USOO674.6689B2 (12) United States Patent (10) Patent No.: US 6,746,689 B2 Fischer et al. (45) Date of Patent: *Jun. 8, 2004

(54) INTRADERMAL-PENETRATION AGENTS 5,863,941 A 1/1999 Liedtke FOR TOPCAL LOCAL ANESTHETIC 5,919,479 A 7/1999 Zhang et al. ADMINISTRATION 5,922,340 A 7/1999 Berde et al. 5,955,112 A 9/1999 Kaplan (75) Inventors: Susi7- Ely. Nuits E. 6,455,0666,120,792 AB1 * 9/20009/2002 JuniFischer et al. Mason, Flemington, NJ (US) FOREIGN PATENT DOCUMENTS (73) Assignee: EpiOept Corporation, Englewood WO WO 93/12744 7/1993 Cliff. NJ (US) WO WO95/ 31.188 11/1995 s WO WO 97/439 89 11/1997 (*) Notice: Subject to any disclaimer, the term of this W W s: 2: past isis'', adjusted under 35 WO WO 01/41746 6/2001 a -- y U dayS. OTHER PUBLICATIONS This patent is Subject to a terminal dis- Berkovitch et al., 1995, “Use of a Eutectic Mixture of Local claimer. Anesthetics for Prolonged Subcutaneous Drug Administra tion”, J. Clin. Pharmacol. 35:295–297. (21) Appl. No.: 10/201,901 Curatolo, 1987, “The Lipoidal Permeability Barriers of the Skin and Alimentary Tract', Pharmaceut. Res. 4:271-277. (22) Filed: Jul. 25, 2002 Klein and Penneys, 1988, “Aloe Vera”, J. Am. Acad. Der (65) Prior Publication Data matol. 18: 714-720. Lubens et al., 1974, "Anesthetic Patch for Painful Proce US 2003/0138505 A1 Jul. 24, 2003 dures Such AS Minor Operations”, Am. J. Dis. Child. O O 128:192-194. Related U.S. Application Data McCafferty et al., 1988, “Comparative in vivo and in vitro (63) Continuation of application No. 09/523.652, filed on Mar. St. fe Persis absorption of Local Anes 10, 2000, now Pat. No. 6,455,066. etics, Br. J. AnaesinoU:04-09. 7 Russo et al., 1980, “Lidocaine Anesthesia: Comparison of (51) Int. Cl." ...... A61K 35/78 Iontophoresis, Injection and Swabbing, Am. J. Hosp. (52) U.S. Cl...... 424/449; 424/744; 424/757; Pharm. 37:843-847. 424/774; 424/778; 424/447; 424/448; 514/646 Sarpotdar and Zatz, 1986, “Evaluation of Penetration (58) Field of Search ...... 424/774, 757, Enhancement of Lidocaine by Nonionic Surfactants 424/778, 447, 448, 449; 514/646 Through Hairless Mouse Skin In Vitro”, J. Pharmaceut. Sci. 75:176-181. (56) References Cited Shelton, 1991, “Aloe Vera: Its Chemical and Therapeutic Properties”, Intl. J. Dermatol. 30:679–683. U.S. PATENT DOCUMENTS Takahashi et al., “In vitro Transport of Sodium Diclofenac 3.814,095 A 6/1974 Lubens across Rat Abdominal Skin: Effect of Selection of Oleagi 3,892,853. A 7/1975 Cobble nous Component and the Addition of Alcohols to the 4,210,670 A 7/1980 Cooke Vehicle', Chem. Pharm. Bull. 39:154-158. 4,748,022 A 5/1988 Busciglio Wang and Strong, 1993, “Monitoring Physical and Chemical 4,765,986 A 8/1988 Liedtke Properties of Freshly Harvested Field-Grown Aloe vera 5,002.9744,917,688 A 4/19903/1991 GeriaNelson et al. Leaves. A PrelimiPreliminary RKeport, t'. Phytothnylounerapy ReS.Kes. 7:S1-S41: 5,120,710 A 6/1992 Liedtke * cited by examiner 5,229,130 A 7/1993 Sharma et al. 5,272,139 A 12/1993 Cary, Jr. Primary Examiner Leon B. Lankford, Jr. 5,279.837 A 1/1994 Hill ASSistant Examiner-Susan D. Coe 5,330.452 A 7/1994 Zook (74) Attorney, Agent, or Firm-Jones Day 5,332,576 A 7/1994 Mantelle 5,356.811 A 10/1994 Coats (57) ABSTRACT 5,411,738 A 5/1995 Hind 5,415.866 A 5/1995 Zook A non-invasive and non-Systemic method for administering 5,466,465. A 11/1995 Royds et al. a local anesthetic. The method comprises topical application 5,589,180 A 12/1996 Hind of a local anesthetic in combination with an intradermal 2: A 2. Fi" penetration agent Selected from the group consisting an aloe 5,810,7862 2 A 9/1998 Jacksone e et al. composition, a triglyceride, and a mixture thereof. 