposomal formulation of bupivacaine, Exparel® (1.3% bupivacaine liposomal injectable suspension).

[0282] The local anesthetic efficacy of these formulations after subcutaneous injection was evaluated in guinea pigs using the pinprick model. This model involves injecting the formulation subcutaneously into the guinea pig to form a wheal (small swelling), pricking the wheal area with a pin, and observing the animal's reaction. Local anesthetic activity is confirmed if the animal does not react to the pinprick.

[0283] F-10, F-11, and F-13 are emulsions prepared according to the present invention, each containing ropivacaine (1% as the HCl salt for F-10, 2% as the HCl salt for F-11, or 2% as the free base for F-13), about 52% soybean lecithin, about 35% sesame oil, about 0.02% EDTA, about 0.1% cysteine, ethanol, and water. Ropivacaine HCl and ropivacaine differ significantly in hydrophobicity from ropivacaine free base, with the HCl salt having a log P of 1.1 and the free base having a log P of 2.9.

[0284] For comparison, a NAROPIN® formulation containing 1% ropivacaine HCl, a liposomal formulation of bupivacaine (Exparel® containing 13.3 mg / mL bupivacaine), and V-10 (a drug-free blank emulsion), the vehicle for F-10, were also tested. For each formulation, the same dose (mg / kg) was administered to six animals, and the number of animals with no response (non-response) was plotted over time ( FIG. 6 ).

[0285] All formulations except V-10 exhibited significant local anesthetic activity. However, the duration of local anesthetic activity (the time to maintain 50% unresponsiveness) varied significantly in the following order: F-11 ≒ F-13 (12-13 hours) > F-10 (9 hours) > Exparel® (5 hours) > NAROPIN® (3 hours). No obvious adverse reactions were observed in the test animals.

[0286] Conclusion: The emulsions of the present invention containing the salt or free base of a local anesthetic not only maintain local anesthetic activity but also provide desirable long-term local anesthetic efficacy. The emulsions of the present invention exhibited a much longer duration of action than the solution formulation NAROPIN® and the liposomal formulation Exparel®. Clearly, the emulsion formulations of the present invention are not as effective as the solution or liposomal formulations. Furthermore, the emulsion formulations of the present invention can provide long-term local anesthetic activity regardless of the hydrophobicity of the LA.

[0287] Example 4 Safety evaluation of ropivacaine emulsion

[0288] The purpose of this study was to determine the maximum tolerated dose (MTD) and local toxicity at the injection site of ropivacaine emulsion (F-32, which has a similar composition to F-53 in Example 1) in Sprague-Dawley (SD) rats by single subcutaneous injection. For comparison, NAROPIN® injection was also tested. The details of the study are summarized in the following table: [Table 2]

[0289] Deaths were observed on day 1 in animals administered NAROPIN® at doses of 44 mg / kg or 88 mg / kg. Clinical observations in animals administered NAROPIN® included abnormal gait, rapid breathing, prone posture, salivation, convulsions, decreased activity / lethargy, hunched posture, and loss of righting reflex. No deaths were observed in animals administered F-32. At 50 mg / kg, animals did not show any signs of toxicity (systemic or local at the injection site). Clinical observations of abnormal gait, decreased activity / lethargy, difficulty breathing, and material (red) around the mouth and nose were observed only at 400 mg / kg between days 2 and 3.

[0290] Conclusion: F-32 is a much safer formulation than NAROPIN®. The MTD is less than 44 mg / kg for NAROPIN® and more than 400 mg / kg for F-32.

[0291] Example 5 Effect of emulsions on wound healing

[0292] In this example, the effect of a ropivacaine emulsion formulation (F-53) on wound healing was evaluated after infiltration / infusion of surgical incisions made on the dorsal skin of minipigs. The incisions were allowed to heal, and 28 days after administration, pig skin at the incision site was harvested and cut into small specimens for tensile testing according to ASTM D638. The specimens were pulled apart at a constant rate until fracture or separation occurred, and the tensile strength (MPa) was recorded and compared between emulsion-treated and saline-treated skin. Tensile strength at 28 days was also similar in saline-infiltrated skin (2.3 MPa ± 0.5 [male], 4.8 ± 1.3 [female]) compared to emulsion-infiltrated skin (3.0 MPa ± 0.7 [male], 3.5 ± 0.5 [female]), and no scarring was observed in either group.

[0293] In conclusion, ropivacaine emulsion did not adversely affect wound healing.

