Pharmaceutical compositions for use in treating pain

Abstract

A pharmaceutical composition for treating postoperative pain is provided. This pharmaceutical composition comprises a lipid-based complex. The lipid-based complex comprises a acetamide anesthetic and at least one lipid, wherein the molar ratio of the acetamide anesthetic to the at least one lipid in the lipid-based complex is at least 0.5:1. The total amount of the acetamide anesthetic is at least 1.5 to 5 times the standard dose for treating postoperative pain with acetamide anesthetics, to achieve improved pain control with a desired prolonged anesthetic effect.

Description

Technical Field

[0001] This disclosure pertains to the use of acetamide anesthetics in pain control. This disclosure pertains to methods of pain control. Prior Technology

[0002] Local anesthetics have been widely used for surgical anesthesia and postoperative analgesia due to their ability to reversibly inhibit voltage-gated sodium channels and block action potentials in nerve fibers. However, at high plasma concentrations, these anesthetics can also interact with other ion channels, causing acute neurotoxicity, cardiotoxicity, and allergic reactions. So-called local anesthetic systemic toxicity (LAST) has always been a potential complication of all local anesthetics, regardless of the route of administration, and can be fatal.

[0003] Ropivacaine, a pure S(-) isomer amide local anesthetic, was introduced in 1996 and approved by the Food and Drug Administration (FDA) in 2000 under the brand name Naropin®. It has relatively low lipophilicity and motor block, and due to its lower cardiotoxicity compared to bupivacaine (Marcaine®), ropivacaine also has a wider safety margin. Naropin® can be administered via various routes of injection, including spinal anesthesia, epidural anesthesia, regional block, and local infiltration. Despite its many advantages over other local anesthetics, the duration of anesthesia after a single administration of 0.5% Naropin® (ropivacaine hydrochloride injection 200 mg) via wound infiltration is only about 6 to 8 hours. This is not enough to cover most of the postoperative recovery time, especially the critical first 3 days after surgery.

[0004] Local anesthetics have limitations due to their short duration of action and the risk of systemic toxicity. Infiltration administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and local anesthetics (e.g., ropivacaine hydrochloride) is also widely used for postoperative pain management. However, some potential safety concerns remain regarding the use of NSAIDs, and the postoperative analgesia provided by local anesthetics typically lasts only about 8 hours. The medical goal is to relieve acute postoperative pain during the critical 2 to 4 days after surgery without the use of opioids. Therefore, there remains an unmet medical need for a longer-lasting, non-opioid, safer, and more effective method of postoperative pain management via single-dose peritoneal administration.

[0005] Whether administered via continuous infusion or repeated bolus, there is a high risk of reaching toxic plasma concentrations or causing local nerve damage when using local anesthetics to achieve prolonged blockade. Evidence supporting the neurotoxicity of local anesthetics comes from analyses of paraesthesia persistence after injection. The severity of the sensory disturbance is related to the duration of the sensory shift. While in most cases the affected nerves recover spontaneously after a period of time, in some cases, such undesirable effects may be prolonged and last for months, or even prevent complete nerve recovery.

[0006] There remains an unmet need for improved use of ropivacaine or other acetamide anesthetics in pain management to achieve both desired prolonged anesthetic effects and beneficial, effective pain control. The compositions and methods disclosed herein fulfill these and other needs. Summary of the Invention

[0007] This disclosure provides a method for treatment using acetamide anesthetics, as disclosed herein, with specific dosage ranges and administration schedules, which exhibit a prolonged effect in pain control. In particular, this disclosure addresses pharmacologically active agents, compositions, methods, and / or administration schedules that offer certain advantages over currently used and / or known in the art, including the ability to achieve equivalent pain control or anesthetic effects with lower frequency of administration or lower doses, and thus reducing the undesirable effects of acetamide anesthetics in individuals with such needs. These advantages will be more clearly presented in the following further description.

[0008] This disclosure provides a sustained-release anesthetic composition, or a method for preparing the sustained-release anesthetic composition, which utilizes freeze-drying (e.g., one-step lyophilization) to obtain a lipid cake comprising an acetamide anesthetic and at least one lipid, wherein the acetamide anesthetic in the lipid-based complex has a molar ratio of at least 0.5:1 to the at least one lipid, and then hydrates the lipid cake with a pharmaceutically acceptable buffer solution to obtain the sustained-release anesthetic composition. This sustained-release anesthetic composition provides rapid anesthetic onset, prolonged duration of local anesthesia, and minimal toxicity.

[0009] On one hand, the anesthetic composition is a pharmaceutical composition for treating postoperative pain in individuals with such needs. According to this disclosure, the pharmaceutical composition comprises a lipid-based complex having an acetamide anesthetic and at least one lipid, wherein the molar ratio of the acetamide anesthetic to the at least one lipid in the lipid-based complex is at least 0.5:1, and the total amount of the acetamide anesthetic in the pharmaceutical composition is at least 1.5 to 5 times the standard therapeutic dose of the acetamide anesthetic. The total amount of the acetamide anesthetic in the pharmaceutical composition may range from about 3 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 200 mg to about 600 mg, from about 300 mg to about 600 mg, from about 300 mg to about 500 mg, and optionally, from about 380 mg, about 475 mg, about 570 mg, or may range from about 3 mg to about 300 mg, from about 10 mg to about 250 mg, and optionally, from about 50 mg, about 152 mg, about 190 mg, or about 228 mg. In some specific examples, the amount of the acetamide anesthetic in the pharmaceutical composition is at least about 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 to 5 times the standard therapeutic dose of the acetamide anesthetic. Other usable acetamide anesthetics include lidocaine, bupivacaine, mepivacaine, levobupivacaine, their bases, or combinations thereof. In some specific cases, the acetamide anesthetic is bupivacaine, ropivacaine, or an alkaloid thereof.

[0010] According to this disclosure, the lipid-based complex comprises an acetamide anesthetic and one or more lipids. In some specific examples, the lipid comprises at least one neutral saturated phospholipid. The at least one neutral saturated phospholipid comprises a saturated fatty acid having a long carbon chain with no more than 18 carbon atoms. In some specific examples, the lipid-based complex is prepared under predetermined conditions for pre-clinical use, such as room temperature, with fatty acids having long carbon chains of 14, 16, and / or 18 carbon atoms.