5,827,529 A 10/1998 Ono et al. 5,840,755 A 11/1998 Liedtke 11 Claims, No Drawings US 6,746,689 B2 1 2 INTRADERMAL-PENETRATION AGENTS active agent. (for example see, Ghosh, T. K. et al. (1993), FOR TOPCAL LOCAL ANESTHETIC Pharm. Tech. 17(3):72–98; Ghosh, T. K. et al. (1993), ADMINISTRATION Pharm. Tech. 17(4): 62-89; Ghosh, T. K. et al. (1993), Pharm. Tech. 17(5):68–76; Pfister et al. Pharm. Tech. 14(9) :132-140, all of are incorporated herein by reference). This is a continuation of application Ser. No. 09/523,652, Ideally penetration agents should be pharmacologically filed Mar. 10, 2000, now U.S. Pat. No. 6,455,066. inert, non-toxic, non-irritating and non-allergenic, compat FIELD OF THE INVENTION ible with the formulation components, have rapid onset of action, and be reversible in their reduction of skin-barrier The invention relates to methods and compositions for properties. The penetration agent should also spread well on intradermal administration of local anesthetics with the aid the Skin with a Suitable skin feel. In practice, all of these of an intradermal-penetration agent. ideal requirements are rarely met, and a need exists for improved penetration agents. (Aungst (1991) Skin Perme BACKGROUND OF THE INVENTION ation Enhancers for Improved Transdermal Drug delivery. Drug administration by topical skin application offers In: High Performance Biomaterial: A Comprehensive Guide distinct advantages over conventional administration meth 15 to Medical and Pharmaceutical Applications, Ed. M. ods. For example, Some drugs cannot be absorbed in the Szycher, pp. 527–538)). digestive tract and intravenous and Subcutaneous adminis The majority of dermal drug formulations and penetration tration by injection is painful and invasive. Furthermore, agents for have been developed for transdermal administra when treating localized conditions by oral and intravenous tion. For example, U.S. Pat. No. 5,229,130 relates to the use administration, the drug is circulated Systemically rather of vegetable oils to enhance transdermal penetration of than restricted to the diseased area. drugs through the skin into the blood stream. U.S. Pat. No. But, unfortunately, because of the skin's drug penetration 5,229,130 teaches that vegetable oils (e.g., almond oil, resistance, only a limited number of drugs are bioavailable babasSu oil, castor oil, Clark A oil, coconut oil, corn oil, via topical application (Ghosh, T. K.; Pfister, W. R.; Yum, S. 25 cotton Seed oil, jojoba oil, linseed oil, mustard oil, olive oil, I. Transdermal and Topical Drug Delivery Systems, Inter palm oil, peanut oil, Safflower oil, Sesame oil, Soybean oil, pharm Press, Inc. p. 7). The skin is a complex multilayer Sunflower-seed oil and wheat germ oil) as transdermal organ with a total thickness of 2-3 mm. The panniculus penetration agents for broad classes of pharmaceutically adipoSuS, a variably thick fatty layer, is below the dermis. active compounds amenable to transdermal administration The dermis is a layer of dense connective tissue that Supports (e.g., antiinfectives; analgesics; anorexics; antihelminthics; the epidermis. The epidermis comprises a layer of epithelial antiarthritics, antiasthmatics, anticonvulsants, antidepres cells and is about 100 um thick. The epidermis is further Sants, antidiabetics, antidiarrheals, antihistamines, antiin classified into a number of layers, of which the Outermost flammatories; antimigraine preparations; and tranquilizers). layer is the stratum corneum (15-20 um thick). The stratum Although transdermal Systems can deliver drugs for the corneum comprises highly dense, keratinized tissue and is 35 treatment of Systemic disease, they are not practical for the skin's main Source of penetration and permeation resis controlling the administration of drugs when the skin is the tance (Montagna, W. and Parakkal, P. F. (1974) The Struc target Site (i.e., intradermal administration). The controlled ture and Function of Skin, Academic Press, New York and release of drugs into the epidermis or dermis, with the Holbrook, K. A. and Wolf, K. (1993) The Structure and assurance that the drug remains primarily localized and does Development of Skin, In: Dermatology in General 40 not enter the blood Stream in Significant amounts requires Medicine, Vol 1, 4th ed., Eds. T. B. Fitzpatrick, A. Z. Eisen, innovative approaches ((Ghosh, T. K.; Pfister, W. R.; Yum, K. Wolff, I. M. Feedberg, and K. F. Austen, McGraw Hill, S. I. (1997) Transdermal and Topical Drug Delivery Inc., New York, pp. 97-145). Systems, p. 521)). Further complicating the matter, the In general, drug administration via the skin is divided into behavior of a penetration agent is strongly dependant on the two categories: 1) transdermal administration and 2) intra 45 drug. That is, a given penetration agent does not