WO2003077885A2

WO2003077885A2 - Free-base formulations of local anesthetics

Info

Publication number: WO2003077885A2
Application number: PCT/US2003/007424
Authority: WO
Inventors: Allan L. Wilcox; Keith R. Bley; Larry Litle; Arturo Angel; Gene Jamieson; Naweed Muhammad; Wendye R. Robbins
Original assignee: Neurogesx, Inc.
Priority date: 2002-03-12
Filing date: 2003-03-11
Publication date: 2003-09-25
Also published as: AU2003225745A8; WO2003077885A3; AU2003225745A1

Abstract

An anesthetic formulation and methods of use are disclosed. The formulation includes an oleaginous base vehicle, a free base anesthetic and a solubility enhancer. Further, the formulation may additionally include penetration enhancers, antioxydants, solubility enhancers, gelling agents, and antimicrobial agents. The inventive formulation may be incorporated into a drug delivery patch or a drug delivery gel. Methods of use and application are also disclosed.

Description

FREE-BASE FORMULATIONS OF LOCAL ANESTHETICS

Inventors: Allan L. Wilcox, Keith R. Bley, Larry Litle, Arturo Angel,

Gene Jamieson, Naweed Muhammad, and Wendye R. Robbins

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to provisional application number

60/364,761 filed on March 12, 2002, and to provisional application number 60/425,212, filed on November 7, 2002. The disclosures of both provisional applications are incorporated herein by reference in their entirety.

TECHNICAL FIELD

[0002] The present invention relates to formulations of local anesthetics and their methods of use. Local anesthetic formulations include an oleaginous base vehicle and a free-base anesthetic, and may also include additional components that enhance the solubility, penetration, stability, and efficacy of the anesthetic.

BACKGROUND

[0003] Cutaneous pain is a symptom of many types of trauma or illness and occurs frequently following medical procedures including actions such as suturing, biopsies, cosmetic surgery, hair epilation, and venipuncture. Topical local anesthetics are extremely beneficial in preventing or ameliorating cutaneous pain and may also be beneficial for treating other pain indications including neuropathic pain, rheumatoid and osteoarthritis, and pain from injuries including muscle, ligament, joint, and bone pain. Because the stimulation of pain receptors results in edema, tenderness, and muscular spasm, it is generally believed that local anesthesia may also play a significant part in the promotion of healing (Eroglu, E., et al., Eur. J. Emerg. Med. (2001) 8(3):199-201; Druker, M., et al., World J. Surg. (1998) 22(4):394-8). [0004] Topical local anesthetic preparations have been available for years.

The majority of topical local anesthetics are liposome- or aqueous-based solutions intended for application to intact or broken skin, or mucous membranes. Typically, oil based vehicles are not readily absorbed by tissue and have required higher concentrations to effect anesthesia. See Woolfson A.D., et al., Concentration- response analysis of percutaneous local anesthetic formulations, Br. J. Anaesth. (1988) 61: 589-592.

[0005] Previous topical local anesthetic formulations include eutectic mixtures of local anesthetics (AstraZeneca's EMLA^® creme), liposome vehicle based . anesthetics (Ferndale Laboratories' ELA-Max^®) and formulations including the anesthetic in hydrate form (Smith & Nephew Healthcare's AMETOP^®). [0006] In addition to these liposomal and aqueous delivery vehicles, alternative drug delivery methods are currently being developed including iontophoresis, a drug delivery method that uses a small external electric current to deliver water-soluble, charged drugs into the skin; a heat-aided drug delivery technology which is combined with a eutectic formulation of the topical anesthesia; and sonophoresis using sound waves.

[0007] Although useful as local anesthetics, these prior products are not particularly stable, may have slow onset, may require the use of a device, and may cause skin irritation. These properties cause substantial drawbacks for their use as local anesthetics. Some previous products - particularly lidocaine/prilocaine combinations - are also associated with vasoconstriction (which retards the absorption of local anesthetics and disrupts the healing process) which is an undesirable side- effect of local anesthetic use.

[0008] Common knowledge in the field of local anesthesia has taught that an aqueous component is required for effective topical anesthesia because release of anesthetics is either too slow from lipophilic vehicles or results in an immeasurable drug delivery rate. The application of a free-base anesthetic in a lipophilic vehicle was found to be especially ineffective if applied to intact skin (Absorption of local anesthetics, Campbell D. and Adriani J., JAMA (1958) 168: 873-7). [0009] Previous products which relied on the efficacy of tetracaine for topical local anesthesia utilized either the acid salt or base form of tetracaine with either an aqueous or liposome vehicle. Salts of local anesthetics are normally employed because they are more soluble and stable than the free-base form of the anesthetic. Previous research has shown that blood drug levels were not detectable when the free- base form of the drug was incorporated in oily ointment base vehicles due to extremely slow absorption rates (Absorption of local anesthetics, Campbell D. and Adriani J., JAMA (1958) 168: 873-7). Formulations of the base form of local anesthetics in oleaginous or hydrophobic base vehicles have previously and commonly been ineffective at producing local anesthesia in both broken and unbroken skin. Furthermore, a model study conducted by Lalor, Flynn, and Weiner (Lalor C. B., Flynn G. L., Weiner, N., J. Pharm. Sci. (1994) 83(11): 1525-8) studied the release and permeation rates characterizing the transport of a topically applied model drug from within its vehicle to the site of action in the skin and found that the drug was released two times slower from a mineral oil base vehicle than from an aqueous base vehicle at approximately equivalent thermodynamic activities. [0010] Previous topical local anesthetic formulations, although useful, have several drawbacks that have rendered their use less than optimal. These drawbacks included limited efficacy if applied to intact skin, reduced efficacy if an excipient had been used to increase the solubility and stability of the anesthetic, the rapid decomposition of anesthetics (particularly amino-ester derived anesthetics such as tetracaine) in aqueous formulations (Smith G.G., Kennedy D.R., Nairn J.G., J. Pharm. Sci. (1974) 63(5): 712-6. Schreier, S., Do Amaral, A. T., Stachissini, A. S., Bianconi, M. L. B., Magn. Reson. (1986) 8(3.4): 166-71), and the slow release of anesthetics from lipophilic vehicles (Campbell, D. and Adriani, J., JAMA (1956) 162: 527-520). [0011] In light of the drawbacks of these prior formulations, there is therefore a need for a topical formulation that is more stable, offers a faster onset and a longer lasting anesthesia than existing technologies, is without the adverse reactions of existing technologies such as vasoconstriction or the uncomfortable itchiness associated with erythema, and may be used without physical stimulation of the skin surface, for example, by heat or by iontophoresis.