[0011] In some specific examples, the lipid-based complex of the anesthetic composition is formed by hydrating a freeze-dried lipid cake with a pharmaceutically acceptable buffer solution with a pH greater than 5.5. Based on the acid dissociation constant of ropivacaine (which is 8.1), theoretically, 0.8% of all available ropivacaine is uncharged at a pH of 6.0. In some specific examples, the lipid cake according to this disclosure is prepared by dissolving nonpolar ropivacaine, phospholipids, and cholesterol in a solvent system (e.g., tert-butanol monosolvent or tert-butanol-water cosolvent), followed by removing the solvent system using freeze-drying technology.

[0012] In certain specific examples, the molar ratio (moldrug:molphospholipid) of the acetamide anesthetic to the phospholipid in the lipid-based complex is at least 0.5:1. This pharmaceutical composition provides a sufficient amount of acetamide anesthetic to the individual in need, thereby prolonging the duration of anesthesia following local administration in vivo. Furthermore, the presence of a predetermined amount of acetamide anesthetic in a free form, unencapsulated in the lipid-based complex, allows for rapid onset of anesthesia and minimizes the maximum plasma concentration (Cmax) of the drug entering the bloodstream instantaneously.

[0013] On the other hand, this disclosure also provides a method for treating postoperative pain in an individual requiring anesthesia. This method may include administering a pharmaceutical composition as disclosed herein via nerve block, field block, or infiltration anesthesia.

[0014] In certain specific cases, postoperative pain is caused by surgery, such as, but not limited to: hernia repair surgery, hallux valgus surgery, urological surgery, orthopedic surgery, obstetric and gynecological surgery, laparoscopic surgery, abdominoplasty, breast surgery, and kidney transplantation procedure (KIX).

[0015] On the other hand, this disclosure provides a method for treating postoperative pain. This method may include administering a dose of a pharmaceutical composition as disclosed herein before or after the start of surgery (during surgery), and particularly within approximately half an hour to three hours, selectively half an hour to two hours, and selectively half an hour to one hour before the completion of surgery, wherein during the postoperative period, the pain score, according to the Numerical Pain Rating Scale (NPRS), decreases by at least 2, wherein this period is at least 48 hours, selectively at least 72 hours, at least 96 hours, or at least 168 hours. The NPRS scale may be 0 to 10, where 0 represents no pain and 10 represents the most severe conceivable pain. In some specific examples, when the composition of this disclosure is administered via nerve block or regional block, the composition may be administered approximately half an hour to one hour before surgery. In other non-limiting specific examples, when the components of this disclosure are administered via local infiltration (which is suitable for hernia repair surgery and hallux valgus surgery), the components may be administered during the course of surgery, typically in the final stage of the surgery, before the final closure of the wound.

[0016] Other inventive objectives, advantages, and novel features of this disclosure will become clearer from the following detailed description taken in conjunction with the accompanying drawings. Simple Explanation of the Diagram

[0017] Figure 1 illustrates the clinical trial design for treating postoperative pain with the anesthetic composition disclosed herein following hernia repair surgery; Figure 1A shows a table comparing the maximum plasma concentration of ropivacaine after treating postoperative pain with the anesthetic composition disclosed in this disclosure at different specified dosages; Figure 2 illustrates the clinical trial results of the anesthetic components disclosed herein, where AUC = area under the pain-time curve; LS = least squares; NPRS = numerical pain assessment scale; the least squares means (LS means) of the ANOVA model include NPRS AUC as the response variable and treatment group as the fixed main effect; NPRS is adjusted for windowed worst observation carried forward (wWOCF) based on the use of rescue medication; * indicates p < 0.05 compared to ropivacaine; Figure 3 illustrates the least squared mean of pain during movement at a dose of 475 mg of the anesthetic composition disclosed herein, compared to ropivacaine. Missing data are estimated using the last observation carried forward (LOCF), and rescue medications are estimated using the worst observation within a given interval. Figure 4 illustrates the clinical trial design for treating postoperative pain with the anesthetic composition disclosed herein following hallux valgus surgery. Implementation

[0018] Unless otherwise stated, the following terms used above and throughout this disclosure shall be understood to have the following meanings.

[0019] The singular forms “a,” “a,” “the,” and “this” used in this article include plural referents unless the context clearly indicates otherwise.

[0020] All figures in this document are to be understood as being modified by “about”, and when referring to measurable values ​​such as amount, duration, etc., it means that the variable includes a specific value of ±10%, preferably ±5%, more preferably ±1%, and even more preferably ±0.1%, which applies to describing the required amount of acetamide anesthetics, unless otherwise stated.

[0021] As used herein, the term "treat, treating, or treatment" includes preventative (e.g., prophylactic), palliative, and curative methods, uses, or outcomes. The term "treatment" or "treatments" may also refer to a composition or agent. In this application, the term "treating" includes detecting, using known techniques, a reduction or alleviation of one or more symptoms or signs of pain, or a reduction in the use of pain control medications. Pain and its symptoms can be assessed using methods known in the field, including but not limited to the 6-point descriptive pain rating scale, the 11-point NPRS, the visual analog scale, the Wisconsin Brief Pain Questionnaire, the Brief Pain Inventory, the McGill Pain Questionnaire and the short-form, and other scoring methods including the Patient Global Assessment (PGA) which incorporates methods of pain management. For an individual, self-report can be used to determine the level of pain, for example, using a scale from 0 (no pain) to 10 (most painful). Optionally, after administration of a disclosed pharmaceutical composition, functional magnetic resonance imaging (fMRI) can be used to determine a reduction in pain in an individual. For example, if the methods disclosed herein reduce one or more pain symptoms in an individual by at least 1% compared to before treatment or in one or more control groups, it can be considered as a treatment approach. Therefore, the aforementioned reduction could be approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or any of the aforementioned values. An individual's treatment can also be assessed by reducing the use of pain control medications (such as opioids or other narcotics) and / or reducing side effects associated with such narcotics (such as opioid-related gastrointestinal symptoms). Additional efficacy questionnaires (such as the postsurgical recovery index) can be used to assess pain and recovery, as well as side effects that may be related to opioid use. In particular, postoperative pain can be acute and / or chronic.The sensation of acute pain may be immediate or last up to 7 days (e.g., approximately 1, 2, 3, 4, 5, 6, or 7 days after surgery).