[0294] Example 6 Compatibility of emulsions with sutures and meshes

[0295] In this example, the compatibility of sutures and mesh with a ropivacaine emulsion formulation (F-53) was evaluated in vitro.

[0296] In this study, each suture tested was cut to a length of 13 inches and soaked in F-53 or normal saline for 7 days at 37°C. Break strength was measured by tensile testing per ASTM D2256. Four types of sutures were tested: PDSII, Prolene, Maxon, and Vicryl. For all sutures tested, F-53-soaked specimens exhibited the same break strength as comparable normal saline-soaked controls after up to 7 days of soaking, indicating that F-53 has the same mechanical effect on sutures as normal saline, and that all sutures exposed to F-53 for up to 7 days did not demonstrate a significant decrease in tensile strength after prolonged exposure to F-53.

[0297] For mesh testing, each mesh sample was cut into strips measuring 0.5" x 1.5" long, with the 1.5" dimension being the longitudinal direction. The strips were submerged (soaked) in F-53 or normal saline at 37°C for 7 days. Three types of mesh were tested (Bard Dulex, Prolene, and Ultrapro). Each strip sample was measured using a tensile test according to ASTM D5035. The break strength of Bard Dulex and Prolene appeared unchanged after immersion in F-53 or normal saline, while the Ultrapro mesh showed a slight decrease in break strength after contact with F-53 or normal saline. F-53 and normal saline had similar effects on the mechanical integrity of the tested meshes.

[0298] In conclusion, the emulsion of the present invention is compatible with sutures or meshes.

[0299] Example 7 In vitro release of ropivacaine emulsion

[0300] In this example, the in vitro release profile of a ropivacaine emulsion formulation was measured and compared to a preliposome formulation prepared according to the composition and process described in Examples 1 and 2 of U.S. Patent No. 9,849,088 B2. The ropivacaine emulsion formulation was prepared using the emulsion process as described in Example 18, while the preliposomes were prepared using the process described in Examples 1 and 2 of U.S. Patent No. 9,849,088 B2. The final compositions are summarized in the following table: [Table 3]

[0301] A USP type 4 dissolution apparatus was used to measure the in vitro release of ropivacaine from the emulsion (coded as F-5-2) and the preliposomal formulation. Figure 5 provides a comparison of the in vitro release profiles.

[0302] Conclusion: The emulsion of the present invention exhibited a very different ropivacaine release profile than the preliposomal formulation, even though the preliposomal formulation has similar ingredients. Compared to the preliposomal formulation, the emulsion exhibited a faster release rate within the first 2 hours and a slower release rate thereafter. Clearly, the emulsion is not bioequivalent to the preliposomal formulation, even though the preliposomal formulation is made from similar ingredients.

[0303] Example 8 Stability of ropivacaine emulsion

[0304] In this example, long-term stability data for ropivacaine emulsion in the composition described in Example 1 is provided in the table below: Stability at 2-8°C [Table 4] Stability at 25°C [Table 5]

[0305] Conclusion: The emulsion of the present invention is stable for 24 months at 2-8° C. and 25° C. Specifically, the emulsion can maintain ropivacaine assay at 90-110% of the label claim, N-oxide at less than 0.2%, ropivacaine-related component A at less than 0.01%, and total impurities at or below 0.2% after 24 months at 2-8° C. and 25° C.

[0306] Example 9 Particle size analysis of ropivacaine emulsion

[0307] In this example, the particle size of a ropivacaine emulsion (F-53) with the same composition as described in Example 1 is measured under different conditions. A dynamic light scattering spectrometer (Malvern Zetasizer Model Nano) was used to measure the mean particle size (reported as the Z-average diameter) of the emulsion droplets before and after dilution with water. Although the particle size changes with the water dilution rate and preparation method, the measured particle size remained consistent with the same sample preparation method. [Table 6]

[0308] Conclusion: The F-53 emulsion of the present invention has a mean particle size of 209 nm. When diluted with water, the particle size ranged from about 213 nm to 2504 nm.

[0309] Example 10 Electron microscopy imaging of ropivacaine emulsion

[0310] In this example, the microscopic structure of a ropivacaine emulsion with the same composition as described in Example 1 was observed using transmission electron microscopy (TEM) and negative staining with a Talos 120L TEM. For comparison, a well-known liposomal drug (Ambisome®) was also imaged.

