SUSTAINED-RELEASE ANESTHETIC COMPOSITIONS AND METHODS OF PREPARING THEM.

Abstract

An anesthetic composition is provided for the local administration of a local anesthetic agent to a subject in need; the anesthetic composition has a lipid-based complex prepared by hydrating a lipid cake containing a local anesthetic agent and a lipid mixture with an aqueous buffer solution at a pH greater than 5.5; a method is also provided for preparing an anesthetic composition using a simpler and more robust method for large-scale manufacturing and for providing a high molar ratio of local anesthetic agent to phospholipid content compared to the prior technique; this anesthetic composition has a prolonged duration of effectiveness tailored to drug administration.

Description

SUSTAINED-RELEASE ANESTHETIC COMPOSITIONS AND METHODS OF PREPARING THEM RELATED APPLICATIONS This application claims the priority benefit of U.S. Provisional Application No. 62 / 650,912, filed on March 30, 2018, which is incorporated herein by reference in its entirety. TECHNICAL FIELD This description relates to a drug delivery system for administering a sustained-release anesthetic composition. This description relates to a method for preparing the drug delivery system. This description also relates to a sustained-release pharmaceutical composition adapted to a drug delivery system, which has a prolonged duration of efficacy. BACKGROUND OF THE INVENTION Several technologies have been reported for developing sustained-release local anesthetics. For example, freebase dibucaine, dibucaine HCl, and bupivacaine HCl were incorporated into polymer matrices with 1,3-bis(p-carboxyphenoxy)propane-sebacic acid anhydride copolymer (1:4) to achieve sustained drug release. On the other hand, multivesicular liposicular (MVL) local anesthetics prepared using a complex procedure (U.S. Patent No. 8,182,835) are used for local anesthetic delivery. To achieve enhanced drug efficacy through a lipid-based delivery vehicle with high drug entrapment (i.e., a high drug-to-lipid ratio), conventional manufacturing of lipid-based formulations with the desired high drug entrapment level typically involves tedious procedures and high production costs. Therefore, there is an unmet need for sustained-release local anesthetics with improved efficacy obtained through simplified manufacturing processes. BRIEF DESCRIPTION OF THE INVENTION This description provides a release anesthetic composition Sustained-release anesthetic or a method for preparing the same by one-step lyophilization to obtain a lipid cake comprising a local anesthetic agent and a lipid mixture, and then hydrating the lipid cake with a pH-controlled buffer solution to form a lipid-based complex containing the local anesthetic agent and the lipid mixture. This sustained-release anesthetic composition provides rapid onset of anesthesia and prolonged duration of local anesthesia with minimal toxicity. In some modalities, the local anesthetic agent is an amide-type anesthetic. In some procedures, the local anesthetic agent is ropivacaine. Other local anesthetic agents that may be used include lidocaine, bupivacaine, and levobupivacaine. In some embodiments, the present description provides a simple and robust manufacturing procedure for preparing an anesthetic composition for locally administering local anesthetics to a subject in need, wherein a hydration step can be performed in the procedure in an ambient environment. In some modalities, the lipid cake is formed with a phospholipid to allow rehydration with a pH regulator to obtain a desired sustained-release anesthetic composition with high association efficiency of the local anesthetic agent at room temperature without raising the temperature, which causes additional energy expenditure or inconveniences in clinical use. According to the present description, the lipid cake comprises a local anesthetic agent and a lipid mixture that includes at least one neutral saturated phospholipid comprising long-chain saturated fatty acids with no more than 18 carbon atoms. The lipid cake is easily preserved, and the anesthetic composition can be prepared by mixing the lipid cake with a pH regulator in a manufacturing plant or prior to clinical use under predetermined controlled conditions, e.g., at room temperature. In some embodiments, the long-chain saturated fatty acids have 14, 16, or 18 carbon atoms. In some embodiments, the lipid cake according to the present description is prepared by dissolving nonpolar ropivacaine, phospholipid and cholesterol in a solvent system, for example, tert-butanol alone or a tert-butanol / water cosolvent, followed by removal of the solvent system using a lyophilization technique. However, the pH value of a pharmaceutically acceptable pH buffer solution can be selected to adjust the ratio of trapped to non-trapped local anesthetic agent in the anesthetic composition. In certain formulations, the molar ratio of local anesthetic agent to phospholipid (molecular drug:molecular phospholipid) in the lipid-based complex of the anesthetic composition is at least 0.5:1, and this can provide a sufficient amount of the local anesthetic agent to a subject who requires it to prolong the duration of anesthesia following local administration in vivo. Furthermore, limiting the amount of non-trapped local anesthetic agent can achieve a rapid onset of anesthesia with minimal exposure to the maximum plasma