necessarily dermal administration. Transdermal administration involves increase the penetration of all drugs (Hori et al. (1989) transport through the skin and into the blood Stream to treat Classification of Percutaneous Absorption. Mechanisms Systemic diseases. One the other hand, intradermal admin Methodology-Drug Delivery, 2nd ed., Eds. R. L. Bronaugh istration is intended to impart a cutaneous effect, while and H. I. Maibach pp. 197-211). keeping the pharmocological effects of the drug localized to 50 Certain aesthetics are advantageous for local administra the intracutaneous regions of drug penetration and deposi tion. Especially amide and ester type local anesthetics (e.g., tion. Ideally, intradermal absorption occurs with little or no lidocaine, tetracaine, bupivacaine, prilocaine, mepivacaine, Systemic absorption or accumulation. procaine, chloroprocaine, ropivacaine, dibucaine, The following Sequence of mechanisms has been pro etidocaine, and benzocaine). Traditionally, pain relief with posed for intradermal absorption: 1) partitioning of the drug 55 local anesthetics involves injection into the area of the nerve from the applied vehicle into the Stratum corneum; 2) fibers to be blocked (Jones M. Gregg A K, Anaesthesia diffusion through the Stratum corneum; 3) partitioning from February 1999; 54(2):200). While topical application of the Stratum into the epidermis. On the other hand, transder local anesthetics might overcome the disadvantages associ mal absorption further involves: 4) diffusion through the ated with injection (especially Systemic dangers), this epidermis; and 5) capillary uptake (Potts et al. (1992) 60 method has not been widely used, mainly, as discussed Percutaneous Absorption. Pharmacology of the Skin, Ed. above, because of the difficulty to get Significant concentra Mukhtar, H. CRC Press, pp. 13–27). tions of local anesthetics through skin barrier. But if a Because of the skins intrinsic resistance to drug penetration agent is used, the danger of Systemic absorption penetration, penetration agents are essential to assist intra increases and this is significant because amide and ester dermal and transdermal drug administration. The term pen 65 anesthetics are Systemically toxic. etration agent has generally been applied to the class of Thus a need exists for penetration agents for intradermal chemicals that increase the partitioning and diffusion of the local anesthetic administration. The agent should have bal US 6,746,689 B2 3 4 anced penetration properties Such the intradermal penetra local anesthetic effect comprising applying to the Subject's tion is maximized and transdermal penetration is minimized. skin a pharmaceutically acceptable topical formulation com Additionally, the agent should be pharmacologically inert, prising a therapeutically effective amount of the local anes non-toxic, non-irritating and non-allergenic, compatible thetic or a pharmaceutically acceptable Salt thereof and a with the formulation components, have rapid onset of action, penetration enhancing amount of an intradermal-penetration and spread well on the Skin with a Suitable skin feel. agent Selected from the group consisting of a triglyceride, an aloe composition, and a mixture thereof. SUMMARY OF THE INVENTION AS used herein the term “intradermal-penetration agent' It has now been found that triglycerides and aloe com means an agent capable of transporting a pharmacologically positions are intradermal-penetration agents for enhancing active compound through the Stratum corneum and into the penetration of topically applied local anesthetics through the epidermis or dermis, while keeping the pharmacological Stratum corneum and into the epidermis or dermis, in the effects restricted to the intracutaneous regions of drug absence of Systemic absorption of the anesthetic. penetration, preferably, with little or no Systemic absorption. In one embodiment, the invention comprises a method for A "penetration enhancing amount of an intradermal administering a local anesthetic in a Subject in need of a 15 penetration agent is an amount which enhances the local local anesthetic. The method comprises applying to the anesthetic penetration rate through the Stratum