Pharmaceutical composition for use in pain treatment

Abstract

A pharmaceutical composition for use in treating postoperative pain is provided. The pharmaceutical composition comprises a lipid-based complex. The lipid-based complex comprises an amide-type anesthetic and at least one lipid, wherein the molar ratio of the amide-type anesthetic to at least one lipid in the lipid-based complex is at least 0.5:1. The total amount of the amide-type anesthetic is at least 1.5 to 5 times the standard therapeutic dose for treating postoperative pain with the amide-type anesthetic to achieve improved pain control along with a desired sustained analgesic effect.

Description

Technology Field

[0001] The present disclosure relates to the use of anesthetic compositions in pain control. The present disclosure relates to a method for controlling pain. Background Technology

[0002] Description of related technology

[0003] 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 levels, these types of anesthetics also interact with other ion channels, causing acute neurotoxicity and cardiotoxicity, as well as allergic reactions. So-called local anesthetic systemic toxicity (LAST) is always a potential complication of all local anesthetics and all routes of administration, and can be fatal.

[0004] Ropivacaine was introduced in 1996 as a pure S(-) isomer amide-type local anesthetic, and in 2000, the Food and Drug Administration (FDA) approved the brand name Naropin ® It was approved as bupivacaine (Marcaine ® Compared to ), lipophilicity and motor blockade are significantly lower, and the safety margin is larger due to reduced cardiotoxicity. Naropin ® It can be administered via various injection routes, including spinal anesthesia, epidural anesthesia, local block, and local infiltration. Despite having many advantages compared to other local anesthetics, 0.5% Naropin via wound infiltration ® The duration of analgesia after a single administration of (200 mg ropivacaine hydrochloride infusion) was only about 6 to 8 hours. This is insufficient to cover a significant amount of postoperative recovery time, particularly the critical 3-day period after surgery.

[0005] Local anesthetics have limitations due to their short duration of action and LAST risk. Infiltration using NSAIDs and local anesthetics (e.g., ropivacaine hydrochloride) is also widely accepted as a therapy for postoperative pain management. However, there are several potential safety issues associated with the use of NSAIDs, and the duration of postoperative pain relief using local anesthetics is generally limited to about 8 hours. The medical goal is to relieve acute postoperative pain without the use of opioids during the critical 2–4 day postoperative period. Therefore, there is an unmet medical need to provide a safer and more effective long-term non-opioid method of managing postoperative pain with a single dose of drug product administered perioperatively.

[0006] When using long-term blockade with local anesthetics via continuous infusion or repeated bolus administration, there is a high risk of reaching toxic plasma concentrations or causing local nerve damage. Evidence supporting the neurotoxicity of local anesthetics has emerged from analyses of the persistence of paresthesia following the injection of local anesthetic drugs. The severity of paresthesia is related to the duration of the altered sensation; in most cases, the affected nerve will recover naturally within a certain period, but in some cases, this unwanted effect may be prolonged and persist for several months, or the nerve may not recover completely.

[0007] Accordingly, there is an unmet need for improved use of ropivacaine or other amide-type anesthetics in pain control to achieve a beneficial and effective method of pain control having a desired prolonged anesthetic effect. The compositions and methods of the present disclosure satisfy this and other needs. (Patent Document 1) US 2015 / 250724 A1

[0008] outline

[0009] The present disclosure provides a method of treatment with a specific dose range and administration schedule for the amide-type anesthetic of the present disclosure that produces such an extended effect for pain control. In particular, the present disclosure relates to a pharmacological active agent, composition, method, and / or administration schedule having specific advantages, including the ability to reduce undesirable effects of the amide-type anesthetic on subjects requiring it by administering at a lower frequency or at a lower dose to obtain an equivalent effect in pain control or anesthetic effect compared to formulations, compositions, methods, and / or administration schedules currently in use or known in the art. These advantages will become clear from the following additional description.

[0010] The present disclosure provides a method for preparing a sustained-release anesthetic composition by obtaining a lipid cake comprising an amide-type anesthetic and at least one lipid (wherein the molar ratio of the amide-type anesthetic to at least one lipid in the lipid-based complex is at least 0.5:1) using lyophilization (e.g., one-step lyophilization), and then hydrating the lipid cake with a pharmaceutically acceptable buffer to obtain the sustained-release anesthetic composition. Such a sustained-release anesthetic composition provides a rapid onset of anesthesia and an extended duration of local anesthesia with minimal toxicity.

[0011] In one embodiment, the anesthetic composition is a pharmaceutical composition for use in treating postoperative pain in subjects requiring it. The pharmaceutical composition according to the present disclosure comprises an amide-type anesthetic and a lipid-based complex of at least one lipid, wherein the molar ratio of the amide-type anesthetic to at least one lipid in the lipid-based complex is at least 0.5:1, and the total amount of the amide-type anesthetic in the pharmaceutical composition is at least 1.5 to 5 times the standard therapeutic dose of the amide-type anesthetic. The total amount of the amide-type anesthetic in the pharmaceutical composition is about 3 mg to about 1000 mg, about 100 mg to about 800 mg, about 200 mg to about 600 mg, about 300 mg to about 600 mg, about 300 mg to about 500 mg, and optionally about 380 mg, about 475 mg, about 570 mg; Or it may be in the range of about 3 mg to about 300 mg, about 10 mg to about 250 mg, and optionally about 50 mg, about 152 mg, about 190 mg, or about 228 mg. In some embodiments, the amide-type anesthetic of the pharmaceutical composition is an amount of 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 amide-type anesthetic. Other amide-type anesthetics that may be used include lidocaine, bupivacaine, mepivacaine, levobupivacaine, bases thereof, or combinations thereof. In some embodiments, the amide-type anesthetic is bupivacaine, ropivacaine, or a base thereof.

[0012] According to the present disclosure, a lipid-based complex comprises an amide-type anesthetic and one or more lipids. In some embodiments, the lipid comprises at least one neutral saturated phospholipid. At least one neutral saturated phospholipid comprises a saturated fatty acid having a long carbon chain having 18 or fewer carbon atoms. In some embodiments, the lipid-based complex is prepared under specific conditions for preclinical use, for example, at ambient temperature, and the saturated fatty acid having a long carbon chain has 14, 16, and / or 18 carbon atoms.