[0311] TEM images are shown in Figures 4A-B. Each particle / droplet present in the emulsion of the present invention has a solid core (i.e., no empty internal void) and does not have a characteristic membrane. The particles / droplets present in the emulsion of the present invention are structurally different from liposome particles, which have a solid core and are surrounded by a characteristic bilayer lipid membrane (see Figure 4C).

[0312] Conclusion: The emulsion of the present invention contains particles of approximately 30 nm to 500 nm, and the emulsion diluted with water contains visible particles of 30 to 2500 nm, consistent with the dynamic light scattering findings in Example 9. The emulsion of the present invention does not contain liposome particles before or after dilution with water.

[0313] Example 11 Injectability of ropivacaine emulsion

[0314] In this example, the injectability of a ropivacaine emulsion with the same composition as described in Example 1 was measured. Injectability is defined as the time required to expel 10 mL of emulsion through a hypodermic needle using a 10 mL plastic syringe.

[0315] Injection time was measured as the time required to expel 10 mL of liquid from a 10 mL syringe through the attached needle or catheter with a force of approximately 25 Newtons or less. An injection force of 25 Newtons is considered acceptable by most physicians. Typical injection forces are measured at 20-30 N (http: / / www.sciencedirect.com / science / article / pii / S1098733903005741?via%3Dihub). Injection times of 5-10 minutes and needle sizes of 18-25G are considered acceptable. ("TAP in Laparoscopic Sleeve Gastrectomy." https: / / videos.exparel.com / video-playlist / 19) The following table provides recorded injection times for ropivacaine emulsion when diluted with water or ethanol. [Table 7]

[0316] CONCLUSIONS: Ten (10) milliliters of ropivacaine emulsion can be injected from a 10 mL plastic syringe through an 18-27 G needle or a 22 G catheter in less than 7 minutes using a force of 25 Newtons.

[0317] Example 12 Viscosity of ropivacaine emulsion upon dilution

[0318] In this example, ropivacaine emulsion (F-53) was diluted with water or normal saline at different ratios, and the viscosity of the diluted emulsion was measured: [Table 8]

[0319] Conclusion: The emulsions of the present invention can be diluted in water at a ratio of 2:1 or greater, or 4:1 or greater, and still maintain injectability.

[0320] Example 13 In vitro release from diluted emulsions

[0321] In this example, ropivacaine emulsion (F-53) was diluted in saline at a volume ratio of 2:1 (viscosity = 21 centipoise) and its in vitro release profile was determined. The in vitro release method included a USP dissolution device with a dialysis membrane. [Table 9]

[0322] Conclusion: The undiluted emulsion and the saline-diluted emulsion of the present invention maintained a sustained release profile for approximately 3 days or 72 hours. The saline-diluted emulsion exhibited a relatively low viscosity, making it easy to inject through a small needle.

[0323] Example 14 Effect of pH on the stability of ropivacaine emulsions

[0324] In this example, the stability of ropivacaine in emulsions of the same composition as described in Example 1 was examined as a function of emulsion pH. Multiple samples were prepared with different pH levels in the same base ropivacaine emulsion composition. Each sample was subjected to heat stress at 121°C for 60 minutes. The increase in impurities after heating is summarized in the table below: [Table 10]

[0325] Conclusion: The best chemical stability was observed at emulsion pH between pH 4 and pH 7. However, at pH 7, the emulsion appeared to have poor physical stability.

[0326] Example 15 Effect of water on the stability of ropivacaine emulsions

[0327] In this example, the physical stability of ropivacaine in emulsions of the same composition as described in Example 1 was examined as a function of the water level in the emulsion. Multiple samples were prepared with different water contents using the same base ropivacaine emulsion composition. The samples were stored at 2-8°C, 25°C, and 40°C and observed for appearance over time. The results are summarized in the table below: [Table 11]

[0328] Conclusion: The emulsions of the present invention undergo a phase transition from water-in-oil to oil-in-water as the water level increases, with 1% water being the transition point. Below this transition point, the emulsion is translucent and essentially water-in-oil. Above the transition point, the emulsion converts to oil-in-water. Up to about 3% water, the emulsion remains predominantly water-in-oil. Between 3% and 10%, the emulsion contains both water-in-oil and oil-in-water components and is creamy. Above 10%, the emulsion changes back to a liquid, but is white and opaque. Water levels below 1% are preferred because such emulsions are translucent (allowing visual inspection), thin liquids (easy to inject), and physically stable for 1.5 years at all three temperatures (2-8°C, 25°C, and 40°C).