corneum, Subject's skin a pharmaceutically acceptable topical formu relative to the penetration rate without the intradermal lation comprising a therapeutically effective amount of the penetration agent. According to the invention, preferred local anesthetic or a pharmaceutically acceptable Salt thereof intradermal-penetration agents include triglycerides and and a penetration enhancing amount of an intradermal aloe compositions. penetration agent Selected from the group consisting of a The term “pharmaceutically acceptable topical formula triglyceride, an aloe composition, and a mixture thereof. In tion' as used herein means any formulation which is phar another embodiment, the pharmaceutically acceptable topi maceutically acceptable for intradermal administration of a cal formulation is in a patch. Preferably, there is no signifi local anesthetic by application of the formulation to the cant Systemic absorption of the local anesthetic. One indi 25 epidermis. According to the invention, a “topical formula cator of non-Systemic absorption is that the duration of local tion' will comprise at least a local anesthetic and an anesthesia imparted by a local anesthetic augmented with a intradermal-penetration agent. The choice of topical formu triglyceride is about the same as that without the triglycer lation will depend or Several factors, including the condition ide. In essence, the duration of a local anesthetic effect to be treated, the physicochemical characteristics of the local augmented by the penetration properties of a triglyceride is anesthetic and other excipients present, their Stability in the equivalent to that without the triglyceride, but, formulation, available manufacturing equipment, and costs advantageously, the effect is more intense, thereby, allowing constraints. for greater efficacy of treatment. This is surprising because AS used herein, a “therapeutically effective amount of a higher local anesthetic intensity would be expected to be local anesthetic' means the amount of the anesthetic accompanied by greater Systemic absorption. 35 required to induce a local anesthetic effect Sufficient to treat In Still another embodiment, the invention relates to a or ameliorate a condition aggravated or induced by Stimu patch comprising a penetration enhancing amount of an lation of Sub-dermal sensory nerve receptors. Preferably, the intradermal-penetration agent Selected from the group con local anesthetic does not penetrate through the skin and into Sisting of a triglyceride, an aloe composition, and a mixture the blood stream. thereof and a therapeutically effective amount of a local 40 AS used herein, the term “Subject” means any animal, anesthetic to administer the local anesthetic in a Subject in preferably a mammal, more preferably a human. need of a local anesthetic effect packaged in association with AS used herein, the term "triglyceride' means any triester instructions, the instructions comprising: applying the patch of glycerol. Triglycerides useful in the invention are repre to the skin. 45 sented by Formula I below: In yet another embodiment, the invention relates to a patch comprising a backing and a preSSure Sensitive acrylic adhesive, which adhesive comprises a therapeutically effec O tive amount of a local anesthetic and a penetration enhanc ing amount of an intradermal-penetration agent Selected HC- o-I-R from the group consisting of a triglyceride, an aloe 50 O composition, and a mixture thereof. HC- o-I-R In another embodiment, the invention relates to a com O position comprising a therapeutically effective amount of a HC- o-I-R local anesthetic or a pharmaceutically acceptable Salt thereof 55 and a penetration enhancing amount of an intradermal penetration agent Selected from the group consisting of a wherein preferred R', R, and R groups are independently triglyceride, an aloe composition, and a mixture thereof. C-C branched or Straight chain hydrocarbon groups with These and other features, aspects, and advantages of the Zero or more double bonds, preferably C-C branched or invention will become better understood with reference to 60 Straight chain hydrocarbon groups with Zero to three double the following detailed description, example, and