[0013] In some embodiments, the lipid-based complex of the anesthetic composition is formed by hydrating a lyophilized lipid cake with a pharmaceutically acceptable buffer at a pH greater than 5.5. Theoretically, uncharged ropivacaine is its p Ka (of ropivacaine p Based on calculations from Ka (which is 8.1), it is 0.8% of ropivacaine available at pH 6.0. In some embodiments, the lipid cake according to the present disclosure is prepared by dissolving nonpolar ropivacaine, phospholipids, and cholesterol in a solvent system, e.g., tertiary-butanol alone or tertiary-butanol / water cosolvent, and then removing the solvent system using freeze-drying technology.

[0014] In a specific embodiment, the molar ratio of amide-type anesthetic to phospholipid in a lipid-based complex (mol 약물 :mole 인지질 ) is at least 0.5:1. The pharmaceutical composition of the present invention can provide a sufficient amount of an amide-type anesthetic to a subject requiring it in order to extend the duration of anesthesia after local administration in vivo. In addition, a predetermined amount of the amide-type anesthetic in a free form not trapped by a lipid-based complex is at a maximum plasma concentration (C max Rapid onset of anesthesia can be achieved while minimizing exposure.

[0015] In another aspect, the present disclosure also provides a method for treating postoperative pain in a subject requiring anesthesia. The method may include administering the pharmaceutical composition of the present disclosure via nerve block, via field block, or via infiltration anesthesia.

[0016] In certain embodiments, postoperative pain is caused by surgery, e.g., to a limited extent, hernia repair surgery, bunionectomy, genitourinary surgery, orthopedic surgery, obstetric surgery, laparoscopic surgery, abdominoplasty, breast surgery, and kidney transplantation procedures (KTX).

[0017] In another aspect, the present disclosure provides a method for treating postoperative pain. The method may comprise administering a dose of the pharmaceutical composition according to the present disclosure before or after the start of surgery (during surgery) and particularly before the completion of surgery, from about thirty minutes (30 minutes) to about three hours, optionally from thirty minutes (30 minutes) to about two hours, and optionally from about 30 minutes to about one hour, wherein the pain reduction is at least about 2 according to the NPRS (Numerical Pain Rating Scale) score for a certain period after surgery, and the period is at least 48 hours, optionally at least 72 hours, at least 96 hours, or at least 168 hours. The NPRS may be a grade from 0 to 10, where 0 is no pain and 10 is the worst pain imaginable. In some embodiments, where the composition according to the present disclosure is administered via nerve block or field block, the composition may be administered from about 30 minutes to about one hour before surgery. In other non-limiting embodiments, where the composition according to the present disclosure is administered through a local infiltration suitable for hernia repair surgery and bunionectomy, the composition may be administered during surgery, generally at the final stage of surgery before the final sealing of the incision.

[0018] Other objects, advantages, and novel features of the present disclosure will become apparent from the following detailed description when taken together with the accompanying drawings. Brief explanation of the drawing

[0019] FIG. 1 illustrates a study design for a clinical trial of an anesthetic composition of the present disclosure for the treatment of postoperative pain after hernia repair surgery. FIG. 1a illustrates a chart comparing the maximum plasma concentration of ropivacaine after treatment of postoperative pain with anesthetic compositions of the present disclosure having various dosages as indicated. FIG. 2 illustrates the results of a study on a clinical trial of an anesthetic composition of the present disclosure, wherein AUC = area under the pain-time curve; LS = least squares; NPRS = numerical pain rating scale; LS mean obtained from an ANOVA model including NPRS AUC as the response and treatment groups as the principal fixed effect; NPRS adjusted for rescue drug use using windowed worst observation carried forward (wWOCF); *p <0.05 vs. ropivacaine; FIG. 3 illustrates the LS mean (SE) pain during exercise for the anesthetic composition of the present disclosure at a dose of 475 mg compared to ropivacaine, where LOCF (last observation carried forward) is for missing data; wWOCF (window lowest observation carried forward) is for rescue drug. FIG. 4 illustrates a study design for a clinical trial of an anesthetic composition of the present disclosure for the treatment of postoperative pain after bunion resection surgery. Specific details for implementing the invention

[0020] Detailed description of a desirable embodiment

[0021] As used above and throughout this disclosure, unless otherwise indicated, the following terms should be understood to have the following meanings.

[0022] As used herein, the singular forms (“a,” “an,” and “the”) include plural objects unless the context clearly indicates otherwise.

[0023] All numbers in this document may be understood as being modified by “about,” which means that when referring to measurable values ​​such as amount, time period, etc., there is a variation of ±10%, preferably ±5%, more preferably ±1%, and even more preferably ±0.1% from the specified value, because such variation is appropriate for obtaining the desired amount of amide-type anesthetic unless otherwise specified.

[0024] As used herein, the terms “treating,” “treated,” or “treatment” include preventive (e.g., preventive), palliative, and curative methods, uses, or results. The terms “treatment” or “treatments” may also refer to compositions or medicines. Throughout this application, “treating” means a method of reducing or delaying one or more symptoms or signs of pain, an improvement in pain detected by techniques known in the art, or a reduction in the use of pain-controlling drugs. Methods recognized in the art are available to evaluate pain and its symptoms. These include, but are not limited to, the 6-point descriptive pain scale, the 11-point NPRS, visual analog scales, the Wisconsin Brief Pain Questionnaire, the Brief Pain Inventory, the McGill Pain Questionnaire and the abbreviated McGill Pain Questionnaire, and other scoring methods including the Patient Global Assessment (PGA) of pain control methods. For human subjects, for example, self-reporting using a grading scale from no pain (0) to maximum pain (10) may be used to identify the level of pain. Optionally, functional magnetic resonance imaging (fMRI) may be used on subjects to confirm reduced pain after administration of the pharmaceutical composition of the present disclosure. For example, the disclosed method is considered a treatment if there is at least a 1% reduction in one or more pain symptoms of the subject compared to the subject before treatment or one or more control subjects. Thus, the reduction may be about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount in between.Treatment in the subject may also be evaluated by a reduction in the use of pain-controlling medications, such as opioids or other analgesics, and / or a reduction in side effects associated with these analgesic drugs, such as gastrointestinal symptoms associated with opioid use. Additional efficacy questionnaires, such as the Postoperative Recovery Index, may be used to assess pain and recovery, as well as side effects that may be associated with opioid use. In particular, postoperative pain may be acute and / or chronic. Acute pain may be experienced immediately or for up to 7 days (e.g., about 1, 2, 3, 4, 5, 6, or 7 days after surgery).

