Pharmaceutical compositions for use in treating pain

Abstract

To provide a pharmaceutical composition for use in treating postsurgical pain.SOLUTION: A pharmaceutical composition comprises a lipid-based complex having a pH of 5.5 to 8.0, wherein the lipid-based complex comprises an amide-type anesthetic and a phospholipid, wherein a molar ratio of the amide-type anesthetic to the phospholipid in the lipid-based complex is in a range of 0.5 to 2 (mol of the amide-type anesthetic) / (mol of the phospholipid), and wherein a total amount of the amide-type anesthetic in the pharmaceutical composition is in a range of about 10 mg to about 800 mg per dose.SELECTED DRAWING: Figure 2

Description

Technical Field

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

Background Art

[0002] Local anesthetics are widely used in surgical anesthesia and postoperative analgesia because they have the ability to reversibly inhibit voltage-dependent sodium channels and block action potentials in nerve fibers. However, when the concentration of this type of anesthetic in the plasma increases, it also interacts with other ion channels, causing acute neurotoxicity, cardiotoxicity, and allergic reactions. So-called local anesthetic systemic toxicity (LAST) is always a potential complication of all local anesthetics, regardless of the route of administration, and can be fatal.

[0003] Ropivacaine was introduced as an amide-type local anesthetic of the pure S(-) isomer in 1996 and was approved by the US Food and Drug Administration (FDA) under the trade name Naropin® in 2000. Ropivacaine has a significantly reduced lipophilicity and motor nerve block compared to bupivacaine (Marcaine®), and its cardiotoxicity is reduced, resulting in a larger safety margin. Naropin® can be administered by various injection routes such as spinal anesthesia, epidural anesthesia, local block, and local infiltration. Despite having many advantages over other local anesthetics, the analgesic duration after a single administration by wound infiltration with 0.5% Naropin® (200 mg ropivacaine hydrochloride injection) was only about 6 to 8 hours. This is insufficient to cover a significant portion of the postoperative recovery time, especially the important three-day postoperative period.

[0004] Local anesthetics have the limitation of a short duration of action and a risk of LAST. The infiltration of local anesthetics (e.g., lidocaine hydrochloride) and NSAIDs are also widely accepted as postoperative pain management regimens. However, there are some potential concerns regarding the safety of using NSAIDs, and the duration of postoperative analgesia by local anesthetics is generally limited to about 8 hours. The medical goal is to relieve acute postoperative pain without using opioids during the important 2 - 4 days after surgery. Thus, there is an unmet medical need to provide a method for postoperative pain management that is long-lasting, opioid-free, safer, and more effective by a single perioperative administration of a formulation.

[0005] When utilizing a long-term block by a local anesthetic either by continuous infusion or repeated bolus administration, there is a high risk of reaching toxic plasma concentrations or inducing local nerve injury. Evidence supporting the neurotoxicity of local anesthetics was obtained from the analysis of the persistence of paresthesia after local anesthetic injection. The severity of paresthesia is related to the length of the altered sensation. In most cases, the affected nerve naturally recovers over a certain period, but in some cases, this undesirable effect may persist for several months, and the nerve may not fully recover due to this undesirable effect.

[0006] Therefore, there is an unmet need for an improved use of lidocaine or other amide-type anesthetics in pain control to achieve a beneficial and effective pain control method with a desired long-term analgesic effect. The compositions and methods of the present disclosure meet these and other needs.

Summary of the Invention

Means for Solving the Problems

[0007] The present disclosure provides a method of treatment with a specific dosage range and dosing schedule of an amide-type anesthetic of the present disclosure that provides this long-term effect on pain control. In particular, the present disclosure is directed to a pharmacologically active agent, composition, method, and / or dosing schedule that has certain advantages compared to agents, compositions, methods, and / or dosing schedules currently in use and / or known in the art, and these advantages include being able to administer at less frequent intervals or at lower doses to obtain an equivalent effect in pain control or anesthetic effect, and thus being able to reduce the undesirable effects of the amide-type anesthetic on subjects in need of the amide-type anesthetic. These advantages will become apparent from the following further description.

[0008] The present disclosure is a method for preparing a sustained-release anesthetic composition or a sustained-release anesthetic composition using lyophilization (e.g., one-step lyophilization), the method comprising 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 of the lipid-based complex is at least 0.5:1, and then hydrating the lipid cake with a pharmaceutically acceptable buffer solution to obtain a sustained-release anesthetic composition. This sustained-release anesthetic composition provides rapid onset of anesthesia and a long duration of local anesthesia with minimal toxicity.

[0009] In one aspect, the anesthetic composition is a pharmaceutical composition for use in treating postoperative pain in a subject in need thereof. The pharmaceutical composition according to the present disclosure comprises a lipid-based complex of an amide-type anesthetic and at least one lipid, and the molar ratio of the amide-type anesthetic to at least one lipid of 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 in the range of 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 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 in the pharmaceutical composition is used in an amount of at least about 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3.0 times, 3.1 times, 3.2 times, 3.3 times, 3.4 times, 3.5 times, 3.6 times, 3.7 times, 3.8 times, 3.9 times, 4.0 times, 4.1 times, 4.2 times, 4.3 times, 4.4 times, 4.5 times, 4.6 times, 4.7 times, 4.8 times, 4.9 times 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, their bases, or combinations thereof. In some embodiments, the amide-type anesthetic is bupivacaine, ropivacaine, or their bases.