[0329] Example 16 Best antioxidant(s) for ropivacaine emulsion

[0330] In this example, the effect of EDTA and cysteine ​​on the stability of ropivacaine emulsions with the same composition as in Example 1 was studied. Multiple lots of emulsions with the same base composition were produced using different concentrations of EDTA and L-cysteine. The emulsions were stored at 25°C and 40°C to study the buildup of impurities, particularly ropivacaine N-oxide. The following table summarizes the results of the study: [Table 12]

[0331] Conclusion: Without an antioxidant, ropivacaine emulsions formed various impurities, including N-oxides. When only sodium EDTA (0.02% or 0.04%) or cysteine ​​(0.1% or 0.2%) was added to ropivacaine emulsions, N-oxides were no longer formed, but other impurities continued to increase. When both sodium EDTA (0.02% or 0.04%) and cysteine ​​(0.1% or 0.2%) were added, the increase of all impurities, including N-oxides, was suppressed. Therefore, the combination of sodium EDTA (0.02% or 0.04%) and cysteine ​​(0.1% or 0.2%) is a preferred antioxidant for the emulsions of the present invention.

[0332] In a subsequent study, additional antioxidants were also added to the same ropivacaine emulsion, including a combination of sodium EDTA and cysteine ​​(0.02% + 0.1%) as follows: [Table 13]

[0333] Each sample was sealed in a glass vial. One F-11 vial was filled with carbon dioxide gas in the vial's headspace before sealing. All vials were heated at 121°C for 2 hours. The impurity content was measured by HPLC before and after heating. The N-oxide levels are shown in the table below: [Table 14]

[0334] Conclusion: Additional antioxidants, including CO2 gas, ascorbyl palmitate, ascorbic acid, methionine, and glutathione, can further suppress the increase of N-oxides under heating. Among them, CO2 gas most significantly improved the stability of ropivacaine.

[0335] Example 17 Particle size and distribution in undiluted emulsions

[0336] In this example, the emulsion (F-53) was measured by dynamic light scattering (DLS) to determine particle size and polydispersity index (PDI) using a Malvern Zetasizer. [Table 15]

[0337] Z-average is reported in nanometers (nm) and is defined as the "intensity-weighted average hydrodynamic size of the ensemble collection of particles measured by DLS." The polydispersity index (PDI) measures the size heterogeneity of the detected particles. A value greater than 0.7 indicates that the sample has a very broad particle size distribution. D(v,0.5) is the volume median diameter D(v,0.5), the diameter above which 50% of the distribution lies and 50% below. Similarly, D(v,0.9) is the diameter below which 90% of the volume distribution lies.

[0338] Conclusion: The emulsions of the present invention have a mean particle size of greater than 100 nm with a broad particle size distribution as indicated by the high PDI values.

[0339] Example 18 Process for preparing emulsions Step 1. Preparation of oil and water phases Add oil and lecithin to a stainless steel compounding vessel. Mix until a smooth paste is formed ("oil phase"). LA (ropivacaine HCl) and other excipients such as antioxidants are dissolved in water. Mix to dissolve the solids and obtain a clear solution ("aqueous phase"). Step 2. Preparation of oil-in-water emulsion The oil and water phases are mixed in a volume or weight ratio of >9:1 (i.e., a final water content of >10%) and mixed in a homogenizer to form an oil-in-water emulsion with average oil droplets greater than 1 micron ("coarse emulsion"). Step 3. Partial Ionization / Deionization and pH Adjustment An amount of alkali or base, such as sodium hydroxide, equivalent to approximately 5-25 mol% of the LA (as the HCl salt) added in step 1 is added to partially convert the ionized LA starting material (ropivacaine HCl) to form non-ionized ropivacaine. If a non-ionized starting material, such as ropivacaine free base, is used, sufficient acid, such as HCl, is added to partially convert the non-ionized LA starting material (ropivacaine) to form 75-95 mol% ionized ropivacaine, and the pH of the emulsion is adjusted. After this step, the emulsion contains both ionized and non-ionized LA or ropivacaine. Only a small amount of acid or base (less than 15% of that required for partial ionization / deionization of the LA) is required to adjust the pH of the emulsion. Step 4. Continue homogenization until the oil-in-water emulsion has an average droplet diameter of 100 nm to 2500 nm, preferably 200 nm to 1000 nm, and most preferably 200 nm to 400 nm. For emulsions of the present invention, an average droplet diameter of less than 100 nm is not preferred because emulsions with an average droplet diameter <100 nm are physically unstable with rapid size growth, tend to release LA rapidly (burst release), and require very long homogenization times (multiple days) to achieve such small droplets. On the other hand, an average droplet diameter greater than 2500 nm is also not preferred because emulsions with an average droplet diameter greater than 2500 nm tend to separate into two phases during step 5 (e.g., cream out), are relatively viscous (difficult to pour), and cannot pass through a 0.2-micron filter (step 7). Emulsions with a mean particle size of 200 nm to 400 nm are the most physically stable, provide desirable LA release rates, and require short processing times (in hours). Step 5. Moisture removal The water in the water-in-oil emulsion in step 4 is removed by vacuum drying, yielding first an oil-in-water emulsion with a water level >10%, then a mixture of oil-in-water and water-in-oil emulsions with a water level of 3% to 10%, then a water-in-oil emulsion primarily with a water level of 1% to 3%, and finally a water-in-oil emulsion with a water level of 1% or less. Any of these emulsion types can be used to provide a long-acting and safe LA drug. Selection of the preferred emulsion type can be achieved in this step by controlling the water level. Step 6. Dilution or viscosity adjustment If necessary, adjust the viscosity of the emulsion in step 5 by adjusting the water content and / or adding a viscosity-reducing agent (e.g., alcohol). Step 7: Sanitizing and filling The emulsion of step 6 is passed through a sterile 0.2-micron pore size filter to sterilize the emulsion, and the filtered emulsion is aseptically filled and sealed into glass vials or syringes.