SUMMARY

[0012] The inventors have discovered the following formulations that may be used to overcome some or all of the drawbacks of the prior formulations. In one embodiment, the formulation includes an oleaginous base vehicle and a free-base anesthetic compound. In one embodiment, the free-base anesthetic may have a Log octanol/water partition coefficient greater than or equal to about 1 and less than or equal to about 5. Log values as used herein are the LoglO scale. In one version of this embodiment, the free-base anesthetic compound may be a benzoate ester or amino-ester, an anilide amino-amide, a naphthoate amino-ester, a benzoic acid, pramoxine, dyclonine, or mexiletine. In another embodiment, the free-base anesthetic may be lidocaine, prilocaine, bupivacaine, mepivocaine, etidocaine, butanilcaine, or trimecaine, or, alternatively, tetracaine, benzocaine, procaine, chlorprocaine, butamben, picrate, or dibucaine. In one version of this embodiment, the free-base anesthetic may be present in an amount between about 0.5% and about 20% by weight. In one version of this embodiment, more than one anesthetic may be used. In one version of this embodiment, the free-base anesthetic is tetracaine. In one version of this embodiment, the oleaginous base vehicle may be mineral oil, petrolatum, a natural oil, a fatty ester, or a fatty alcohol. In a further version of this embodiment, the natural oils may be cottonseed oil, sesame oil, peanut oil, mink oil or jojoba oil. In a further version of this embodiment, the fatty ester may be propylene glycol dicaprylate caprate, cetearyl octanoate, isopropyl myristate, isopropyl palmitate, isopropyl lanolate, acetylated lanolin, decyl oleate or hexyl laurate. In a further version of this embodiment, the fatty alcohol may be isohexadecyl, stearyl, lauryl, cetyl or oleyl alcohol. The oleaginous base may contain one or more humectants. In one version of this embodiment, the humectants may be glycerin, lanolin, or propylene glycol. [0013] In another embodiment, the formulation includes an oleaginous base vehicle, a free-base anesthetic and a solubility enhancer. In one version of this embodiment, the solubility enhancer may be an alcohol, esters of hydrocarbons, dimethylsiloxane, essential terpenes from plants, terpenols, pentadecalactone, acetone, ethylene and diethylene glycol ethers, polyethylene glycol ethers or esters. In one version, the alcohols may be benzyl alcohol, diethylene glycol monoethyl ether, propylene glycol, 2-hexyl-l-decanol, isopropyl alcohol, hexylene glycol, or α- terpenol. In one version, the esters of hydrocarbons may be benzoate, isopropyl acetate, glycerol monostearate, glyceryl esters, or bornyl acetate. In one version of this embodiment, the solubility enhancer is present in an amount between about 1% and about 20% by weight.

[0014] In a further embodiment, the formulations described in the previous embodiments may contain one or more of a penetration enhancer, an antioxidant, a gelling agent, and an antimicrobial agent in addition to the oleaginous base vehicle and free-base anesthetic or the oleaginous base vehicle, free-base anesthetic, and solubility enhancer. In one version of this embodiment, the penetration enhancer may be saturated or unsaturated fatty acids and esters, oxazolidinones, hydrophobic lactams, menthol, eugenol, and capsaicin. In another embodiment, the penetration enhancer may be ethyl oleate. In another version of this embodiment, the penetration enhancer may be present in an amount between about 1 percent and about 20 percent by weight. In one version of this embodiment, the antioxidant has a Log octanol/water partition coefficient about or greater than one. In one version of this embodiment, the antioxidant may be octyl gallate, tocopherols, ascorbyl palmitate, butylated hydroxyanisole, ascorbyl palmitate, butylated hydroxyl anisole, tocopherols excipient, tocopherol acetate or butylated hydroxytoluene. In one version of this embodiment, the antioxidant is present in an amount between about 0.001% and about 5% by weight. In another version of this embodiment, the gelling agent may be an alkene copolymer. The alkene copolymer of the gelling agent may be a butylene- ethylene-styrene copolymer in combination with an ethylene-propylene-styrene copolymer. In one version, the gelling agent may be present in an amount between about 0.01% and about 10% by weight, ϊn another version of this embodiment, the antimicrobial agent may be a paraben (e.g., methyl-, propyl-, or butylparaben), methyl salicylate, phenethyl alcohol, or resorcinol.

[0015] In further embodiments of the invention, the local anesthetic formulation described in the previous embodiments may be incorporated into a drug delivery patch, gel, or lotion. The drug delivery patch may be a reservoir based patch, a matrix patch, a multi-laminate drug in adhesive patch, or a monolithic drug in adhesive patch. The drug delivery patch may also be a drug in adhesive type patch where the adhesive-drug layer contains the local anesthetic formulation described in the previous embodiments and a polymeric material, a hydrophobic adhesive, and a diffusion enhancer. The polymeric material may be hydrophobic or a polyacrylate. The hydrophobic adhesive may be a polyisobutylene, a silicone, or an acrylate. [0016] In one embodiment, the formulation includes tetracaine, an oleaginous base vehicle, and benzyl alcohol. In one version of this embodiment, the oleaginous base vehicle is a mineral oil. In one version of this embodiment, the tetracaine is present in an amount between about 0.5 percent by weight and about 20 percent by weight. In another version of this embodiment, the tetracaine is present in an amount of about 2 percent by weight. In one version of this embodiment, the benzyl alcohol is present in an amount between about 1 percent by weight and about 20 percent by weight. In another version of this embodiment, the benzyl alcohol is present in an amount of about 5 percent by weight. In one version of this embodiment, the formulation also includes a penetration enhancer, which may be, but is not limited, to ethyl oleate. In one version of this embodiment, the penetration enhancer is present in an amount of about 10 percent by weight.