[0010] 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. The at least one neutral saturated phospholipid comprises a saturated fatty acid having a long carbon chain with 18 or fewer carbon atoms. In some embodiments, the lipid-based complex is prepared under predetermined 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.

[0011] In some embodiments, the lipid-based complex of the anesthetic composition is formed by hydrating a lyophilized lipid cake with a pharmaceutically acceptable buffer solution having a pH higher than 5.5. The theoretically uncharged ropivacaine is 0.8% of the available ropivacaine at pH 6.0 based on calculations from its pKa (the pKa of ropivacaine is 8.1). In some embodiments, the lipid cake according to the present disclosure is prepared by dissolving non-polar ropivacaine, phospholipid, and cholesterol in a solvent system, for example, tert-butanol alone or a tert-butanol / water co-solvent, and then removing this solvent system using lyophilization techniques.

[0012] In certain embodiments, the molar ratio (mol 薬物 :mol リン脂質 ) of the amide-type anesthetic to the phospholipid in the lipid-based complex is at least 0.5:1. The pharmaceutical composition of the present invention can provide a sufficient amount of the amide-type anesthetic to a subject in need to extend the duration of anesthesia after in vivo topical administration. In addition, a predetermined amount of the amide-type anesthetic in the free form not captured by the lipid-based complex can minimize the maximum plasma concentration (C max ) to achieve a rapid onset of anesthesia.

[0013] In another aspect, the present disclosure also provides a method for treating postoperative pain in a subject in need of anesthesia. The method may include administering the pharmaceutical composition of the present disclosure via a nerve block, via a peripheral anesthesia, or via an infiltration anesthesia.

[0014] In certain embodiments, postoperative pain is caused by surgeries such as, but not limited to, hernia repair surgery, hemorrhoidectomy surgery, urological surgery, plastic surgery, obstetric surgery, laparoscopic surgery, abdominoplasty, breast surgery, and kidney transplantation procedure (KTX).

[0015] In yet another aspect, the present disclosure provides a method for treating postoperative pain. The method may include administering the dosage of the pharmaceutical composition according to the present disclosure within about half an hour (30 minutes) to about 3 hours before surgery, optionally within half an hour (30 minutes) to about 2 hours, optionally within half an hour to about 1 hour, or after the start of surgery (during surgery), particularly before the completion of surgery. The pain reduction is at least about 2 according to the Numerical Pain Rating Scale (NPRS) 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 can be a scale from 0 to 10, where 0 is no pain and 10 is the worst imaginable pain. In some embodiments, when the composition according to the present disclosure is administered via nerve block or peripheral anesthesia, the composition may be administered from about half an hour to about 1 hour before surgery. In other non-limiting embodiments, when the composition according to the present disclosure is administered via local infiltration, which is suitable for hernia repair surgery and hemorrhoidectomy surgery, the composition may be administered during surgery, usually at the final stage of the surgery before the final closure of the incision.

[0016] Other objects, advantages, and novel features of the present disclosure will become more apparent from the following detailed description when considered in conjunction with the accompanying drawings.

Brief Description of the Drawings

[0017]

Figure 1

Figure 1A

Figure 2

Figure 3

Figure 4

Mode for Carrying Out the Invention

[0018] When used above and throughout the present disclosure, the following terms shall be understood to have the following meanings unless otherwise specified.

[0019] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0020] All numbers in this specification, when referring to measurable values such as amounts, durations of time, etc., may be understood to be modified by "about" to mean including variations of ±10%, preferably ±5%, more preferably ±1%, still more preferably ±0.1% from the specified value, unless otherwise specified. This is because such variations are appropriate for obtaining the desired amount of the amide-type anesthetic.

[0021] As used herein, the terms "treating," "treated," or "treatment" include prophylactic (e.g., preventive), palliative, and curative methods, uses, or results. The term "treatment" or "therapy" can also refer to a composition or pharmaceutical. 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 amount of pain-suppressing drug used. To assess pain and its symptoms, methods recognized in the art can be utilized. These include, but are 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 short form, the McGill Pain Questionnaire, and other scoring methods including the Patient Global Assessment (PGA) of pain control methods. For human subjects, self-report using, for example, a graduated scale from (0) painless to (10) maximum pain can be used to identify the level of pain. Optionally, functional magnetic resonance imaging (fMRI) could be used on a subject to identify a reduction in pain after administration of the pharmaceutical composition of the disclosure. For example, the disclosed method would be considered 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 can be about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount in between. Treatment in a subject can also be evaluated by a reduction in the amount of pain control drugs such as opioids or other analgesics, and / or a reduction in side effects associated with such analgesics such as gastrointestinal symptoms associated with opioid use. Use of additional efficacy questionnaires such as the postsurgical recovery index could allow assessment of not only pain and recovery but also potential side effects associated with opioid use.In particular, postoperative pain can be acute pain and / or chronic pain. Acute pain can be experienced immediately or within 7 days (e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after surgery).

[0022] The terms "subject" and "patient" can refer to a vertebrate having or at risk of developing pain or a disease associated with pain, or a vertebrate for which pain treatment or management is considered necessary. Subjects include all warm-blooded animals such as mammals including primates, more preferably humans. Non-human primates are also subjects. The term "subject" includes domesticated animals such as cats and dogs, livestock (e.g., cows, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mice, rabbits, rats, guinea pigs, etc.). Thus, veterinary uses and pharmaceutical formulations are contemplated herein.