concentration (Cmax). In some modalities, the present description also provides methods for producing analgesia or pain relief in a subject in need, comprising: administering the anesthetic composition to the subject according to the present description. In some modalities, the present description provides methods for controlling pain or for the prophylactic treatment of pain in a subject, comprising: administering to the subject the anesthetic composition according to the present description. Other objectives, advantages, and novel features of the description will become more evident from the following detailed description when taken together with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A is a graph representing 50% of the paw withdrawal threshold using a Von Frey test; in which an anesthetic composition according to the present description (ropivacaine composition) is our test item and ropivacaine injectable solution (unformulated ropivacaine) and commercially available liposomal extended-release bupivacaine (bupivacaine ER) are used as reference items. Saline, ropivacaine composition, ropivacaine injectable solution, and bupivacaine ER were administered intraplantarly after the paw incision; error bars represent the standard error of the mean (SEM); and *: P < 0.05 compared to the bupivacaine ER group; BBL = baseline before surgery; ABL = baseline after surgery. Figure IB is a graph representing the percentage of maximum possible effects (%MPE), calculated from the 50% withdrawal threshold using the formula %MPE = (threshold after treatment-ABL) / (BBL-ABL) x 100%; where the error bars represent the standard error of the mean (SEM); *: P<0.05 compared to the ER Bupivacaine group. An MPE greater than 30% is considered effective; Figure 2A is a graph representing the 50% paw withdrawal threshold using a Von Frey test, in which an anesthetic composition according to the present description (ropivacaine composition) is our test item and bupivacaine ER is used as the reference item. Saline, the ropivacaine composition, and bupivacaine ER were administered using a sciatic nerve block technique. The error bars represent the standard error of the mean (SEM); and Figure 2B is a graph showing the percentage of maximum possible effects (% iviA / a / zuzo / ui MPE), which were calculated from the 50% withdrawal threshold using the formula %MPE = (Threshold after treatment - Initial pre-dosing) / (Threshold after treatment - Initial pre-dosing) x 100%, the cut-off threshold was 15 g. The error bars represent the standard error of the mean (SEM). An MPE above 30% is considered effective. DETAILED DESCRIPTION OF THE INVENTION As previously used and throughout the description, the following terms, unless otherwise stated, shall be understood to have the following meanings. As used in this document, the singular forms un / una and el / la include the plural reference unless the context clearly indicates otherwise. All numbers in this document may be understood as modified by approximately, which, when referring to a measurable value such as an amount, a time duration and the like, is intended to encompass variations of ±10%, ±5%, ±1%, or ±0.1% of the specified value, as such variations are appropriate to obtain a desired amount of drug, unless otherwise specified. Association efficiency (AE) represents the amount of drug trapped in a lipid-based complex containing local anesthetic agents in an anesthetic composition and is calculated as the ratio of the amount of a drug in a separated lipid-based complex to the amount of that drug in the anesthetic composition. The separated lipid-based complex can be obtained from the anesthetic composition using any method known in the art. In some modalities, the separated lipid-based complexes are obtained from an anesthetic composition prepared by centrifugation methods, such as conventional centrifugation, density gradient centrifugation, or differential centrifugation, or by filtration methods, such as diafiltration, gel filtration, or membrane filtration. The term "treat," "treats," or "treatment" as used in this document includes preventive (e.g., prophylactic), palliative, and curative methods, uses, or outcomes. The terms "treatment" or "treatments" may also refer to compositions or medications. The term "treats" encompasses the reduction or delay of one or more symptoms or signs of pain or the complete relief of pain detected by known techniques. There are recognized methods in the art for assessing pain and pain symptoms, such as pain scoring and the 50% withdrawal threshold. For example, a described method of use of a sustained-release anesthetic composition is considered an objective treatment if there is at least a 1% reduction in one or more pain symptoms in a subject compared to the subject before treatment or control subjects.Therefore, the reduction can be approximately 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% reduction, or any amount of reduction between these values. Local anesthetic agents Local anesthetic agents as used in this document include one or more groups of substances that cause loss of sensation in a circumscribed area of ​​a subject by depressing excitation at nerve endings or inhibiting conduction in peripheral nerves. In some applications, local anesthetic agents are amide-type anesthetics. The typical amide-type anesthetic structure contains a lipophilic portion and a hydrophilic