[0025] The term “subject” may refer to a vertebrate at risk of developing pain or a pain-inducing disease, or a vertebrate considered to require pain treatment or management. Subjects include all warm-blooded animals, such as mammals including primates, and more preferably, humans. Non-human primates are also subjects. The term “subject” includes domesticated animals such as cats and dogs, livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mice, rabbits, rats, gerbils, guinea pigs, etc.). Accordingly, veterinary uses and medical formulations are considered herein.

[0026] "Association Efficiency (AE)" represents the amount of drug captured in the lipid-based complex and is calculated as the ratio of the amount of drug in the separated lipid-based complex to the total amount of drug in the original composition before separation. The separated lipid-based complex can be obtained by any method known in the art. In some embodiments, the separated lipid-based complex is obtained by centrifugation methods, e.g., traditional centrifugation, density gradient centrifugation, differential centrifugation, or by filtration methods, e.g., volume filtration, gel filtration, and membrane filtration.

[0027] The term “standard therapeutic dose” may refer to an amount of an indicated therapeutic agent to produce a desired effect or result for a compartment particularly similar to the present disclosure, exemplified by the equilibrium of the drug with hard tissues, such as soft tissue, muscle, and fat, particularly with tissues with poor perfusion. The standard therapeutic dose may be determined by a person skilled in the art. For the standard therapeutic dose suitable for each indication, references to relevant anesthetics, including approved medicines listed in the United States Pharmacopoeia (USP) and the Drugs@FDA library sponsored by the U.S. Food and Drug Administration, may be made, but not limited to, the United States Pharmacopoeia (USP) and the Drugs@FDA library. The therapeutic dose may be infiltrated or injected into the surgical site. For example, the standard therapeutic dose of injectable ropivacaine HCl solution (Naropin®) for pain management after hernia surgery by local infiltration is less than 300 mg, specifically 2 mg to 200 mg. In one embodiment, the standard therapeutic dose of free ropivacaine solution for injection or infiltration for pain treatment after bunionectomy is 50 mg. In another embodiment, the standard therapeutic dose for bupivacaine hydrochloride injection USP (by Hospira) is up to 225 mg when epinephrine is 1:200,000 and 175 mg when epinephrine is absent. The standard therapeutic dose may be determined based on the type of surgery and may be established by a person skilled in the art.

[0028] amide-type anesthetic

[0029] The term "amide anesthetic" refers to a group of one or more substances that cause loss of sensation in the external area of ​​a subject resulting from the inhibition of nerve terminal excitation or inhibition of peripheral nerve conduction processes. A typical amide anesthetic structure contains a lipophilic portion and a hydrophilic portion connected by -NHCO- bonds. Suitable amide anesthetics include, but are not limited to, lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrocaine, articaine, and prilocaine and their free bases. In certain embodiments, the amide anesthetic is the ropivacaine base.

[0030] Geological-based complexes and geological

[0031] A lipid-based complex according to the present disclosure comprises one or more lipids and an amide-type anesthetic. In one embodiment, the lipid-based complex may be prepared and stored for a long period to extend the shelf life of the composition. The lipid-based complex may be formed by hydrating a lipid cake containing one or more lipids and an amide-type anesthetic immediately before clinical use.

[0032] The lipid cake described above may comprise one or more phospholipids and amide-type anesthetics in the absence of sterols. Alternatively, the lipid cake may comprise one or more phospholipids and amide-type anesthetics having one or more sterols, e.g., cholesterol, in an amount of 50% or less of the total lipids. In certain embodiments, the molar percentage of cholesterol relative to total lipids is about 0% to 50%, and optionally about 33% to 40%. In some embodiments, the phospholipid(s) and cholesterol are present in a molar ratio of 1:1 to 3:1.

[0033] A lipid cake may be prepared by 1) dissolving one or more lipids and amide-type anesthetics in a solvent system to form a liquid structure containing one or more solvents to form a homogeneous solution, and 2) removing the solvent(s) to solidify the formulation of the lipids and amide-type anesthetics(s). Solvent removal may be performed using known techniques such as freeze-drying. Examples of solvent systems suitable for freeze-drying include, but are not limited to, other non-aqueous solvents such as acetone, acetonitrile, ethanol, n-propanol, isopropanol, n-butanol, methanol, dichloromethane, dimethyl sulfoxide, and tertiary-butanol and tertiary-butanol / water co-solvent systems in the presence or absence of carbon tetrachloride.

[0034] In some embodiments, the lipid of the lipid-based complex comprises one or more phospholipids and cholesterol, and the molar ratio of the amide-type anesthetic to the phospholipid of the lipid-based complex is at least 0.5:1, and optionally, 0.5:1 to 2:1, e.g., 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.