[0017] A further embodiment of the invention provides a drug delivery patch that includes one or more of the formulation described above and a patch. Specific patches that may be used are described in detail in the Detailed Description section below.

[0018] A further embodiment of the invention provides methods of applying the above described formulations. In one version of this embodiment, the a local anesthetic formulation as described in the previous embodiments may be applied topically, may be applied to an individual's broken or intact skin, and may be applied using a drug delivery patch or gel formulation; the individual to whom the invention is applied may be a mammal, and, in particular, a human. Specific details of these methods are described in the Detailed Description section below. [0019] In another embodiment, the invention provides a method for treating pain in an individual by applying a local anesthetic formulation as described in the previous embodiments to an individual in an amount effective to treat pain. In one version of this embodiment, the individual is a mammal; and, in another version of this embodiment, the individual is a human. Specific details of these methods are described in the Detailed Description section below.

[0020] Another embodiment of the invention provides a suture treated with a local anesthetic formulation as described in the previous embodiments. In one version of this embodiment, the treated suture includes a suture and an anesthetic formulation incorporated into at least a portion of the suture or present on at least a portion of the surface of the suture.

DETAILED DESCRIPTION

[0021] In this section, we first describe various formulations that may be used in the invention together with detailed descriptions of the various components of the formulations. We then describe various methods of using the formulations of the invention, and present experimental results, demonstrating the efficacy and advantages of the formulations of the present invention.

Formulations

[0022] Formulations of the invention generally contain an oleaginous base vehicle and a free-base anesthetic. In certain embodiments, the formulations also contain various additional components, which may be used for adjusting the viscosity, increasing the shelf-life and stability of the formulation, or enhancing skin penetration. For example, in addition to the oleaginous vehicle and a free-base anesthetic, formulations may include solubility enhancers, penetration enhancers, antioxidants, gelling agents, and anti-microbial agents. We describe in detail below specific examples of these additional components that may be used in the invention. [0023] In one embodiment, the invention provides a formulation that includes an oleaginous base vehicle, a free-base anesthetic, and a solubility enhancer. This formulation may also include additional components including but not limited to penetration enhancers, antioxidants, gelling agents, and anti-microbial agents. We describe in detail below the oleaginous base vehicles, free-base anesthetics, solubility enhancers, and additional components that may be used in this formulation. In one version of this embodiment the formulation includes an oleaginous base vehicle, tetracaine, and benzyl alcohol.

[0024] In another embodiment, the invention provides a formulation that includes an oleaginous base vehicle, a free-base anesthetic, a solubility enhancer, and a penetration enhancer. This formulation may also include additional components including but not limited to antioxidants, gelling agents, and anti-microbial agents. We describe in detail below the oleaginous base vehicles, free-base anesthetics, solubility enhancers, penetration enhancers, and additional components that may be used in this formulation.

[0025] The formulations of the invention may be prepared using methods commonly known in the art, including, but not limited to, the preparation methods described in detail below.

[0026] In this application, unless the context makes clear otherwise, we use the terms "formulation" and "composition" inter-changeably. Oleaginous Base Vehicle

[0027] Generally, any oleaginous, anhydrous, or hydrophobic base vehicle capable of containing and releasing the free-base anesthetics of the invention may be used.

[0028] In one embodiment of the invention, the base vehicle is an oleaginous based vehicle. In one embodiment of the invention, the oleaginous base vehicle is a mineral oil, petrolatum, natural oil, fatty ester, or fatty alcohol, or combinations thereof. Natural oils that may be used include but are not limited to cottonseed, sesame, peanut, mink or jojoba oils, or combinations thereof. Examples of fatty esters include but are not limited to propylene glycol dicaprylate caprate, cetearyl octanoate, isopropyl myristate, isopropyl palmitate, isopropyl lanolate, acetylated lanolin, decyl oleate or hexyl laurate, or combinations thereof. Fatty alcohols include but are not limited to isohexadecyl, stearyl, lauric, cetyl or oleyl alcohols, or combinations thereof. Additionally, humectants such as glycerin, lanolin or propylene glycol, or combinations thereof may be added to the formulations to increase efficacy and feel.

Free-base Anesthetic

[0029] Generally, any compound may be used as the free-base anesthetic provided it may be contained in the oleaginous base vehicle and may have an anesthetic effect.

[0030] In one embodiment of the invention, the free-base anesthetic is any anesthetic with an octanol/water partition coefficient (P) with Log P greater than or equal to 1 and less than or equal to 5. In one embodiment of the invention, the anesthetic is selected from one or more amino-type anesthetics and ester-type anesthetics. In one embodiment of the invention, the anesthetic is selected from lidocaine, prilocaine, bupivacaine, mepivacaine, etidocaine, butanilcaine, trimecaine, tetracaine, benzocaine, procaine, chloroprocaine, butamben picrate, dibucaine, pramoxine, dyclonine, and mexiletine, and combinations thereof. In one embodiment of the invention, the free-base anesthetic is tetracaine. Generally, the free-base anesthetic may be present in any amount allowing effective anesthesia by the applied formulation. In one embodiment of the invention, the free-base anesthetic is present in an amount between about 0.5 percent and about 20 percent by weight. This weight percentage range was shown to be efficacious because less that about 0.5 percent did not allow a noticeable effect on solubility while greater than about 20 percent by weight increased the anesthetic solubility in the delivery vehicle to a point where the anesthetic no longer penetrated skin effectively.

[0031] In various embodiments of the invention, the formulation includes one, two, three, or more than three free-base anesthetics.

Solubility Enhancers

[0032] A solubility enhancer is a substance that increases dissolution of a compound in a medium thereby increasing solubility of the compound. Generally, any compound may be used as a solubility enhancer that is effective in increasing anesthetic solubility.