[0023] "Association efficiency" (AE) represents the amount of drug incorporated into the lipid-based complex and is calculated by 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 such as conventional centrifugation, density gradient centrifugation, fractionation centrifugation, or filtration methods such as diafiltration, gel filtration, and membrane filtration.

[0024] The term "standard therapeutic dose" can refer to the amount of a therapeutic agent indicated to bring about a desired effect or result, and in particular can refer to compartments similar to those of the present disclosure, exemplified by the equilibration of drugs with poorly perfused tissues such as soft tissue, muscle and fat; and hard tissue, bone, etc. The standard therapeutic dose can be determined by a person skilled in the art. Standard therapeutic doses suitable for each indication can be found by referring to relevant anesthetic references such as the United States Pharmacopeia (USP) and approved pharmaceuticals (not limited to these) 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, the standard therapeutic dose of an injectable ropivacaine hydrochloride solution (Naropin®) for managing pain after hernia surgery by local infiltration is less than 300 mg, particularly 2 mg to 200 mg. In one embodiment, the standard therapeutic dose of a free ropivacaine solution for injection or infiltration for the treatment of pain after bunionectomy is 50 mg. In another embodiment, the standard therapeutic dose of bupivacaine hydrochloride injection USP (manufactured by Hospira) is up to 225 mg containing epinephrine 1:200,000 and 175 mg without epinephrine. The standard therapeutic dose can be determined based on the type of surgery and can be established by a person skilled in the art.

[0025] Amide-type anesthetics The term "amide-type anesthetics" refers to one or more groups of substances that cause loss of sensation around a subject by suppressing the excitation of nerve endings or inhibiting the conduction process of peripheral nerves. The structure of typical amide-type anesthetics contains a lipophilic part and a hydrophilic part connected by an -NHCO- bond. Suitable amide-type anesthetics include, but are not limited to, lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pirocaine, articaine, prilocaine, and their free bases. In a particular embodiment, the amide-type anesthetic is ropivacaine base.

[0026] Lipid-based complexes and lipids The lipid-based complex according to the present disclosure comprises one or more lipids and an amide-type anesthetic. In one embodiment, this lipid-based complex is manufactured to extend the shelf life of the composition and may be stored for a long time. 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.

[0027] The above lipid cake may contain one or more phospholipids and an amide-type anesthetic in the absence of sterols. Alternatively, this lipid cake may contain an amide-type anesthetic and one or more phospholipids with one or more sterols, such as cholesterol, at 50% or less relative to the total lipid amount. In certain embodiments, the mole % of cholesterol relative to the total lipid is about 0% to 50%, optionally about 33% to 40%. In some embodiments, the phospholipid(s) and cholesterol are in a molar ratio of 1:1 to 3:1.

[0028] The above lipid cake can be prepared by 1) dissolving one or more lipids and an amide-type anesthetic in a solvent system to form a liquid structure containing one or more solvents to form a homogeneous solution, and 2) removing the solvent to solidify the formulation of the lipid and the amide-type anesthetic(s). The removal of the solvent can be carried out using known techniques such as lyophilization (freeze-drying). Examples of solvent systems suitable for lyophilization include, but are not limited to, tert-butanol and tert-butanol / water co-solvent systems, with or without other non-aqueous solvents such as acetone, acetonitrile, ethanol, n-propanol, isopropanol, n-butanol, methanol, dichloromethane, dimethyl sulfoxide, and carbon tetrachloride.

[0029] In some embodiments, the lipids of the lipid-based complex comprise one or more phospholipids and cholesterol, and the molar ratio of the amide-type anesthetic to the phospholipids of the lipid-based complex is at least 0.5:1, optionally between 0.5:1 and 2:1, for example, 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 above-mentioned one or more lipids are selected from the group consisting of dilipid chain lipids such as phospholipids, diglycerides, and dialiphatic glycolipids; single lipids such as sphingomyelin and glycosphingolipids; sterols such as cholesterol and its derivatives; and combinations thereof. Examples of phospholipids according to the present disclosure include 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 soy 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-Gioleoyl-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-glycero-3-phospho-(1'-myo-inositol) (ammonium salt) (DOPI), cardiolipin, L-α-phosphatidylcholine (EPC), and L-α-phosphatidylethanolamine (EPE) are included, but not limited to these.,

[0031] Examples of phospholipids include dimyristoyl phosphatidylcholine (DMPC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), dipalmitoyl phosphatidylcholine (DPPC), dioleoyl phosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS), dioleoyl 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-glycero-3-phosphate (sodium salt) (DMPA), but are not limited to these.

[0032] Suitable phospholipids according to the present disclosure are saturated phospholipids derived from two saturated long carbon chain fatty acids, each fatty acid having at least 12 carbons, or at least 14 carbons; and a long carbon chain of 20 carbons or less, or 18 carbons or less, or 16 carbons or less. In some embodiments, suitable saturated phospholipids according to the present disclosure are selected from the group consisting of DLPC, DMPC, DPPC, and combinations thereof.

