MXPA05006771A - Ester combination local anesthetic. - Google Patents

Abstract

The present invention provides compositions and methods for improved local anesthesia and/or analgesia, in which onset of action is rapid, the risk of toxicity is low, and the effect is sustained. More particularly, the present invention provides a combination of at least two ester anesthetics for administration to a subject, where at least one ester anesthetic provides a rapid onset of action and at least one ester anesthetic provides sustained activity. The compositions of the present invention are useful for the production of analgesia and/or anesthesia and are particularly useful for the prophylaxis and/or treatment of pain.

Description

AN ESTÉSICO LOCAL WITH COMBINATION OF ESTER BACKGROUND OF THE INVENTION Local anesthetics are drugs that produce reversible loss of sensation in a specific area of the body. Most of the agents - clinically useful local anesthetics consist of an aromatic chain linked by a carbonyl containing half lina through a carbon chain to a substituted amino group. There are 2 main classes, defined by the nature of the carbonyl-containing linking group. Agents with an ester linkage include cocaine, procaine, tetracaine, benzocaine, amethocaine, and chloroprocaine. Those with an amide bond include lidocaine, prilocaine, mepivacaine, ropivocaine, etidocaine, levobupivacaine, and bupivacaine. There are important practical differences between these two classes of local anesthetic agents. Esters are chemically less stable than amides, and are rapidly hydrolyzed in the body by plasma cholinesterases and other esterases. This metabolism in general prevents the esters from accumulating to toxic levels in vivo, even with prolonged or repeated doses. Amides are metabolized less quickly, mainly by liver proteases, so they can increase to toxic levels with repeated or large doses. In current clinical practice, local ester-based anesthetics have been largely replaced by those in the amide class. Different amide-based local anesthetics usually become inactive by a common path. More importantly, all local anesthetics share the same basic toxicity profile, for example, central nervous system toxicity and arrhythmia attacks and death from cardiac toxicity. The toxicities of all local anesthetics are additive. However, because amide-based local anesthetics have much slower metabolism than ester-based anesthetics, combinations of amide-based local anesthetics have the potential for additive toxicity of two compounds that are slowly eliminated by the body. The much faster metabolism of local anesthetics based on ester practically prevents additive toxicity by drug absorption, although additive toxicity would be expected if two local anesthetics based on ester were given by direct intravenous injection. Similar problems are found with repeated doses of local anesthetics based on amide, where the toxicity of the second dose is added to that of the first dose, due to its slow metabolism and inactivation. Local anesthetics interrupt impulse conduction in the peripheral nerves by blocking sodium channels from the intracellular part of the cell membrane. This causes a local decrease in the level and degree of depolarization of the nerve membrane, so that the threshold potential for transmission is not reached. There is no effect on the reserve or threshold potential, although the refractory period and re-polarization can be extended.

Local anesthetics are applied topically to the skin, eye, ear, nose, and mouth, as well as other mucous membranes. Typically, infiltration techniques are used to provide anesthesia for minor surgical procedures. Amide anesthetics are commonly used with a median duration of action. The place of action is in non-myelinated nerve terminals. The beginning is very fast with infiltration techniques. However, the duration of local anesthesia is variable, and depends on the amount of medication injected as well as the physical properties of the local anesthetic. In general, local anesthetics that are more soluble in lipid have a slower onset, but a longer duration of effect, than local anesthetics that are less soluble in lipid. The conduction anesthesia can be divided into smaller nerve blocks and larger blocks of deeper nerves or trunks with a wide dermatomal distribution. The beginning of the anesthesia of conduction varies from several minutes for local anesthetics that are relatively insoluble in lipid, up to almost an hour for local anesthetics that are very soluble in lipid. The duration of the anesthesia of conduction varies from 60 minutes for local anesthetics that are relatively insoluble in lipid until many hours for local anesthetics that are very soluble in lipid. You can also deposit solutions of local anesthetics in the epidural space. The injected local anesthetic solution produces analgesia by blocking conduction in the intradural spinal nerve roots. Again, lipid-soluble local anesthetics will have a slower onset, but a longer duration of effect, than local anesthetics relatively insoluble in lipid. Localized or systematic toxic reactions may occur, for example, by accidental intrathecal or intravascular injection, excessive administration dose, etc. Systematic reactions to local anesthetics mainly involve the central nervous system (CNS) and the cardiovascular system. The initial symptoms of CNS toxicity involve sensations of slight hair loss, dizziness and circumoral paraesthesia, which may precede auditory and / or visual disturbances such as difficulty focusing and buzzing. Other signs include chills, muscle contraction, and shivering initially involving muscles of the face and distal parts of the extremities. Finally, generalized seizures occur, progressing to CNS depression and coma. Respiratory depression can result in respiratory arrest. Normally cardiovascular toxicity occurs in doses and blood concentrations that are higher than those required to produce CNS toxicity. Extremely high concentrations of local anesthetics reduce the activity of the spontaneous cardiac regulator in the breast node resulting in sinus bradycardia and sinus arrest. They also exert a negative ionotropic action on isolated cardiac tissue. Bupivacaine and etidocaine have been reported to cause profound and rapid cardiovascular depression in some patients after accidental intravascular injection. In fact, an analysis of the Medline database reveals that 1 02 deaths from bupivacaine (for example, heart failure, myocardial infarction, accidental overdose, etc.) occurred between 1 990 and 1 997. Local anesthetics currently used they often suffer from a limited duration of action, which is too short to mitigate most postoperative pain, or from a slow onset of effect, which limits the utility in the operating room where a rapid onset is necessary to avoid dilatory surgery. The start of activity is a particularly important problem for local anesthesia, in contrast to spinal anesthesia where the onset of the anesthetic effect is invariably rapid. See, for example, Hauch et al. , Reg. Anesth 1 5:81 -85 (1990). Local amide anesthetics often suffer from safety issues, since localized and systematic toxic reactions to these anesthetics lead to cardiovascular and CNS toxicity. In addition, currently used local anesthetics such as lidocaine produce pain and discomfort (eg, urticaria) when administered. In view of the aforementioned, there has been a need for many years in the art for local anesthetic and / or analgesic formulations which have a rapid onset, a long duration of action, minimal toxic side effects, and easy administration. The present invention satisfies this and other needs by providing long-lasting local anesthetic and / or analgesic formulations that produce a prolonged duration of nerve block, faster onset of action, minimal toxicity, greater efficacy, and ease of administration.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides compositions and methods for analgesia and / or improved local anesthesia, in which the onset of action is rapid, the risk of toxicity is low, and the effect is continuous. At least two ester anesthetics are combined, wherein at least one provides a rapid onset of action and at least one provides continuous activity. Being very important, because the combination of ester anesthetics produces minimal toxicity due to the very fast metabolism in the blood, each one can be given in sufficient quantities to exert its maximum pharmacological benefit. For example, both the fast-acting ester anesthetic and the long-acting ester anesthetic are administered in maximum doses, providing a rapid onset of effect and a maximum duration of effect, respectively. The low risk of toxicity associated with administering a combination of ester anesthetics also provides the possibility for repeated administrations of a maximum dose, which can not be done safely with amide anesthetics. The compositions are used for the production of analgesia and / or anesthesia and are particularly useful for the prophylaxis and / or treatment of pain. As local anesthetics, the compositions are useful for regional anesthesia, for example, topical anesthesia, infiltration anesthesia, field obstruction anesthesia, peripheral nerve obstruction anesthesia, epidural anesthesia, spinal anesthesia, obstruction anesthesia and combinations thereof. In one aspect, the present invention provides a method for local anesthesia, the method comprising administering a combination of at least two ester anesthetics. In another aspect, the present invention provides a method for analgesia, the method comprising administering a combination of at least two ester anesthetics. In yet another aspect, the present invention provides a pharmaceutical composition for local anesthesia, the pharmaceutical composition comprising: (a) a combination of at least two ester anesthetics; and (b) a pharmaceutically acceptable carrier. However, in yet another aspect, the present invention provides a pharmaceutical composition for analgesia, the pharmaceutical composition comprising: (a) a combination of at least two ester anesthetics; and (b) a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the time course of sciatic nerve obstruction with 2.0% lidocaine (upper panel), 0.5% debupivacaine (central panel), and a combination of 0.17% tetracaine and 2.3% 2- chloroprocaine (lower panel). Figure 2 shows the beginning and duration of a rat sciatic nerve obstruction after administration of 2% 2-chloroprocaine. Figure 3 shows the beginning and duration of a sciatic nerve obstruction after administration of either of the two, 0.22% tetracaine (upper panel) or 0.5% tetracaine (lower panel).