[0022] The term "subject" can refer to a vertebrate that has (or is at risk of developing) pain or a disease that causes pain, or a vertebrate that is considered to require pain treatment or management. Subjects include all warm-blooded animals, such as mammals (including primates), and preferably humans. Non-human primates are also subjects. The term "subject" includes domesticated animals (such as cats, dogs, etc.), livestock (for example, cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (for example, mice, rabbits, rats, gerbils, guinea pigs, etc.). Therefore, this article covers veterinary uses and medical formulations.

[0023] "Association efficiency (AE)" represents the amount of drug embedded in a lipid-based complex, calculated as the ratio of the amount of drug in the separated lipid-based complex to the total amount of drug in the initial composition before separation. The separated lipid-based complex can be obtained by any method known in the art. In some specific examples, the separated lipid-based complex is obtained by centrifugation (e.g., conventional centrifugation, density gradient centrifugation, differential centrifugation) or filtration (e.g., dialysis filtration, gel filtration, and membrane filtration).

[0024] The term "standard therapeutic dose" can refer to the amount of a specified therapeutic agent that produces the desired effect or result, particularly in a cavity similar to that described herein, exemplified by a drug conversion method in tissues that are difficult to perfuse (such as soft tissues (muscle, fat, and such tissues) and hard tissues (bone, or such tissues)). Standard therapeutic doses can be determined using techniques commonly used in the art. Appropriate standard therapeutic doses for each indication can be found in relevant anesthetic literature, including but not limited to the United States Pharmacopeia (USP) and approved drug products listed in the Drugs@FDA library sponsored by the US Food and Drug Administration. The therapeutic dose can be infiltrated or injected into the surgical site. For example, for pain management after hernia surgery, the standard therapeutic dose for local infiltration of ropivacaine hydrochloride solution (Naropin®) is less than 300 mg, particularly 2 mg to 200 mg. In some specific examples, the standard treatment dose of free ropivacaine solution for injection or infiltration is 50 mg for pain management following hallux valgus surgery. In another specific example, the standard treatment dose of bupivacaine hydrochloride injection (USP) (from Hospira) used in combination with epinephrine (1:200,000) is as high as 225 mg, while the standard treatment dose without epinephrine is 175 mg. Standard treatment doses can be determined according to the type of surgery and can be established using conventional techniques in the art. Acetamide anesthetics

[0025] The term "acetamide anesthetic" refers to one or more substances that cause sensory loss in a defined area of ​​an individual by inhibiting the excitation of nerve endings or the conduction of peripheral nerves. A typical acetamide anesthetic structure comprises a lipophilic moiety and a hydrophilic moiety, linked by a -NHCO- bond. Suitable acetamide anesthetics include, but are not limited to: lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrocaine, articaine, and prilocaine, and their bases. In some specific examples, the acetamide anesthetic is the ropivacaine base. lipid matrix complex and lipids

[0026] The lipid-based complex disclosed herein comprises one or more lipids and a acetamide anesthetic. In one specific example, the lipid-based complex can be stored long-term after manufacturing, extending the shelf life of the components. The lipid-based complex may be obtained by hydrating a lipid cake containing one or more lipids and a acetamide anesthetic immediately before clinical use.

[0027] The aforementioned lipid cake may contain one or more phospholipids and acetaminophen anesthetics, but no sterols. Additionally, the lipid cake may contain acetaminophen anesthetics, one or more phospholipids, and one or more sterols (e.g., cholesterol), the amount of which is no more than 50% relative to the total lipid mass. In some specific examples, the cholesterol molar percentage based on total lipids is about 0% to 50%, selectively about 33% to 40%. In some specific examples, the molar ratio of phospholipids to cholesterol is 1:1 to 3:1.

[0028] Lipid cakes can be prepared by: 1) dissolving one or more lipids and a acetamide anesthetic in a solvent system to form a liquid structure comprising a homogeneous solution formed by one or more solvents; 2) removing the solvent to solidify the lipid and acetamide anesthetic formulation. Known techniques can be used to remove the solvent, such as lyophilization. Examples of suitable solvent systems for lyophilization include, but are not limited to, tert-butanol and tert-butanol-water cosolvent systems, and may or may not contain other non-aqueous phase solvents such as acetone, acetonitrile, ethanol, n-propanol, isopropanol, n-butanol, methanol, dichloromethane, dimethyl sulfoxide, or carbon tetrachloride.

[0029] In some specific examples, the lipids of the lipid-based complex include one or more phospholipids and cholesterol, and the molar ratio of acetamide anesthetics to phospholipids in the lipid-based complex is at least 0.5:1, selectively between 0.5:1 and 2:1, such as about 0.5:1, about 0.8:1, about 1:1, about 1.2:1, about 1.5:1, about 1.8:1, or about 2:1.

[0030] The one or more lipid systems mentioned are selected from the group consisting of dilipid lipids (such as phospholipids, diglycerides, dilipoglycolipids), monolipid lipids (such as sphingomyelins and glycosphingomyelins), sterols (such as cholesterol and its derivatives) and combinations thereof. Examples of phospholipids based on this disclosure include, but are not limited to: 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine (1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine). 1-Sn-glycero-3-phosphocholine (PSPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoy-1-sn-glycero-3-phosphocholine (DOPC), and hydrogenated soybean phosphocholine (hydrogenated soybean phosphocholine) Soy phosphatidylcholine (HSPC), 1,2-dimyristoyl-sn-glycero-3-phosphate-(1'-rac-glycerol)(sodium salt), DMPG, 1,2-dipalmitoyl-sn-glycero-3-phosphate-(1'-rac-glycerol)(sodium salt)DPPG), 1-palmitoyl-2-stearoyl-sn-glycero-3-phospho-(1'-rac-glycerol)(sodium salt), PSPG), 1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol)(sodium salt) (salt), DSPG), 1,2-dioleoyl-sn-glycero-3-phosphate-(1'-rac-glycerol), DOPG), 1,2-dimyristoyl-sn-glycero-3-phosphate-L-serine (sodium salt), DMPS), 1,2-dipalmitoyl-sn-glycero-3-phosphate-L-serine (sodium salt), DPPS), 1,2-distearoyl-sn-glycero-3-phosphate-L-serine (sodium salt). (sodium salt), DSPS), 1,2-dioleoyl-sn-glycero-3-phosphate-L-serine (DOPS), 1,2-dimyristoyl-sn-glycero-3-phosphate (sodium salt), DMPA), 1,2-dipalmitoyl-sn-glycero-3-phosphate (sodium salt), DPPA), 1,2-distearoyl-sn-glycero-3-phosphate (sodium salt), DSPA, 1,2-dioleoyl-sn-glycero-3-phosphate (sodium salt), DSPA, 1,2-dioleoyl-sn-glycero-3-phosphate (sodium salt),2-Dioleoyl-sn-glycero-3-phosphate (sodium salt) (DOPA), 1,2-dipalmitoyl-sn-glycero-3-phosphate ethanolamine (DPPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate ethanolamine (POPE), 1,2-distearoyl-sn-glycero-3-phosphate ethanolamine (1,2-distearoyl-sn-glycero-3-phosphate ethanolamine) 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-myo-inositol)(ammonium salt) (DSPI), 1,2-distearoyl-sn-glycero-3-phosphoinositol (ammonium salt), 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol)(ammonium salt), cardiolipin, L-α-phosphatidylcholine (EPC), and L-α-phosphatidylethanolamine (EPE).