[0033] In some embodiments, the lipid-based complex comprises liposomes 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 an unsaturated phospholipid, the determined amount being less than 10 mol percent based on the total amount of phospholipids, for example, about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.

[0034] Anesthetic composition The terms "anesthetic composition" and "pharmaceutical composition for use in the treatment of pain" are used interchangeably. In certain embodiments, the anesthetic composition comprises a lipid-based complex and an unencapsulated local anesthetic. In some embodiments, the lipid-based complex comprises multilamellar vesicles and a local anesthetic agent entrapped therein. The term "entrap" or "entrapping" refers to the bilayer membrane of the multilamellar vesicle enclosing, embedding, or associating with the target drug.

[0035] The particle size distribution of the lipid-based complex according to the present disclosure can be determined by various known methods in the art. In some embodiments, the average particle size of the lipid-based complex of the anesthetic composition is 1 μm or more, optionally greater than 5 μm, for example, in the range of 5 μm to 50 μm, or 10 μm to 25 μm. Alternatively, the volume median particle size (D 50) is 1 μm or more, optionally 5 μm or more, for example 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 median particle size (D 50 ) refers to a particle size of 5 μm or more or 7 μm or more at which the cumulative ratio of the lipid-based complex composed of aggregated particles is 50% in the cumulative particle size distribution. In some embodiments, the median particle size (D 50 ) refers to a particle size at which the cumulative ratio of the lipid-based complex composed of aggregated particles is 50% and is 25 μm or less, 20 μm or less, or 15 μm or less, optionally 5 μm to 25 μm, 5 μm to 20 μm, or 5 μm to 15 μm in the cumulative particle size distribution.

[0036] In some embodiments, the particle size (D 90 ) when the cumulative ratio in the cumulative particle size distribution of the lipid-based complex of the anesthetic composition is 90% is in the range of 10 μm or more, for example 10 μm to 300 μm, 20 μm to 300 μm, 20 μm to 200 μm, or 20 μm to 100 μm. In addition, the lower limit of D 90 is, for example, 25 μm or more or 30 μm or more, but is not limited thereto. In addition, the shape of the aggregated particles of the lipid-based complex for improving the association efficiency per unit dose is not particularly limited.

[0037] In some embodiments, the pharmaceutical composition for use in treating pain comprises multilamellar vesicles, a portion of an amide-type anesthetic trapped by the multilamellar vesicles, and a portion of the amide-type anesthetic in a free form (not trapped), also referred to as the free form. The particle size distribution of the multilamellar vesicles together with the trapped amide-type anesthetic of the lipid-based complex according to the present disclosure can be determined by various known methods in the art. In some embodiments, the particle size of the multilamellar vesicles together with the trapped amide-type anesthetic of the anesthetic composition according to the present disclosure is 1 μm or more, optionally more than 5 μm, for example 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 50 ) of the lipid-based complex in the anesthetic composition according to the present disclosure is 1 μm or more, optionally more than 5 μm, for example in the range of 5 μm to 100 μm, or 10 μm to 50 μm.

[0038] In some embodiments, the lipid-based complex is formed by hydrating a lipid cake containing an amide-type anesthetic with a pharmaceutically acceptable buffer solution having a pH higher than 5.5. The anesthetic composition thus obtained may provide a sustained release of the amide-type anesthetic in a usable state, or may be diluted with an aqueous buffer solution or other suitable diluent before administration. In some embodiments, the aqueous buffer solution has a pH range of 5.5 to 8.0, optionally 6.0 to 7.5 or 6.5 to 7.0.

[0039] Suitable aqueous buffers according to the present disclosure include, but are not limited to, citrate, acetate, malate, piperazine, succinate, 2-(N-morpholino)ethanesulfonic acid (MES), histidine, bis-tris, phosphate, ethanolamine, N-(2-acetamido)iminodiacetic acid (ADA), carbonate, N-(2-acetamido)-2-aminoethanesulfonic acid (ACES), 1,4-piperazinediethanesulfonic acid (PIPES), 3-morpholino-2-hydroxypropanesulfonic acid (MOPSO), imidazole, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), triethanolamine, lysine, tris, and glycylglycine solutions. The amount of unbound amide-type anesthetic in the composition can be adjusted based on the partition coefficient of the anesthetic by selecting an appropriate pH value of the aqueous buffer solution based on the clinical indication and the total infusion volume.

[0040] In some embodiments, the aqueous buffer solution comprises histidine at a concentration in the range of 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 embodiments, the aqueous buffer solution comprises phosphate at a concentration in the range of 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.

[0042] The amount of the free form of the amide-type anesthetic is a function of the association efficiency (AE) of the lipid-based complex of the anesthetic composition, and this association efficiency is determined by centrifugation. Mathematically, the amount of the free form of the amide-type anesthetic is expressed as follows. A 非捕捉 =A 総 ×(1 - AE) In the above formula, A 非捕捉 is the amount of unbound amide-type anesthetic, and A総 is the total amount of the amide-type anesthetic in the anesthetic composition, and AE is obtained by dividing the amount of the amide-type anesthetic in the lipid-based complex by the total amount of the amide-type anesthetic in the anesthetic composition. AE according to the present disclosure is at least 60%, optionally 60% - 99%, 70% - 95%, and 80% - 90%.