DETAILED DESCRIPTION OF THE INVENTION I. Definitions As used herein, the following terms have the meanings ascribed to them unless otherwise specified. As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary experience in the material to which the present invention is directed. Although any of the methods, devices, and materials similar or equivalent to those described herein may be used in the practice or testing of the invention, preferred methods, devices and materials are described herein. The term "local anesthesia" refers to anesthesia characterized by the loss of sensation only in the area of the body where an anesthetic agent or a combination of anesthetic agents is administered. Local anesthesia may result, for example, of the contact of an anesthetically effective amount of a local anesthetic with sensory nerve processes in the place where the painful stimulus is present, or may result from the inhibition of nerve transmission in a nerve or nerves near the place in which which is present the painful stimulus. As used herein, the term "anesthetically effective amount" refers to an amount of an anesthetic agent or a combination of anesthetic agents that produces an anesthetic effect, for example, a total or partial loss of sensation, inhibition of sensory perception , or inhibition of motor function. Preferably, the anesthetically effective amount produces minimal toxic side effects. The term "anesthetic" refers to an agent that causes loss of sensation in a human or other mammal with or without loss of consciousness. More particularly, the term "local anesthetic" refers to an anesthetic agent that induces local anesthesia by reversibly inhibiting the conduction and / or excitation of the peripheral nerve. Suitable local anesthetics for use in the present invention include, but are not limited to, ester-based anesthetics, amide-based anesthetics, ester analogs of amide-based anesthetics, and ester analogs of other anesthetics. Ester-based anesthetics include, but are not limited to, cocaine, procaine, 2-chloroprocaine, tetracaine, benzocaine, amethocaine, chlorocaine, butamben, dibucaine, and the like. Amide-based anesthetics include, but are not limited to, lidocaine, prilocaine, mepivacaine, ropivocaine, etidocaine, levobupivacaine, bupivacaine, and the like. Other suitable anesthetics for use in the present invention include, but are not limited to, aconitine ester analogues, dichlonin, ketamine, pramoxine, safrole, and salicylic alcohol. Such ester analogs may contain an ester group at any site within the structure. The terms "ester anesthetic" and "ester-based anesthetic" are used interchangeably herein to refer to the class of compounds having the structure set forth in Formula 1: R or R? Ar (Formula 1), wherein R1 and R2 are independently selected from the group consisting of H and a structural fragment having a cyclic, branched or linear saturated or unsaturated structure containing one to two carbon atoms in the which carbon atoms can be optionally substituted with a substituent selected from the group consisting of -OH, -OR3, -02CR3, -SH, -SR3, -SOCR3, -NH2, -NHR3, -NH (R3) 2 , -NHCOR3, -NRCOR3, -I, Br, -Cl, -F, -CN, -C02H, -C02R3, -CHO, -COR3, -CONH2, -CONHR3, -CON (R3) 2, -COSH, - COSR3, -N02, -SO3H, -SOR3 and -S02R3, wherein R3 is a cyclic, branched or linear saturated or unsaturated alkyl group containing from one to ten carbons, and wherein Ar is an aromatic substituent selected from the group It consists of phenyl, naphthyl, anthracyl, fenantril, furan, pyrrole, thiophene, benzofuran, benzothiophene, quinoline, isoquinoline, midazole, triazole, oxazole, and pyridine. Ar can be optionally substituted with a substituent selected from the group consisting of -OH, -OR, -02CR, -SH, -SR, -SOCR, -NH2 -NHR, -NHCl, NH (R) 2, -NHCOR , -NRCOR, -I, -Br, -Cl, -F, .CN-, -C02H, -C02R, -CHO, -COR, -CONH2, CONHR, -CON (R) 2, -COSH, -COSR, -N02, -SO3H, -SOR, and -S02R, wherein R is the same as defined above for R1 and R2. Other ester anesthetics including, but not limited to, benzolecgonine, butacaine, cocaethylene, and meperidine are also within the scope of the present invention. The term "ester analogs of amide-based anesthetics" refers to amide-based anesthetic compounds wherein the amide group (NH) is replaced with an oxygen atom (O), as set forth in Formula 2: (Formula 2 ), wherein R1 and R2 are independently selected from the group consisting of H and a structural fragment having a cyclic, branched or linear, saturated or unsaturated structure containing from one to ten carbon atoms in which the carbon atoms can be optionally substituted with a substituent selected from the group consisting of -OH, -OR3, -02CR3, -SH, -SR3, -SOCR3, -NH2, -NHR3 +, NH (R3) 2, -NHCOR3, -NRCOR3, - I, -Br, -Cl, -F, -CN, -C02H, -C02R3, -CHO, -COR3, -CONH2, -CONHR3, -CON (R3) 2, -COSH, -COSR3, -N02, -S03H , -SOR3, and -S02R3, wherein R3 is a cyclic, branched or linear saturated or unsaturated alkyl group containing from one to ten carbons, and wherein Ar is an aromatic substituent selected from the group consisting of phenyl, naphthyl, anthracyl, fenantril, furan, pyrrole, thiophene, benzofuran, benzothiophene, quinoline, isoquinoline, imidazole, thiazole, oxazole, and pyridine. Ar can be optionally substituted with a substituent selected from the group consisting of -OH, -OR, -02CR, -SH, -SR, -SOCR, -NH2, -NHR, -NHCl, -NH (R) 2, -NHCOR, -NRCOR, -I, -Br, -Cl, -F, -CN-, -C02H, -C02R, -CHO, -COR, -CONH2, -CONHR, -CON (R) 2, -COSH, -COSR, -N02, -S03H, -SOR, and -S02R, wherein R is the same as defined above for R1 and R2. Examples of ester analogues of amide-based anesthetics include, but are not limited to, lidocaine ester analogs, prilocaine, mepivacaine, ropivocaine, etidocaine, levobupivacaine, bupivacaine, dibucaine, and the like. Other ester analogues of amide-based anesthetics including, but not limited to, oxetazine, pentobarbital, thiamylal, and thiopental are also within the scope of the present invention. Such ester analogs have an amide group (N-H) which is replaced with an oxygen atom (O). The term "analgesia" refers generally to the reduction of pain or to the complete elimination of pain in a human or other mammal suffering from pain. As used herein, the term "analgesically effective amount" refers to an amount of an anesthetic agent or a combination of anesthetic agents that produces a reduction in pain or a complete elimination of pain in a human or other mammal. Preferably, the analgesically effective amount produces minimal toxic side effects. The term "single dose forms" refers to physically discrete units as unit doses for human patients or other mammals. Each unit contains a predetermined amount of active material calculated to produce the desired onset, tolerance capacity, and therapeutic effects, in association with a convenient pharmaceutical excipient (eg, an ampoule). The term "administration" refers to oral administration, administration as a suppository, topical contact, mucosal administration, or administration by parenteral routes, for example, intradermal, intravenous, subcutaneous, intramuscular, intra-arteriole, intraperitoneal, intraventricular, intracranial, epidural. , spinal, rectal, vaginal, and similar, to a patient. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, the implantation of a slow release device (e.g., an osmotic mini-pump), transdermal patches, etc. The most convenient route will depend on the nature and severity of the condition being treated. Infiltration methods (eg, injection methods), which include subcutaneous injection, injection into peri-surgical tissue, peripheral nerve obstructions, regional intravenous obstruction anesthesia, serosal delivery, and neuraxial (eg, epidural, caudal, efe) , are preferred routes for the compounds of the present invention. Other convenient methods of administration include, but are not limited to, placement of stoppers coated with a combination of ester anesthetics, administration of intratracheal ester anesthetic., and administration of ester anesthetic in the balloon of an endotracheal tube. The term "combination of at least two ester anesthetics" refers to at least two ester anesthetic compounds supplied in either a sequential or simultaneous manner so that the combination provides improved local anesthesia with a rapid onset, a long duration of action, minimal toxicity, and / or easy administration. Such combinations are sufficiently safe to be administered repeatedly by any method known to one skilled in the art. The term "vasoconstrictor" refers to an agent that induces or