[0031] Examples of phospholipids include, but are not limited to: dimyristylphosphatidylcholine (DMPC), 1,2-dilauryl-sn-glycerol-3-phosphate choline (DLPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), 1,2-dienyl-1-sn-glycerol-3-phosphate choline (DOPC), 1,2-dioleoyl-sn-glycerol-3-phosphate serine (DOPS), dioleoylphosphatidic acid (DOPA), lecithinylcholine (eggPC), phosphatidylethanolamine (eggPE), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate ethanolamine (POPE), cardiolipin, and 1,2-dimyristyl-sn-glycerol-3-phosphate (sodium salt) (DMPA).

[0032] Suitable phospholipids in this disclosure are saturated phospholipids derived from two saturated long-chain fatty acids, each fatty acid having a long carbon chain of at least 12 carbons, alternatively at least 14 carbons and no more than 20 carbons, alternatively 18 carbons or 16 carbons. In some specific examples, suitable saturated phospholipids in this disclosure may be selected from the group consisting of DLPC, DMPC, and DPPC and combinations thereof.

[0033] In some specific examples, the lipid-based complex comprises liposomes and acetamide anesthetics. The liposomes comprise one or more lipids, including suitable phospholipids as disclosed herein, a positively or negatively valent phospholipid, and a defined amount of unsaturated phospholipids, wherein, based on the total amount of phospholipids, the defined amount of unsaturated phospholipids is less than 10% mole percent, for example: 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. Anesthetic composition

[0034] The terms "anesthetic composition" and "pharmaceutical composition for the treatment of pain" are used interchangeably throughout this document. In some specific examples, an anesthetic composition comprises a lipid-based complex and an unencapsulated local anesthetic. In some specific examples, the lipid-based complex comprises multilamellar vesicles and a local anesthetic encapsulated within the multilamellar vesicles. The terms "encapsulation" or "encapsulation process" refer to the coating, embedding, or association of the target drug substance with the bilayer membrane of the multilamellar vesicle.

[0035] The particle size of the lipid-based complexes disclosed herein can be determined by various methods known in the art. In some specific examples, the lipid-based complexes in the anesthetic composition have an average particle size of not less than 1 micrometer (μm) and selectively greater than 5 micrometers, such as in the range of 5 to 50 micrometers or between 10 and 25 micrometers. Additionally, the volume median particle diameter (D50) of the lipid-based complexes in the anesthetic composition is not less than 1 micrometer; and selectively not less than 5 micrometers, ranging from, for example, 5 to 50 micrometers, 5 to 40 micrometers, 5 to 30 micrometers, 5 to 20 micrometers, or 5 to 15 micrometers. In some specific examples, the median diameter (D50) refers to the particle diameter when the cumulative percentage of the lipid-based complex composed of aggregated particles in the cumulative particle size distribution is 50%, which is 5 micrometers, greater than 7 micrometers, or greater. In some specific examples, median diameter (D50) refers to the particle diameter at which the cumulative percentage of the lipid matrix complex composed of aggregated particles is 50% in the cumulative particle size distribution, which is 25 micrometers or less, 20 micrometers or less, or 15 micrometers or less; and selectively from 5 micrometers to 25 micrometers, 5 micrometers to 20 micrometers, or 5 micrometers to 15 micrometers.

[0036] In some specific examples, the lipid-based complex of the anesthetic component, when the cumulative percentage of the cumulative particle size distribution is 90% (D90), has a particle diameter of not less than 10 micrometers, such as between 10 and 300 micrometers, between 20 and 300 micrometers, between 20 and 200 micrometers, or between 20 and 100 micrometers. Furthermore, the lower limit of D90 is, for example, but not limited to, 25 micrometers or greater, or 30 micrometers or greater. Additionally, the shape of the agglomerated particles of the lipid-based complex is not particularly limited to improve the association efficiency per unit dose.

[0037] In some specific examples, the pharmaceutical composition for treating pain includes polycystic liposomes, a portion of which contains a nitroglycerin anesthetic, and a portion of which is in a free form, also referred to as a free nitroglycerin anesthetic (unencapsulated). The particle size distribution of the polycystic liposomes containing the nitroglycerin anesthetic in the lipid-based complex of this disclosure can be determined by various methods known in the art. In some specific examples, the particle size of the polycystic liposomes containing the nitroglycerin anesthetic in the anesthetic composition of this disclosure is not less than 1 micrometer and selectively greater than 5 micrometers, such as between 5 micrometers and 200 micrometers, between 10 micrometers and 100 micrometers, or between 10 micrometers and 50 micrometers. Furthermore, the median diameter (D50) of the lipid-based complex in the anesthetic composition of this disclosure is not less than 1 micrometer and selectively greater than 5 micrometers, such as between 5 micrometers and 100 micrometers, or between 10 micrometers and 50 micrometers.

[0038] In some specific examples, the lipid-based complex is formed by hydrating a lipid cake containing a nitroglycerin anesthetic with a pharmaceutically acceptable buffer solution with a pH greater than 5.5. The resulting anesthetic composition provides a sustained release of the nitroglycerin anesthetic, which may be immediately available or diluted with a buffer solution or other suitable diluent prior to administration. In some specific examples, the buffer solution has a pH range of 5.5 to 8.0, and selectively between 6.0 and 7.5, or between 6.5 and 7.0.