appended bonds. Preferably, the triglyceride is derived from a natural claims. Source, Such as from an animal (e.g., tallow, lard, beef fat, DETAILED DESCRIPTION OF THE butterfat, and fish oils, Such as herring) or a vegetable. INVENTION Vegetable oils are particularly preferred for use with the 65 invention, for example, but not limited to, nut oils, Such as In one embodiment, the invention comprises a method for almond oil and walnut oil; castor oil; coconut oil; corn oil; administering a local anesthetic in a Subject in need of a cotton Seed oil; jojoba oil; linseed oil; grape Seed oil, rape US 6,746,689 B2 S 6 Seed oil; mustard oil, olive oil; palm and palm kernel oil; enol acetate, dihydormorphine, dimenoxadol, dimenoxadol, peanut oil; Safflower oil; Sesame oil, Soybean oil; Sunflower dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, Seed oil; crambe oil; wheat germ oil; cocoa butter; or dip ip an one, ept a Zo cine, etho he pta Zine, mixtures thereof. Soybean oil is a preferred vegetable oil for ethylmethylthiambute ne, etonitaZene, fentanyl, use with the invention. If desired, the vegetable oils may be hydrocodone, hydromorphone, hydroxype thidine, processed, for example by hydrogenation. isomethadone, ketobemidone, levorphanol, lofentanil, AS used herein, the term "aloe composition” means any meperidine, meptazinol, metazocaine, methadone, metopon, extract or processed form of a plant of genus aloe, family morphine, myrophine, nalbuphine, narceline, nicomorphine, Liliaceae. For example, aloe extracts and processed forms of norlevorphanol, normethadone, normorphine, norpipanone, aloe for use with the invention may be obtained from aloe opium, oxycodone, oxymorphine, papave retum, arbrorescens, aloe barbandensis, or aloe ferox species of pentazocine, phenadoxone, phenazocine, phenoperidine, aloe. Any part of the plant may be processes or extracted, piminodine, pirtramide, proheptazine, promedol, propiram, Such as the leaf, Stem, or flower. Examples of Suitable aloe propoxyphene, remifentanil, Sufentanil, tilidine, and phar compositions include aloe arbrorescenS leaf extract maceutically acceptable Salts thereof, or mixtures thereof. (Maruzen Pharmaceuticals, Morristown, N.J.); aloe barban 15 For example see U.S. Pat. No. 5,589,480 (e.g., morphine or densis leaf extract (Florida Food Products, Inc., Eustis, Fla.); morphine Sulfate), and others. aloe barbandensis flower extract (Tri-K, Industries, Furthermore, in order to improve the effectiveness and Emerson, N.J.), aloe barbandensis gel (Active Organics, tolerance of the present topically effective therapy, local Dallas, Tex.); and aloe ferox leaf extract (Maruzen anesthetics with different pharmacodynamicS and pharma Pharmaceuticals, Morristown, N.J.). The preferred aloe cokinetics may be combined in a pharmaceutically accept composition for use with the invention is aloe barbandensis able topical formulation. A preferred combination of local gel, which is the fresh mucilaginous gel obtained from the anesthetics is lidocaine and prilocaine and another preferred parenchymatous tissue in the leaf center-referred to herein combination is lidocaine and tetracaine. as “aloe-Vera gel”. The phrase “pharmaceutically acceptable salt(s)', as used AS used herein, the term “local anesthetic' means any 25 herein, unless otherwise indicated, means those Salts that drug that provides local numbness or analgesia or any drug retain the biological effectiveness and properties of neutral that provides a regional blockage of nociceptive pathways local anesthetics and that are not otherwise unacceptable for (afferent and/or efferent). The local anesthetic can be any pharmaceutical use. Pharmaceutically acceptable Salts local anesthetic known or to be developed. Examples of include Salts of acidic or basic groups, which groups may be local anesthetics Suitable for use with the invention include: present in the local anesthetics. The local anesthetics used in ambucaine, amolanone, amylcaine, benoXinate, benzocaine, present invention that are basic in nature are capable of betoxycaine, biphenamine, bupivacaine, butacaine, forming a wide variety of Salts with various inorganic and butamben, butanilicaine, but ethamine, butoxycaine, organic