[0340] Example 19 In this example, small-angle X-ray scattering (SAXS) was used to optically compare the structure of a ropivacaine emulsion formulation prepared using the process described in Example 18 and a preliposome formulation ("proliposome") prepared according to the composition and process described in Examples 1 and 2 of U.S. Patent No. 9,849,088 B2. The compositions of the test samples are summarized in Example 7.

[0341] SAXS was performed using a Bruker SAXS instrument equipped with a rotating anode generator and a Highstar multiwire detector. Samples were mounted in a He chamber on an automated goniometer. To prevent air scattering, He gas was purged into the chamber before each sample was collected. Data were smoothed and integrated over a 360° circle from 0.8° to 4.7° with a width of 0.02°.

[0342] The d value or "lattice spacing," which represents the average spacing or distance (in nanometers or nm) between the repeating and ordered structures in each sample tested, was calculated according to Bragg's law and is shown in FIG.

[0343] Conclusion: The emulsion from the present invention has a d value of 3.76 nm, while the preliposomal formulation has a d value of 2.8 nm, indicating that the emulsion in the present invention has a significantly higher average interparticle distance than the proliposomal formulation. The SAXS data in Figure 7 show that the emulsion from the present invention is structurally different from the proliposomal formulation.

[0344] Example 20 In this example, FTIR was used to spectroscopically compare a ropivacaine emulsion formulation prepared using the process described in Example 18 and a preliposomal formulation ("proliposome") prepared according to the composition and process described in Examples 1 and 2 of U.S. Pat. No. 9,849,088 B2.

[0345] An Agilent Cary 630 FTIR equipped with a DialPath permeation liquid sampler and Microlab PC software was used for data acquisition. The detection range was set to 4000–650 (full range), 140 scans, a resolution of 4 cm, and a path length of 50 μm. Each sample was measured neat or undiluted.

[0346] As shown in Figures 8A-B, FTIR detected two bands; one at 3300 cm -1 And the other one is 2800cm -1 This is because the absorption intensity varies significantly between the two samples measured. Figure 8B shows the absorption intensity between 2500 cm and 3700 cm. -1 8B is an enlarged cross section of FIG. 8A.

[0347] Conclusion: The emulsions of the present invention are spectroscopically different from proliposomal formulations.

[0348] Example 21 This example describes prophetic compositions for other amide-type local anesthetics in emulsion compositions of the present invention. Each composition can be prepared using the same or similar processes as described in Example 18. [Table 16] [Table 17]

[0349] Each of the above formulations is expected to have the pharmacological activity, excellent safety, and desirable physical and chemical properties of LA, as observed in the ropivacaine emulsions of the present invention (Examples 1 to 20).

[0350] Modifications and variations of the present invention will be obvious to those skilled in the art from the foregoing detailed description and are intended to be within the scope of the following claims. The teachings of all documents cited herein are specifically incorporated by reference.