[0033] In one embodiment of the invention, the solubility enhancer is selected from one or more of the following: alcohols such as benzyl alcohol, esters of hydrocarbons such as cetearyl ethyl hexanoate, cyclopentadecalactone (omega- pentadecalactone), isopropyl myristate, sorbitan monolaurate (Arlacel-20), and diverse excipients such as dimethylsiloxane, and essential terpenes from flowers and plants including peanut oil, lanolin, Eucalyptus oil and Tea tree oil and various terpenols. The solubility enhancer may also be any combination of the above described components. The terpenes may also provide the gels with anti-microbial properties. Other examples of esters of hydrocarbons include benzyl benzoate, isopropyl acetate, glycerol monostearate, glyceryl esters, and bornyl acetate. Other examples of alcohols include diethylene gycol monoethyl ether, propylene glycol, eugenol, 2-hexyl-l- decanol, isopropyl alcohol, hexylene glycol, and α-terpenol. In other embodiments of the invention, the solubility enhancer is acetone, ethylene or diethylene glycol ethers, polyethylene glycol, ethers, or esters.

[0034] Benzyl alcohol, when used as a solubility enhancer, may also be a fast acting anesthetic, a penetration enhancer, and an antimicrobial agent. When tetracaine is the desired anesthetic, a combined effect has been observed between benzyl alcohol and tetracaine, in that the benzyl alcohol increases the efficacy of tetracaine at depressing cold sensation and the irritation caused by topical capsaicin. The combined effect of benzyl alcohol on tetracaine efficacy at depressing cold sensation and capsaicin induced irritation is discussed below in the experimental section with particular reference to the data presented in table 3. [0035] Generally, the solubility enhancer may be present in any amount allowing enhanced dissolution of the anesthetic in the oleaginous base vehicle. In addition to acting as a solubility enhancer the solubility enhancer component of the formulation may also act as a penetration enhancer, and in this case the solubility enhancer is generally present in an amount allowing enhanced dissolution of the anesthetic in the oleaginous base vehicle and allowing enhanced penetration of the anesthetic into the desired tissue.

[0036] In one embodiment of the invention, the solubility enhancer is present in an amount of between about 1 percent and about 20 percent by weight.

Penetration Enhancers

[0037] Generally, any compound may be used that is effective in facilitating penetration of the anesthetic into the tissue.

[0038] In one embodiment of the inventive formulation, the penetration enhancer is selected from one or more of the following: esters of saturated and unsaturated fatty acids (e.g., ethyl oleate), oxazolidinones (e.g., 4-decyl-2- oxazolidinone (SR-38)), hydrophobic lactams (e.g., azone), menthol, eugenol, capsaicin and dimethyl sulfoxide. Hydrophobic alkanols and carboyxlic acids (e.g., oleyl alcohol and oleic acid) were found not to function well as penetration enhancers because they render the formulation less effective.

[0039] Generally, the penetration enhancer may be present in any amount allowing enhanced penetration into the desired tissue.

[0040] In one embodiment of the invention, the penetration enhancer is present in an amount of between about 1 percent and 20 percent by weight.

Antioxidants

[0041] Generally, any compound may be used that is effective in stabilizing the formulation, providing the antioxidant compound is soluble in the formulation. [0042] In one embodiment of the invention, the antioxidant is selected from one or more of the following: β-carotene, tocopherols (including β -tocopherols), octyl gallate, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tocopherol acetate, tocopherols excipient, and known compounds that are hydrophobic (where hydrophobic as used here means having a water/octanol partition coefficient (P) of Log P > 1). As used here a tocopherol excipient is a vegetable oil solution containing not less than 50.0 percent of total tocopherols, of which not less than 80.0% consists of varying amounts of beta, gamma, and delta tocopherols.

[0043] Generally, the antioxidant may be present in any amount allowing enhanced stabilization of the formulation. In one embodiment, the antioxidant is present in an amount between about 0.001% and about 5% by weight.

Gelling Agents

[0044] Generally, any compound may be used that is effective in optimizing the viscosity of the gel.

[0045] In one embodiment of the invention, the gelling agent is an alkene copolymers. In one embodiment of the invention, the gelling agent is butylene- ethylene-styrene copolymer (Chem. Abst. Reg. No. 57271-36-0) or ethylene- propylene-styrene copolymer (Chem. Abst. Reg. No. 25608-79-1).

[0046] Generally, the gelling agent may be present in any amount allowing enhancement of the formulation viscosity. In one embodiment, the gelling agent is present in an amount between about 0.01% and about 10% by weight.

Antimicrobial Agents

[0047] Generally, any compound may be used that is effective in reducing or preventing build up of microbial load in the formulation.

[0048] In one embodiment of the invention, the antimicrobial agent is selected from one or more of the following: parabens (e.g., methylparaben, propylparaben, butylparaben), methyl salicylate, phenethyl alcohol, and resorcinol.

Specific Formulations and Preparation Methods

[0049] In one embodiment of the invention, the formulation includes the following components: tetracaine (2% by weight); benzyl alcohol (5% by weight); ethyl oleate (10% by weight); and Versagel™ M200 (83% by weight).

[0050] In another embodiment of the invention, the formulation includes the following components: tetracaine (2% by weight); benzyl alcohol (5% by weight); P T/US03/07424 ethyl oleate (10% by weight); butylated hydroxyl toluene (BHT) (0.02% by weight) and Versagel™ M200 (82.98% by weight).

[0051] One process that may be used for preparation of the above formulations includes the following steps: (1.) Weigh Versagel¹ M200 in a manufacturing vessel; (2.) Weigh and add tetracaine, ethyl oleate and benzyl alcohol in a separate vessel; (3.) Agitate the mixture from step 2 with a propeller mixer until all the tetracaine is dissolved; (4.) Add the solution from step 3 to the manufacturing vessel of step 1; and (5.) Agitate the dispersion with propeller mixing until the system is well mixed. Generally, any process known in the art may be used for preparation of the formulations described in this application.