[0043] In certain embodiments, the molar ratio (mol 薬物 :mol 脂質 , D:PL) of the amide-type anesthetic to the lipid(s) of 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 embodiments, the median diameter (D 50 ) of the population of particles of the lipid-based complex is 1 μm or more, for example, 5 μm or more, and optionally within the range of 5 μm - 200 μm, 5 μm - 190 μm, 5 μm - 180 μm, 5 μm - 170 μm, 5 μm - 160 μm, 5 μm - 150 μm, 5 μm - 140 μm, 5 μm - 130 μm, 5 μm - 120 μm, 5 μm - 110 μm, 5 μm - 100 μm, 10 μm - 100 μm, 12 μm - 100 μm, 14 μm - 100 μm, 16 μm - 100 μm, 18 μm - 100 μm, or 20 μm - 100 μm.

[0044] The concentration of the amide-type anesthetic in the anesthetic composition may be higher than 2 mg / mL in order to obtain a clinical therapeutic effect. Suitable concentrations of the amide-type anesthetic include, but are not limited to, at least 10 mg / mL, 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, particularly in the range up to 19 mg / mL. The limited amount of the unbound amide-type anesthetic in the anesthetic composition of the present disclosure can provide the advantage of achieving a higher maximum tolerated dose (depending on the plasma anesthetic concentration that causes central nervous system and cardiovascular toxicity), and can also be used to provide a rapid onset of efficacy.

[0045] For clinical use, the free form of the amide-type anesthetic in certain embodiments of the present disclosure 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-type anesthetic in the lipid-based complex functions as a depot for gradually releasing the amide-type anesthetic into the local environment to maintain a therapeutically effective dose at the local site. In some embodiments, the half-life of ropivacaine resulting from a single subcutaneous administration of the anesthetic composition according to the present disclosure is extended by at least 10-fold 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 significantly extended beyond the duration of unformulated ropivacaine.

[0046] The pharmaceutical composition according to the present disclosure exhibits a significant sustained release profile of the therapeutic agent, resulting in an immediate and long-term pain reduction of 2 to 4 on a scale of 0 to 10 according to the Numerical Pain Rating Scale (NPRS) score during the postoperative period after administration of a clinically relevant dose of the local anesthetic. For example, the pharmaceutical composition of the present disclosure extends the half-life of the locally administered liposomal anesthetic composition. The composition of the present invention shows low average pain at all points according to the NPRS score at time intervals of 24 hours, 48 hours, 72 hours, 4 days, or 1 week in humans, compared to when a free anesthetic or a commercially available anesthetic is administered, and may significantly reduce the total postoperative pain.

[0047] The lipid-based complex according to the present disclosure would be capable of being administered perineurally, in the surgical field, or to the surgical wound. The terms "postoperative pain" and "post-surgical pain" are used interchangeably herein and refer to pain caused by various surgeries. In some embodiments, postoperative pain is caused by hernia repair surgery, urological surgery, hemorrhoid surgery, abdominal surgery, thoracic surgery, plastic surgery (including but not limited to vanionectomy, vertebroplasty, acromioplasty, vertebroplasty, total knee or hip replacement), obstetric surgery, breast surgery, dental surgery, abdominoplasty, breast surgery, kidney transplantation procedure (KTX) or any type of laparoscopic surgery.

[0048] The pharmaceutical composition according to the present disclosure may be injected, infused or applied using a standard syringe and needle. The infusion of the pharmaceutical composition according to the present disclosure may be performed via a subcutaneous, intradermal, or intramuscular route.

[0049] In another embodiment, the pharmaceutical composition according to the present disclosure is administered as a nerve block for prophylactic treatment of a pain-associated condition, for example, preoperative administration for the treatment of postoperative pain, in a subject in need thereof. In some embodiments, the pharmaceutical composition according to the present disclosure is administered as a nerve block such as a Quadratus Lumborum Block (QLB).

[0050] Peripheral nerve block involves introducing a drug near or into a peripheral nerve to reduce pain or provide anesthesia.

[0051] In another embodiment, the pharmaceutical composition according to the present disclosure is administered to the surgical field as a peripheral anesthesia such as a Mayo block of a plurality of foot nerves for bunionectomy, a transversus abdominis plane block (TAPB) for laparotomy or cesarean section, and a site-specific local anesthesia method for total hip or knee arthroplasty.

[0052] The present disclosure will be further described with reference to the following specific and non-limiting examples.

Example

[0053] The following examples illustrate the preparation and properties of specific embodiments of the present disclosure.

[0054] Example 1 Preparation of Anesthetic Composition 1,2-Dimyristoyl-sn-glycero-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.

[0055] To prepare the lipid cake, ropivacaine was combined with the indicated lipid complex such that the drug-to-phospholipid ratio (D:PL) was 1.458 μmol / μmol, i.e., phosphatidylcholine:cholesterol:ropivacaine = 2:1:2.9. After mixing this lipid and ropivacaine, it was dissolved in tert-butanol or a co-solvent system of tert-butanol / water (1 / 1, volume / volume) to form a liquid structure. After freezing this liquid structure, it was lyophilized overnight to obtain a lipid cake of the amide-type anesthetic.

[0056] To prepare the lipid structure for the vehicle control, phospholipid:cholesterol in a molar ratio of 2:1 was weighed and then dissolved in tert-butanol. After freezing the obtained sample, it was lyophilized overnight to obtain a lipid cake for the vehicle control.