portion connected by an —NHCO— linkage. Suitable amide-type anesthetics include, but are not limited to, lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrocaine, articaine, and prilocaine. In certain applications, the local anesthetic agent is ropivacaine. Lipid cake The lipid cake comprises a mixture of lipids and one or more local anesthetic agents, which can be manufactured, stored long-term to extend the shelf life of the composition, and hydrated immediately prior to clinical use in an ambient environment. The lipid mixture described above may comprise one or more sterol-free phospholipids or may comprise one or more phospholipids with a sterol molar percentage, particularly with respect to cholesterol, of no more than 50% of the total lipid mixture. In certain embodiments, the cholesterol molar percentage based on the lipid mixture is approximately 0% to 50% and, optionally, approximately 25% to 40% or 33% to 35%. In some embodiments, the phospholipid(s) and cholesterol are in a molar ratio of 1:1 to 3:1. The lipid cake can be prepared by 1) dissolving a lipid mixture and one or more local anesthetic agents in a solvent system to form a homogeneous solution comprising one or more solvents, and 2) removing the solvent(s) to solidify the lipid mixture and local anesthetic agent formulation. Solvent removal can be accomplished using techniques known as freeze-drying (lyophilization). Examples of solvent systems suitable for lyophilization include, but are not limited to, tert-butanol and tert-butanol / water cosolvent 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. Anesthetic composition The term anesthetic composition refers to a product suitable for local administration. In certain formulations, an anesthetic composition comprises a lipid-based complex and a non-encapsulated local anesthetic agent. In some formulations, the lipid-based complex includes multilamellar vesicles and a local anesthetic agent encapsulated within the multilamellar vesicles. The term encapsulation or entrapment refers to the bilayer membrane of multilamellar vesicles that encapsulates, embeds, or associates a target drug substance. The particle size distribution of the lipid-based complex as described herein 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 not less than 1 µm; and optionally, it is greater than 5 µm, such as in the range of 5 µm to 50 µm, or from 10 µm to 25 µm. Alternatively, the volume median particle diameter (D50) of the lipid-based complex of the anesthetic composition is not less than 1 µm; and, optionally, not less than 5 µm, such as 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 forms, the mean particle diameter (D50) refers to a particle diameter in which the cumulative percentage of lipid-based complex made of the agglomerated particles that is 50% in the cumulative particle size distribution is 5 pm or more or 7 pm or more.In some modalities, the average particle diameter (D50) refers to a particle diameter in which the cumulative percentage of lipid-based complex made of the agglomerated particles that is 50% in the cumulative particle size distribution is 25 pm or less, 20 pm or less, or 15 pm or less. In some formulations, the particle diameter in a cumulative percentage of 90% in a cumulative particle size distribution (D90) of the lipid-based complex of the anesthetic composition is no less than 10 µm, such as in the range of 10 µm to 300 µm, 20 µm to 200 µm, or 20 µm to 100 µm. Furthermore, the lower limit of D90 is not specifically restricted to 25 µm or more or 30 µm or more. Additionally, the shape of the agglomerated particle of the lipid-based complex to enhance the efficacy of the unit-dose combination is not specifically restricted. To prepare the anesthetic composition for use, the lipid cake is hydrated with an aqueous pH buffer solution to a pH value not less than 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0. In some modalities, the aqueous pH buffer solution is in a pH range of 5.5 to 8.0 and, optionally, 6.0 to 7.8, 6.0 to 7.5, 6.3 to 7.5, 6.5 to 7.5, 6.7 to 7.5 or 6.8 to 7.5. Suitable aqueous buffer solutions according to the present description 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-piperazindiethanesulfonic acid (PIPES), 3-morpholino-2-hydroxypropanesulfonic acid (MOPSO), imidazole, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), and 4-(2-hydroxyethyl)perazine-1-ethanesulfonic acid. (HEPES), triethanolamine, lysine, tris, and glycylglycine. The amount of amide-type anesthetic not trapped in the composition can be adjusted based on the anesthetic's distribution coefficient by selecting an appropriate pH value for the aqueous pH buffer solution based on the clinical indication and the total injection dose. In some forms, the aqueous buffer solution comprises histidine at a concentration ranging from 1 mM to 200 mM, from 10 mM to 150 mM, or from 40 mM to 120 mM. In some forms, the aqueous buffer solution comprises phosphate at a concentration ranging from 1 mM to 200 mM, from 10 mM to 180 mM, or from 40 mM to 160 mM. The amount of untrapped amide-type anesthetic is a function of the association efficiency (AE) of the anesthetic composition, which is determined by a centrifugation method. Mathematically, the amount of untrapped amide-type anesthetic is expressed as follows: Anoatrapado=Atotal X (1—AE) where Anoatrapado is the amount of amide-type anesthetic not trapped; Atotal is