Methods of Use of Formulations

[0052] In one embodiment of the invention, the formulations described above are used for the treatment or prevention of pain. The formulations may be used for the treatment of various types of pain, including but not limited to cutaneous pain, neuropathic pain, rheumatoid arthritis, and osteoarthritis. The formulations may also be used to treat pain associated with various procedures including, but not limited to dental procedures, plastic surgery, flexible sigmoidoscopy, fiber optic procedures, transtracheal injections, circumcision, wart removal, cystoscopy, bronchoscopy, esophagoscopy, or proctoscopy. Dental procedures include but are not limited to general dentistry, orthodontial, periodontal procedures, tooth cleaning and tooth extraction. Plastic surgery procedures include, but are not limited to cosmetic and reconstructive surgery.

[0053] Formulations of this invention may be used to treat pain associated with all areas of the body. Specific areas of the body that may be treated include, but are not limited to skin (intact and broken), mucous membrane, intrapulmonary tissue, transmucosal tissue, retrobulbar tissue, conjunctival tissue, peri auricular tissue, the mouth (tongue, gums, cheek membrane, tonsils, hypopharynx); the nostril, esophagus, trachea, bronchii, urethra, vagina, cervix, intra- vesicles, perineum, anus, and peri- rectum.

[0054] The formulations described above may generally be delivered using any known drug delivery method, including but not limited to topical applications of sprays, gels, sutures and patches. For information on the general use and application of local anesthetics see Local Anesthetics by Rudolph H. de Jong, 1994; Mosby. [0055] In one embodiment of the invention, the formulation is applied topically to an individual. The formulations of the invention have been shown to be effective when applied to intact skin and the inventors believe the formulation will also be effective when applied to broken skin. The individual to whom the local anesthetic is topically applied may be of any species that would benefit from the ameliorative properties of the formulation. In one embodiment of the invention, the individual is a mammal. In one embodiment of the invention, the individual is a human. The individual may be, but is not limited to, primates, farm animals, sports animals, pet animals, and domesticated animals.

[0056] As used in this patent, "treatment," "treating" or similar words is an approach for obtaining beneficial or desired results, including and preferably clinical results. Treatment can involve optionally either the amelioration of symptoms of the pain or disease, the prevention of symptoms of the pain or disease, the reduction or removal of the cause of the pain or disease, or the delaying of the progression of the pain or disease.

[0057] In another embodiment of the invention an individual is pretreated with a formulation described in this patent prior to the individual undergoing a medical procedure. Such pretreatment may assist in treating pain associated with the medical procedure. Generally, individuals undergoing any medical procedures may benefit from pretreatment using formulations described in this patent. Individuals undergoing medical procedures including but not limited to procedures described elsewhere in this patent may benefit from pretreatment. Individuals undergoing biopsies, cosmetic surgery, dermal abrasions, dermal peels, skin exfoliation, wart removal, phlebotomy, suturing of wounds, dental procedures, stripping of varicose veins, excision of keloids or scars, bunionectomy, removal of ingrown toe nails, body piercing, and tattooing may benefit from pretreatment. Pretreatment may occur at any time prior to the individual undergoing the medical procedure including, but not limited to immediately prior to the treatment or within an hour prior to the beginning of the procedure. Another aspect of this invention includes pretreatment of the individual within a day prior to the beginning of the procedure or within a week, days, hours, or minutes prior to the beginning of the procedure. Treatment with methods and formulations of this invention may also occur during or after a medical procedure.

Topical Application of Gel Formulation

[0058] The formulations described above may be applied to the individual to be treated as a gel formulation. In this embodiment, the formulation may be applied using known methods of topical gel application including by means of aerosol, spraying, pumping, brushing, swabbing, or combinations thereof.

Patch Drug Delivery Method

[0059] The anesthetic formulations, may be incorporated into drug delivery patches. The patch types may include liquid reservoir based patches, microdispersed or microreservoir system, matrix type patches, and multilaminate and monolithic drug in adhesive type patches. As used herein, microdispersed or microreservoir systems consist of dispersed particles or droplets incorporated in a an adhesive matrix. The adhesive-drug layer is a formulated matrix base containing a polymeric material. The formulated matrix base may include hydrophobic adhesives such as polyisobutylenes (PIB), silicones, acrylates, and other hydrophobic adhesives. The polymeric material contained within the matrix base may be a hydrophobic polymeric material such as polyacrylates. PIB matrices usually contain high molecular weight PIB for cohesive strength, low molecular weight polymers for tack and resins for optimization of properties. A patch containing a hydrophobic anesthetic compound in a PIB matrix may require the addition of diffusion enhancers because of the mutual affinity of the polymer and anesthetic compound. Silicones contain various amounts of free silanol groups (Si-OH) that can be functionalized for specific properties. Acrylates are copolymerized acrylate esters produced by a solution or an emulsion process that may include other monomers. Options for production of adhesives based on acrylates allows for design of hydrophobic adhesive matrices. Suture Drug Delivery Method

[0060] The anesthetic formulations described in this patent may also be incorporated into at least a portion of a suture or may be present on the surface of at least a portion of a suture. Sutures may include, but are not limited to fine thread, staple, pins or other material used surgically to close wounds or join tissues. The sutures may be absorbable or non absorbable. The suture types may include, but are not limited to thread, staples, polyglycolic acid (PGA), plain catgut, chromic monofilament catgut, polypropylene monofilament, polyamide, black braided silk or coated polyester. A suture including an anesthetic formulation described in this patent may be manufactured using methods well known in the art, including but not limited to external coating post extrusion.

[0061] A suture comprising an anesthetic formulation described in this patent may be used in procedures including, but not limited to, closing of wounds or lacerations of an individual that may occur through injury or medical procedure. Sutures or staples comprising an anesthetic formulation described in this patent may be used to join bone, cartilage, skin or tissue that may have been damaged during injury or medical procedure.

Examples Example 1 Effectiveness Testing Procedures

[0062] In vivo efficacy of the topical local anesthetic formulation was measured by quantitative sensory testing (QST), a diagnostic and non-invasive procedure that measures thermal sensory thresholds allowing the study of small- diameter (nociceptor) pain sensory fibers. Previous research in the field of anesthesia (e.g., conducted by Dr. Howard Maibach and colleagues at the University of California San Francisco, J. Invest. Dermatol. (1999) 113(3):304-7) has suggested that measurements of cold sensitivity are as sensitive as any other modality to detect and compare the effectiveness of different local anesthetics. Cold sensitivity testing to measure formulation efficacy was conducted using a computerized QST instrument equipped with a 1.5 x 1.5 cm thermode. The inventive formulations were also tested against irritation caused by topical capsaicin.