initiates vasoconstriction, and thereby increasing potency, reducing the maximum systematic concentration, and prolonging the duration of action of an ester anesthetic of the present invention by locating the active anesthetic in local tissues Suitable vasoconstrictors include, but are not limited to, adrenaline (epinephrine), phenylephinephrine, anti-otensin, phenylpropanolamine, and combinations thereof. Adrenaline (epinephrine) and phenylephrinephine are commonly used as vasoconstrictors and can be added in concentrations ranging from approximately 1 in 80,000 to 1 in 500,000, preferably in a concentration of approximately 1 in 200,000 (5 μg / ml). The term "corticosteroid" refers to any of the steroid hormones produced by the adrenal cortex or its synthetic equivalents, such as cortisol and aldosterone. Corticosteroids that are useful in the present invention for prolonging nerve block in vivo include, but are not limited to, glucocorticoids, such as dexamethasone, cortisone, hydrocortisone, prednisone, other glucocorticoids administered orally routinely or by injection, and salts pharmaceutically acceptable and combinations thereof. Other glucocorticoids include beclomethasone, betamethasone, flunisolide, prednisone methyl, parametasone, prednisolone, triamcinoloma, alclometasone, amcinonide, clobetasol, fludrocortisone, diflurosone, diacetate, acetonide fluocinolone, fluorometalone, flurandrenolide, halcinonide, medrisone, mometasone, and pharmaceutically acceptable salts and combinations of the same. The term "permeability enhancer" refers to an agent that aids in the passage of an ester anesthetic within a tissue or through a cell membrane. Suitable permeability enhancers for use in the present invention include, but are not limited to, bile salts such as sodium cholate, sodium glycocholate, sodium glycodeoxycholate, taurodeoxycholate, sodium deoxycholate, sodium linocolate chenocolate, chenodeoxycholate, ursocholate, ursodeoxycholate, hydrodeoxycholate, dehydrocholate, glycoquenolate, tauroquenocolate, and taurokenedeoxycholate. Other penetration enhancers may also be used such as urea, sodium dodecyl sulfate (SDS), dimethyl sulfoxide (DMSO), sodium lauryl sulfate, salts and other saturated and unsaturated fatty acid derivatives, surfactants, bile salt analogues, bile salt derivatives, or such synthetic penetration enhancers as described in Pat. From the USA No. 4, 746.508. The terms "lipophilic solvent" and "amphiphilic solvent" are used interchangeably herein to refer to solvents that can be added to the compositions of the present invention to prolong nerve block in vivo. Such solvents are well known to those skilled in the art and can be obtained from the pharmaceutical composition according to claim 18, characterized in that a variety of commercial sources. Examples of suitable solvents for use in the present invention include, but are not limited to, alcohols such as ethanol added in a dose equivalent to about 1% alcohol, and polyoxyethylene sorbitan derivatives such as polysorbate-80 or Tween., added in an equivalent concentration between approximately 1% and approximately 3%. The term "regulatory agent" refers to a substance that decreases a change in the acidity of a solution when an acid or base is added to the solution. Such regulatory agents are well known to those skilled in the art. Typically, the compositions of the present invention are regulated, for example, with bicarbonate, to maintain a slightly alkaline or slightly acidic pH. Regulating the solution also speeds up the start rate and increases the duration of the medication effect. In general, the compositions of the present invention are regulated to maintain the highest possible pH that is not associated with anesthetic precipitation and provide an appropriate shelf life. The pH is then adjusted to decrease the catalyzed hydrolysis of base and / or acid of the ester group of an ester anesthetic in vitro. The term "rapid onset of action" refers to the onset of an anesthetic effect that begins within at least 10 minutes of anesthetic administration, for example, when it is delivered for infiltration anesthesia, and can be at least about 5 minutes. minutes, preferably at least about 2 minutes, or less. Suitable anesthetics for this purpose include procaine and 2-cIoroprocaine. Preferably, the anesthetic is 2-chloroprocaine. The terms "continuous activity", "prolonged period of action", and "long duration of effect" are used interchangeably herein to refer to the situation where an anesthetic effect of a single dose, for example, when supplied by anesthesia of infiltration, is maintained for at least about 1 hour, preferably at least about 2 hours, more preferably at least 4 hours, even more preferably at least about 6 hours, or more. II. Overview The present invention provides compositions and methods for analgesia and / or improved local anesthesia characterized by a rapid onset, a long duration of effect, and a low risk of toxicity. At least two ester anesthetics are combined, wherein at least one provides a rapid onset of action and at least one provides continuous activity. Given a lot of tone, because the combination of ester anesthetics produces minimal toxicity due to very rapid metabolism in the blood, each can be given in both quantities, safe and sufficient to provide a rapid onset and a long duration of action of local anesthesia. In contrast, combinations of anesthetically effective amounts of amide anesthetics are not possible due to the high risk of toxic side effects. In addition, the low risk of toxicity associated with administering a combination of ester anesthetics provides the possibility for repeated administrations, which can not be done safely with amide anesthetics. The compositions of the present invention are used for the production of analgesia and / or anesthesia and are particularly useful for the prophylaxis and / or treatment of pain. As local anesthetics, the compositions are useful for regional anesthesia, for example, topical anesthesia, infiltration anesthesia, field obstruction anesthesia, peripheral nerve obstruction anesthesia, epidural anesthesia, spinal anesthesia, obstruction anesthesia, and combinations of the same. II I. Description of Modalities In one aspect, the present invention provides a method for loco anesthesia, the method comprising administering a combination of at least two ester anesthetics. In one embodiment, at least one of the ester anesthetics provides a rapid onset of action, and at least one of the ester anesthetics provides a long duration of effect. In another embodiment, the combination of at least two ester anesthetics produces minimal toxic side effects. In yet another embodiment, the combination of at least two ester anesthetics is repeatedly administered, for example, at least 2, 3, 4, 5, 6, 7, 8, or more times. However, in yet another embodiment, the combination of at least two ester anesthetics is administered by continuous infusion. In a further embodiment, the combination of at least two ester anesthetics is administered either either aggressively or chronically for prophylaxis and / or pain treatment. One skilled in the art will know of the duration of acute or chronic administration necessary to achieve such prophylaxis and / or treatment. In a preferred embodiment, one of the ester anesthetics is procaine or 2-chloroprocaine. Preferably, the ester anesthetic is 2-chloroprocaine. In another preferred embodiment, one of the ester anesthetics is tetracaine. In a particularly preferred embodiment, one of the ester anesthetics is 2-chloroprocaine and one of the ester anesthetics is tetracaine. In one embodiment, the combination of 2-chloroprocaine and tetracaine is used for regional anesthesia selected from the group consisting of topical anesthesia, infiltration anesthesia, field obstruction anesthesia, peripheral nerve obstruction anesthesia, epidural anesthesia, spinal anesthesia, anesthesia of obstruction, and combinations of the same. In a further embodiment, the combination of at least two ester anesthetics are administered as a single pharmaceutical formulation. In a first embodiment, the pharmaceutical formulation further comprises a regulatory agent. In a second embodiment, the pharmaceutical formulation further comprises a vasoconstrictive agent. Preferably, the vasoconstrictive agent is epinephrine or phenylephrinephrine. In a third embodiment, the pharmaceutical formulation further comprises a corticosteroid. Preferably, the corticosteroid is a glucocorticoid selected from the group consisting of