the total amount of amide-type anesthetic in the anesthetic composition; and AE is obtained by dividing the amount of amide-type anesthetic trapped in the lipid-based complex by the total amount of amide-type anesthetic in the anesthetic composition. AE according to the present description is at least 60% and, optionally, from 70% to 99%. In certain modalities, the molar ratio of amide-type anesthetic to phospholipid (drug:phospholipid, D:PL) of the lipid base complex is at least 0.5:1, including but not limited to 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, or 1.5:1. In certain modalities, the median diameter (D50) of the lipid base complex is not less than 1 µm and, optionally, not less than 5 µm, such as in a 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; The D90 of the lipid-based complex is not less than 10 pm, such as in a range of 10 pm to 300 pm, 20 pm to 200 pm, or 20 pm to 100 pm. The concentration of amide-type anesthetic in the anesthetic composition must be greater than 2 mg / ml to achieve a clinical therapeutic benefit. Suitable concentrations of amide-type anesthetics include, but are not limited to, 2 mg / ml to 30 mg / ml and 10 mg / ml to 20 mg / ml. The limited amount of anesthetic not trapped in the anesthetic compositions described in the iviA / a / zuzo / ui description may provide the benefit of achieving a higher maximum tolerable dose (depending on the plasma concentration of anesthetic that causes central nervous system and cardiovascular toxicity) and may be used to provide rapid onset of efficacy. For clinical use, the anesthetic efficacy (AE) in certain formulations described ranges from 70% to 99.9%, 75% to 99.5%, 80% to 99.5%, 85% to 99.5%, 90% to 99.5%, or 95% to 99.5%. The remaining lipid-based complex acts as a reservoir to gradually release the amide-type anesthetic into the local environment in a manner that maintains a therapeutically effective dose at the local site. In some formulations, the half-life of ropivacaine, derived from a single subcutaneous administration of a ropivacaine composition as described, is at least 10 times longer than that of unformulated ropivacaine. The duration of the anesthetic effect following administration of the ropivacaine composition as described extends significantly beyond that of unformulated ropivacaine. Multilaminar vesicle The term multilaminar vesicle, as used herein, refers to a particle characterized by having an aqueous interior space sequestered from an external medium by a membrane of one or more bilayers forming a vesicle. The bilayer membranes of multilaminar vesicles are typically composed of lipids, i.e., amphiphilic molecules of synthetic or natural origin comprising spatially separated hydrophobic and hydrophilic domains. In certain embodiments of the present description, a multilaminar vesicle is one in which more than one lipid bilayer forms the membrane. In general, the bilayer membrane of multilamellar vesicles comprises a mixture of lipids comprising dialyphatic chain lipids, such as phospholipids, diglycerides, dialyphatic glycolipids; simple lipids, such as sphingomyelin and glycosphingolipids; steroids, such as cholesterol and its derivatives; and combinations thereof. Examples of phospholipids according to the present disclosure include, but are not limited to, l,2-dilauro¡l-sn-glycero-3-phosphocholine (DLPC), l,2-dim¡r¡l-sn-glycero-3-phosphocholine (DMPC), l,2-dipalmito¡l-sn-glycero-3-phosphocholine (DPPC), l-palmito¡l-2-stearoyl-sn-glycero-3-phosphocholine (PSPC), l-palmito¡l-2-oleo¡l-sn-glycero-3-phosphatidylcholine (POPC), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), phosphatidylcholine hydrogenated soybean (HSPC), 1,2-d¡m¡r¡stoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (sodium salt) (DMPG), l,2-d¡palmito¡l-sn-glycero-3-phospho-(r-rac-glycerol) (sodium salt) (DPPG),l-palmitoyl-2-estearoyl-sn-glycero-3-phospho-(r-rac-glycerol) (sodium salt) (PSPG), l,2-diestearoyl-sn-glycero-3-phospho-(r-rac-glycerol) (sodium salt) (DSPG), l,2-dioleoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (DOPG), l,2-d¡m¡r¡stoyl-sn-glycero-3-phospho-L-ser¡na (sodium salt) (DMPS), l,2-d¡palmitoyl-sn-glycero-3-phospho-L-ser¡na (sodium salt) (DPPS), iviA / a / zuzo / uil,2-diestearoyl-sn-glycero-3-phospho-L-sernia (sodium salt) (DSPS), 1,2-dioleoyl-sn-glycero-3-phospho-L-sernia (DOPS), 1,2-dimristoyl-sn-glycero-3-phosphate (sodium salt) (DMPA), 1,2-dipalmtoyl-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), l,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), l-palmtoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), l,2-destearoyl-sn-glycero-3-phosphoethanolamine (DSPE), l,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), l,2-dipalmitoyl-sn-glycero-3-phospho-(r-myoinositol) (amonium salt) (DPPI), l,2-d¡estearoyl-sn-gl¡cero-3-phospho¡nos¡tol (amonium salt) (DSPI), l,2-dioleo¡l-sn-glycero-3-phospho(Γ-myoinositol) (sal de ammonium) (DOPI), cardiolipin, Lo-phosphatidylcholine (EPC), y Lo-phosphatidylethanolamine (EPE)., Examples of phospholipids include, but are not limited to, dimyristoyl phosphatidylcholine (DMPC), 1,2-dilauro¡l-sn-gl¡cero-3-phosphocol¡na (DLPC), dipalmitoylphosphatidylcholine (DPPC), diolylphosphatidylglycerol (DOPG), l,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), l,2-d¡oleo¡l-sn-gl¡cero-3-fosfat¡dylser¡na (DOPS), dioleilfosfatídico (DOPA), phosphatidylcholina de huevo (PC de huevo), phosphatidylethanolamine (PE de huevo), l-palm¡to¡l-2-oleo¡l-sn-glycero-3-phosphatidyl¡lethanolam¡na (POPE), cardiolipin yl,2-d¡minstoyl-sn-glycero-3-phosphate (sodium salt) (DMPA). The phospholipids suitable according to the present description are saturated phospholipids derived from two long-chain saturated fatty acids, wherein each fatty acid has a long carbon chain of at least 12 and not more than 20 carbons. In some embodiments, the saturated phospholipids suitable according to the present description are selected from the group consisting of DLPC, DMPC, DPPC, and combinations thereof. In some embodiments, the lipid mixture comprises suitable phospholipids according to the present description, such as a positively or negatively charged phospholipid, and a specified amount of unsaturated phospholipid, wherein the specified amount is less than 10% molar percent based on the total amount of phospholipids, for example, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%. Local anesthesia and prophylactic pain treatment The anesthetic composition as described herein is for use in local anesthesia and may be administered perineurally or into a surgical wound to treat pain. In some cases, the pain is postoperative pain or labor pain. In some cases, the anesthetic composition is administered subcutaneously, intracutaneously, or intramuscularly to treat a painful condition in a patient who requires it. In some modalities, local anesthesia includes field block and infiltration anesthesia. Field block involves injecting a local anesthetic agent around the boundaries of the area to be anesthetized, without attempting to locate specific nerves. Infiltration anesthesia involves injecting a local anesthetic agent directly into the area of ​​the nerve endings. In some modalities, the composition as described herein is administered as a nerve block as a prophylactic treatment of a painful condition, such as administration before surgery for the treatment of post-surgical pain, in a subject who requires it. A nerve block involves introducing an agent near or into a peripheral nerve to reduce pain or to provide numbness. The types of nerve blocks include, among others, motor, sensory, differential and autonomic blocks and, in addition, include, among others, the brachial plexus (axillary, interscalene, supraclavicular, infraclavicular), individual nerve blocks of the upper limbs (median, radial, ulnar, musculocutaneous, axillary), sciatic, ankle, metatarsal, oral, femoral, popliteal fossa, saphenous, distal, digital, deep peroneal, superficial peroneal, tibial, sural and saphenous. The description will be further described with reference to the following specific, non-limiting examples. EXAMPLES The following examples illustrate the preparation and properties of certain modalities of the present description. EXAMPLE 1 Preparation of ropivacaine compositions with various phospholipids Phospholipids, including DLPC, DMPC, DPPC, DOPG, DOPC, DOPS, DOPA, egg PC, egg PE, POPE, cardiolipin, and DMPA, were 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. To prepare lipid cakes, ropivacaine was combined with different lipid mixtures as indicated in Table 1 at a drug-to-phospholipid (D:PL) ratio of 1.458 pmol / pmol, i.e., phospholipid:cholesterol:ropivacaine = 2:1:2.9. The lipids and ropivacaine were mixed and then dissolved in tert-butanol or a tert-butanol / water cosolvent system (1 / 1, vol / vol) to form the liquid structures. Each liquid structure sample was frozen for 30 to 60 minutes and then lyophilized overnight to obtain a lipid cake. To prepare the lipid structures for vehicle control, a lipid mixture with a DMPC:cholesterol molar ratio of 2:1 was weighed and then dissolved in tert-butanol. The resulting sample was frozen for 60 minutes and then lyophilized overnight to obtain a vehicle lipid cake. The lipid cakes were hydrated with 50 mM histidine pH regulator to pH 6.5 at a temperature not lower than 25°C / room temperature (TA) for 2 to 10 minutes to form the vehicle and ropivacaine compositions respectively, followed by characterization of association efficiency and particle size distribution. EXAMPLE 2 Characterization of ropivacaine compositions The association efficiency (AE) of each of the preparations described in Example 1 was determined as follows. Two hundred microliters of each ropivacaine composition were transferred to a centrifuge and centrifuged for 5 min at 3000 x g at 4°C. After decanting the supernatant, the separated lipid-based complex was obtained and resuspended to a final volume of 200 mL. A reference absorbance standard was established for each drug (e.g., ropivacaine) based on test drug solutions of known concentration. The amounts of drug substance in both the original ropivacaine composition and the separated lipid-based complex were measured using an ultraviolet / visible (UV / Vis) spectrophotometer. The AE represents the ratio of the amount of drug substance in the separated lipid-based complex to the amount of drug substance in the original ropivacaine composition.The D:PL of the separated lipid-based complex was calculated by multiplying the D:PL of the lipid cake by AE and was denoted as the resulting D:PL. The particle size of each ropivacaine composition was measured using a laser diffraction particle size analyzer (LA-950V2, Horiba or Mastersizer 3000, Malvern). The volumetric mean diameter (D50) of the ropivacaine-containing lipid-based