[0063] The QST testing was performed on 4 locations (2 per arm) of the subject's forearms. The different steps in QST were the following:

1) Two locations on the ventral aspects of each arm were identified and outlined with a marker.

2) Baseline QST was performed at each location.

3) An adhesive, sponge-like dam, with an approximate size of a silver dollar, was placed at each location in order to maintain the study drug on the skin. 4) A different preparation was placed on each location and the creams or gels were covered to create an occlusive dressing. Furthermore, at least one of the locations per subject included a placebo or vehicle gel.

5) QST was repeated at the same site after the creams/gels were placed at 30, 60 and 90-min intervals.

6) In addition, subjects were evaluated for skin reactions and possible uncomfortable sensations.

[0064] Prevention of irritation caused by topical capsaicin was evaluated under the following protocol.

1) Two locations are identified on the ventral aspect of each arm; the locations are outlined with a permanent marker. Each location will be approximately a 1.5 centimeter circle.

2) An adhesive, sponge-like dam is placed at each location in order to maintain the study solution on the skin.

3) A different solution of local anesthetic is placed at each location on the subject's ventral forearm for 30 minutes. After the 30 minute period the local anesthetic will be wiped off and Zostrix™ (an OTC cream containing 0.075% capsaicin (w/w)) applied for up to 120 minutes. The subjects rate their pain every 15, 30, 45, and 60 minutes on a 0-10 pain scale (Visual Analog Score (VAS) scale).

Results for Example 1

[0065] Gel formulations containing 2% tetracaine were compared to creams containing either aloe vera, different vehicle gels, EMLA^®, or ELA-Max^®. In these tests a topical local anesthetic formulations of the invention were found to produce marked reductions in cold sensitivity thresholds, as displayed in Table la. Sample compositions of the tested tetracaine formulations are listed in Table 2a. The combined effect of benzyl alcohol and tetracaine at depressing cold sensation and irritation caused by topical capsaicin is shown in the experimental results of Table 3. [0066] Tables la-d display the percent depression in cold sensation after 30 minutes or longer for EMLA^®, ELA-Max^® and various gel formulations of the inventive topical local anesthetic. The data shows that marked percent depressions in cold sensation can be quickly and effectively produced using various formulations of the invention and shows that the range of percent depression in cold sensation achieved using the inventive formulation depends on the composition of the inventive formulation. Table lc shows the depression of cold sensation over a period of 90 minutes for formulations that do not include a solubility enhancer. Table Id shows the depression of cold sensation over the same time period for formulations that contain anesthetics other than tetracaine. Particular formulations from both sets show significant depressions in cold sensation. The compositions of these formulations can be found seen in tables 2c and 2d, respectively.

[0067] Table 3 and Figure 1 demonstrate the combined effect of solubility enhancers, such as benzyl alcohol, on the efficacy of tetracaine at depressing cold sensation and irritation caused by topical capsaicin. The efficacy of benzyl alcohol (formulation #2) and tetracaine (formulation #3) is approximately the same, but when the benzyl alcohol and tetracaine are combined (as in formulation #1), a much greater effect on cold sensation depression is observed (Table 3).

[0068] Figure 1 shows the average VAS score (discussed above) as a function of time for various formulations applied to unbroken skin of human subjects. Figure 1 presents results for application of (1) a pure Versagel™ M200 formulation (represented by the diamonds legend in Figure 1); (2) 5% by weight of benzyl alcohol in Versagel™ M200 (squares); (3) 2% by weight tetracaine in Versagel™ M200 (triangles); and (4) a formulation including 5% by weight benzyl alcohol, 2% by weight of tetracaine, and formulation 54A, 10% by weight of ethyl oleate in Versagel™ M200 (circles). As can be seen from the results in Figure 1, pain suppression achieved by the benzyl alcohol and tetracaine mixture is substantially superior to pain suppression achieved by the other formulations. [0069] The combined effect of benzyl alcohol and tetracaine may also be seen from the data presented in Table 1. In these results, formulation 18 A, which, as Table 2a displays, is comprised of 2% tetracaine, 4% benzyl alcohol, 4% clove oil, and 90% Versagel™ M200, where Versagel™ M200, supplied by Penreco Corporation (of Dickinson, TX), is a mineral oil based vehicle with gelling hydrocarbons added to increase viscosity of the preparation. Formulation 18A produced a 33% depression in cold sensation at 30 minutes. Formulation 42A, which as Table 2a displays, is comprised of 2% tetracaine, 5% benzyl alcohol, 5% eugenol, 10 % pentadecalactone, and 78% Versagel™ M200 produced a 38% depression in cold sensation at 30 minutes. If the combined effect of benzyl alcohol and tetracaine is not utilized, as 03/07424 with embodiment 32C of the inventive formulation, a percent depression in cold sensation of 26% is effectively achieved. Formulation 32C is comprised of 2% tetracaine, 4% eugenol, 10% pentadecalactone, and 84% Versagel™ M200. [0070] In this patent, "fast acting" means a 10% or higher measurable depression in pain or cold sensation at 30 minutes after application of the topical local anesthetic.

Table la. Effectiveness of 2% Tetracaine Gels in Comparison to ELA-Ma and EMLA^® Cream

1. °/

2. SEM is the standard error of the measurement.

3. The area under the curve (AUC) represents the sum of the percent change from baseline response at 30, 60, or 90 min. after application.

4. N = number of measurements 03 07424

Table lb. Time-dependent Effectiveness of 2% Tetracaine Gels

* Actual time points were 35, 80 and 90 minutes. Table lc. Time-dependent Effectiveness of 2% Tetracaine Gels Lacking Solubility

Enhancer

Table 2a. Percent Compositions of Tetracaine Gels (%w/w)

Table 2c. Percent Composition of Formulations Lacking Solubility Enhancer %w/

Table 3.