[0035] One or more lipids are selected from the group consisting of digaliphatic chain lipids, e.g., phospholipids, diglycerides, digaliphatic glycolipids; single lipids, e.g., sphingomyelin and glycosphingolipids; sterols, e.g., cholesterol and derivatives thereof; and combinations thereof. Examples of phospholipids according to the present disclosure are, without limitation, 1,2-dilauroyl- sn -Glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl- sn -Glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl- sn -Glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-stearoyl- sn -Glycero-3-phosphocholine (PSPC), 1-palmitoyl-2-oleoyl- sn-Glycero-3-phosphatidylcholine (POPC), 1,2-distearoyl- sn -Glycero-3-phosphocholine (DSPC), 1,2-dioleoyl- sn -Glycero-3-phosphocholine (DOPC), hydrogenated soybean phosphatidylcholine (HSPC), 1,2-dimyristoyl- sn -glycero-3-phospho-(1'-rac-glycerol)(sodium salt)(DMPG), 1,2-dipalmitoyl- sn -glycero-3-phospho-(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)(DSPG), 1,2-dioleoyl- sn -glycero-3-phospho-(1'-rac-glycerol)(DOPG), 1,2-dimyristoyl- sn -Glycero-3-phospho-L-serine (sodium salt) (DMPS), 1,2-dipalmitoyl- sn -Glycero-3-phospho-L-serine (sodium salt) (DPPS), 2-distearoyl- sn -Glycero-3-phospho-L-serine (sodium salt) (DSPS), 1,2-dioleoyl- sn -Glycero-3-phospho-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) (DOPA), 1,2-dipalmitoyl- sn -Glycero-3-phosphoethanolamine (DPPE), 1-palmitoyl-2-oleoyl- sn -Glycero-3-phosphoethanolamine (POPE), 1,2-distearoyl- 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)(DPPI), 1,2-distearoyl- sn -Glycero-3-phosphoinositol (ammonium salt) (DSPI), 1,2-dioleoyl- sn It includes glycero-3-phospho-(1'-myo-inositol)(ammonium salt) (DOPI), cardiolipin, L-α-phosphatidylcholine (EPC), and L-α-phosphatidylethanolamine (EPE).

[0036] Examples of phospholipids are, but are not limited to, dimyristoyl-phosphatidylcholine (DMPC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), dipalmitoylphosphatidylcholine (DPPC), dioleol-phosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS), dioleol-phosphatidic acid (DOPA), egg-phosphatidylcholine (egg-PC), phosphatidylethanolamine (egg-PE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE), cardiolipin, and 1,2-dimyristoyl- sn - Contains glycero-3-phosphate (sodium salt) (DMPA).

[0037] Suitable phospholipids according to the present disclosure are saturated phospholipids derived from two saturated long-carbon chain fatty acids, wherein each fatty acid has at least 12 carbons, alternatively at least 14 carbons; and a long carbon chain of 20, alternatively 18, or 16 or fewer carbons. In some embodiments, suitable saturated phospholipids according to the present disclosure are selected from the group consisting of DLPC, DMPC, DPPC, and combinations thereof.

[0038] In some embodiments, the lipid-based complex comprises a liposome and an amide-type anesthetic. The liposome comprises one or more lipids including a suitable phospholipid according to the present disclosure, a positively or negatively charged phospholipid, and a determined amount of unsaturated phospholipid, wherein the determined amount is less than 10% molar percentage based on the total amount of phospholipids, for example, about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.

[0039] Anesthetic composition

[0040] The terms "anesthetic composition" and "pharmaceutical composition for use in pain treatment" are used interchangeably. In certain embodiments, the anesthetic composition comprises a lipid-based complex and a non-encapsulated local anesthetic. In some embodiments, the lipid-based complex comprises a multilayer vesicle and a local anesthetic encapsulated in the multilayer vesicle. The terms "encapsulate" or "encapsulate" refer to the bilayer membrane of the multilayer vesicle that encapsulates, embeds, or associates the target drug substance.

[0041] The particle size distribution of the lipid-based complex according to the present invention can be determined by various methods known in the art. In some embodiments, the average particle size of the lipid-based complex of the anesthetic composition is 1 μm or greater; optionally greater than 5 μm, e.g., in the range of 5 μm to 50 μm, or 10 μm to 25 μm. Alternatively, the volume-median particle diameter (D) of the lipid-based complex of the anesthetic composition 50 ) is 1 μm or greater; optionally 5 μm or greater, e.g., in the range of 5 μm to 50 μm, 5 μm to 40 μm, 5 μm to 30 μm, 5 μm to 20 μm, or 5 μm to 15 μm. In some embodiments, the central particle diameter (D 50) refers to the particle diameter at which the cumulative percentage of lipid-based complexes composed of aggregated particles in the cumulative particle size distribution is 50%, and is 5 μm or more or 7 μm or more. In some embodiments, the median particle diameter (D 50 ) refers to a particle diameter in which the cumulative percentage of a lipid-based complex composed of aggregated particles in the cumulative particle size distribution is 50%, and is 25 μm or less, 20 μm or less, or 15 μm or less; and optionally 5 μm to 25 μm, 5 μm to 20 μm, or 5 μm to 15 μm.

[0042] In some embodiments, the particle size at the 90% cumulative percentage in the cumulative particle size distribution (D90) of the lipid-based complex of the anesthetic composition is 10 μm or more, e.g., 10 μm to 300 μm, 20 μm to 300 μm, 20 μm to 200 μm, or 20 μm to 100 μm. Also, D 90 The lower limit of is, for example, 25 μm or more or 30 μm or more without limitation. In addition, the shape of the aggregated particles of the lipid-based complex to improve assembling efficiency per unit dose is not particularly limited.

[0043] In some embodiments, a pharmaceutical composition for use in pain treatment comprises a multilayer vesicle, a portion of an amide-type anesthetic captured by the multilayer vesicle, and a portion of a free-form amide-type anesthetic also referred to as a free-form amide-type anesthetic (not captured). The particle size distribution of the multilayer vesicles together with the captured amide-type anesthetic in the lipid-based complex according to the present disclosure may be determined by various methods known in the art. In some embodiments, the particle size of the multilayer vesicles together with the captured amide-type anesthetic in the anesthetic composition according to the present disclosure is 1 μm or greater; optionally, greater than 5 μm, e.g., in the range of 5 μm to 200 μm, 10 μm to 100 μm, or 10 μm to 50 μm. Alternatively, the median diameter (D) of the lipid-based complex in the anesthetic composition according to the present disclosure 50 ) is 1 μm or larger; optionally 5 μm or larger, e.g., 5 μm to 100 μm, or in the range of 10 μm to 50 μm.