[0057] The lipid cake of the anesthetic or vehicle control was hydrated with a buffer solution at pH 6.5 - 6.8 at a temperature above ambient temperature (AT) (25 °C) to form an anesthetic composition and a vehicle control composition, respectively, and then the characteristics of the association efficiency and particle size distribution were evaluated.

[0058] Characterization of Anesthetic Compositions The association efficiency (AE) of each preparation as described above was determined as follows. An aliquot of 200 microliters of each sample of the anesthetic composition was centrifuged at 3000 × g for 5 minutes at 4 °C to obtain a lipid-based complex. After decanting the supernatant, the lipid-based complex was resuspended in a final volume of 200 μL. Based on a solution of the test drug with a known concentration, a reference absorbance standard was set for each drug (e.g., ropivacaine). 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 amount in the lipid-based complex to the drug amount 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 AE and denoted as "Resultant D:PL".

[0059] The particle size of each anesthetic composition was measured using a laser diffraction analyzer (LA-950V2, Horiba, Ltd.). The median diameter (D 50 ) of the lipid-based complex formed by hydrating the lyophilized lipid cake with a pharmaceutically acceptable buffer solution (e.g., 50 mM histidine buffer at pH 6.5) was examined.

[0060] The lipid-based complex in the anesthetic composition was determined to have a drug-to-phospholipid ratio of approximately 1.32. The median diameter (D 50 ) of the population of particles of the lipid-based mixture in this anesthetic composition was approximately 5 μm to 10 μm.

[0061] Example 2 Treatment of pain in adult subjects after inguinal hernia repair In adult subjects after inguinal hernia repair, a Phase I / II, randomized, double-blind, comparative control, dose-escalation study was conducted to evaluate the safety, PK, and efficacy of a single postoperative administration of the anesthetic composition according to the present disclosure (designated TLC590), compared to Naropin® by single-injection infiltration local administration.

[0062] In this study, approximately 64 evaluable subjects who met all entry criteria in four cohorts were enrolled. Dose escalation for single postoperative administration of TLC590 was performed using consecutive dose levels, compared to Naropin®. Dose escalation was determined by review of treatment-related adverse events (TEAE) and all serious adverse events (SAE) by a Safety Monitoring Committee (SMC).

[0063] The inclusion criteria were as follows. 1. Ability and willingness to provide written informed consent. 2. Males or females aged 18 to 65 years. 3. Scheduled to undergo primary, unilateral Lichtenstein inguinal hernia repair using mesh and able to use an anesthetic regimen. 4. The ASA physical status classification is 1 or 2, 5. Female subjects are eligible only if they are not pregnant, not lactating, have no planned pregnancy during the trial, agree to use an acceptable form of contraception, or male subjects are eligible only if they are sterile or agree to use a reliable method of contraception for the duration of the trial, starting at least 1 week after the administration of the blinded study drug. 6. The body mass index is 35 kg / m 2 or less.

[0064] Subjects were enrolled in each cohort in a 3:1 ratio. Each cohort consisted of subjects receiving doses of TLC590 or an active comparator (Naropin® 150 mg; [0.5%, 5 mg / mL]) according to a randomized schedule and a dose escalation scheme (Figure 1).

[0065] To maintain objectivity, the study drug was administered and managed by an independent unblinded team including the injection staff, pharmacist, and clinical researcher. The subjects, the principal investigator, and all other facility staff who interacted directly with the subjects, evaluated safety and efficacy, and collected subject data remained blinded and were not to communicate or discuss any study information with the unblinded team.

[0066] The groups and interventions were designed as follows. Group Experiment: TLC590 group TLC590 (ropivacaine composition) is a sustained-release liposomal formulation of ropivacaine and is a white aqueous suspension with a ropivacaine concentration of approximately 19 mg / mL. Active comparator: Naropin® The Naropin® injection contains ropivacaine hydrochloride. Strength: 150 mg / 30 mL (5 mg / mL) Size: 30 mL fill, in a 30 mL single-dose vial.

[0067] Intervention Drug: TLC590 (ropivacaine composition) The TLC590 lipid cake was reconstituted with the TLC590 reconstitution solution to form a TLC590 anesthetic composition. Drug: Naropin (registered trademark) Local infiltration of Naropin (registered trademark) to provide anesthesia for surgery and analgesia in postoperative pain management. Naropin (registered trademark) 150 mg [0.5%, 5 mg / mL] × 30 mL Other names: Naropin (registered trademark), 0.5% injection

[0068] The primary evaluation items were as follows: Safety and tolerability: (i) The number of SAEs and treatment-related serious AEs (to determine the MTD) [Time frame: Up to 30 days after IP administration for screening]

[0069] The secondary evaluation items were as follows. 1. The intensity of pain at rest and during movement was evaluated using an 11-point NPRS with scores from 0 (no pain) to 10 (the worst possible pain). 2. Overall patient assessment (PGA) of pain control methods (poor, fair, good, or excellent). 3. AUC of NPRS at rest and during movement. 4. Cumulative percentage of subjects with no pain (defined as NPRS at rest being 0 or 1) at the scheduled time points. 5. Percentage of subjects with no pain (defined as NPRS at rest being 0 or 1) at the scheduled time points. 6. Cumulative percentage of subjects who did not use rescue analgesics at 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, and 96 hours. 7. Time until the first use of rescue analgesics after surgery. 8. Total postoperative usage of various types of rescue analgesics at 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, and 96 hours. 9. Average daily consumption of rescue analgesics by type at 24 hours, 48 hours, 72 hours, and 96 hours. 10. Integrated analgesia score using NPRS scores and rescue analgesic consumption. 11. Cumulative percentage of subjects who did not use postoperative antiemetic treatment between 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, and 96 hours. 12. Incidence of all adverse events by severity and relevance. 13. Exposure-response relationship between PK parameters and NPRS scores.