[0039] Suitable buffer solutions disclosed herein include, but are not limited to: citrate, acetate, malate, piperazine, succinate, 2-(N-morpholino)ethanesulfonic acid (MES), histidine, bis(2-hydroxyethyl)amino(trimethylol)methane, phosphate, ethanolamine, N-(2-acetamido)iminodiacetic acid (ADA), carbonate, N-(2-acetamido)-2-aminoethanesulfonic acid (ACES), 1,4-piperazinediethanesulfonic acid (PIPES), and 3-morpholino-2-hydroxypropanesulfonic acid. Solutions containing acetaminophen, lysine, tris(2-hydroxyethyl)-1-aminoethanesulfonic acid (BES), 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), triethanolamine, lysine, tris(hydroxyethyl)-1-aminoethanesulfonic acid, and glycylglycine. The appropriate buffer solution pH is selected based on the clinical indication and total injection dose, and the amount of unencapsulated acetaminophen in the composition is adjusted based on the partition coefficient of the anesthetic.

[0040] In some specific examples, the buffer solution contains histidine in concentrations ranging from 1 mM to 200 mM, 10 mM to 150 mM, 20 mM to 140 mM, 30 mM to 130 mM, or 40 mM to 120 mM.

[0041] In some specific examples, the buffer solution contains phosphoric acid in concentrations ranging from 1 mM to 200 mM, 10 mM to 180 mM, 10 mM to 170 mM, 10 mM to 160 mM, 10 mM to 150 mM, 10 mM to 100 mM, 10 mM to 75 mM, 15 mM to 75 mM, 15 mM to 50 mM, or 20 mM to 50 mM.

[0042] The amount of free acetamide anesthetics is a function of the lipid-based complex association efficiency (AE) in the anesthetic composition, which can be determined by centrifugation. Mathematically, the amount of unencapsulated acetamide anesthetics can be expressed as follows: A untrapped = A total × (1-AE) Where A untrapped is the amount of unencapsulated acetaminophen; A total is the total amount of acetaminophen in the anesthetic composition; and the association efficiency AE is obtained by dividing the amount of acetaminophen in the lipid-based complex by the total amount of acetaminophen in the anesthetic composition. The association efficiency in this disclosure is at least 60%, and selectively, between 60% and 99%, 70% and 95%, and 80% and 90%.

[0043] In certain specific examples, the molar ratio (d: PL) of acetamide anesthetic to lipid in the lipid-based complex is at least 0.5:1, including but not limited to: 0.7:1, 0.9:1, 1.2:1, 1.4:1 or 2:1. In certain specific examples, the median diameter (D50) of a group of particles in the lipid-based complex is not less than 1 micrometer, for example, not less than 5 micrometers, and optionally, the range may be between: 5 micrometers to 200 micrometers, 5 micrometers to 190 micrometers, 5 micrometers to 180 micrometers, 5 micrometers to 170 micrometers, 5 micrometers to 160 micrometers, 5 micrometers to 150 micrometers, 5 micrometers to 140 micrometers, 5 micrometers to 130 micrometers, 5 micrometers to 120 micrometers, 5 micrometers to 110 micrometers, 5 micrometers to 100 micrometers, 10 micrometers to 100 micrometers, 12 micrometers to 100 micrometers, 14 micrometers to 100 micrometers, 16 micrometers to 100 micrometers, 18 micrometers to 100 micrometers, or 20 micrometers to 100 micrometers.

[0044] The concentration of acetamide anesthetics in the anesthetic composition can be higher than 2 mg / mL to achieve clinical therapeutic benefits. Suitable concentrations of acetamide anesthetics include, but are not limited to: at least 10 mg / mL, between 2 mg / mL and 30 mg / mL, between 10 mg / mL and 30 mg / mL, between 10.5 mg / mL and 30 mg / mL, between 11 mg / mL and 30 mg / mL, between 11.5 mg / mL and 30 mg / mL, between 12 mg / mL and 30 mg / mL, between 12.5 mg / mL and 30 mg / mL, between 10 mg / mL and 25 mg / mL, between 10.5 mg / mL and 25 mg / mL, between 11 mg / mL and 25 mg / mL, between 11.5 mg / mL and 25 mg / mL, between 12 mg / mL and 25 mg / mL, between 12.5 mg / mL and 25 mg / mL, between 15 mg / mL and 25 mg / mL, and particularly 19 mg / mL. The anesthetic composition disclosed herein contains a limited dose of unencapsulated anesthetic that achieves a high maximum tolerated dose (depending on the plasma concentration of the anesthetic that would cause central nervous system and cardiovascular toxicity) and can be used to provide the benefit of rapid onset of action.

[0045] For clinical applications, in specific examples of this disclosure, the free form of acetaminophen anesthetics may be between about 1% and about 50%, about 5% and about 40%, or about 10% and about 30%. The acetaminophen anesthetics retained in the lipid-based complex can serve as a drug reservoir, gradually releasing the acetaminophen anesthetics into the local environment in a manner that maintains a therapeutically effective dose in the local area. In some specific examples, after a single subcutaneous administration of the anesthetic composition of the present invention, the ropivacaine half-life is at least 10 times longer than that of ropivacaine solution. Furthermore, the duration of anesthetic effect is significantly prolonged with the administration of the anesthetic composition of the present invention compared to ropivacaine solution.

[0046] The pharmaceutical composition disclosed herein exhibits significant therapeutically prolonged release properties and, compared to clinically administered local anesthetics, provides immediate and sustained pain reduction over a period postoperatively, reducing pain scores to 2 to 4 on a numerical pain assessment scale scale of 0 to 10. For example, the pharmaceutical composition disclosed herein prolongs the half-life of locally administered liposomal anesthetic compositions. Based on numerical pain assessment scale scores, this composition consistently demonstrates lower average pain levels in the human body compared to free-state anesthetics or commercially available anesthetics, and significantly reduces total pain at 24 hours, 48 ​​hours, 72 hours, 4 days, or 1 week postoperatively.