dexamethasone, cortisone, hydrocortisone, prednisone, other glucocorticoids administered orally routinely or by injection, and pharmaceutically acceptable salts and combinations thereof. In a fourth embodiment, the pharmaceutical formulation further comprises a tissue permeability enhancer, as described above. In a fifth embodiment, the local anesthetic formulation is supplied as a liquid (eg, solution). Preferably, the liquid contains local and auxiliary anesthetics at convenient concentrations for immediate use without dilution or additional mixing. In a sixth embodiment, the local anesthetic formulation is supplied as a lyophilized powder that can be reconstituted with water prior to injection. In yet another embodiment, the combination of at least two ester anesthetics is supplied topically or by infiltration. Preferably, infiltration delivery achieves a peripheral nerve obstruction, an epidural nerve obstruction, a caudal nerve obstruction, or combinations thereof. In another aspect, the present invention provides a method for analgesia, the method comprising administering a combination of at least two ester anesthetics. In one embodiment, at least one of the ester anesthetics provides a rapid onset of action, and at least one of the ester anesthetics provides a long duration of effect. In another embodiment, the combination of at least two ester anesthetics produces minimal toxic side effects. In yet another embodiment, the combination of at least two ester anesthetics is administered repeatedly, for example, at least 2, 3, 4, 5, 6, 7, 8, or more times. However, in yet another embodiment, the combination of at least two ester anesthetics is administered by continuous infusion. In a further embodiment, the combination of at least two ester anesthetics is administered either acutely or chronically for prophylaxis and / or pain treatment. One skilled in the art will know of the duration of chronic or acute administration necessary to achieve such prophylaxis and / or treatment. In yet another modality, an analgesically effective amount of the ester anesthetics provides prophylaxis and / or treatment for neuropathic pain, trauma, or tissue ischemia. In a preferred embodiment, one of the ester anesthetics is procaine or 2-chloroprocaine. Preferably, the ester anesthetic is 2-chloroprocaine. In another preferred embodiment, one of the ester anesthetics is tetracaine. In a particularly preferred embodiment, one of the ester anesthetics is 2-chloroprocaine and one of the ester anesthetics is tetracaine. In one embodiment, the combination of 2-chloroprocaine and tetracaine is used for the prophylaxis and / or treatment of pain. In a further embodiment, the combination of at least two ester anesthetics is administered as a single pharmaceutical formulation. In a first embodiment, the pharmaceutical formulation further comprises a regulatory agent. In a second embodiment, the pharmaceutical formulation further comprises a vasoconstrictive agent. Preferably, the vasoconstrictive agent is (b) a pharmaceutically acceptable carrier. In one embodiment, at least one of the ester anesthetics provides a rapid onset of action, and at least one of the ester anesthetics provides a long duration of effect. In another embodiment, the combination of at least two ester anesthetics produces minimal side toxic effects. In yet another embodiment, the combination of at least two ester anesthetics is administered repeatedly, for example, at least 2, 3, 4, 5, 6, 7, 8, or more times. However, in yet another embodiment, the combination of at least two ester anesthetics is administered by continuous infusion. In a further embodiment, the combination of at least two ester anesthetics is administered either acutely or chronically for prophylaxis and / or pain treatment. In a preferred embodiment, one of the ester anesthetics is procaine or 2-chloroprocaine. Preferably, the ester anesthetic is 2-chloroprocaine. In another preferred embodiment, one of the ester anesthetics is tetracaine. In a particularly preferred embodiment, one of the ester anesthetics is 2-chloroprocaine and one of the ester anesthetics is tetracaine. In one embodiment, 2-chloroprocaine is present in a concentration of from about 0.1% to about 10%, preferably from about 1% to about 6%, more preferably from about 1% to about 3%. In another embodiment, tetracaine is present at a concentration of approximately -23-epinephrine or phenylephrinephrine. In a third embodiment, the pharmaceutical formulation further comprises a corticosteroid. Preferably, the corticosteroid is a glucocorticoid selected from the group consisting of dexamethasone, cortisone, hydrocortisone, prednisone, other glucocorticoids orally administered routinely or by injection, and pharmaceutically acceptable salts and combinations thereof. In a fourth embodiment, the pharmaceutical formulation further comprises a tissue permeability enhancer, as described above. In a fifth embodiment, the local anesthetic formulation is supplied as a liquid (e.g., solution). Preferably, the liquid contains local and auxiliary anesthetics at convenient concentrations for immediate use without dilution or additional mixing. In a sixth embodiment, the local anesthetic formulation is supplied as a lyophilized powder that can be reconstituted with water prior to injection. In yet another embodiment, the combination of at least two ester anesthetics is supplied topically or by infiltration. Preferably, infiltration delivery achieves a peripheral nerve obstruction, an epidural nerve obstruction, a caudal nerve obstruction, or combinations thereof. In yet another aspect, the present invention provides a pharmaceutical composition for local anesthesia, the pharmaceutical composition comprising: (a) a combination of at least two ester anesthetics; and 0.05% to about 1%, preferably from about 0.1% to about 0.75%, more preferably from about 0.1% to about 0.5%. In a further embodiment, the combination of 2-chloroprocaine and tetracaine is used for regional anesthesia selected from the group consisting of topical anesthesia, infiltration anesthesia, field obstruction anesthesia, peripheral nerve obstruction anesthesia, epidural anesthesia, spinal anesthesia, Obstruction anesthesia, and combinations thereof. In another embodiment, the pharmaceutical formulation further comprises a regulatory agent. In yet another embodiment, the pharmaceutical formulation further comprises a vasoconstrictive agent. Preferably, the vasoconstrictive agent is epinephrine or phenylephrinephrine. However, in yet another embodiment, the pharmaceutical formulation further comprises a corticosteroid. Preferably, the corticosteroid is a glucocorticoid selected from the group consisting of dexamethasone, cortisone, hydrocortisone, prednisone, other glucocorticoids orally administered routinely or by injection, and pharmaceutically acceptable salts and combinations thereof. In a further embodiment, the pharmaceutical formulation further comprises a tissue permeability enhancer, as described above. In yet another embodiment, the local anesthetic formulation is supplied as a liquid (eg, solution). Preferably, the liquid contains local and auxiliary anesthetics at convenient concentrations for immediate use without dilution or additional mixing. However, in yet another embodiment, the local anesthetic formulation is supplied as a lyophilized powder that can be reconstituted with water prior to injection. However, in yet another embodiment, the present invention provides a pharmaceutical composition for analgesia, the pharmaceutical composition comprising: (a) a combination of at least two ester anesthetics; and (b) a pharmaceutically acceptable carrier. In one embodiment, at least one of the ester anesthetics provides a rapid onset of action, and at least one of the ester anesthetics provides a long duration of effect. In another embodiment, the combination of at least two ester anesthetics provides minimal toxic side effects. In yet another embodiment, the combination of at least two ester anesthetics is administered repeatedly, for example, 2, 3, 4, 5, 6, 7, 8, or more times. However, in yet another embodiment, the combination of at least two ester anesthetics is administered by continuous infusion. In a further embodiment, the combination of at least two ester anesthetics is administered either acutely or chronically for prophylaxis and / or pain treatment. In a further embodiment, an analgesically effective amount of the ester anesthetics provides prophylaxis and / or treatment for neuropathic pain, trauma, or tissue ischemia.

