WO1996033706A1

WO1996033706A1 - Compositions and methods for inducing dermal analgesia

Info

Publication number: WO1996033706A1
Application number: PCT/US1996/005833
Authority: WO
Inventors: Vithal J. Rajadhyaksha; Sanjay Sehgal
Original assignee: Pharmetrix, Inc.
Priority date: 1995-04-28
Filing date: 1996-04-25
Publication date: 1996-10-31
Also published as: AU5578096A

Abstract

Compositions and methods for the topical delivery of anesthetic agents to subjects in need thereof. The compositions are emulsified creams which contain at least one, and preferably two or more anesthetic agents, a cell envelope disordering compound, a lipophilic permeation enhancer, a polyoxyethylene ether, a solubilizing agent, a self-emulsifying agent and water. These multi-component systems effectively allow the penetration of the active agents to produce both a rapid onset and longer duration of anesthesia for the tissue to which the composition is applied, preferably under occlusion.

Description

COMPOSITIONS AND METHODS FOR INDUCING DERMAL ANALGESIA

BACKGROUND OF THE INVENTION

Local anesthetics produce anesthesia by blocking nerve impulse conduction in sensory and motor nerve fibers. Nerve impulses are initiated by membrane depolarization, effected by the opening of a sodium ion channel and an influx of sodium ions. Local anesthetics inhibit the channel's opening by binding to a receptor on the channel's interior. The degree of blockage on an isolated nerve depends not only on the amount of anesthetic agent, but also on the rate of nerve stimulation.

The properties of the various clinically important local anesthetic agents include potency, speed of onset and duration of anesthesia. The physicochemical properties which influence anesthetic activity include lipid solubility, protein binding, and pKa. Lipid solubility appears to be a primary determinant of intrinsic potency. Considering that the nerve membrane is basically a lipoprotein matrix, highly lipophilic compounds tend to penetrate the matrix more easily and require fewer molecules to block the conduction of signals, thereby contributing to enhanced potency. The duration of anesthesia is primarily associated with the degree of protein binding of the various local anesthetics. Conduction blockade is believed to occur following the interaction of local anesthetics with a protein receptor located within the sodium channel of the nerve membrane. Chemical compounds which possess a greater affinity for and bind more tightly to the receptor site remain within the channel for a longer period of time, resulting in a prolonged duration of anesthesia. The onset of conduction block is determined primarily by the pKa of the individual compounds, that is, the pH at which the ionized (charged) and non-ionized (uncharged) forms are present in equal amounts.

Percutaneous local anesthesia, which would render relatively minor surgical procedures such as venipuncture and insertion of catheters painless, is of particular value in pediatric practice. Since infiltration anesthesia is in itself painful, a topical preparation which allows the anesthetic to penetrate the stratum corneum and anesthetize the underlying pain receptor is much needed.

It is generally accepted that the absorption of drugs through the skin involves passive diffusion. The main factor modulating transdermal absorption flux is thought to be penetration of the stratum corneum. The stratum corneum, although relatively thin, is compact, highly keratinized and therefore quite impermeable to pharmaceutically active agents. Such impermeability of the skin is highly essential to the well being of a living organism. This impermeability serves as a barrier to the ingress of pathogens and toxic materials and the egress of physiological fluids. Because of the impermeable nature of the stratum corneum, it has long been sought to temporarily modify the barrier property of this layer in order to enhance the penetration of topically applied agents.

Thus, to be topically effective, local anesthetics must penetrate through the skin and a lipophilic nerve structure. This is feasible when these anesthetic agents are in the uncharged lipophilic form, usually as free bases. Since the most frequently used local anesthetics contain a tertiary or secondary amino group and are present in aqueous solution in equilibrium between ionized and non-ionized forms, the pH of the formulation and the pKa of the compound are extremely important for drug penetration. The activity at the site of action, however, is due to the protonated or ionized form.

A number of local anesthetics possess an aromatic and an amine group which are separated by a lipophilic hydrocarbon chain. These compounds are typically esters or amides of benzoic acid derivatives. The clinically useful local anesthetic agents fall essentially into one of two chemically distinct groups, the amino ester and the amino amides. One difference between the two groups of compounds resides in their chemical stability. Esters are typically hydrolyzed much more rapidly than amides. In vivo, the amino esters are hydrolysed primarily in plasma by cholinesterase whereas the amino amides undergo enzymatic degradation in the liver. Local anesthetics are administered either as the free base or the acid-addition salt or a combination thereof. Free bases tend to be irritating due to the high concentrations of the crystalline compound and high pH used in the compositions. Acid-addition salts, in comparison, have very low skin permeability. Although it is the cationic form of a local anesthetic agent which blocks the transmission of impulses within the nerve, it is the uncharged or unionized base form which penetrates and diffuses into the tissue after topical or parenteral administration.