[0044] In some embodiments, the lipid-based complex is formed by hydrating a lipid cake containing an amide-type anesthetic with a pharmaceutically acceptable buffer at a pH greater than 5.5. The anesthetic composition thus obtained can provide sustained-release of the amide-type anesthetic, which is ready for use or diluted with an aqueous buffer or other suitable diluent before administration. In some embodiments, the aqueous buffer is in a pH range of 5.5 to 8.0, and optionally 6.0 to 7.5 or 6.5 to 7.0.

[0045] Suitable aqueous buffers according to the present disclosure are, without limitation, citrate, acetate, maleate, piperazine, succinate, 2-( N -Morpolino)ethansulfonic acid (MES), histidine, bis-tris, phosphate, ethanolamine, N -(2-acetamido)iminodiacetic acid (ADA), carbonate, N-(2-acetamido)-2-aminoethanesulfonic acid (ACES), 1,4-piperazine diethanesulfonic acid (PIPES), 3-morpholino-2-hydroxypropanesulfonic acid (MOPSO), imidazole, N,N It includes bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), triethanolamine, lysine, tris, and glycylglycine solutions. The amount of unencapsulated amide-type anesthetic in the composition can be adjusted based on the distribution-coefficient of the anesthetic by selecting an appropriate pH value for the aqueous solution based on clinical indications and the total injection dose.

[0046] In some embodiments, the aqueous buffer contains histidine at a concentration 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.

[0047] In some embodiments, the aqueous buffer contains phosphate at a concentration ranging from 1 mM to 200 mM, 10 mM to 180 mM, 10 mM to 170 mM, 10 mM to 160 mM, 10 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.

[0048] The amount of the free-form amide-type anesthetic is a function of the association efficiency (AE) of the lipid-based complex of the anesthetic composition determined by the centrifugation method. Mathematically, the amount of the free-form amide-type anesthetic is expressed as follows:

[0049]

[0050] Here, A 비포집 is the amount of uncaptured amide-type anesthetic; A 총 is the total amount of amide-type anesthetic in the anesthetic composition; A EAE is obtained by dividing the amount of amide-type anesthetic in the lipid-based complex by the total amount of amide-type anesthetic in the anesthetic composition. The AE according to the present disclosure is at least 60%, and optionally 60% to 99%, 70% to 95%, and 80% to 90%.

[0051] In a specific embodiment, the molar ratio of amide-type anesthetic to lipid(s) in the lipid-based complex (mol 약물 :mole 지질 , D:PL) is at least 0.5:1 and includes, without limitation, 0.7:1, 0.9:1, 1.2:1, 1.4:1, or 2:1. In certain embodiments, the median diameter (D) of the particle population of the lipid-based complex. 50 ) is 1 μm or more, e.g. 5 μm or more; and optionally, is within the range of 5 μm to 200 μm, 5 μm to 190 μm, 5 μm to 180 μm, 5 μm to 170 μm, 5 μm to 160 μm, 5 μm to 150 μm, 5 μm to 140 μm, 5 μm to 130 μm, 5 μm to 120 μm, 5 μm to 110 μm, 5 μm to 100 μm, 10 μm to 100 μm, 12 μm to 100 μm, 14 μm to 100 μm, 16 μm to 100 μm, 18 μm to 100 μm, or 20 μm to 100 μm.

[0052] The concentration of the amide-type anesthetic in the anesthetic composition may be higher than 2 mg / mL to achieve clinical therapeutic benefits. Suitable concentrations of amide-type anesthetics are, without limitation, at least 10 mg / mL, and include 2 mg / mL to 30 mg / mL, 10 mg / mL to 30 mg / mL, 10.5 mg / mL to 30 mg / mL, 11 mg / mL to 30 mg / mL, 11.5 mg / mL to 30 mg / mL, 12 mg / mL to 30 mg / mL, 12.5 mg / mL to 30 mg / mL, 10 mg / mL to 25 mg / mL, 10.5 mg / mL to 25 mg / mL, 11 mg / mL to 30 mg / mL, 11.5 mg / mL to 25 mg / mL, 12 mg / mL to 25 mg / mL, 12.5 mg / mL to 25 mg / mL, 15 mg / mL to 25 mg / mL, and particularly include a range of 19 mg / mL. A limited amount of unencapsulated amide-type anesthetic in the anesthetic composition of the present disclosure may provide the advantage of achieving a higher maximum tolerable dose (depending on the plasma anesthetic concentration that causes central nervous system and cardiovascular toxicity) and may be used to provide rapid onset of efficacy.

[0053] For clinical use, in certain embodiments of the present disclosure, the free-form amide anesthetic may be in the range of about 1% to about 50%, about 5% to about 40%, or about 10% to about 30%. The remaining amide anesthetic in the lipid-based complex acts as a depot for gradually releasing the amide anesthetic into the local environment in a manner that maintains a therapeutically effective amount at the local site. In some embodiments, the half-life of ropivacaine derived from a single subcutaneous administration of the anesthetic composition according to the present disclosure is extended by at least 10 times compared to the half-life of unformulated ropivacaine. The duration of the anesthetic effect after administration of the anesthetic composition of the present disclosure is extended far beyond the duration of unformulated ropivacaine.

[0054] The pharmaceutical composition according to the present disclosure exhibits a significantly extended-release profile of the therapeutic agent and yields an immediate and prolonged reduction in pain of 2 to 4 on a Numerical Pain Rating Scale (NPRS) score of 0 to 10 during the postoperative period for administration of a clinically appropriate dose of the local anesthetic. For example, the pharmaceutical composition of the present disclosure extends the half-life of a locally administered liposomal anesthetic composition. The composition may exhibit significantly reduced total pain and lower mean pain on an NPRS score at all points in humans over time intervals of 24, 48, 72 hours, 4 days, or 1 week compared to that of the administered free anesthetic or commercially available anesthetic.