In Versagel T¹M™ M200

Example 2 Effectiveness of Formulation 54A Methods:

[0071] Gel formulation 54A (table 2b) comprised of 5% Benzyl alcohol and

10% ethyl oleate was applied to an area of about 800 square centimeters on the shin and thigh of test subjects. Two hours after application, the clinical effects of the gel were tested by two methods. Using the sharp point of an unraveled paper clip, subjects were tested for sensitivity to light touch and stronger pressure. Sensitivity to strong pressure was tested by determining whether the subjects felt a "sharp" or "dull" sensation upon pushing the pointed end of the paper clip deep into the skin tissue without breaking the skin. The Clinical Effect Observations listed below are as compared with untreated skin. Hence, "Yes" means that the light touch sensation was not appreciably different than untreated skin and "No" means that light touch sensation was blocked or absent.

Results:

[0072] The results of the sensitivity to light and strong touch with a paper clip point can be seen in table 4.

Table 4 Clinical Observations During Treatment With Formulation 54A

* each X indicates location of a single application area

[0073] The anesthetic effect of the drug was more pronounced over the thigh application area than the over the skin on the shin. All of the patients with thigh application areas felt only "dull" pressure when probed with the paper clip point. No "sharp" sensations were reported. However, there was variability in light touch between patients. Some felt none, others could still feel light touch sensations. The majority of the patients could feel light touch over the shin. Only one patient had a "complete" effect over the shin in which he did not feel light touch and felt only dull pressure with the paper clip point. The majority of patients felt "sharp" sensations from the clip pressure over the shin.

[0074] Many patients reported sensing the "light touch" of the paper clip in certain parts of the application zone, but no sensations in other areas within the same application zone. One patient still had a full anesthetic effect on the thigh after 7 hours, experiencing lack of light touch sensation and lack of dull sensation to deep probe of the paper clip point. However, the duration of effect also exhibited variability. Another patient noted some return of light touch on the thigh and some "sharp" sensation by 5 hours post application. In general, the effect over the shin application areas seemed to dissipated more quickly. [0075] All patients (without placebo) had fairly uniform redness from vasodilation involving the application area by 20-30 min. The red area appeared more "patchy" by 1 1/2 to 2 hours. When the gel was removed, the redness of the vasodilation dissipated within minutes. Patients with placebo demonstrated no vasodilatory affect. No cardiac changes were noted within the application area. [0076] These results demonstrate long lasting effects of this formulation in decreasing the sensitively of patients to light touch and sharp touch. [0077] It is understood that the examples and embodiments described in this patent are for illustrative purposes only and that various modifications or changes will be suggested to persons skilled in the art and are to be included within the disclosure in this application and scope of the claims. All publications, patents and patent applications cited in this patent are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application were specifically and individually indicated to be so incorporated by reference.

Claims

CLAIMSWhat is claimed is:

1. A composition comprising an oleaginous base vehicle, at least one free-base anesthetic compound, and a solubility enhancer.

2. The composition of claim 1, wherein the free-base anesthetic has a log octanol/water partition coefficient greater or equal to about 1 and less than or equal to about 5.

3. The composition of claim 1 , wherein the free-base anesthetic compound is an amino-type anesthetic, an ester-type anesthetic, pramoxine, dyclonine, or mexiletine, or combinations thereof.

4. The composition of claim 1 , wherein the free-base anesthetic compound is selected from the group consisting of lidocaine, prilocaine, bupivacaine, mepivacaine, etidocaine, butanilcaine, trimecaine, tetracaine, benzocaine, procaine, chloroprocaine, butamben picrate, and dibucaine, and combinations thereof.

5. The composition of claim 1, wherein the free-base anesthetic compound is tetracaine.

6. The composition of claim 1, wherein the free-base anesthetic is present in an amount of between about 0.5 percent and about 20 percent by weight.

7. The composition of claim 1, wherein the oleaginous base vehicle is selected from the group consisting of mineral oil, petrolatum, natural oils, fatty esters, and fatty alcohols and combinations thereof.

8. The composition of claim 7, wherein the natural oils are selected from the group consisting of cottonseed oil, sesame oil, peanut oil, mink oil, and jojoba oils and combinations thereof; wherein the fatty esters are selected from the group consisting of propylene glycol dicaprylate caprate, cetearyl octanoate, isopropyl myristate, isopropyl palmitate, isopropyl lanolate, acetylated lanolin, decyl oleate and hexyl laurate and combinations thereof; and wherein the fatty alcohols are selected from the group consisting of isohexadecyl, stearyl, lauryl, cetyl and oleyl alcohols and combinations thereof.

9. The composition of claim 7, wherein the oleaginous base vehicle further comprises one or more humectants selected from the group consisting of glycerin, lanolin, and propylene glycol, and combinations thereof.

10. The composition of claim 1, wherein the solubility enhancer is selected from the group consisting of alcohols, esters of hydrocarbons, dimethylsiloxane, essential terpenes from plants, terpenols, pentadecalactone, acetone, ethylene and diethylene glycol ethers, polyethylene glycol, ethers and esters and combinations thereof.

11. The composition of claim 10, wherein the alcohols are selected from the group consisting of benzyl alcohol, diethylene gycol monoethyl ether, propylene glycol, 2-hexyl-l-decanol, isopropyl alcohol, hexylene glycol, eugenol and α-terpenol and combinations thereof; and wherein the esters of hydrocarbons are selected from the group consisting of benzyl benzoate, isopropyl acetate, isopropyl myristate, glycerol monostearate, glyceryl esters, cetearyl ethyl hexanoate, cyclopentadecalatone, sorbitan monolaurate and bornyl acetate and combinations thereof.

12. The composition of claim 1, wherein the solubility enhancer is present in an amount of between about 1 percent and about 20 weight percent.

13. The composition of claim 1 , wherein the solubility enhancer is benzyl alcohol.

14. The composition of claim 1, further comprising a penetration enhancer selected from the group consisting of esters of saturated and unsaturated fatty acids, dimethyl sulfoxide, oxazolidinones, hydrophobic lactams, menthol, eugenol and capsaicin.