[0070] The changes from the above screening were analyzed statistically. The therapy of TLC590 via single-injection local administration at doses of 190 mg, 380 mg, 475 mg, and 570 mg resulted in a beneficial clinical response according to any one or more of the above endpoints.

[0071] Results A total of 64 subjects were randomized into four cohorts. In this trial, no events of severe adverse events or local anesthetic systemic toxicity (LAST) were observed. All four dose groups of TLC590 showed the same safety and tolerability as 150 mg of ropivacaine. Even at 570 mg, the mean maximum plasma unbound ropivacaine concentration of TLC590 was lower than the mean maximum plasma unbound ropivacaine concentration of the ropivacaine group. The mean plasma concentration of the TLC590 volume plateaued for about 24 hours and then decreased, and the observed t1 / 2 was significantly longer than that of the ropivacaine group, and C max was the C of 300 mg of 7.5 mg / mL ropivacaine solution for infiltration maxIt was less than one-fifth of (2.7 mg / mL) (Regional Anesthesia and Pain Medicine 23(2): 189-196, 1998) (Figure 1A). All four doses of TLC590 reduced postoperative pain as measured by the mean value of the area under the pain curve (AUC) by the least squares (LS) method of the NPRS compared to the ropivacaine group. At TLC590 475 mg, compared to ropivacaine, the intensity of pain during movement and at rest decreased continuously, statistically significantly, and clinically meaningfully over time (Figure 2) (all p < 0.05; the highest p-value was 0.0131), and the reduction in pain compared to ropivacaine was maintained up to 168 hours later (Figure 3). The median time to the first rescue analgesic was 3.2 times longer in the TLC590 475 mg group than in the ropivacaine group (42 hours vs. 13 hours). Most (58.3%) of the patients treated with TLC590 (475 mg) did not use any rescue opioids during the study period. In patients who used rescue opioids, the median time to the first postoperative opioid use was approximately 4 times the median time in the ropivacaine group (13.0 hours vs. 3.3 hours). The mean value of the total opioid use up to 96 hours postoperatively was 54% less than the total opioid use in the ropivacaine group.

[0072] Conclusion TLC590 demonstrated similar safety and tolerability to ropivacaine, no LAST events occurred, provided immediate and long-term pain reduction compared to ropivacaine, and reduced or eliminated the need for opioids. Subjects administered TLC590 475 mg showed superior effects compared to ropivacaine, an approved drug at clinically relevant doses, with reduced mean pain at all points and significantly reduced total pain at time intervals up to 4 days postoperatively.

[0073] Example 3 Treatment of Pain in Adult Subjects after Bunionectomy A Phase II, randomized, double-blind, comparative placebo-controlled trial was conducted to evaluate the safety, PK, and efficacy of a single postoperative administration of TLC590 by single-injection infiltration in adult subjects after bunionectomy, compared to Naropin® or bupivacaine and placebo.

[0074] Approximately 223 eligible subjects were enrolled in this study. The trial was divided into two parts. Part 1: Blinded pharmacokinetic study of TLC590 and Naropin® Approximately 48 subjects were randomly assigned in a 1:1:1:1 ratio to treatment with 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 by a centralized, two-way web response system (IWRS). An unblinded interim analysis was performed to examine the safety, efficacy, and pharmacokinetics of the three doses of TLC590 and Naropin® in Part 1 of the study. Part 2: Efficacy and safety of TLC590 versus bupivacaine and placebo In Part 2 of this trial, approximately 150 subjects who met all entry criteria were enrolled and randomly assigned in a 1:1:1 ratio to treatments of TLC590 228 mg, bupivacaine, and placebo. The randomization schedule was assigned by a centralized IWRS. The study design scheme is shown in Figure 4.

[0075] The changes from the above screening were analyzed statistically. Treatment with TLC590 via single-injection infiltration at doses of 152 mg, 190 mg, and 228 mg resulted in a beneficial clinical response according to any one or more of the above endpoints.

Claims

1. A pharmaceutical composition for use in treating post-operative pain, the pharmaceutical composition comprising a lipid-based complex, the lipid-based complex comprising an amide-type anesthetic and at least one lipid, the molar ratio of the amide-type anesthetic to the at least one lipid in the lipid-based complex being at least 0.5:1, and the total amount of the amide-type anesthetic in the pharmaceutical composition being at least 1.5-5 times the standard therapeutic dose for treating post-operative pain with the amide-type anesthetic.

2. 2. The pharmaceutical composition of claim 1, wherein the total amount of the amide-type anesthetic is in the range of about 3 mg to about 1000 mg.

3. 2. The pharmaceutical composition of claim 1, wherein the total amount of the amide-type anesthetic is in the range of about 100 mg to about 800 mg.