Effective tissue penetration can be achieved after topical administration of (i) a water soluble salt in aqueous solution, (ii) a base in alcoholic solvent, or (iii) an oil-in-water emulsion. In an aqueous solution of the hydrochloride salt of a local anesthetic only a very small portion of the unionized base form, which is dependent on pKa, is suitable for tissue penetration. Consequently, the local anesthetics which are salts must be used in high concentration to be effective topically. Use of such a high concentration, however, poses a risk of toxic complications. Suitable concentrations of a local anesthetic base can be obtained by dissolving it in an alcohol solvent for use in sprays and ointments. However, these compositions do not contain water, which would precipitate the local anesthetic base, and consequently have poor permeation through intact skin. Enhancement of drug absorption through the intact skin has been a challenge for researchers for many years. Most of the studies carried out to date have shown that the stratum corneum of the skin acts as a protective barrier against the exterior environment. It is now well documented that dermal permeation of pharmaceutical agents can be enhanced very effectively with penetration enhancers. A penetration enhancer is generally considered to be one or more compounds which reversibly alter the skin as a barrier and thereby increase the flux of a desired pharmaceutical agent across the skin. In the past, penetration enhancers for promoting skin permeation of local anesthetics were utilized. For instance, dimethyl sulfoxide and dimethyl acetamide, were added to local anesthetic formulations and apparently increased transdermal permeation of the local anesthetic, but their adverse side effects were unacceptable (see, Akerman, Acta Anaesthesiol Scand 70:90-91 (1978)).

Since the early investigations of penetration enhancers, the search has continued for an effective topical formulation of an analgesic which can provide rapid onset and long duration of analgesia.

Currently available topically used anesthetic preparations are generally ineffective or only partially effective when applied onto intact skin. One such preparation is EMLA cream which is applied as a thick layer under occlusion. The time of onset for anesthesia with EMLA cream is approximately 1 hour or more. This length of time is not very practical for a number of clinical procedures. For example, application of EMLA under occlusion can be particularly cumbersome and difficult for young children undergoing venipuncture. Moreover, EMLA is formulated at pH 9.0 to incorporate the anesthetic agents in base form. The skin, which has an acidic pH (approximately 5 to about 5.5), is sensitive to such a high basic pH and significant skin irritation can result. What is needed in the art is a topical anesthetic composition which provides a rapid and deep anesthesia, by providing high skin concentration but at the same time would not promote systemic absorption. Surprisingly, the present invention provides such compositions as well as methods for their preparation and use.

SUMMARY OF THE INVENTION

The present invention provides compositions for the topical delivery of anesthetic agents to subjects in need thereof. The compositions are emulsified creams which contain at least one, and preferably two or more anesthetic agents, a cell envelope disordering compound, a lipophilic permeation enhancer, a polyoxyethylene ether, a solubilizing agent, a self-emulsifying agent and water. These multi-component systems effectively allow the penetration of the active agents to produce both a rapid onset and longer duration of anesthesia for the tissue to which the composition is applied, preferably under occlusion.

The present invention further provides methods for administering one or more topical anesthetic agents to a subject. In these methods, multi-component compositions are provided which are then contacted with an area of skin or mucous membrane, under occlusion, to administer the local anesthetic.

BRIEF DESCRD7TION OF THE DRAWINGS

Figures 1 and 2 illustrate the cumulative amounts of lidocaine and prilocaine, respectively, which penetrate human skin from six cream formulations.

DETAD ED DESCRIPTION OF THE INVENTION

Abbreviations and Definitions

The abbreviations used herein are as follows: EMLA, eutectic mixture of local anesthetics (see for example, U.S. Patent Nos. 4,529,601 and 4,562,060, the disclosures of which are incorporated herein by reference); and PEG, polyethylene glycol. As used herein, the term "alkyl" refers to either a saturated or an unsaturated, chiral or achiral, hydrocarbon radical which may be straight-chain or branched-chain (for example, ethyl, isopropyl, t-amyl, 2-heptenyl, or 2,5-dimethylhexyl). Preferred alkyl groups are those containing 1 to 24 carbon atoms. All numerical ranges in this specification and claims are intended to be inclusive of their upper and lower limits. The terms "fatty acid," "fatty alcohol," "fatty acid ester" and the like, refers to long hydrocarbon chain carboxylic acids, alcohols and esters, respectively in which the hydrocarbon portions are typically alkyl groups containing from 10 to 24 carbon atoms.