In a preferred embodiment, one of the ester anesthetics is procaine or 2-chloroprocaine. Preferably, the ester anesthetic is 2-chloroprocaine. In another preferred embodiment, one of the ester anesthetics is tetracaine. In a particularly preferred embodiment, one of the ester anesthetics is 2-chloroprocaine and one of the ester anesthetics is tetracaine. In one embodiment, 2-chloroprocaine is present in a concentration of from about 0.1% to about 10%, preferably from about 1% to about 6%, more preferably from about 1% to about 3%. In another embodiment, tetracaine is present at a concentration of from about 0.05% to about 1%, preferably from about 0.1% to about 0.75%, more preferably from about 0.1% to about 0.5%. In one embodiment, the combination of 2-chloroprocaine and tetracaine is used for the prophylaxis and / or treatment of pain. In another embodiment, the pharmaceutical formulation further comprises a regulatory agent. In yet another embodiment, the pharmaceutical formulation further comprises a vasoconstrictive agent. Preferably, the vasoconstrictive agent is epinephrine or phenylephrinephrine. However, in yet another embodiment, the pharmaceutical formulation further comprises a corticosteroid. Preferably, the corticosteroid is a glucocorticoid selected from the group consisting of dexamethasone, cortisone, hydrocortisone, prednisone, other glucocorticoids administered orally routinely or by injection, and pharmaceutically acceptable salts and combinations thereof. In a further embodiment, the pharmaceutical formulation further comprises a tissue permeability enhancer, as described above. In yet another embodiment, the local anesthetic formulation is supplied as a liquid (eg, solution). Preferably, the liquid contains local and auxiliary anesthetics at convenient concentrations for immediate use without dilution or additional mixing. However, in yet another embodiment, the local anesthetic formulation is supplied as a lyophilized powder that can be reconstituted with water prior to injection. IV. Compositions Most local anesthetics are bases that are almost insoluble in water unless they are protonated. The solubility is greatly increased by the preparation of protonated amine salts of the amine moiety contained within the ester anesthetic. These salts are commonly prepared by the reaction of various organic and inorganic acids with the basic amine moiety of the anesthetic to produce a protonated amine salt. Representative inorganic acids may include hydrochloric, sulfuric, phosphoric, etc. Representative organic acids include acetic, benzoic, oxalic, citric, methylsulfonic, etc. Notwithstanding the above, the local anesthetic may also be supplied as a water / lipid emulsion, in which at least one of the local anesthetics is supplied as half of the non-protonated basic amine. For injection use, for example, infiltration methods, the combination of ester anesthetics will be provided as a diluted solution. For example, 2-chloroprocaine may be present in a concentration of from about 0.1% to about 10%, preferably from about 1% to about 6%, more preferably from about 1% to about 3%, even more preferably about 1. 0, 1 .5, 2.0, 2.3, 2.5, or 3% where a solution expressed as 1% contains 1 g of substance in 100 ml. Accordingly, a 1% solution of 2-chloroprocaine contains 10 mg / ml of 2-chloroprocaine. Tetracyne may be present in a concentration of from about 0.05% to about 1%, preferably from about 0.1% to about 0.75%, more preferably from about 0.1% to about 0.5%, even more preferably about 0.1., 0.17, 0.2, 0.22, 0.3, 0.4, or 5%. Typically, the solution will be regulated, for example, with bicarbonate, to maintain a slightly alkaline or slightly acidic pH. Regulating the solution also accelerates the rate of onset and increases the duration of drug effect, but is limited by the tendency of local anesthetics to precipitate in solution under highly alkaline conditions. In general, solutions will be regulated to maintain the highest possible pH that is not associated with anesthetic precipitation and provides the appropriate shelf life for the solution. The pH will be adjusted to decrease catalyzed hydrolysis of base and / or acid of the ester group in vitro. In the case of a lipid / water emulsion which supplies at least one of the local anesthetics as a non-protonated basic amine moiety, the pH will be adjusted as necessary to maintain the local anesthetic in the non-protonated state. The compositions of the present invention may also be provided in a lyophilized form. Such compositions may include a regulator, for example, bicarbonate, for reconstitution before administration, or the regulator may be included in the lyophilized composition for reconstitution with, for example, water. The lyophilized composition may further comprise a convenient vasoconstrictor, for example, epinephrine. In one embodiment of the present invention, the lyophilized composition is provided in a syringe, optionally packaged in combination with the regulator for reconstitution, so that the reconstituted anesthetic composition can be administered immediately to a patient. The pharmaceutical compositions will contain, as the active ingredient, the combination of ester anesthetics or a pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, carriers, diluents, tissue penetration enhancers, solubilizers, and auxiliaries. Other therapeutic agents can be included, for example, vasoconstrictors, anti-inflammatory agents, antibiotics, and revulsives. The compounds can be formulated using conventional techniques such as those described in Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1 985) and "odern Pharmaceutics", Marcel Dekker, I nc. 3rd Ed. (G.S. Banker &; C.T. Rhodes, Eds.). The pharmaceutically acceptable salts of the active agents (e.g., acid addition salts) can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-l nterscience, 1992). Most local anesthetics produce some degree of vasodilation, and can be rapidly absorbed after local injection. Consequently, a vasoconstrictor can be irrigated to increase potency, reduce the maximum systematic concentration, and prolong the duration of action by locating the active anesthetic molecule in local tissues. Adrenaline (epinephrine) and phenylepinephine are commonly used as vasoconstrictors, and can be irrigated at concentrations ranging from approximately 1 in 80,000 to approximately 1 in 500,000, usually in a concentration of approximately 1 in 200,000 (5μg / ml ). In particular, the duration of action is prolonged by the addition of adrenaline when used for infiltration anesthesia and peripheral nerve obstructions. Adrenaline can also increase the duration of extradural anesthesia. Corticosteroids which are useful for prolonging nerve block in vivo include glucocorticoids such as dexamethasone, cortisone, hydrocortisone, prednisone, and others administered orally either routinely or by injection. Other glucocorticoids include beclomethasone, betamethasone, flunisolide, prednisone methyl, methasone, prednisolone, triamcinoloma, alclometasone, amcinonide, clobetasol, fludrocortisone, diflurosone diacetate, fluocinolone acetonide, fluorometalone, flurandrenolide, halcinonide, medrisone, and mometasone, and pharmaceutically acceptable salts and mixtures thereof. Permeability enhancers may also be included. Permeability enhancers are used to assist in the passage of an ester anesthetic within a tissue or through a cell membrane. Typical enhancers may include bile salts such as sodium cholate, sodium glycocholate, sodium glycodeoxycholate, taurodeoxycholate, sodium deoxycholate, sodium chelocholate, chenodeoxycholate, ursocholate, ursodeoxycholate, hydrodeoxycholate, dehydrocholate, glycoquenolate, taurokenocholate, and taurokenedeoxycholate. Other penetration enhancers may also be used such as urea, sodium dodecyl sulfate (SDS), dimethyl sulfoxide (DMSO), sodium lauryl sulfate, salts and other saturated and unsaturated fatty acid derivatives, surfactants, bile salt analogues, bile salt derivatives, or such synthetic penetration enhancers as described in Pat. From the USA No. 4,746,508. Amphiphic and / or lipophilic solvents can be added to the vehicle to prolong local nerve block anesthesia. These materials are well known to those skilled in the art and can be obtained from a variety of commercial sources. Examples of solvents include alcohols such as ethanol added in a dose equivalent to about 1% alcohol, polyoxyethylene sorbitan derivatives such as polysorbate-80 or Tween, added in an equivalent concentration between 1% and 3%. For topical use, the compositions of the present