[0055] The lipid-based complex according to the present disclosure may be administered perineal, at the surgical site, or at the surgical site. The terms “postsurgical pain” and “post-operative pain” are used interchangeably herein and refer to pain caused by various surgeries. In some embodiments, post-operative pain is caused by hernia repair surgery, genitourinary surgery, hemorrhoid surgery, abdominal surgery, thoracic surgery, orthopedic surgery, e.g., but not limited to, bunionectomy, vertebroplasty, acromioplasty, kyphoplasty, total knee or hip replacement, gynecological surgery, breast surgery, dental surgery, abdominoplasty, breast surgery, kidney transplant procedure (KTX), or any type of laparoscopic surgery.

[0056] The pharmaceutical composition according to the present disclosure may be injected, dripped, or applied using a standard syringe and needle. The injection of the pharmaceutical composition according to the present disclosure may be via a subcutaneous, intradermal, or intramuscular route.

[0057] In another embodiment, the pharmaceutical composition according to the present disclosure is administered as a nerve blocker as a prophylactic treatment for a painful condition, such as preoperative administration for the treatment of postoperative pain, in subjects requiring it. In some embodiments, the pharmaceutical composition according to the present disclosure is administered as a nerve blocker, such as Quadratus Lumborum Block (QLB).

[0058] Peripheral nerve block involves introducing a substance near or into a peripheral nerve to reduce pain or provide numbness.

[0059] In another embodiment, the pharmaceutical composition according to the present disclosure is administered to the surgical field as a field blocker, such as a Mayo block of the polypodial nerve for bunionectomy, a TAPB (Transversus Abdominis Plane Block) for laparotomy or cesarean section, and a site-specific anesthesia technique for hip or knee replacement.

[0060] The present disclosure will be further described with reference to the following specific non-limiting embodiments.

[0061] Examples

[0062] The following examples illustrate the manufacture and characteristics of specific embodiments of the present disclosure.

[0063] Example 1

[0064] Preparation of anesthetic compositions

[0065] 1,2-Dimiristoil- snGlycero-3-phosphocholine 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), and ropivacaine was purchased from Apollo Scientific (Cheshire, UK) or Dishman Pharmaceuticals and Chemicals. All other chemicals were purchased from Sigma-Aldrich.

[0066] To prepare the lipid cake, it was combined with a lipid complex as indicated by a drug-to-phospholipid ratio (D:PL) of 1.458 μmol / μmol, namely phosphocholine:cholesterol:ropivacaine = 2:1:2.9. The lipid and ropivacaine were mixed and then dissolved in tertiary-butanol or a tertiary-butanol / water co-solvent system (1 / 1 vol / vol) to form a lipid structure. After freezing the liquid structure, it was freeze-dried overnight to obtain a lipid cake of the amide-type anesthetic.

[0067] To prepare the lipid structure for the vehicle control, phospholipid:cholesterol in a 2:1 molar ratio was weighed and dissolved in tertiary-butanol. The resulting sample was frozen and then freeze-dried overnight to obtain the lipid cake of the vehicle control.

[0068] A lipid cake of an anesthetic or a vehicle control was hydrated with a buffer solution of pH 6.5 to 6.8 at a temperature above ambient temperature (AT) (25℃) to form an anesthetic composition and a vehicle control composition, respectively, and then the aggregation efficiency and particle size distribution were characterized.

[0069] Determination of characteristics of anesthetic composition

[0070] The association efficiency (AE) of each of the preparations described above was determined as follows. A 200-microliter aliquot of each sample of the anesthetic composition was centrifuged at 3000 xg for 5 minutes at 4°C to obtain the lipid-based complex. After separating the supernatant, the lipid-based complex was resuspended to a final volume of 200 μL. Reference absorbance standards for each drug substance (e.g., ropivacaine) were established based on a solution of the test drug substance at a known concentration. The drug amounts in both the original anesthetic composition and the lipid-based complex were measured using an ultraviolet / visible (UV / Vis) spectrophotometer. AE represents the ratio of the drug dose in the lipid-based complex to the amount of drug substance in the original anesthetic composition. The D:PL of the lipid-based complex was calculated by multiplying the D:PL of the lyophilized lipid cake by the AE and indicated as "Result D:PL".

[0071] The particle size of each anesthetic composition was measured using a laser diffraction analyzer (LA-950V2, Horiba). The median diameter (D) of the lipid-based complex formed by hydrating the lyophilized lipid cake with a pharmaceutically acceptable buffer (e.g., 50 mM histidine buffer at pH 6.5) was 50 ) investigated.

[0072] It was determined that the lipid-based complex in the anesthetic composition has a drug produced for a phospholipid ratio of approximately 1.32. The median diameter (D) of the lipid-based mixture particle population in the anesthetic composition. 50 ) is about 5 μm to 10 μm.

[0073] Example 2 Pain treatment in adult subjects after inguinal hernia repair surgery

[0074] Naropin via single infiltrative local administration in adult subjects following inguinal hernia repair surgery ®A Phase I / II, randomized, double-blind, comparator-controlled dose-escalation study to evaluate the safety, PK, and efficacy of a single postoperative application of an anesthetic composition (represented as TLC590) according to the present disclosure in comparison to

[0075] Approximately 64 evaluable subjects meeting all entry criteria were enrolled in this study across four cohorts. The dose escalation for a single postoperative administration of TLC590 was Naropin ® It was performed using sequential dose levels in comparison. Dose escalation was determined by a review of treatment-related adverse events (TEAEs) and all serious adverse events (SAEs) by the Safety Monitoring Committee (SMC).

[0076] The inclusion criteria are as follows:

[0077] 1. We can provide written consent and are willing to provide it;

[0078] 2. Male or female aged 18 to 65;

[0079] 3. You are scheduled to undergo primary general Liechtenstein inguinal hernia repair with mesh, and anesthesia may be used;

[0080] 4. It has one or two ASA physical state classifications;

[0081] 5. Female subjects are eligible only if: not breastfeeding; not planning to become pregnant during the study; committing to use an acceptable form of contraception; or male subjects must be sterile for the duration of the study or committed to using a reliable method of contraception for at least one week after administration of the blinded study drug;

[0082] 6. Body Mass Index ≤ 35 kg / m² 2 It must be.