The term "base" as used herein means the un-ionized form of the anesthetic that can furnish an electron pair to form a "salt" with an organic or inorganic acid. The term "topical administration" or "topical application" is meant directly laying or spreading upon epidermal tissue, especially outer skin or membrane, including the skin or mucosal membrane of the oral, nasal, ocular, anal or vaginal cavities.

The term "therapeutically effective amount" is intended to mean the amount of drug sufficient to produce an anesthetic effect when applied topically. These amounts are known in the art or may be determined by methods known in the art, and typically range from about 1 to 20,000 mg per human adult and preferably about 10 to 10,000 mg and most preferably range from about 20 to 5,000 mg of the anesthetic agent per application, depending upon the anesthetic agents chosen.

The term "onset of anesthesia" is intended to mean the time to peak effect on the individual nerves. Onset of anesthesia principally depends upon the lipid solubility, molecular size, and the concentration of available unionized form of the local anesthetic. Thus, anesthetics with a high lipid solubility or a low pKa or both, have a more rapid onset of anesthesia.

The term "duration of anesthesia" as used herein means the period of time during which the local anesthetic measurably blocks nerve conduction. The foregoing depends upon all the factors listed for onset of anesthesia, as well as on the extent of protein binding of the anesthetic agent.

As used herein, all numerical ranges are meant to be inclusive of their upper and lower limits. Unless noted otherwise, all percentages in the compositions of the invention are on a weight-to-weight basis.

Embodiments of the Invention

In one aspect, the present invention provides pharmaceutical compositions which are useful for the delivery of anesthetic agents. The compositions can be administered to a subject in need of rapid onset and long duration of topical analgesia. The compositions are oil-in-water emulsions containing one or more anesthetic agents, a cell envelope disordering compound, a lipophilic permeation enhancer, a polyoxyethylene ether, a solubilizing agent, a self-emulsifying agent and water. Preferably, the compositions have a pH of about 6 to about 8.

The cream compositions of the present invention provide both a rapid onset of anesthesia as well as a longer duration of anesthesia than is provided by present commercial preparations. The active agents in these compositions are compounds which are typically considered to be local anesthetic agents. In particular, the anesthetic agents which are useful in the present invention include, but are not limited to, lidocaine, prilocaine, mepivacaine, bupivacaine, dibucaine, etidocaine, procaine, tetracaine, propoxycaine, chloroprocaine, benzocaine, cocaine, hexylcaine, piperocaine, oxyprocaine, proparacaine and combinations thereof. In preferred embodiments, the local anesthetic agents are lidocaine, prilocaine, tetracaine and combinations thereof. More preferably, the local anesthetic agent is either a mixture of lidocaine and prilocaine or a mixture of lidocaine and tetracaine. The local anesthetic agents are present in the compositions in an amount of from about 0.1 % to about 15%, preferably from about 0.5% to about 10%, and more preferably from about 1 % to about 5%. In a most preferred embodiment, a combination of prilocaine and lidocaine is used in which each of the agents is present in an amount of from 2 to 3 % . In addition to the anesthetic agents, the present compositions comprise a number of agents which aid the penetration of the anesthetic agent through the stratum corneum or which solubilize the pharmaceutically active species. One group of these enhancers is termed the cell envelope disordering compound. Cell envelope disordering compounds are those compounds which are known in the art as being useful in disrupting or disordering the lipid structure of the stratum corneum cell-envelopes. In this manner, the compounds are thought to assist the penetration of pharmaceutical agents which are formulated in topical preparations containing one or more cell envelope disordering compounds. A number of cell-envelope disordering compounds have been described in European Patent Application No. 43,738, published June 13, 1982 and incorporated herein by reference. The cell envelope disordering compounds which are preferred for use in the present invention include l-alkylhexahydro-2H-azepin-2-ones, l-alkyl-2-pyrrolidones, N,N-diethyl lauramide, hexamethylene lauramide, and 4-alkyloxazolidin-2-ones. More preferably, the cell envelope disordering compound is l-dodecylhexahydro-2H-azepin-2-one, N-hexyl-2- pyrrolidone, N-octyl-2-pyrrolidone, N-dodecyl-2-pyrrolidone, 4-decyloxazolidin-2-one, N,N-diethyl lauramide or hexamethylene lauramide. Most preferably, the cell envelope disordering compound is 4-decyloxazolidin-2-one. Additionally, mixtures of cell envelope disordering compounds may be used. For use in the compositions and methods of the present invention, the cell envelope disordering compound will preferably be present in an amount of from about 0.1 % to about 10%, by weight, more preferably from about 1 % to about 6% by weight. In a particularly preferred embodiment, 4-decyl oxazolidin-2-one is present in the composition in an amount of from about 1 % to about 6%. In addition to the cell envelope disordering compounds, other ingredients provide a balance of lipophilicity and hydrophilicity which also enhances the penetration of the anesthetic agent. The compounds which provide this balanced enhancement are polyoxyethylene ethers and lipophilic permeation enhancers.