invention may be in the form of emulsions, creams, gelatin, solutions, and ointments containing, for example, up to about 10% by weight, preferably up to about 5% by weight of the combination of ester anesthetics. For parenteral administration, the compositions may be in the form of sterile injectable solutions and sterile packaged powders. Preferably, the injectable solutions are formulated at a pH of about 4.5 to about 7.5. Some examples of suitable excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia in gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, metallic salt, syrup, and methylcellulose. The formulations may also include lubricating agents such as talc, magnesium stearate, and mineral oil; repellent agents, emulsifying and suspending agents; preservatives such as methyl- and propylhydroxy benzoates, sweetening agents, and flavoring agents. The compositions may also comprise biodegradable polymer beads and dextran and cyclodextrin inclusion complexes. V. Methods of Administration The combination of ester anesthetics can be administered as a single injection or continuously through a resident catheter, or it can be administered topically to the skin, mucous membranes, etc. The solution containing the combination of ester anesthetics can be administered repeatedly, for example, at least 2, 3, 4, 5, 6, 7, 8 or more times, or the ester anesthetic which provides a long duration of effect. it can be administered separately in repeated doses, for example, at least 2, 3, 4, 5, 6, 7, 8, or more times, after the administration of the ester anesthetic combination, or the solution can be administered through continuous infusion. The compositions of the present invention can be administered by any of the accepted modes of administration of agents having similar utilities, for example, by parenteral, topical or mucosal routes, for example, intradermal, intravenous, subcutaneous, intramuscular, epidural, rectal, vaginal, etc. The most convenient route will depend on the nature and severity of the condition being treated. Infiltration methods, which include peripheral nerve obstructions, serosal and neuraxial delivery, eg, epidural, caudal, efe, are preferred routes for the compounds of this invention. Other convenient methods of administration include, but are not limited to, placement of stoppers coated with a combination of ester anesthetics, administration of intratracheal ester anesthetics, and administration of ester anesthetics in the balloon of an endotracheal tube. The compositions of the present invention can be administered for the production of analgesia and / or anesthesia and are particularly useful for the prophylaxis and / or treatment of pain. As local anesthetics, the compositions are useful for regional anesthesia, for example, topical anesthesia, infiltration anesthesia, peri-surgical tissue infiltration anesthesia, field obstruction anesthesia, peripheral nerve obstruction anesthesia, epidural anesthesia, spinal anesthesia, anesthesia of obstruction, and combinations thereof. In addition, the compositions can be administered for the relief of pain associated with vein puncture, lumbar puncture, myringotomy, and arterial cannulation. The compositions have other therapeutic applications including treatment and / or prophylaxis of neuropathic pain, trauma, and tissue ischemia. As used herein, the term "topical anesthesia" refers to the administration of the compositions of the present invention to mucous membranes, upper and lower airways, skin, and the like. Examples of mucous membranes include, but are not limited to, the nose, mouth, esophagus, tracheobronchial tree, and genitourinary apparatus. The topical anesthetic formulations of the present invention are useful in the relief of pain due to dermatosis, hemorrhoids, and minor burns, as well as in the reduction of pain associated with sigmoidoscopy and in upper airway anesthesia prior to direct laryngoscopy. Topical anesthesia of the skin includes administration through patches or other deposit systems, through bandages, gauzes containing local anesthetics, and through creams, ointments, sprays, or other transdermal drug delivery systems known to one of experience in the subject. As used herein, the term "infiltration anesthesia" refers to the administration of the compositions of the present invention through extravascular placement in the area to be anesthetized. Preferably, the anesthetic infiltration formulations of the present invention are administered by injection. The injection is in an immediate area of a painful or surgical stimulus, or in the tissues through which the nerves transmit pain signals. As used herein, "peripheral nerve obstruction anesthesia" refers to the administration of the present invention through extravascular placement in tissues immediately adjacent to major nerves such as the nerves of the upper extremities (e.g., interscalene obstruction). , supraclavicular obstruction, infraclavicular obstruction, axillary obstruction, median nerve obstruction, radial nerve obstruction, musculocutaneous nerve obstruction, ulnar nerve obstruction, finger obstruction), nerves of the lower extremities (eg, lumbar plexus obstruction, sciatic nerve obstruction, femoral nerve obstruction, obturator nerve obstruction, lateral femoral cutaneous nerve obstruction, fibular nerve obstruction, tibia nerve obstruction, ankle obstruction), as well as obstruction of major plexuses (eg, cervical plexus, brachial plexus, celiac plexus, sacral plexus, femoral plexus). As used herein, the term "epidural anesthesia" refers to anesthesia caused by solutions of local anesthetic injected into the caudal, sacral or epidural space. The term "spinal anesthesia" refers to anesthesia after an injection of local anesthetic into the lumbar subarachnoid space. Preferably, spinal anesthesia is carried out with a formulation containing a combination of 2-chloroprocaine and tetracaine. The term "obstruction anesthesia" refers to an injection of a local anesthetic into a limb isolated by a tourniquet. In contrast to amide-based local anesthetics, ester anesthetics are metabolized very rapidly and become inactive in the blood and many tissues of the body. Therefore, ester anesthetics have a much lower potential for toxicity because their systemic concentrations are very small, except when administered by direct intravenous injection. As a result of very low systemic concentrations, ester anesthetics offer the potential for at least two different ester anesthetics to be combined at their respective maximum doses to provide improved analgesic and / or local anesthetic activity. Such combinations are not possible with amide anesthetics because their much slower metabolism leads to high concentrations of the anesthetic in the tissue and blood. Since the toxicity of all local anesthetics is additive, the high tissue and blood concentrations that would result from a combination of maximum doses of two amide anesthetics would possibly expose the patient to a significant risk of systemic toxicity, including seizures, cardiovascular collapse, and death. In addition, because the toxicity problem has been overcome with the compositions of the present invention, an analgesically and / or anesthetically effective amount, optimal of each ester anesthetic can be administered to a patient in need thereof. In contrast, when combinations of amide anesthetics are administered, it is necessary to use sub-optimal doses of each amide anesthetic due to the high blood levels expected of each amide anesthetic and the documented additive toxicity of local anesthetics. For example, the anesthetically effective amounts of lidocaine (2%) and bupivicaine (0.5%), if used in combination, would have a very high toxicity and could potentially cause death. See, for example, Mets et al. , Anesth. Analg., 75:61 1-614 (1992). Naguib et al., Drug Saf. , 18: 221-250 (1998); Kytta et al., Reg. Anesth. 