complex formed by hydrating the lipid cake with 50 mM histidine pH buffer (pH 6.5) or phosphate pH buffer (pH 7.0) was examined and compared in Table 1. Lipid cakes comprising DMPC, DLPC, or DPPC demonstrated very similar EA (90%, 90%, and 92%, respectively). However, the median diameter (D50) of the ropivacaine-containing lipid complex differed. The D50 of the resulting lipid-based complex containing iviA / a / zuzo / ui ropivacaine in the ropivacaine compositions of the hydration lipid cakes with DMPC, DLPC, and DPPC was 6.6 ± 0, 12.7 ± 0.4, 7.8 ± 0.1, and 14.9 ± 0.1 pm, respectively. Table 1 shows a summary of the results. TABLE 1 The EA and median diameter (D50) of selected ropivacaine compositions with various phospholipids Lipid Composition Chain Length / Degree of Unsaturation D50 (pm) AE (%) Resulting D:PL DMPC:cholesterol = 2:1a 14:0 / 14:0 6.6 ± 0.0 96.1 1.40 DMPC:cholesterol = 2:lb 14:0 / 14:0 12.7 ± 0.4 90 1.32 DLPC:cholesterol = 2:lb 12:0 / 12:0 7.8 ± 0.1 90 1.32 DPPC:cholesterol = 2:lb 16:0 / 16:0 14.9 ± 0.1 92 1.34 Egg PC:cholesterol = 2:lb 16:0 / 18:1 5.7 ± 0.0 NA* NA DOPG:cholesterol = 2:lb 18:1 / 18:1 5.5 ± 0.4 NANA DOPC:cholesterol = 2: lb 18:1 / 18:1 3.7 ± 0.0 NANA DOPS:cholesterol = 2: lb 18:1 / 18:1 5.8 ± 0.1 NANA Cardiolipin:cholesterol 2:lb 18:1 / 18:1 / 18:1 / 18:1 15.3 ± 0.5 NANA *NA (not applicable): The compositions could not be analyzed due to unacceptable viscosity, which caused a failure in the centrifugation stage of the characterization protocol, even after additional centrifugation time had been applied. Hydrated by phosphate pH regulator. Hydrated by histidine pH regulator. EXAMPLE 3 Preparation of ropivacaine compositions with various combinations of phospholipids The sources of phospholipids, cholesterol, ropivacaine, and all other chemicals were described in Example 1. For the preparation of lipid cakes, ropivacaine was combined with different lipid mixtures in the molar ratio phospholipids-cholesterol:ropivacaine = 2:1:2.9, where the phospholipids were a combination of DMPC and one of the other phospholipids described in Table 2 with a molar ratio of DMPC:the other phospholipid = 1.8:0.2. The lipids and ropivacaine were mixed and then dissolved in tert-butanol to form the liquid structures. Each sample of the liquid structure was frozen for 30 to 60 minutes and then lyophilized overnight to obtain a lipid cake. iviA / a / ¿u¿o / ui Lipid cakes were hydrated with 50 mM histidine pH regulators to pH 6.5 at room temperature to form ropivacaine compositions, followed by characterization of association efficiency and particle size distribution. The resulting lipid-based complex containing ropivacaine in the ropivacaine compositions from lipid cake hydration, consisting of a combination of DMPC / DLPC, DMPC / DPPC, DMPC / egg PC, DMPC / egg PE, or DMPC / POPE, demonstrated very similar EA (90%, 91%, 91%, 91%, and 91%, respectively). The median diameter (D50) of the lipid-based complex containing ropivacaine in the ropivacaine compositions also showed similar results. The D50 of the lipid-based complex resulting from the ropivacaine compositions obtained by hydrating lipid cakes with a combination of DMPC / DLPC, DMPC / DPPC, DMPC / egg PC, DMPC / egg PE, or DMPC / POPE was 11.4 ± 0.3, 14.3 ± 0.1, 11.6 ± 0.0, 11.5 ± 0.0, and 11.0 ± 0.3 pm, respectively. Table 2 shows a summary of the results. TABLE 2 The EA and median diameter (D50) of selected ropivacaine compositions with various phospholipid combinations Lipid composition D50 (pm) AE (° / o) Resulting D:PL DMPC:DLPC:cholesterol = 1.8:0.2:1 11.4 ± 0.3 90 1.32 DMPC:DPPC:cholesterol = 1.8:0.2:1 14.3 ± 0.1 91 1.32 DMPC:Egg PC:cholesterol = 1.8:0.2:1 11.6 ± 0.0 91 1.32 DMPC:Egg PE:cholesterol = 1.8:0.2:1 11.5 ± 0.0 91 1.33 DMPC:POPE:cholesterol = 1.8:0.2:1 11.0 ± 0.3 91 1.32 DMPC:DOPG:cholesterol = 1.8:0.2:1 9.5 ± 0.0 NA* NA DMPC:DOPC:cholesterol = 1.8:0.2:1 8.2 ± 0.0 NANA DMPC:DOPS:cholesterol = 1.8:0.2:1 7.8 ± 0.0 NANA DMPC:DOPA:cholesterol = 1.8:0.2:1 8.1 ± 0.0 NANA DMPC:Cardiolipina:cholesterol = 1.8:0.2:1 6.6 ± 0.0 NANA DMPC:DMPA:cholesterol = 1.8:0.2:1 6.6 ± 0.0 NANA *NA (not applicable): The compositions could not be analyzed due to unacceptable viscosity, which caused a failure in the centrifugation stage of the characterization protocol, even after additional centrifugation time had been applied. EXAMPLE 4 Anesthetic effect in a rat model with a paw incision Sprague-Dawley rats were used to evaluate anesthetic efficacy after paw incision as described in Pain. 1996 Mar; 64(3):493-501. The rat housing facility was operated on a 12-hour light / 12-hour dark circadian cycle, and experiments were performed during the daytime portion of the circadian cycle only. A ropivacaine composition was prepared as an embodiment of the anesthetic composition according to the present description (ropivacaine composition) as per Example 1, in which a DMPC:cholesterol:ropivacaine lipid cake (2:1:2.9) was hydrated with 50 mM histidine pH regulator to pH 6.8. Unformulated ropivacaine was prepared by dissolving ropivacaine in water for injection at 19.0 mg / ml. A commercially available FDA-approved extended-release liposomal bupivacaine formulation (ER Bupivacaine) was purchased from Pacira Pharmaceuticals, Inc.The in vivo efficacy of the ropivacaine composition, unformulated ropivacaine, saline solution, and bupivacaine ER was compared after intraplantar injection following foot incision at