Polyoxyethylene ethers also aid in the penetration of pharmaceutical agents into the stratum corneum. Polyoxyethylene ethers which are suitable for use in the present invention include di- and triethyleneglycol mono- and dialkyl ethers. Preferably, the polyoxyethylene ether is diethyleneglycol monomethyl ether, diethyleneglycol monoethyl ether, diethyleneglycol monopentyl ether, diethyleneglycol monohexyl ether, diethyleneglycol monooctyl ether, diethyleneglycol monolauryl ether, diethyleneglycol dimethyl ether, diethyleneglycol diethyl ether, diethyleneglycol dipentyl ether, diethyleneglycol dihexyl ether, diethyleneglycol dioctyl ether, diethyleneglycol dilauryl ether, triethyleneglycol monomethyl ether, triethyleneglycol monopentyl ether, triethyleneglycol monooctyl ether, triethyleneglycol monolauryl ether, triethyleneglycol dimethyl ether, triethyleneglycol diethyl ether, triethyleneglycol dihexyl ether, triethyleneglycol dioctyl ether and triethyleneglycol dilauryl ether. Particularly preferred are the monoalkyl ethers of diethyleneglycol and triethyleneglycol.

For use in the compositions and methods of the present invention, the polyoxyethylene ethers will preferably be present in an amount of from about 0.1 % to about 10%, by weight, more preferably from about 1 % to about 6% by weight. In a particularly preferred embodiment, the polyoxyethylene ether is triethyleneglycol monomethyl ether which is present in an amount of from about 1 % to about 6%, more preferably from about 2% to about 4%. The lipophilic permeation enhancers which are useful in the present invention can be any of a variety of fatty acids, fatty acid esters, fatty alcohols and ethers of fatty alcohols. Preferably, the lipophilic permeation enhancer is oleic acid, hexyl dodecanol, octyl dodecanol, decyl dodecanol, isocetyl alcohol, decyl oleate, octyl stearate, oleyl erucate, hexyl laurate, cetearyl alcohol, isopropyl myristate, isopropyl palmitate, glyceryl laurate, glycol stearate, myreth-3-myristate, isocetyl stearate, isopropyl isostearate, butyl stearate, propylene glycol isostearate, propylene glycol dipelargonate, propylene glycol dicaprylate/dicaprate, isostearyl isostearate, octyldodecyl myristate, propylene glycol monolaurate, propylene glycol monooleate, polyethylene glycol monolaurate and polyethylene glycol dipelargonate. The lipophilic permeation enhancers will typically be present in the compositions of the invention in an amount of from about 0.1 % to about 20% , preferably from about 0.5% to about 10% , and more preferably in an amount of from about 1 % to about 6%. In a particularly preferred embodiment, the lipophilic permeation enhancer is 2-octyl dodecanol which is present in an amount of from 1 % to 10%, more preferably from about 2% to about 5%.

In addition to the enhancers noted above, the compositions of the present invention also contain small amounts of species typically considered to be solvents or solvent additives which aid in solubilizing the anesthetic agents. By solubilizing the local anesthetics, the solubilizing agents further increase the penetration of the anesthetic agents into the stratum corneum.

The solubilizing agents used in the present invention are preferably propylene glycol, isopropanol, ethanol, glycerol, polyethylene glycol 100 to polyethylene glycol 600 and mixtures thereof, butylene diol, dimethyl isosorbide or N-methyl-2- pyrrolidone, and combinations of the above. Polyethylene glycols (PEGs) are typically represented as polyethylene glycol followed by a number which represents the average molecular weight of a mixture of polyethylene glycols. For example, polyethylene glycol 100 refers to polyethylene glycols of an average molecular weight 100 daltons. Alternatively, ethers and esters of polyethylene glycols are often referred to as PEG-X ester or ether, in which X represents a number of repeating oxyethylene groups. In preferred embodiments, the solubilizing agent is propylene glycol, or polyethylene glycol 100 to polyethylene glycol 600, more preferably propylene glycol. As noted above, the solubilizing agents are typically present in small amounts, of from about 0.5% to about 15%, preferably from about 1 % to about 10% , more preferably from about 2% to about 6%. The precise amount of the solubilizing agent will typically depend on the type and amount of anesthetic agent being used. The amount of the solubilizing agent will be toward the upper limits for those anesthetics which are more hydrophobic, and near the lower limits for those anesthetics which are considered hydrophilic. For example, compositions containing a mixture of lidocaine and prilocaine (each at about 2-3%), the solubilizing agent is preferably propylene glycol, in an amount of about 1-5%.