[0047] The lipid-based complex disclosed herein can be applied to the perineurium, surgical area, or surgical wound. The terms "postsurgical pain" and "post-operative pain" are used interchangeably herein and refer to pain caused by various surgical procedures. In some specific cases, postoperative pain is caused by hernia repair surgery, urological surgery, hemorrhoid surgery, abdominal surgery, thoracic surgery, orthopedic surgery, including but not limited to hallux valgus surgery, vertebroplasty, acromioplasty, kyphoplasty, total knee or hip replacement surgery, obstetric and gynecological surgery, breast surgery, dental surgery, abdominoplasty, kidney transplantation, or any type of laparoscopic surgery.

[0048] The pharmaceutical composition disclosed herein can be administered by injection, infusion, or using standard syringes and needles. The pharmaceutical composition disclosed herein can be administered via subcutaneous, intradermal, or intramuscular routes.

[0049] In another specific example, the pharmaceutical composition disclosed herein is administered for nerve block as a preventative treatment of pain conditions (such as pre-operative administration to an individual in need of treatment for postoperative pain). In some specific examples, the pharmaceutical composition disclosed herein is administered for nerve block, such as quadratus lumborum block (QLB).

[0050] Peripheral nerve block involves directing medication to or within a peripheral nerve to reduce pain or paralyze it.

[0051] In another specific example, the pharmaceutical composition disclosed herein is administered to the surgical area for regional blockade, such as: Mayo block for multiple foot nerves in hallux valgus surgery, Transversus Abdominis Plane Block (TAPB) for open laparotomy or tegumentation, and site-specific regional anesthesia techniques for total knee or hip replacement surgery.

[0052] The disclosure is further described below with reference to specific, non-limiting embodiments. Example

[0053] The following experimental examples are used to disclose the preparation and properties of certain embodiments of the present invention. Example 1 Preparation of anesthetic components

[0054] 1,2-Dimyristyl-sn-glycerol-3-phosphocholine (DMPC) was purchased from NOF Corporation (Tokyo, Japan) or Lipoid GmbH (Ludwigshafen, Germany). Cholesterol was purchased from Sigma-Aldrich (Darmstadt, Germany) or Dishman Pharmaceuticals and Chemicals (Gujarat, India), while ropivacaine was purchased from Apollo Scientific (Cheshire, UK) or Dishman Pharmaceuticals and Chemicals. All other chemicals were purchased from Sigma-Aldrich.

[0055] To prepare lipid cakes, ropivacaine and a lipid mixture were combined at a drug-to-phospholipid ratio of 1.458 μmol / μmol (D:PL), i.e., phospholipid:cholesterol:ropivacaine = 2:1:2.9. The lipids and ropivacaine were mixed and dissolved in tert-butanol or a tert-butanol-water co-solvent (volume ratio 1:1) to form a liquid phase. This liquid phase was frozen and then freeze-dried for an additional day to obtain lipid cakes of the acetamide anesthetic.

[0056] A phospholipid:cholesterol ratio of 2:1 was weighed and dissolved in tert-butanol to prepare a lipid structure as a carrier control group. The resulting sample was frozen and then freeze-dried for the next day to obtain a lipid cake for the carrier control group.

[0057] At a temperature not lower than room temperature (AT) (25°C), lipid cakes of anesthetic agents or carrier control groups were hydrated with a buffer solution with a pH of 6.5 to 6.8 to form an anesthetic agent composition and a carrier control group composition, respectively. The association efficiency and particle size distribution were then measured. Qualitative analysis of anesthetic components

[0058] The association efficiency of the samples prepared above will be determined using the methods described below. Equal volumes of 200 μL of each anesthetic composition sample were centrifuged at 3000 x g for 5 minutes at 4°C to obtain the lipid-based complex. After removing the supernatant, the lipid-based complex was resuspended in 200 μL. A reference standard for the absorbance of each drug (e.g., ropivacaine) was established using a test drug solution of known concentration. The amount of drug in the original anesthetic composition and the lipid-based complex was measured using a UV / Vis spectrophotometer. The association efficiency is equivalent to the ratio of the amount of drug in the lipid-based complex to the amount of drug in the original anesthetic composition. The D:PL of the lipid-based complex was calculated by multiplying the D:PL of the freeze-dried lipid cake by the association efficiency, and this was referred to as the "final D:PL".

[0059] The particle size of each anesthetic component was measured using a laser diffraction spectrometer (LA-950V2, Horiba). The median diameter (D50) of the lipid-based complex, which was formed by hydrating freeze-dried lipid cakes with a pharmaceutically acceptable buffer solution (e.g., 50 mM histidine buffer solution with a pH of 6.5), was measured.

[0060] The lipid-based complex in the anesthetic composition was determined to have a final drug-to-phospholipid ratio of approximately 1.32. The median diameter (D50) of the lipid-based complex particles in the anesthetic composition was approximately 5 to 10 micrometers. Example 2 Pain management in adults after inguinal hernia repair surgery

[0061] A phase I / II randomized, double-blind, comparator-controlled, dose-escalation trial was conducted to evaluate the safety, pharmacokinetics, and efficacy of a single local infiltration administration of the anesthetic composition disclosed herein (denoted as TLC590) compared to Naropin® in adult individuals following inguinal hernia repair surgery.

[0062] This trial recruited approximately 64 evaluable subjects who met the inclusion criteria across four cohorts. When compared to Naropin®, dose escalation of TLC590 after a single postoperative dose was performed using a sequential dose level approach. The dose escalation was determined by the safety monitoring committee (SMC) through review of treatment-related adverse events (TEAEs) and all serious adverse events (SAEs).

[0063] The criteria for inclusion in the trial are as follows: 1. Able and willing to sign a written informed consent form; 2. Men or women aged 18 to 65 (inclusive); 3. Scheduled for Liechtenstein inguinal hernia repair using a mesh device, and able to use this anesthesia protocol; 4. ASA Physical Status Classification score of 1 or 2; 5. Female participants must meet the following criteria to be considered suitable: not pregnant, not breastfeeding, not planning to become pregnant during the trial, and consenting to an acceptable form of contraception; or male participants must be sterilized or consent to use an effective method of contraception during the trial and for at least one week after administration of the investigational drug. 6. Body mass index (BMI) ≤ 35 kg / m².

[0064] Subjects were recruited to each group at a ratio of 3:1. Subjects in each group received a single dose of TLC590 or the active control drug [Naropin® 150 mg; (0.5%, 5 mg / mL)] according to the randomization plan and dose escalation protocol (Figure 1).