4. 2. The pharmaceutical composition of claim 1, wherein the total amount of the amide-type anesthetic is in the range of about 300 mg to about 600 mg.

5. 5. The pharmaceutical composition of claim 4, wherein the post-operative pain is caused by hernia repair surgery.

6. 2. The pharmaceutical composition of claim 1, wherein the total amount of the amide-type anesthetic is in the range of about 3 mg to about 300 mg.

7. 2. The pharmaceutical composition of claim 1, wherein the total amount of the amide-type anesthetic is in the range of about 10 mg to about 250 mg.

8. The pharmaceutical composition according to claim 6, wherein the postoperative pain is caused by a bunionectomy surgery.

9. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises at least 10 mg / mL of the amide-type anesthetic.

10. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 15 mg / mL to 25 mg / mL of the amide-type anesthetic.

11. 2. The pharmaceutical composition of claim 1, wherein the molar ratio of said amide-type anesthetic to said at least one lipid of said lipid-based complex is from 0.5:1 to 2:

1.

12. 2. The pharmaceutical composition of claim 1, wherein the at least one lipid comprises a neutral saturated phospholipid.

13. 13. The pharmaceutical composition of claim 12, wherein the neutral saturated phospholipid comprises one or more saturated fatty acids, each of which independently comprises a carbon chain having 18 or fewer carbon atoms.

14. 13. The pharmaceutical composition of claim 12, wherein the neutral saturated phospholipid is selected from the group consisting of dimyristoylphosphatidylcholine (DMPC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), dipalmitoylphosphatidylcholine (DPPC), and combinations thereof.

15. 2. The pharmaceutical composition of claim 1, wherein said at least one lipid consists essentially of one or more neutral saturated phospholipids and sterols.

16. 16. The pharmaceutical composition of claim 15, wherein the sterol is cholesterol.

17. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein the amide type anesthetic is selected from the group consisting of lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrocaine, articaine, prilocaine, and combinations thereof.

18. 17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the lipid-based complex has a median diameter in the range of 5 μm to 200 μm.

19. The lipid-based complex is (a) providing a lipid cake comprising the amide-type anesthetic and the at least one lipid; (b) hydrating the lipid cake with a pharma- ceutically acceptable buffer solution having a pH of 5.5 to 8.0 to form the lipid-based complex; 17. The pharmaceutical composition according to any one of claims 1 to 16, which is prepared by

20. 1. A pharmaceutical composition for use in the treatment of pain in a subject in need of anesthesia via nerve block, via peripheral anesthesia, or via infiltration anesthesia, said pharmaceutical composition comprising: Lipid-based complexes containing amide-type anesthetics and neutral saturated phospholipids Including, the neutral saturated phospholipids comprise saturated fatty acids, each of which independently comprises a carbon chain having less than 18 carbons; the molar ratio of the amide-type anesthetic to the neutral saturated phospholipids in the lipid-based complex is at least 0.5:1; and the median diameter of the lipid-based complex is in the range of 5 μm to 200 μm; A pharmaceutical composition for use, wherein the total amount of said amide-type anesthetic in said pharmaceutical composition is from about 3 mg to about 1000 mg.

21. 21. The pharmaceutical composition for use according to claim 20, wherein said total amount of said amide-type anesthetic is about 475 mg.

22. 22. The pharmaceutical composition for use according to claim 21, wherein said pharmaceutical composition comprises from about 10 mg / mL to about 30 mg / mL of said amide-type anesthetic.

23. 1. A method for treating postoperative pain in a subject requiring anesthesia, comprising: Administering the pharmaceutical composition of claim 1 via a nerve block, via peripheral anesthesia, or via infiltration anesthesia. The method includes:

24. 24. The method of claim 23, wherein the post-operative pain is caused by hernia repair surgery.

25. 25. The method of claim 24, wherein the total amount of the amide-type anesthetic is in the range of about 100 mg to about 800 mg.

26. 25. The method of claim 24, wherein the total amount of the amide-type anesthetic is in the range of about 300 mg to about 600 mg.

27. 24. The method of claim 23, wherein the post-operative pain is caused by a bunionectomy surgery.

28. 28. The method of claim 27, wherein the total amount of the amide-type anesthetic is in the range of about 3 mg to about 300 mg.

29. 28. The method of claim 27, wherein the total amount of the amide-type anesthetic is in the range of about 10 mg to about 250 mg.

30. 1. A method for treating post-operative pain, comprising: Administering the pharmaceutical composition of claim 1 within about half an hour to three hours before surgery or during surgery. wherein the reduction in pain is at least about 2 according to an NPRS score on a scale of 0 to 10 for a period of time following surgery, said period being at least 48 hours.

31. 31. The method of claim 30, wherein the period of time is at least 72 hours.

32. 31. The method of claim 30, wherein the period is at least 96 hours.

33. 31. The method of claim 30, wherein the period of time is at least 168 hours.

34. 31. The method of claim 30, wherein the total amount of the amide-type anesthetic is in the range of about 100 mg to about 800 mg.

35. 31. The method of claim 30, wherein the surgery is a hernia repair surgery and the total amount of the amide-type anesthetic is in the range of about 300 mg to about 600 mg.

36. 31. The method of claim 30, wherein the surgery is a bunionectomy surgery and the total amount of the amide-type anesthetic is in the range of about 3 mg to about 300 mg.

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