a dose of 1.9 mg for the ropivacaine composition and unformulated ropivacaine and 1.33 mg for bupivacaine ER (equipolent dose) per incision. Before surgery, baseline body weight (BBL) measurements were taken from 27 rats 1 to 3 days prior to surgery; after surgery, baseline body weight (ABL) measurements were taken from 27 rats 30 minutes post-surgery. For formal studies, rats exhibiting a baseline BBL threshold value greater than 9 g and a baseline ABL threshold value less than 4 g were used. The final total of 20 rats was randomly assigned to 4 groups (5 rats per group). While under anesthesia with 2–3.5% isoflurane in 100% oxygen, each rat received a 1-cm longitudinal plantar incision on the left hind foot with three additional incisions made in the fascia. Each rat received a single intraplantar injection of saline solution (100 µL), ropivacaine composition (100 µL of 19.0 mg / ml), bupivacaine ER (100 µL of 13.3 mg / ml) or unformulated ropivacin (100 µL of 19.0 mg / ml).The 50% paw withdrawal threshold for each rat was obtained using the Dixon top-down method at the BBL time point (-1 to -3 days), the ABL time point, and designated time points (0.5, 1, 2, 3, 4.5, 6, 7, and 24 hours) after intraplantar injection. The anesthetic efficacy of the ropivacaine composition (diamond), unformulated ropivacaine (triangle), bupivacaine ER (square), and saline (circle) after paw incision is shown in Figures 1A and 1B. The mean 50% paw withdrawal threshold was plotted for each treatment group; data presented as 50% paw withdrawal threshold (g) were plotted against time (Figure 1A). The percentage of maximum possible effect (%MPE) for each treatment was calculated from the 50% paw withdrawal threshold using the formula %MPE = (Threshold after treatment - ABL) / (BBL - ABL) x 100%. The %MPE for each treatment was plotted; data presented as %MPE were plotted against time (Figure 1B). The onset time of the ropivacaine formulation and the unformulated ropivacaine was similar, with the withdrawal threshold increased from 1.83 ga 13.00 g and 1.74 ga 11.47 g, respectively, at time point T = 0.5 hours. The onset time of the ropivacaine composition was earlier than that of bupivacaine ER, which showed an increase in the withdrawal threshold of 1.80 g and 6.51 g at time point T = 0.5 hours. The ropivacaine composition produced the most prolonged analgesic action (lasting at least 6 hours) compared to bupivacaine ER (less than 5 hours). EXAMPLE 5 Anesthetic effect in a rat model of sciatic nerve pain implanted with a cuff Sprague-Dawley rats were used to evaluate anesthetic efficacy after implantation of a sciatic nerve cuff as described in Pain. 1999 Oct;83(l):37-46. The rat housing facility was operated on a 12-hour light / 12-hour dark circadian cycle, and experiments were performed during the daytime portion of the circadian cycle only. A ropivacaine composition was prepared as an embodiment of the anesthetic composition described herein (ropivacaine composition) according to Example 1, wherein a DMPC:cholesterol:ropivacaine lipid cake (2:1:2.9) was hydrated with 50 mM histidine pH regulator to pH 68. A commercially available, FDA-approved, liposomal extended-release bupivacaine formulation (ER Bupivacaine) was purchased from Pacira Pharmaceuticals, Inc.The in vivo efficacy of the ropivacaine, ER Bupivacaine, and saline compositions was compared following the sciatic nerve injection technique after sciatic nerve cuff implantation in rats at a dose of 25 mg / kg for the ropivacaine composition and 25 mg / kg and 35 mg / kg for ER Bupivacaine. While under anesthesia, a 3- to 4-mm PE 60 or PE 90 tube was placed over the sciatic nerve of the left leg. The muscle and skin were brought into contact with the cuff using 2 to 3 sutures. Baseline data were collected 2 to 3 weeks after cuff implantation to confirm pain induction. Rats exhibiting a pain threshold below 4 g were used for the formal studies. A total of 21 rats were randomly divided into 3 groups (of 7 rats each) and received either ropivacaine (25 mg / kg), bupivacaine ER (25 mg / kg), or bupivacaine ER (35 mg / kg) via a dosage block technique at the sciatic nerve. Four rats received saline treatment as a control.The 50% paw withdrawal threshold for each rat was obtained using the Dixon top-down method at pre-dosing and designated time points (1, 3, 4, 5, 6, 7, 8 and 9 hours) after dosing. The anesthetic efficacy of the ropivacaine (25 mg / kg, open triangle), bupivacaine (25 mg / kg, open circle; 35 mg / kg, inverted closed triangle), and saline (closed circle) composition after dosing is shown in Figure 2A and Figure 2B. The mean 50% paw withdrawal threshold was plotted for each treatment group; data presented as the 50% paw withdrawal threshold (g) were plotted against time (Figure 2A). The percentage of maximum possible effect (%MPE) for each treatment was calculated from 50% of the paw withdrawal threshold using the formula %MPE = (Treatment Threshold - Initial Pre-dosing) / (Baseline Pre-dosing Threshold) x 100%. The cutoff threshold was 15 g in this study. The %MPE for each treatment was plotted. The data presented as %MPE were plotted against time (Figure 2B).The ropivacaine composition produced the longest-lasting analgesic effect (> 9 hours) compared to bupivacaine ER (less than 8 hours) for the 25 mg / kg and 35 mg / kg groups. A mean effective dose (MED) percentage greater than 30% was considered effective.