Claims

1. An emulsion composition comprising: (a) an amide-type local anesthetic in a concentration of up to 4% by weight of the emulsion; (b) an oil phase comprising lecithin and vegetable oil in a weight ratio of 2:1 to 5:4, at a concentration of about 20% to 99.8% by weight of the emulsion; and (c) aqueous phase; Including, An emulsion composition, wherein said emulsion comprises particles or droplets having an average diameter of about 100 to 2500 nanometers.

2. (i) the amide type local anesthetic is a member selected from the group consisting of lidocaine, bupivacaine, prilocaine, levobupivacaine, ropivacaine, mepivacaine, etidocaine, articaine, dibucaine and pharma- ceutically acceptable salts thereof; and / or (ii) the amide-type local anesthetic is ropivacaine free base, a pharma- ceutically acceptable ropivacaine salt or a mixture thereof; and / or (iii) the vegetable oil is a member selected from the group consisting of sesame oil, soybean oil, olive oil, and combinations thereof, preferably the vegetable oil is sesame oil; and / or (iv) the lecithin is a member selected from the group consisting of LIPOID S75, LIPOID S100, LIPOID E80, Phospholipon 90G, and combinations thereof; The composition of claim 1.

3. 3. The composition of claim 1 or 2, wherein the emulsion further comprises a water-miscible organic solvent selected from the group consisting of ethanol, propylene glycol, glycerol and liquid polyethylene glycol, optionally at a concentration of 2% to 12% by weight.

4. The composition according to any one of claims 1 to 3, wherein the emulsion is of the water-in-oil type, the oil-in-water type or a mixture thereof.

5. The composition of any one of claims 1 to 4, wherein the emulsion has a viscosity of about 2 to 600 centipoise.

6. The composition of any one of claims 1 to 5, wherein the emulsion has a pH of from about 4 to about 7.

7. The composition of any one of claims 1 to 6, wherein the composition is a translucent or white opaque liquid and is filterable through a 0.2 micron filter.

8. 8. The composition of claim 1, wherein greater than 90% by weight of the amide local anesthetic is non-covalently bound to emulsion oil droplets.

9. The composition of any one of claims 1 to 8, wherein the emulsion oil droplets are non-liposomal and substantially free of liposomal bilayer structures.

10. 10. The composition of any one of claims 1 to 9, wherein the emulsion is diluted with saline in a volume ratio of 2:1 or more (saline:emulsion) or diluted with water in a volume ratio of 4:1 or more (water:emulsion) prior to administration.

11. The composition according to any one of claims 1 to 9, wherein the emulsion is administered to a human or animal subject by injection, wound infiltration, infusion, epidural anesthesia, local anesthesia or nerve block.

12. The composition of any one of claims 1 to 10, wherein the emulsion is oil-in-water when the water content is greater than about 50% by weight of the emulsion, or water-in-oil when the water content is less than about 5% by weight of the emulsion, or a mixture thereof when the water content is from about 5% to about 50% by weight of the emulsion.

13. 1. An emulsion composition for use in a method for relieving pain, comprising: Subjects were administered the following: an amide-type local anesthetic at a concentration of 4% or less by weight of the emulsion; an oil phase comprising lecithin and vegetable oil in a weight ratio of 2:1 to 5:4, at a concentration of about 20% to 99.8% by weight of the emulsion; and water phase, administering an effective amount of an emulsion comprising Including, An emulsion composition, wherein the emulsion comprises particles or droplets having an average diameter of from about 100 nm to about 2500 nm.

14. 14. The emulsion composition for use according to claim 13, wherein the amide type local anesthetic is a member selected from the group consisting of lidocaine, bupivacaine, prilocaine, levobupivacaine, ropivacaine, mepivacaine, etidocaine, articaine, dibucaine and pharma-ceutically acceptable salts thereof.

15. The emulsion composition for use according to claim 13, wherein the amide type local anesthetic is ropivacaine, a pharma- ceutically acceptable ropivacaine salt or a mixture thereof.

16. The following: an amide-type local anesthetic at a concentration of 4% or less by weight of the emulsion; an oil phase comprising lecithin and vegetable oil in a weight ratio of 2:1 to 5:4, at a concentration of about 20% to 99.8% by weight of the emulsion; and water phase, Use of an emulsion comprising: The emulsion comprises particles or droplets having an average diameter of about 100 nm to about 2500 nm.

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