[0065] To maintain objectivity, the investigational drug was managed and administered by an independent, non-blinded team, including the injector, pharmacist, and clinical research specialist. Subjects, researchers, and all other staff members who interacted directly with subjects at the trial site, assessed safety and efficacy, and collected subject data remained blinded and were prohibited from communicating or discussing any trial information with the non-blinded team.

[0066] The design of the arms and interventions is as follows: Grouping (Arms)

[0067] Experimental group: TLC590 Group: TLC590 (Ropivacaine composition) is a sustained-release liposomal formulation of ropivacaine, which is a white aqueous suspension with a concentration of approximately 19 mg / mL of ropivacaine.

[0068] Active control drug: Naropin® Naropin® Injection contains ropivacaine hydrochloride. Strength: 150 mg / 30 ml (5 mg / ml), Size: 30 ml, filled in a single 30 ml vial. Interventions

[0069] Drug: TLC590 (component of ropivacaine) TLC590 lipid cakes are resuspended in a TLC590 resuspension solution to form the TLC590 anesthetic composition.

[0070] Drug: Naropin® Naropin® is used for local infiltration to administer anesthesia for the procedure and for postoperative pain management. Naropin® 150 mg (0.5%, 5 mg / mL) x 30 mL Other drug name: Naropin®, 0.5% injection solution.

[0071] The primary outcome measures are listed below: Safety and tolerability: (i) the number of serious adverse events and related adverse events occurring after treatment (used to determine the maximum tolerated dose (MTD)) [timeframe: from screening to 30 days after surgical administration] and;

[0072] The secondary outcome measures are listed below: 1. Assess pain intensity at rest and during movement using an 11-point numerical pain assessment scale with a rating range of 0 (no pain) to 10 (most severe imaginable pain). 2. Patient Global Assessment (PGA) for pain control methods (Poor, Average, Good, Excellent). 3. Area under the curve (AUC) of the Digital Pain Assessment Scale at rest and during exercise. 4. The cumulative proportion of subjects who were pain-free (defined as having a resting digital pain assessment score of 0 or 1) at the specified time points. 5. The proportion of subjects who were pain-free (defined as having a resting digital pain assessment score of 0 or 1) at the specified time points. 6. The cumulative percentage of subjects who did not use rescue analgesics at 12, 24, 36, 48, 72 and 96 hours post-operation. 7. The time between the first use of rescue pain medication after surgery. 8. Total dosage of each type of emergency analgesic at 12, 24, 36, 48, 72 and 96 hours post-surgery. 9. Average daily usage of various types of emergency analgesics at 24, 48, 72, and 96 hours post-surgery. 10. The integrated analgesic score is derived from the numerical pain assessment scale score and the amount of emergency analgesics used. 11. The cumulative percentage of subjects who did not use postoperative antiemetic treatment at 12, 24, 36, 48, 72 and 96 hours postoperatively. 12. The occurrence of all adverse events based on severity and correlation analysis. 13. Exposure-response relationship between pharmacokinetic parameters and scores on the Digital Analgesia Scale.

[0073] The changes in the above screening were analyzed statistically. Treatment with TLC590 at single local infiltration doses of 190 mg, 380 mg, 475 mg, and 570 mg resulted in beneficial clinical responses at one or more of the trial endpoints shown above. result

[0074] A total of 64 subjects were randomly assigned to four groups. No serious adverse events or local anesthetic systemic toxicity (LAST) were observed during the trial. All four TLC590 dose groups showed similar safety and tolerability to the 150 mg ropivacaine. Even at 570 mg TLC590, the mean maximum plasma concentration of unbound ropivacaine was still lower than that of the ropivacaine group. The mean plasma concentration of TLC590 decreased after approximately 24 hours of plateauing, and its half-life (t½) was significantly longer than that of the ropivacaine group. Its maximum plasma concentration was less than one-fifth of that of the maximum plasma concentration (2.7 mg / mL) after infiltration with 300 mg ropivacaine solution (7.5 mg / mL) (Regional Anesthesia and Pain Medicine 23(2): 189-196, 1998) (Figure 1A). Compared to the ropivacaine group, all four doses of TLC590 reduced postoperative pain, estimated by the area under the least squares mean of the pain curve on the Digital Nucleus Pain Assessment Scale. For the 475 mg TLC590, compared to ropivacaine, the reduction in pain intensity during movement or at rest was sustained, statistically significant, and clinically meaningful over time (all p < 0.05; highest p < 0.0131) (Figure 2); the pain reduction lasted for more than 168 hours compared to ropivacaine (Figure 3). The median time from first dose of rescue analgesia in the 475 mg TLC590 group was 3.2 times longer than in the ropivacaine group (42 hours vs. 13 hours). Among patients treated with 475 mg of TLC590, the majority (58.3%) did not use any rescue opioids during the trial. Among those who did use rescue opioids, the median time to first dose of opioids postoperatively was four times longer than in the ropivacaine group (13 hours vs. 3.3 hours), and the average total opioid usage at 96 hours postoperatively was 54% less than in the ropivacaine group. in conclusion

[0075] TLC590 demonstrated similar safety and tolerability to ropivacaine, with no systemic toxicity events associated with local anesthetics. Compared to ropivacaine, it provided immediate and long-lasting pain reduction, thereby reducing or eliminating the need for opioids. Subjects receiving 475 mg of TLC590 showed advantages over those receiving clinically appropriate doses of the approved drug (ropivacaine), exhibiting lower average pain at all times and a significant reduction in total pain over the 4-day postoperative period. Example 3 Pain management in adults after hallux valgus surgery

[0076] We conducted a phase II randomized, double-blind, comparator-and-placebo-controlled trial to evaluate the safety, pharmacokinetics, and efficacy of a single postoperative administration of TLC590 via local infiltration to adult individuals following hallux valgus surgery, relative to Naropin® or bupivacaine and placebo.