The compositions of the present invention further comprise a self- emulsifying agent. The self-emulsifying agent, or self-emulsifying base, provides stabilization to the emulsion formed when the above components are mixed with water. By stabilizing the emulsion, the anesthetic agents are kept in an environment in which they are surrounded and in contact with the solubilizing agents and enhancers. Thus the emulsion provides the preferred vehicle for delivery of the anesthetic agents through the skin. Self-emulsifying agents enable the spontaneous formation of stable emulsions, without the need of adding a surfactant. Typically, emulsification can be achieved by heating demineralized water to a temperature of about 5 to 20°C above the melting point of the bases used, followed by cooling with moderate stirring. Some of the non-ionic self- emulsifying agents that can be used for preparing oil/ water emulsions include Tefose 63, Tefose 1500, Tefose 2000, Tefose 2561 and Gelot 64 (all available from Gattefosse Corporation, Elmsford, New York, USA); Cetiol-HE, Emerest 2407, Emerwax 1266, Emulgade CLB, Emulgade 1000 NI, Lanette N and Lanette SX (all available from Henkel Corporation, Hoboken, New Jersey, USA). In addition to the stearic acid esters of polyethylene glycols (of, for example PEG-6 in which the number 6 refers to the number of oxyethylene groups), other fatty acid esters (of from C₂ to C₂₄) of PEGs containing from 2 to 200 oxyethylene groups could be used as an emulsifying base. Preferred fatty acid esters of PEGs include, PEG-2 distearate, PEG-2 laurate, PEG-3 dipalmitate, PEG-4 distearate, PEG-4 laurate, PEG-4 oleate, PEG-5 glyceryl stearate, PEG-6 palmitate, PEG-6 stearate, PEG-8 laurate, PEG-10 oleate, PEG-10 glyceryl oleate, PEG-14 laurate, PEG-15 glyceryl isostearate, PEG-18 palmitate, PEG-20 glyceryl stearate, PEG-25 glyceryl trioleate, PEG-75 laurate, PEG-120 glyceryl stearate, PEG-150 oleate and PEG-150 stearate.

In some embodiments, anionic self-emulsifying agents are preferred. These bases include Sedefos 75 (a mixture of glycol stearate, PEG-2 stearate and trilaneth-4-phosphate, which is available from Gattefosse Corporation) and Emulgade F (a cetearyl alcohol and PEG-40 castor oil with sodium cetearyl sulfate, which is available from Henkel Corporation).

In preferred embodiments, the self-emulsifying agent is a stearic acid ester of PEG-6, preferably Tefose 63. The remainder of the present compositions is water, preferably distilled water, more preferably distilled, de-ionized water.

In the most preferred embodiments of the invention, the pharmaceutical compositions comprise a mixture of lidocaine and prilocaine (each preferably in an amount of about 1 % to 5%), 4-decyloxazolidin-2-one (preferably in an amount of about 1 % to 5%), triethyleneglycol monomethyl ether (preferably in an amount of about 1 % to 5%), 2-octyldodecanol (preferably in an amount of about 1 % to 5%), propylene glycol (preferably in an amount of about 1 % to 5%), a stearic acid ester of PEG-6 and water.

Preparation of the compositions of the present invention typically involves mixing the components for a sufficient period of time and at a suitable temperature to ensure complete formation of an emulsion. The components used in the compositions are either commercially available or can be synthesized by procedures known to those of skill in the art. In particular, lidocaine, prilocaine, bupivacaine, dibucaine, procaine, tetracaine, benzocaine, cocaine and proparacaine are all available from Sigma Chemical Company (St. Louis, Missouri, USA). Cell envelope disordering compounds can be prepared by standard methods. For example, N-alkylation of a lactam can be achieved by treating a lactam with an alkyl halide in the presence of a base (see U.S. Patent Nos. 3,991,203 and 4,422,970). Procedures for the preparation of 4-alkyloxazolidin-2-ones are described in U.S. Patent No. 4,960,771, the disclosure of which is incorporated herein by reference. Procedures for the preparation of l-alkyl-hexahydro-2H-azepin-2-one and hexamethylene lauramide are provided in U.S. Patent Nos. 4,316,893 and 4,837,026, respectively. The disclosures of these patents are incorporated herein by reference. The polyoxyethylene ethers used in the present invention are all commercially available from sources such as Sigma Chemical Company (St. Louis, Missouri, USA). Similarly, the lipophilic permeation enhancers and solubilizing agents are available from Gattefosse Corporation (New York, New York, USA); Henkel Corporation Cospha (Ambler, Pennsylvania, USA); and Sigma Chemical Company.