[0083] Subjects were enrolled in each cohort at a ratio of 3:1. Each cohort was assigned to either TLC590 or an active comparator drug (Naropin) according to the randomization schedule and dose escalation plan. ® It included subjects to be administered a dose of 150 mg ([0.5%, 5 mg / mL]) (Fig. 1).

[0084] To maintain objectivity, the study drug was administered and administered by an independent, unblinded team including injectors, pharmacists, and the Clinical Research Association. All subjects, investigators, and other field personnel who directly interact with subjects, evaluate safety and efficacy, and collect subject data remained blinded and must not communicate or discuss study information with unblinded teams.

[0085] The sectors and interventions were designed as follows:

[0086] sector

[0087] Experiment: TLC590 Group:

[0088] TLC590 (ropivacaine composition) is a sustained-release liposomal formulation of ropivacaine, which is a white aqueous suspension having a ropivacaine concentration of about 19 mg / mL.

[0089] Active comparator: Naropin ® :

[0090] Naropin ® The injection contains ropivacaine HCl. Strength: 150 mg / 30 mL (5 mg / mL)

[0091] Size: 30 mL filled into a 30 mL single-dose vial.

[0092] Intervention

[0093] Drug: TLC590 (Ropivacaine composition).

[0094] A TLC590 lipid cake was reconstituted with a TLC590 reconstitution solution to form a TLC590 anesthetic composition.

[0095] Drug: Naropin®

[0096] Naropin to generate analgesia for surgery anesthesia and postoperative pain management ® Local infiltration of. Naropin ® 150 mg [0.5%, 5 mg / mL] x 30 mL

[0097] Other names: Naropin ® , 0.5% injection solution.

[0098] Primary outcome measures are listed below: Safety and tolerability: (i) Number of SAEs and treatment-related severe AEs (to determine MTD) [Period: Screening up to 30 days after IP administration] and;

[0099] The second result measurement is as follows:

[0100] 1. Pain intensity during rest and exercise was evaluated using an 11-point NPRS ranging from 0 (no pain) to 10 (most severe pain).

[0101] 2. Patient Comprehensive Assessment of Pain Control Methods (PGA) (Poor, Average, Good, or Excellent).

[0102] 3. AUC of NPRS during rest and exercise

[0103] 4. Cumulative percentage of pain-free subjects (defined as NPRS at rest of 0 or 1) at scheduled time points.

[0104] 5. The proportion of pain-free subjects (defined by NPRS at rest of 0 or 1) at the scheduled time.

[0105] 6. Cumulative percentage of subjects who did not use rescue analgesics for 12, 24, 36, 48, 72, and 96 hours.

[0106] 7. Time of first use of rescue analgesics after surgery.

[0107] 8.Total postoperative consumption of each type of rescue analgesic for 12, 24, 36, 48, 72, and 96 hours.

[0108] 9. Average daily consumption of relief analgesics by type over 24, 48, 72, and 96 hours.

[0109] 10. Integrated analgesic score using NPRS score and rescue analgesic consumption.

[0110] 11. Cumulative proportion of subjects who did not use postoperative analgesic therapy for 12, 24, 36, 48, 72, and 96 hours.

[0111] 12. Incidence of all adverse events based on severity and relevance.

[0112] 13. Exposure-response relationship between PK parameters and NPRS scores.

[0113] Changes from the above screen were statistically analyzed. Therapy with TLC590 via single infiltrative topical administration at doses of 190 mg, 380 mg, 475 mg, and 570 mg produced beneficial clinical responses according to any one or more of the aforementioned endpoints.

[0114] result

[0115] A total of 64 subjects were randomized into four cohorts. No serious adverse events or incidents of local anesthetic systemic toxicity (LAST) were observed in the study. All four TLC590 dose groups demonstrated safety and tolerability similar to ropivacaine 150 mg. Even at 570 mg, the mean peak plasma unconjugated ropivacaine concentration for TLC590 was lower than that of the ropivacaine group. The mean plasma concentration for the TLC590 dose remained steady for approximately 24 hours before decreasing, and a significantly longer t½ was observed compared to the ropivacaine group, and C maxIt was reduced to less than 1 / 5 of the 300 mg infiltration 7.5 mg / mL ropivacaine solution (2.7 mg / mL) (Regional Anesthesia and Pain Medicine 23(2): 189-196, 1998)( Fig. 1a All four doses of TLC590 reduced postoperative pain compared to the ropivacaine group, as measured by the least squares (LS) mean area (AUC) under the pain curve for NPRS. For TLC590 475 mg, there was a sustained, statistically significant, and clinically meaningful reduction in pain intensity during exercise and rest over time compared to ropivacaine (all p<0.05, highest p-value 0.0131). Fig. 2 Reduced pain vs. ropivacaine was maintained for 168 hours ( Fig. 3 The median time to the first rescue analgesic was 3.2 times longer for the TLC590 475 mg group than for the ropivacaine group (42 hours vs. 13 hours). The majority of patients (58.3%) treated with TLC590 (475 mg) did not use any rescue opioids throughout the study. Among those who used rescue opioids, the median time to the first opioid use after surgery was approximately four times longer for the ropivacaine group (13.0 hours vs. 3.3 hours). Average total opioid consumption was 54% less than in the ropivacaine group during the 96 hours after surgery.

[0116] conclusion

[0117] TLC590 demonstrated safety and tolerability similar to ropivacaine without last events, and reduced or eliminated the need for opioids by providing immediate and long-lasting pain reduction compared to patients using ropivacaine. Subjects administered 475 mg of TLC590 showed superiority over clinically relevant doses of the approved drug ropivacaine, having lower mean pain at all points and a significant reduction in total pain over a time interval of 4 days post-surgery.