15. The composition of claim 14, wherein the penetration enhancer is ethyl oleate.

16. The composition of claim 14, wherein the penetration enhancer is present in an amount of between about 1 percent and about 20 percent by weight.

17. The composition of claim 1, further comprising an antioxidant selected from the group consisting of octyl gallate, tocopherols, tocopherol esters, ascorbyl palmitate, butylated hydroxyanisole, and butylated hydroxytoluene.

18. The composition of claim 17, wherein the antioxidant has a Log octanol/water partition coefficient greater than one.

19. The composition of claim 17, wherein the antioxidant is present in an amount of between about 0.001 percent and about 5 percent by weight.

20. The composition of claim 1, further comprising a gelling agent selected from the group consisting of alkene copolymers and a butylene-ethylene-styrene copolymer in combination with an ethylene-propylene-styrene copolymer.

21. The composition of claim 20, wherein the gelling agent is present in an amount of between about 0.01 weight percent and about 10 weight percent.

22. The composition of claim 1, further comprising an antimicrobial agent selected from the group consisting of parabens (e.g., methyl-, propyl-, or butylparaben), methyl salicylate, phenethyl alcohol, and resorcinol.

23. A drug delivery patch comprising a patch, an oleaginous base vehicle, a free-base anesthetic, and a solubility enhancer.

24. The drug delivery patch of claim 23, wherein the solubility enhancer is benzyl alcohol.

25. The drug delivery patch of claim 23 , wherein the patch is selected from the group consisting of liquid reservoir based patches, microdispersed or microreservoir system, matrix patches, multi-laminate drug in adhesive patches, and monolithic drug in adhesive patches.

26. The drug delivery patch of claim 23, wherein the patch is a drug in adhesive patch comprising an adhesive-drug layer comprising the oleaginous base vehicle, the free-base anesthetic, the solubility enhancer, and a polymeric material.

27. The drug delivery patch of claim 26, wherein the polymeric material is hydrophobic.

28. The drug delivery patch of claim 26, wherein the polymeric material is a polyacrylate.

29. The drug delivery patch of claim 26, wherein the adhesive-drug layer further comprises a hydrophobic adhesive selected from a polyisobutylene, a silicone, or an acrylate.

30. The drug delivery patch of claim 26, wherein the adhesive-drug layer further comprises a diffusion enhancer.

31. A method for treating pain in an individual comprising topically applying to an individual the composition of claim 1.

32. The method of claim 31 , wherein the free-base anesthetic has a log octanol/water partition coefficient greater or equal to about 1 and less than or equal to about 5.

33. The method of claim 31 , wherein the composition is applied topically as a gel formulation.

34. The method of claim 31 , wherein the composition is incorporated into a drug delivery patch.

35. The method of claim 34, wherein the drug delivery patch is the drug delivery patch of claim 25.

36. The method of claim 31 , wherein the composition is applied to intact skin.

37. The method of claim 31 , wherein the individual is a mammal.

38. The method of claim 37, wherein the mammal is a human.

39. A method for treating pain in an individual comprising applying to an individual a composition comprising a free-base anesthetic, an oleaginous base vehicle and a solubility enhancer, wherein the free-base anesthetic is present in an amount effective to treat pain in the individual.

40. The method of claim 39, wherein the solubility enhancer is benzyl alcohol.

41. The method of claim 39, wherein the application is topical.

42. The method of claim 39, wherein the individual is a mammal.

43. The method of claim 42, wherein the individual is a human.

44. The method of claim 39, wherein the pain is pain associated with a dental procedure, a plastic surgery procedure, or a medical procedure selected from the group consisting of fiber optic procedures, transtracheal injections, circumcision, wart removal, cystoscopy, bronchoscopy, esophagoscopy, urologic procedures and proctoscopy.

45. The method of claim 39, wherein the composition is applied to intact skin.

46. The method of claim 39, wherein the oleaginous base vehicle is a mineral oil.

47. The method of claim 39, wherein the free-base anesthetic is tetracaine.

48. The method of claim 47, wherein the individual is a human and the tetracaine is present in the composition in an amount effective to anesthetize a volume of the human adjacent to the topical application of the composition within 30 minutes of application.

49. The method of claim 39, wherein free-base anesthetic is tetracaine and the tetracaine is present in an amount of between about 0.5 percent and about 20 percent by weight.

50. The method of claim 39, wherein the tetracaine is present in an amount of about 2 percent by weight.

51. A composition comprising tetracaine, an oleaginous base vehicle, and benzyl alcohol.

52. The composition of claim 51 , wherein the oleaginous base vehicle is a mineral oil.

53. The composition of claim 51 , wherein the tetracaine is present in an amount of between about 0.5 percent and about 20 percent by weight.

54. The composition of claim 51 , wherein the tetracaine is present in an amount of about 2 percent by weight.

55. The composition of claim 51 , further comprising a penetration enhancer.

56. The composition of claim 55, wherein the penetration enhancer is ethyl oleate.

57. The composition of claim 56, wherein the ethyl oleate is present in an amount between 1% and 20% percent by weight.

58. The composition of claim 57, wherein the ethyl oleate is present in an amount of about 10% percent by weight.

59. The composition of claim 51 , wherein the benzyl alcohol is present in an amount between about 1 percent and about 20 percent by weight.

60. The composition of claim 59, wherein the benzyl alcohol is present in an amount of about 5 percent by weight.

61. A treated suture comprising a suture, and an anesthetic formulation comprising an oleaginous base vehicle, a free-base anesthetic, and a solubility enhancer; wherein the anesthetic formulation is incorporated into at least a portion of the suture or is present on at least a portion of the surface of the suture.

62. The suture of claim 61, wherein the suture is an absorbable suture selected from the group consisting of polyglycotic acid braided, chromic gut, and plain gut

63. The suture of claim 61, wherein suture is a non-absorbable suture selected from the group polypropylene monofilament, nylon monofilament, polyester braided, braided silk, and virgin silk.