Claims

1. An anesthetic composition for local administration to a subject in need thereof, characterized in that it comprises: a lipid-based complex comprising: an amide-type anesthetic in free base form, and a lipid mixture comprising at least one neutral saturated phospholipid and a ester in the presence of an aqueous buffer solution at a pH of 5.5 to 8.0, wherein the at least one neutral saturated phospholipid is derived from saturated fatty acids, each fatty acid independently comprising a carbon chain of no more than 18 carbons; wherein the lipid-based complex has a mean diameter of not less than 1 pm; and the molar ratio of the amide-type anesthetic to the phospholipid in the lipid-based complex is at least 0.5:

1.

2. The anesthetic composition according to claim 1, further characterized in that the neutral saturated phospholipid is selected from the group consisting of dimyristoylphosphatidylcholine (DMPC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), and dipalmitoylphosphatidylcholine (DPPC).

3. The anesthetic composition according to claim 1, further characterized in that the lipid mixture additionally comprises an unsaturated phospholipid present in an amount less than 10% molar percentage based on the total amount of phospholipids. 4.- The anesthetic composition according to claim 3, further characterized in that the unsaturated phospholipid is l-palmitoyl-2-oleoyls / 7-glycero-3-phosphoethanolamine (POPE), phosphatidylethanolamine (egg PE) or egg phosphatidylcholine (egg PC).

5. The anesthetic composition according to claim 1, further characterized in that the molar percentage of esteral in the lipid mixture is not more than 50%.

6. The anesthetic composition according to claim 1, further characterized in that the at least one neutral saturated phospholipid and the steral are in a molar ratio of 1:0.01 to 1:

1. 7.- The anesthetic composition according to claim 1, further characterized in that the steral is cholesterol.

8. The anesthetic composition according to claim 1, further characterized in that the amide-type anesthetic is lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrocaine, articaine, or prilocaine.

9. The anesthetic composition according to claim 1, further characterized in that the amide-type anesthetic is ropivacaine. > tu r\ c N 18 S* 10. The anesthetic composition according to claim 1, further characterized in that the mean diameter of the lipid-based complex is in the range of 5 pm to 50 pm.

11. The anesthetic composition according to claim 1, further characterized in that the mean diameter of the lipid-based complex is in the range of 5 pm to 20 pm.

12. The anesthetic composition according to claim 1, further characterized in that the anesthetic composition has an association efficacy (AE) of at least 60% for the amide-type anesthetic.

13. The anesthetic composition according to claim 1, further characterized in that the anesthetic composition has an AE of 70-99% for the amide-type anesthetic.

14. The anesthetic composition according to claim 1, further characterized in that the molar ratio of the amide-type anesthetic to phospholipid in the lipid-based complex varies from 0.5:1 to 2:

1.

15. The anesthetic composition according to claim 1, further characterized in that the molar ratio of the amide-type anesthetic to phospholipid in the lipid-based complex varies from 0.7:1 to 2:

1.

16. The anesthetic composition according to claim 1, further characterized in that the molar ratio of the amide-type anesthetic to phospholipid in the lipid-based complex varies from 0.7:1 to 1.5:

1.

17. An anesthetic composition for use in the treatment of pain in a subject requiring anesthesia, wherein the anesthetic composition comprises: a lipid-based complex comprising: an amide-type anesthetic in free base form; and a lipid mixture including at least one neutral saturated phospholipid and a sterol in the presence of an aqueous buffer solution at pH 5.5 to 8.0, wherein the at least one neutral saturated phospholipid is derived from saturated fatty acids, each fatty acid independently comprising a carbon chain of no more than 18 carbons; wherein the lipid-based complex has a mean diameter ranging from 1 pm to 30 pm and the molar ratio of the amide-type anesthetic to the phospholipid in the lipid-based complex is at least 0.5:

1.

18. The anesthetic composition for use in accordance with claim 17, wherein the amide-type anesthetic is lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrocaine, articaine, or prilocaine.

19. The anesthetic composition for use according to claim 17, wherein the neutral saturated phospholipid is selected from the group consisting of dimyristoylphosphatidylcholine (DMPC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), and dipalmitoylphosphatidylcholine (DPPC).

20. The anesthetic composition for use in accordance with claim 17, wherein the anesthetic composition is administered perineurally or in a surgical wound.

21. The anesthetic composition for use in accordance with claim 17, 5 wherein the pain is post-surgical pain or labor pain.

22. The anesthetic composition for use in accordance with claim 17, wherein the anesthetic composition is administerable as a nerve block.

23. The anesthetic composition for use in accordance with claim 17, wherein the anesthetic composition is administerable as a field block.