[0118] Example 3: Pain treatment in adult subjects after bunion resection

[0119] Naropin via single infiltration local administration in adult subjects after bunionectomy ® Alternatively, a Phase II, randomized, double-blind comparative- and placebo-controlled study was conducted to evaluate the safety, PK, and efficacy of a single postoperative administration of TLC590 compared to bupivacaine and placebo.

[0120] Approximately 223 eligible subjects were enrolled in this study. The study was divided into two parts:

[0121] Part 1: TLC590 and Naropin ® For the blinded pharmacokinetics study, approximately 48 subjects were randomized in a 1:1:1:1 ratio to receive TLC590 152 mg (8 mL), TLC590 190 mg (10 mL), TLC590 228 mg (12 mL), or Naropin® (50 mg, 10 mL). The randomization schedule was assigned via the Interactive Web Response System (IWRS). In Part 1 of the study, TLC590 and Naropin ® A non-blinded interim analysis was performed to examine the safety, efficacy, and pharmacokinetics of three different doses.

[0122] Part 2: Efficacy and Safety of TLC590 Compared to Bupivacaine and Placebo. Approximately 150 subjects were enrolled in Part 2 of the study, and they met all entry criteria with a 1:1:1 randomization ratio to TLC590 228 mg, bupivacaine, and placebo treatments. The randomization schedule was assigned by the centralized IWRS. The study design plan is shown in Figure 4.

[0123] Changes from the above screen were statistically analyzed. Therapy with TLC590 via single infiltrative topical administration at doses of 152 mg, 190 mg, and 228 mg produced beneficial clinical responses according to any one or more of the aforementioned endpoints.

Claims

Claim 1 A pharmaceutical composition for use in treating postoperative pain, comprising a lipid-based complex at pH 5.5 to 8.0, wherein the lipid-based complex comprises an amide-type anesthetic in a free base form and a neutral saturated phospholipid, wherein the molar ratio of the amide-type anesthetic in a free base form to the neutral saturated phospholipid in the lipid-based complex is between 0.5:1 and 2:1, and the total amount of the amide-type anesthetic in a free base form of the pharmaceutical composition is in the range of 300 mg to 600 mg per dose. Claim 2 A pharmaceutical composition according to claim 1, wherein the total amount of an amide-type anesthetic in the form of a free base is 475 mg per dose. Claim 3 A pharmaceutical composition according to claim 1, wherein postoperative pain is induced by hernia repair surgery. Claim 4 A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises an amide-type anesthetic in the form of a free base of 10 mg / mL to 30 mg / mL. Claim 5 A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises an amide-type anesthetic in the form of a free base of 15 mg / mL to 25 mg / mL. Claim 6 A pharmaceutical composition according to claim 1, wherein the neutral saturated phospholipid comprises one or more saturated fatty acids, and each saturated fatty acid independently comprises a carbon chain having 18 or fewer carbon atoms. Claim 7 A pharmaceutical composition according to claim 1, wherein the neutral saturated phospholipid is selected from the group consisting of dimyristoyl phosphatidylcholine (DMPC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), dipalmitoyl phosphatidylcholine (DPPC), and combinations thereof. Claim 8 A pharmaceutical composition according to claim 1, wherein the lipid-based complex further comprises a sterol. Claim 9 A pharmaceutical composition according to claim 8, wherein the sterol is cholesterol. Claim 10 A pharmaceutical composition according to claim 1, wherein the amide-type anesthetic is selected from the group consisting of lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pirocaine, articaine, prilocaine, and combinations thereof. Claim 11 A pharmaceutical composition according to claim 1, wherein the central diameter of the lipid-based complex is in the range of 5 μm to 200 μm. Claim 12 A pharmaceutical composition for use in treating postoperative pain in subjects requiring anesthesia via nerve block, field block, or infiltration anesthetic, wherein the pharmaceutical composition comprises a lipid-based complex at pH 5.5 to 8.0 comprising an amide-type anesthetic in the form of a free base and a neutral saturated phospholipid, wherein the neutral saturated phospholipid comprises a saturated fatty acid, and each saturated fatty acid independently comprises a carbon chain having fewer than 18 carbon atoms; the molar ratio of the amide-type anesthetic in the form of a free base to the neutral saturated phospholipid in the lipid-based complex is between 0.5:1 and 2:1; the median diameter of the lipid-based complex is in the range of 5 μm to 200 μm; and the total amount of the amide-type anesthetic in the form of a free base of the pharmaceutical composition is 300 mg to 600 mg per dose. Claim 13 A pharmaceutical composition according to claim 12, wherein the total amount of an amide-type anesthetic in the form of a free base is 475 mg per dose. Claim 14 A pharmaceutical composition according to claim 12, wherein the pharmaceutical composition comprises an amide-type anesthetic in the form of a free base of 10 mg / mL to 30 mg / mL. Claim 15 A pharmaceutical composition according to Clause 12, wherein postoperative pain is induced by hernia repair surgery. Claim 16 A pharmaceutical composition according to claim 12, wherein the amide-type anesthetic is selected from the group consisting of lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pirocaine, articaine, prilocaine, and combinations thereof. Claim 17 A pharmaceutical composition according to claim 12, wherein the amide-type anesthetic is ropivacaine. Claim 18 A pharmaceutical composition according to claim 12, wherein the neutral saturated phospholipid is selected from the group consisting of DMPC, DLPC, DPPC and combinations thereof. Claim 19 In claim 12, the lipid-based complex is a pharmaceutical composition further comprising a sterol. Claim 20 A pharmaceutical composition according to claim 19, wherein the sterol is cholesterol. Claim 21 A pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is administered within 30 minutes to 3 hours prior to surgery or during surgery, and the pain reduction is at least 2 according to an NPRS score of grades 0 to 10 during a certain period after surgery, and said certain period is at least 48 hours. Claim 22 A pharmaceutical composition according to claim 21, wherein the specified period is at least 72 hours. Claim 23 A pharmaceutical composition according to claim 21, wherein the specified period is at least 96 hours. Claim 24 A pharmaceutical composition according to claim 21, wherein the specified period is at least 168 hours. Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete

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