16: 89-94 (1991). Local anesthetics currently used, such as lidocaine, cause pain and discomfort (for example, urticaria) when administered to a patient. By contrast, the compositions of the present invention, for example, a combination of 2-chloroprocaine and tetracaine, produce a much lower level of pain and discomfort. Accordingly, such compositions are not only easier to administer, but are also better tolerated by a patient when administered. The present invention provides at least one ester anesthetic having a rapid onset of action, wherein the onset of the anesthetic effect begins within at least about 10 minutes of anesthetic administration, for example, when supplied by infiltration anesthesia, and it can be at least about 5 minutes, preferably at least about 2 minutes, or less. Suitable anesthetics for this purpose include procaine and 2-chloroprocaine. Preferably, the anesthetic is 2-chloroprocaine. The present invention also provides at least one ester anesthetic having a prolonged period of action, wherein a single dose anesthetic effect, eg, when delivered by infiltration anesthesia, is maintained for at least about 1 hour, of preferably at least about 2 hours, more preferably at least 4 hours, even more preferably at least about 6 hours, or more. As with all local anesthetics, the dose administered will vary depending on the anesthetic procedure, the vascularity of the tissues, the depth of anesthesia, the degree of muscle relaxation required, the duration of anesthesia desired, and the patient's physical condition. Preferably, the smallest concentration and dose required to produce the desired result should be used. The dose should be adjusted appropriately for children, the elderly, debilitated patients, and patients with liver and / or heart disease. The following principles are not intended to imply any dose limitation that may be used in the methods and compositions of the present invention, but may indicate some principles for the formulation. The following principles generally refer to a single maximum dose, wherein the amount can be increased by fractionation of the dose. As described above, the rapid inactivation of ester-based anesthetics after administration provides a wide margin of safety for repeated administration of the anesthetic combination. For example, the dose of 2-chloroprocaine given as a single injection in adults can be, without epinephrine, about 10, about 25, about 50, to about 100 mg / kg. Although clinical principles have suggested a maximum total dose of 800 mg, more recent data suggest that a much higher dose can be administered without toxic effects, eg, a maximum of about 1500 mg, of approximately 2500 mg, of approximately 5000 mg, normally no more than about 10,000 mg. The addition of epinephrine, for example, at a concentration of 1: 200,000, allows an increase of approximately 20% in the anesthetic dose. Previous principles have suggested a single maximal dose of tetracaine of approximately 20 mg for spinal anesthesia. However, such doses may be exceeded, to a maximum of about 50 mg, of about 200 mg, usually not exceeding about 400 mg. The maximum individual dose of procaine is approximately 1000 mg. For higher doses, care must be taken not to inject the anesthetic directly into a blood vessel. The compositions are preferably formulated in a single dose form. The term "single dose forms" refers to physically discrete units suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired onset, tolerance capacity, and therapeutic effects, in association with a convenient pharmaceutical excipient (e.g., an ampoule). In addition, more concentrated compositions should be prepared, from which more dilute single-dose compositions can then be produced. Therefore, the more concentrated compositions will substantially contain more than an anesthetically or analgesically effective amount of the compounds of the present invention, for example, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times the amount. The compounds of the present invention, or their pharmaceutically acceptable salts, are administered in an analgesically and / or anesthetically effective amount. The duration of action and / or potency of the local anesthetic drug effect will increase compared to the local anesthetic effect of formulations containing only a single local anesthetic based on ester, and will produce a duration of anesthesia equal to or greater than that produced by more toxic formulations of local anesthetics based on amide (see, Examples 2 and 3). Therefore, the dose and dosing schedule can be adjusted accordingly. It will be understood that although the proportion of the two ester-based local anesthetics will be fixed in the formulation, the total volume of the formulation actually administered will be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the compound itself administered and its relative activity, age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. The anesthetic combination of the invention can be examined for activity in various well-known assays (eg, batrachotoxin displacement assay (BTX) (McNeal et al., J Med. Chem. 28: 381 (1 985)), method of staple for patch (see, Neher and Sakmann, "The Patch Clamp Technique" Scientific American "pp. 44-51 (1992); Hamil et al. , Pflugera Arch. 391: 85 (1981); assay of intact isolated nerve, eg, isolated frog sciatic nerve; blockade of cutaneous truncus muscle reflex (CTM R) in guinea pigs (Bulbring ef al., J. Pharmacol. Exp. Therap. 85: 78-84 (1 945); Blig ht ef al., J. Buy. Neurology 296: 614-633 (1990; Choi et al., Life Sci. 61: PL177-84 (1 997)) Evaluation of sympathetic and motor function during sciatic nerve obstruction in the rat is described, for example, in Grant ef al., Anesth, Analg., 75: 889-94 (1992), and Thalham mer ef, Anestheslology 82: 1 013-25 (1995) VI Examples The following examples are presented to illustrate, but without limit, the declared invention Example 1: Formulations Solution for Injection A Solution for Injection B Ingredient Amount Sodium chloride 0.9% (0.9g / 1 00 mL) Epinephrine 2 g / ml NaBicarbonate As necessary to avoid hydrolysis of catalyzed acid ester in vitro; not exceed amounts capable of inducing precipitation of the free base form of the local anesthetic. 2-chloroprocaine 30 mg / ml Tetracaine 3 mg / ml Water for injection Up to 1 00 ml Solution for Injection C Ointment Ingredient Quantity% 2-chloroprocaine 30 mg / ml Tetracaine 5 mg / ml White wax 5 White Petrolatum Up to 1 00 mi Cream ing rediente | Quantity% Phase olea ginosa 2-chloroprocaine 30 mg / ml Tetracaine 5 mg / ml Espermaceti 12.5 White wax 12.0 Almond oil 55.5 Aqueous phase Sodium borate 0.5 Stronger rose water 2.5 Purified water 16.5 Aromatic rose oil 0.02 Gel Example 2: Comparison of Local Anesthetics Administered Individually or in Combination The beginning and deviation of sciatic nerve block by lidocaine, bupivacaine, tetracaine, and 2-chloroprocaine were examined in studies conducted in rats. Three different modalities were examined: (1) pain (for example, retraction when tightening); (2) proprioception (for example, the ability to place the leg firmly on the table); and (3) motor resistance (for example, the downward pressure that the leg can exert on a balance). In each case, the same volume of local anesthetic agent was examined. The modality of interest was retraction when tightening. Each local anesthetic was examined in 5 rats of almost identical age and size. The results are shown in Fig. 1 . The upper panel in Figure 1 shows the time course of sciatic nerve obstruction with 2.0% lidocaine, the strongest concentration of commercially available lidocaine. At this concentration, lidocaine produced an almost immediate onset of obstruction (ie, 100% at the first time point examined, occurring 2 minutes after the injection). However, the duration of the sensory obstruction was approximately 45 minutes, at which point it began to decrease. The central panel in Figure 1 shows the time course of sciatic nerve obstruction with an identical volume of 0.5% bupivacaine injected near the rat sciatic nerve. The onset of sensory obstruction was 4 times slower than with 2.0% lidocaine, requiring 8 minutes to achieve complete sensory obstruction in all animals examined. However, a good sensory obstruction persisted up to 60 minutes, at which point it began to decrease. The lower panel in Figure 1 shows the time course of sciatic nerve obstruction to administer a combination of tetracaine and 2-chloroprocaine. The formulation contained 0.17% tetracaine and 2.3% 2-chloroporcaine. This experiment demonstrates that administration of a combination of local anesthetics provides an onset of sensory obstruction that was as rapid as with lidocaine (e.g., with full onset for approximately 2 minutes) and a duration of continuous activity (e.g., complete sensory obstruction). ) that was substantially longer than with lidocaine alone. In fact, the duration of complete sensory obstruction exceeds that observed with bupivacaine. In itself, administration in a single injection of a combination of local ester anesthetics such as tetracaine and 2-chloroporcain may provide a beginning of sensory obstruction comparable to lidocaine and a duration of continuous sensory obstruction equal to or greater than bupivacaine.