In preferred embodiments, the water is mixed with the solubilizing agent in one vessel to form a substantially aqueous solution. In a second vessel, the self- emulsifying agent, lipophilic enhancer, and polyoxyethylene ether are warmed and mixed. Once the components of the second vessel have been suitably melted, the cell envelope disordering compound and the anesthetic agent(s) are added. The resulting mixture is added to the aqueous mixture and blended until complete emulsification has occurred. The compositions may also contain optional components which enhance their cosmetic appeal or acceptability, for example, pigments, fragrances, perfumes, and the like. Additionally, components which reduce any local skin irritation may also be incorporated into the compositions. In another aspect, the present invention provides methods of delivering one or more topical anesthetic agents to a subject in need of analgesia. These methods comprise administering the compositions of the present invention to the skin or mucous membranes of the subject. For operations of a peripheral or minor nature involving the skin, like removal of superficial skin lesions and plastic surgery, or intradermal allergen testing, split skin grafting, treatment of painful ulcers, and venipuncture, topical application of local anesthetics is ideal. The present invention thus provides delivery methods for use in the aforementioned applications, and others known to those of skill in the art.

At present, the most successful commercially available preparation for dermal anesthesia is a lidocaine-prilocaine cream. The cream consists of an emulsion containing 5% by weight of the eutectic mixture of lidocaine and prilocaine bases (EMLA) in water which is thickened with Carbopol^® (see, Broberg, et al., EP 0002425 (1981) and U.S. Patent Nos. 4,529,601 and 4,562,060). However, an application time of 60 minutes under occlusion is required to achieve anesthesia to pin-prick tests. The present invention provides a method for delivering one or more topical anesthetic agents to a subject. In this method, a composition comprising a therapeutically effective amount of at least one topical anesthetic agent in admixture with a cell envelope disordering compound, a polyoxyethylene ether, a lipophilic permeation enhancer, a solubilizing agent, a self-emulsifying agent and water is provided and contacted with an area of skin or mucous membrane on the subject to deliver the topical anesthetic agents to the subject. Preferably, the topical anesthetic agents are lidocaine, tetracaine and/or prilocaine, the cell envelope disordering compound is 4-decyloxazolidin-2-one, the polyoxyethylene ether is triethyleneglycol monomethyl ether, the lipophilic permeation enhancer is 2-octyldodecanol, and the solubilizing agent is propylene glycol. The particular treatment regimen will depend on a number of variables known to those of skill in the art. Thus, the final diagnosis and treatment is left to the expertise of the practitioner and the subject. Suitable subjects for the present invention include humans as well as other mammals, for example, dogs, cats, pigs, goats, mice, sheep, rabbits, cows and horses. In clinical and veterinary practice, the dosage of any anesthetic agent should be as small as possible to achieve the desired analgesia, and the administration of the anesthetic should be as short as possible. In accordance with these outlines, the present invention provides compositions which enhance the penetration of local anesthetic agents and provide both rapid onset and long duration of analgesia. The enhanced penetration obtained with the present compositions results in lower overall amounts of anesthetic which are used to provide suitable analgesia. For local treatment, the present compositions are applied to the afflicted situs. The dosage, rate of application, place of application, and other treatment parameters are generally to be determined by a skilled practitioner depending on the active agent being used, the site of application, and the effectiveness of the penetration enhancing components which are used.

One of skill in the art will also understand that the compositions of the present invention will preferably be used with an occlusive dressing. For example, the oil-in-water formulations of the present invention can be applied topically to the skin of a patient, then covered with an occlusive dressing for a period of time sufficient for analgesia to occur. The dressing is then removed and excess formulation is wiped off prior to conducting a pain-free venipuncture, particularly in children. Alternatively, the compositions can be prepared and prepackaged in patches having a removable backing for easy application. The patches may further comprise a thin layer of a dye around the patch's periphery. During the time of application, and the induction of anesthetic effect, the released dye serves to mark the anesthetized area of the subject to which it was applied.

Accordingly, the present invention provides a method of inducing dermal analgesia in a subject comprising contacting an area of skin or mucous membrane on the subject with a patch containing a composition of the present invention for a period of time sufficient to induce dermal analgesia in the subject.

The foregoing description and the following examples are offered primarily for illustration and not as limitations. It will be readily apparent to those of ordinary skill in the art that the operating conditions, materials, procedural steps and other parameters of the compositions and methods described herein may be further modified or substituted in various ways without departing from the spirit and scope of the invention.

EXAMPLES

In the examples below, the percentages listed for the various compositions refer to the pe rrcceennttaaggee of the individual ingredients in the composition on a weight to weight basis.