[0077] This trial recruited approximately 223 suitable participants. The trial consisted of two parts: Part 1: Blinded Pharmacokinetics of TLC590 and Naropin®. Approximately 48 subjects were randomized in a 1:1:1:1 ratio to receive 152 mg (8 mL) of TLC590, 190 mg (10 mL) of TLC590, 228 mg (12 mL) of TLC590, or 50 mg (10 mL) of Naropin®. Randomization was performed using a centralized interactive web response system (IWRS). Unblinded interim analysis was conducted to examine the safety, efficacy, and pharmacokinetics of the three doses of TLC590 and Naropin® in Part 1 of the trial. Part 2: Efficacy and safety of TLC590 relative to bupivacaine and placebo. Part 2 of this trial recruited approximately 150 participants who met all inclusion criteria and were randomly assigned in a 1:1:1 ratio to receive 228 mg of TLC590, bupivacaine, or placebo, respectively. Randomization was performed using a centralized interactive network response system. The trial design is shown in Figure 4.

[0078] Changes in the above screening were statistically analyzed. A beneficial clinical response could be determined based on one or more of the above trial endpoints after treatment with single local infiltration doses of 152 mg, 190 mg, and 228 mg of TLC590.

[0079] none

[0080] Domestic storage information (please note in order of storage institution, date, and number) none Overseas storage information (please note in the order of storage country, institution, date, and number) none

Claims

1. A pharmaceutical composition for administration to a nerve periphery, surgical area, or surgical wound to treat postoperative pain, comprising: a lipid-based complex, wherein the lipid-based complex comprises an acetamide anesthetic and a lipid; wherein the pH of the lipid-based complex is between 5.5 and 8.0, and the molar ratio of the acetamide anesthetic to the lipid in the lipid-based complex is between 0.5:1 and 2:1; wherein the total amount of the acetamide anesthetic in the pharmaceutical composition ranges from 3 mg to 300 mg; and wherein the acetamide anesthetic is selected from the group consisting of lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, articaine, prilocaine, their bases, and combinations thereof.

2. The pharmaceutical composition as described in claim 1, wherein the postoperative pain is caused by hallux valgus surgery.

3. The pharmaceutical composition as described in claim 1, wherein the total amount of the acetamide anesthetic ranges from 10 mg to 250 mg.

4. The pharmaceutical composition as described in claim 1, wherein the total amount of the acetamide anesthetic is 152 mg.

5. The pharmaceutical composition as described in claim 1, wherein the total amount of the acetamide anesthetic is 190 mg.

6. The pharmaceutical composition as claimed in claim 1, wherein the total amount of the acetamide anesthetic is 228 mg.

7. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises 10 mg / mL to 30 mg / mL of the acetamide anesthetic.

8. The pharmaceutical composition as claimed in claim 1, wherein the molar ratio of the acetamide anesthetic to the lipid in the lipid-based complex is between 0.5:1 and 1.5:

1.

9. The pharmaceutical composition as claimed in claim 1, wherein the lipid comprises a neutral saturated phospholipid.

10. The pharmaceutical composition as claimed in claim 9, wherein the neutral saturated phospholipid comprises one or more saturated fatty acids, each of which independently comprises a carbon chain having no more than 18 carbon atoms.

11. The pharmaceutical composition as claimed in claim 9, wherein the neutral saturated phospholipid is selected from the group consisting of dimyristylphosphatidylcholine (DMPC), 1,2-dilauryl-sn-glycerol-3-phosphocholine (DLPC), dipalmitylphosphatidylcholine (DPPC), and combinations thereof.

12. The pharmaceutical composition as claimed in claim 1, wherein the lipid is primarily composed of one or more neutral saturated phospholipids and one sterol.

13. The pharmaceutical composition as described in claim 12, wherein the sterol is cholesterol.

14. The pharmaceutical composition as claimed in any one of claims 1 to 13, wherein the median diameter of the lipid-based complex ranges from 5 micrometers to 200 micrometers.

15. A pharmaceutical composition as claimed in any one of claims 1 to 13, wherein the lipid-based complex is prepared by the following steps: (a) providing a lipid cake comprising: the acetamide anesthetic; and the lipid; and (b) hydrating the lipid cake with a pharmaceutically acceptable buffer solution with a pH of 5.5 to 8.0 to form the lipid-based complex.

16. The use of a lipid-based complex in the preparation of a pharmaceutical composition for treating postoperative pain in a peripheral nerve, surgical area, or surgical wound of an individual requiring anesthesia, wherein the lipid-based complex comprises an acetamide anesthetic and a neutral saturated phospholipid, the neutral saturated phospholipid comprising saturated fatty acids, each saturated fatty acid independently comprising a carbon chain with fewer than 18 carbon atoms; wherein the pH of the lipid-based complex is between 5.5 and 8.0, and the molar ratio of the acetamide anesthetic to the neutral saturated phospholipid in the lipid-based complex is between 0.5:1 and 2:1; wherein the median diameter of the lipid-based complex ranges from 5 micrometers to 200 micrometers; wherein the total amount of the acetamide anesthetic in the pharmaceutical composition ranges from 3 mg to 300 mg; and wherein the acetamide anesthetic is selected from the group consisting of lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, articaine, prilocaine, their bases, and combinations thereof.

17. The use as described in claim 16, wherein the postoperative pain is caused by hallux valgus surgery.

18. The use as described in claim 16, wherein the total amount of the acetamide anesthetic ranges from 10 mg to 250 mg.

19. The use as described in claim 16, wherein the total amount of the acetamide anesthetic is 152 mg.

20. The use as described in claim 16, wherein the total amount of the acetamide anesthetic is 190 mg.

21. The use as described in claim 16, wherein the total amount of the acetamide anesthetic is 228 mg.

22. The use as described in claim 16, wherein the pharmaceutical composition comprises 15 mg / mL to 25 mg / mL of the acetamide anesthetic.

23. Use of a pharmaceutical composition as claimed in claim 1 for the preparation of a medicament for treating postoperative pain caused by hallux valgus surgery, wherein the pharmaceutical composition is administered to an individual requiring anesthesia via nerve block, regional block, or infiltration anesthesia.

24. The use as described in claim 23, wherein the pharmaceutical composition is administered to the individual requiring anesthesia within half an hour to three hours before surgery or during surgery, wherein, Based on the numerical pain assessment scale score on a scale of 0 to 10, a decrease in pain score greater than 2 within a period of time after surgery, where the period is greater than 48 hours.

25. The use as described in claim 24, wherein the period is greater than 72 hours.

26. The use as described in claim 24, wherein the period is greater than 96 hours.

27. The use as described in claim 24, wherein the period is greater than 168 hours.

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