Example 3: Demonstration of Synergy of Local Anesthetics Administered in Combination Figure 2 shows the beginning and duration of a rat sciatic nerve obstruction after administration of 2% 2-chloroprocaine. The duration of the obstruction was substantially shorter without co-administration of tetracaine, with complete sensory block, lasting only about 30 minutes. further, the onset of obstruction with administration of 2-chloroprocaine was slower than with co-administration of tetracaine, suggesting that tetracaine acts synergistically to increase the onset of 2-chloroprocaine anesthesia. Figure 3 shows the onset and duration of a sciatic nerve obstruction after the administration of either 0.22% tetracaine (upper panel) or 0.5% tetracaine (lower panel). Notably, both concentrations of tetracaine failed to produce adequate sensory obstruction (for example, less than 60% of sensory obstruction). In contrast, complete sensory obstruction was achieved when co-administered, tetracaine at a low concentration with 2-chloroprocaine (see, Figure 1, lower panel). In addition, the partial sensory obstruction produced by the administration of either 0.22% tetracaine or 0.5% tetracaine showed not only a slow onset, but also dissipated rapidly. Several studies using different doses of tetracaine confirmed these results, since not a single rat showed continuous and deep sensorial blockage with no tetracaine concentration examined. All the animals used were evaluated for correct placement of local anesthetic injection in proximity to the sciatic nerve demonstrating prolonged, complete motor block (data not shown). Therefore, these results show that tetracaine by itself is a poor local anesthetic to produce sensory block of the rat sciatic nerve with rapid onset and a long duration of effect. Furthermore, these results demonstrate that the rapid onset and long duration of effect achieved when administering a combination of tetracaine and 2-chloroprocaine is clearly more than the sum of the independent effects of tetracaine and 2-chloroprocaine alone. More particularly, in the absence of 2-chloroprocaine, the dose of tetracaine does not provide adequate sensory obstruction at any point in time. Similarly, in the absence of tetracaine, 2-chloroprocaine produces a sensory obstruction that is very transient. Only the combination of the two local anesthetics is capable of producing a sensory obstruction that lasts for more than 60 minutes. In themselves, tetracaine and 2-chloroprocaine, when administered in combination, act synergistically to provide safe, complete, rapid and long-lasting local anesthetic activity. Example 4: Determination of Neurotocixity After Local Anesthetic Administration Fragment fibular nerve slices were taken for evaluation with light microscopy five days after injection with local anesthetic (s). In particular, each nerve was cut and total axonal stones were taken to ensure any axonal loss. Five nerves were examined for each treatment condition. Axonal fibular calculations five days after control (metallic salt), bupivacaine, and 2.3% injections of 2-chloroprocaine / 0.17% tetracaine were 2063 ± 30 (SEM), 1959 ± 81, and 1993 + 45, respectively. There was no significant difference in total axonal stones between bupivacaine, 2-chloroprocaine / tetracaine, and metallic salt controls. In contrast, the total axonal calculations for nerves treated with 2.0% lidocaine were 1602 ± 167, which was significantly reduced by the metal salt controls, demonstrating significant neurotoxicity after administration of lidocaine. Cuts were also taken through the sciatic nerve five days after injection with local anesthetic (s) and examined for gross pathological damage. The light microscopic slices of the sciatic nerve in the approximate location of 2.3% injection of 2-chloroprocaine / 0.17% tetracaine and 0.5% bupivacaine were indistinguishable by metallic salt controls, while the sciatic nerves in place of the injections of 2.0% of lidocaine demonstrated remarkable edema and nerve damage, indicating significant neurotoxicity after administration of lidocaine. These experiments demonstrate that the combination of 2-chloroprocaine / tetracaine is not neurotoxic and is histopathologically indistinguishable by metallic salt controls. By contrast, 2.0% of lidocaine demonstrated significant neurotoxicity both at the level of pericardial injection and in the nerve of the distal fibula. All publications and patent applications cited in this specification are incorporated herein by reference as if each individual publication or patent application was particularly and individually indicated to be incorporated by reference. Although the above-mentioned invention has been described in some detail as illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications can be made to this without departing from the spirit or scope of the appended claims.

Claims (1)

1. CLAIMS 1. A method for local anesthesia, the method comprising: administering a combination of at least two ester anesthetics. The method according to claim 1, characterized in that at least one of said ester anesthetics provides a rapid onset of action, and at least one of said ester anesthetics provides a long duration of effect. 3. The method according to claim 2, characterized in that one of said ester anesthetics is procaine or 2-chloroprocaine. 4. The method according to claim 2, characterized in that one of said ester anesthetics is tetracaine. The method according to claim 2, characterized in that one of said ester anesthetics is 2-cIoroprocaine and one is tetracaine. The method according to claim 2, characterized in that said combination of at least two ester anesthetics is administered as a single pharmaceutical formulation. The method according to claim 6, characterized in that said pharmaceutical formulation further comprises a regulatory agent. The method according to claim 6, characterized in that said formulation further comprises a vasoconstrictive agent. The method according to claim 8, characterized in that said vasoconstrictive agent is epinephrine or phenylephrinephrine. The method according to claim 6, characterized in that said formulation further comprises a corticosteroid. eleven . The method according to claim 6, characterized in that said formulation further comprises a tissue permeability enhancer. The method according to claim 2, characterized in that said combination of ester anesthetics is supplied topically. The method according to claim 2, characterized in that said combination of ester anesthetics is supplied by infiltration. The method according to claim 1 3, characterized in that said infiltration reaches a peripheral nerve obstruction. The method according to claim 13, characterized in that said Infiltration reaches an epidural nerve obstruction. 16. The method according to claim 13, characterized in that said infiltration reaches a caudal nerve obstruction. 17. A pharmaceutical composition for local anesthesia, said pharmaceutical composition comprising: (a) a combination of at least two ester anesthetics; and (b) a pharmaceutically acceptable carrier. 18. The pharmaceutical composition according to claim 17, characterized in that at least one of said ester anesthetics provides a rapid onset of action, and at least one of said ester anesthetics provides a long duration of effect. 19. The pharmaceutical composition according to claim 18, characterized in that one of said ester anesthetics is procaine or 2-chloroprocaine. 20. The pharmaceutical composition according to claim 18, characterized in that one of said ester anesthetics is tetracaine. twenty-one . The pharmaceutical composition according to claim 1 8, characterized in that one of said ester anesthetics is 2-chloroprocaine and one is tetracaine. 22. The pharmaceutical composition according to claim 21, characterized in that said 2-chloroprocaine is present in a concentration of about 1% to about 3%. 23. The pharmaceutical composition according to claim 21, characterized in that said tetracaine is present in a concentration of about 0.1% to about 0.5%. 24. The pharmaceutical composition according to claim 17, characterized in that said pharmaceutical formulation further comprises a regulatory agent. 25. The pharmaceutical composition according to claim 17, characterized in that said formulation further comprises a vasoconstrictive agent. 26. The pharmaceutical composition according to claim 25, characterized in that said vasoconstrictive agent is epinephrine or phenylephrinephrine. 27. The pharmaceutical composition according to claim 17, characterized in that said formulation further comprises a corticosteroid. 28. The pharmaceutical composition according to claim 17, characterized in that said formulation further comprises a tissue permeability enhancer. RES UM EN The present invention provides compositions and methods for analgesia and / or improved local anesthesia, wherein the onset of action is rapid, the risk of toxicity is low, and the effect is continuous. More particularly, the present invention provides a combination of at least two ester anesthetics for administration to a subject, wherein at least one ester anesthetic provides a rapid onset of action and at least one ester anesthetic provides continuous activity. The compositions of the present invention are useful for the production of analgesia and / or anesthesia and are particularly useful for the prophylaxis and / or treatment of pain.