EXAMPLE 1

This example illustrates the preparation of an oil-in-water cream formulation containing lidocaine and prilocaine.

Propylene glycol (2.5%) was added to water (65%) with stirring at room temperature. A self-emulsifying agent, Tefose-63™ (20%) was melted in triethyleneglycol monomethyl ether (2.5%) and 2-octyldodecanol (2.5%) by gentle warming to 55 °C. To the melt was added 4-decyloxazolidinone (2.5 %), followed by prilocaine base (2.5%) and lidocaine base (2.5%). The resulting clear melt was added to the aqueous phase with stirring and then blended for at least 15 minutes at room temperature. The resulting anesthetic cream (25 g) had a pH of 6.8 and is referred to as Formulation A, below.

EXAMPLE 2

This example provides other anesthetic cream formulations which were prepared according to the procedure provided in Example 1. Table 1 below provides the compositions for six formulations (including formulation A, from Example 1) which were prepared. Formulations A-E were evaluated versus EMLA below in Example 4.

Table 1 Anesthetic Cream Formulations

Component Formulation ( by weight)

A B C D E F

Lidocaine 2.5 2.5 2.5 2.5 2.5 2.5

Prilocaine 2.5 2.5 2.5 2.5 2.5 2.5*

4-Decyloxazolidinone 2.5 0 2.5 2.5 0 2.5

Triethyleneglycol monomethyl 2.5 2.5 2.5 0 2.5 2.5 ether

2-Octyldodecanol 2.5 2.5 0 0 0 2.5

Propylene glycol 2.5 2.5 2.5 2.5 2.5 2.5

Tefose-63™ 20 20 20 20 20 20

Water 65 67.5 67.5 70 70 65

* Tetracaine was substituted for Priloca une in th is formul auon.

EXAMPLE 3

This example illustrates the preparation of another oil-in-water cream formulation containing lidocaine and prilocaine.

Propylene glycol (2.5%) was added to water (64%) with stirring at room temperature. A self-emulsifying agent, Tefose-63™ (20%) was melted in isopropyl palmitate (5.0%) and oleic acid (1.0%) by gentle warming to 55°C. To the melt was added 4-decyloxazolidinone (2.5%), followed by prilocaine base (2.5%) and lidocaine base

(2.5%). The resulting clear melt was added to the aqueous phase with stirring and then blended for at least 15 minutes at room temperature.

EXAMPLE 4

This example illustrates the evaluation of formulations A through E from the table in Example 2 in comparison with the commercially available EMLA cream (from Astra Pain Control AB, which also contains 2.5 % of lidocaine and 2.5% of prilocaine). The compositions were evaluated in an in vitro skin permeation experiment using human skin fixed on flow-through cells. Three replicates were run for each formulation. The skin and cells were equilibrated at 32 °C and 100 mg of each cream was applied to the donor side of the cell under occlusion. The receptor side of each cell contained 0.9% saline solution. Samples were collected from the receptor side at 20, 40, 60, 90 and 120 minute intervals and analyzed by HPLC for lidocaine and prilocaine. The results are presented in Table 2 below and illustrated in Figures 1 and 2.

Table 2 Comparison of Cumulative Amounts (μg) of Anesthetic Permeating Through The Skin

Cumulative Amounts (μg) of Prilocaine

Time (min) A B C D E EMLA

0.00 0 0 0 0 0 0

20.00 4.36 1.74 0.18 2.57 1.89 1.06

40.00 9.94 4.61 1.05 6.63 6.02 4.17

60.00 16.29 7.62 2.57 12.13 10.11 8.79

90.00 26.74 12.78 6.30 18.39 18.07 18.40

120.00 35.25 18.53 11.30 26.37 26.24 29.25

Cumulative Amounts (μg) of Lidocaine

Time (min) A B C D E EMLA

0.00 0 0 0 0 0 0

20.00 3.31 1.36 0.18 2.13 1.72 1.05

40.00 7.36 3.48 0.90 5.47 5.09 3.33

60.00 11.89 5.80 2.14 9.53 8.30 6.83

90.00 19.28 9.66 5.10 14.03 14.32 . 13.79

120.00 25.18 13.84 8.85 20.02 20.51 21.41

As Table 2 and Figures 1 and 2 illustrate, Formulation A provides both rapid onset and significant permeation of anesthetic through human skin. Formulations B- E, from which one or more of the components of formulation A were omitted, were significantly less effective at providing rapid cumulative amounts of prilocaine and lidocaine in the receptor compartment. Moreover, a comparison of formulation A and the commercially available EMLA cream shows that the composition of the present invention is superior in providing cumulative amounts of lidocaine and prilocaine through the skin at every time point tested.

AU publications, patents and patent applications mentioned in this specification are herein incorporated by reference into the specification to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference.

The above description is illustrative and not restrictive. Many variations of the invention will become apparent to those of skill in the art upon review of this disclosure. Merely by way of example a variety of dosages, and protocols for treatment may be used without departing from the scope of the invention. The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the appended claims along with their full scope of equivalents.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition for the topical delivery of anesthetics, comprising:

(a) a therapeutically effective amount of one or more local anesthetic agents;

(b) a cell envelope disordering compound;

(c) a polyoxyethylene ether;

(d) a lipophilic permeation enhancer;

(e) a solubilizing agent;

(f) a self-emulsifying agent; and

(g) water.

2. A composition in accordance with claim 1 having a pH of from about 6 to about 8.

3. A composition in accordance with claim 1, wherein said local anesthetic agents are selected from the group consisting of lidocaine, prilocaine, mepivacaine, bupivacaine, dibucaine, etidocaine, procaine, tetracaine, propoxycaine, chloroprocaine, benzocaine, cocaine, hexylcaine, piperocaine, oxyprocaine and proparacaine.

4. A composition in accordance with claim 1 , wherein said local anesthetic agents are present in an amount of from 0.1 % to about 20% each, by weight.

5. A composition in accordance with claim 1, wherein said local anesthetic agents are lidocaine and prilocaine.

6. A composition in accordance with claim 1 , wherein said local anesthetic agents are lidocaine and tetracaine.

7. A composition in accordance with claim 1 , wherein said cell envelope disordering compound is selected from the group consisting of l-alkyl-2-pyrrolidone, l-alkylhexahydro-2H-azepin-2-one, N,N-diethyl lauramide, hexamethylene lauramide, and 4-alkyloxazolidin-2-one.

8. A composition in accordance with claim 1, wherein said cell envelope disordering compound is present in an amount of from about 0.1 % to about 10%, by weight.

9. A composition in accordance with claim 1 , wherein said polyoxyethylene ether is selected from the group consisting of diethyleneglycol monoalkyl ether, diethyleneglycol dialkyl ether, triethyleneglycol monoalkyl ether and triethyleneglycol dialkyl ether.

10. A composition in accordance with claim 1, wherein said polyoxyethylene ether is present in an amount of from about 0.5% to about 30% , by weight.

11. A composition in accordance with claim 1 , wherein said lipophilic permeation enhancer is selected from the group consisting of octyl dodecanol, isopropyl myristate and oleic acid.

12. A composition in accordance with claim 1 , wherein said lipophilic permeation enhancer is present in an amount of from about 0.1 % to about 10%.

13. A composition in accordance with claim 1 , wherein said solubilizing agent is a member selected from the group consisting of propylene glycol, glycerol, ethanol, isopropanol, butylene diol, polyethylene glycol 100 to polyethylene glycol 600, N-methyl-2-pyrrolidone, dimethyl isosorbide and combinations thereof.

14. A composition in accordance with claim 1 , wherein said solubilizing agent is present in an amount of from about 0.1 % to about 10%.

15. A composition in accordance with claim 1 , wherein said mixture of local anesthetics comprises lidocaine and prilocaine, said cell envelope disordering compound is 4-decyloxazolidin-2-one, said polyoxyethylene ether is triethyleneglycol monomethyl ether, said lipophilic permeation enhancer is 2-octyldodecanol, and said solubilizing agent is propylene glycol.

16. A method for delivering one or more topical anesthetic agents to a subject comprising:

(a) providing a composition comprising a therapeutically effective amount of at least one topical anesthetic agents in admixture with a cell envelope disordering compound, a polyoxyethylene ether, a lipophilic permeation enhancer, a solubilizing agent, a self-emulsifying agent and water; and

(b) contacting an area of skin or mucous membrane on said subject with said composition to deliver said topical anesthetic agents to said subject.

17. A method in accordance with claim 16, wherein said topical anesthetic agents are selected from the group consisting of lidocaine, tetracaine and prilocaine, said cell envelope disordering compound is 4-decyloxazolidin-2-one, said polyoxyethylene ether is triethyleneglycol monomethyl ether, said lipophilic permeation enhancer is 2- octyldodecanol, and said solubilizing agent is propylene glycol.

18. A method in accordance with claim 16, wherein said contacting further comprises the use of an occlusive dressing.

19. A method in accordance with claim 16, wherein said composition of said anesthetic agent is contained in a patch, said patch having a dye around its periphery to mark said contacted skin area.

20. A method of inducing dermai analgesia comprising contacting an area of skin or mucous membrane on a subject with a patch, said patch further comprising a composition of claim 1 , for a period of time sufficient to induce dermal analgesia in said subject.