acids. Pharmaceutically acceptable acid addition carticaine, chloroprocaine, cocaethylene, cocaine, Salts of basic local anesthetics used in the present invention cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, 35 are those that form non-toxic acid addition Salts, i.e., Salts diperodon, dyclonine, ecogonidine, ecogonine, euprocin, comprising pharmacologically acceptable anions, Such as fenalcomine, formocaine, hexylcaine, hydroxyteteracaine, the hydrochloride, hydrobromide, hydroiodide, nitrate, isobutyl p-aminobenzoate, leucinocaine, levoxadrol, Sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, acetate, lactate, Salicylate, citrate, tartrate, pantothenate, methyl chloride, myrtecaine, nae paine, octacaine, 40 bitaritrate, ascorbate, Succinate, maleate, gentisinate, Orthocaine, oxetha Zaine, parenthoxycaine, phenacaine, fumarate, gluconate, glucaronate, Saccharate, formate, phenol, piperocaine, piridocaine, polidocanol, pramoxine, benzoate, glutamate, methaneSulfonate, ethaneSulfonate, prilocaine, procaine, propanocaine, proparacaine, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., propipocaine, propoxycaine, pseudococaine, pyrrocaine, 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The ropivacaine, Salicyl alcohol, tetracaine, tolycaine, 45 local anesthetics of the present invention that include an trimecaine, Zolamine, or a pharmaceutically acceptable Salt amino moiety may form pharmaceutically acceptable Salts thereof, or a mixture thereof. with various amino acids, in addition to the acids mentioned The amide and ester type local anesthetics are preferred. above. Suitable base salts are formed from bases which form Amide type local anesthetics are characterized by an amide non-toxic Salts and examples are the aluminium, calcium, functionality, while ester type local anesthetics contain an 50 lithium, magnesium, potassium, Sodium, Zinc and diethano ester functionality. Preferred amide type local anesthetics lamine Salts. For a review on pharmaceutically acceptable are: lidocaine, bupivacaine, prilocaine, mepivacaine, salts see Berge et al., J. Pharm. Sci., 66, 1-19 (1977), etidocaine, ropivacaine, dibucaine, and mixtures thereof. incorporated herein by reference. Preferred ester type local anesthetics are: tetracaine, According to the present invention, any combination of an procaine, benzocaine, chloroprocaine, their pharmaceuti 55 aloe composition and a triglyceride may be used, for cally acceptable Salt, or a mixture thereof. The most pre example, a mixture of Soybean oil and aloe-Vera gel. ferred local anesthetic is lidocaine. The intradermal-penetration agent/local anesthetic com The meaning of “local anesthetic' also encompasses bination of the invention may be administered via a topical drugs not traditionally associated with local anesthetic prop formulation or via a patch comprising the topical formula erties but which have a local anesthetic effect, for example, 60 tion. Preferably, the topical formulations and patch Systems non-narcotic analgesics, Such as, acetylsalicylic acid, provide controlled release of the local anesthetic into the ketoprofen, piroXicam, diclofenac, indomethacin, ketorolac, dermis. Vioxx(E), and CelebreX(R), narcotic and opioid analgesics, In one embodiment of the invention, the topical formu Such as alfentanil, allylprodine, alphaprodine, anileridine, lation comprises a carrier System. Pharmaceutically effective benzylmorphine, benzitramide, buprenorphine, butorphanol, 65 carriers include, but are not limited to, Solvents (e.g., clonitaZene, codeine, desomorphine, dextromoramide, alcohols, poly alcohols, water), creams, lotions, ointments, deZocine, diampromide, dihydrocodeine, dihydrocodeine oils, plasters, liposomes, powders, emulsions, US 6,746,689 B2 7 8 microemulsions, and buffered Solutions (e.g., hypotonic or the area may be covered with a dressing. The term buffered saline) or any other carrier known in the art for “dressing, as used herein, means a covering designed to topically administering pharmaceuticals. A more complete protect a topically applied drug formulation. “Dressing listing of art-known carriers is provided by reference texts includes coveringS Such as a bandage, which may be porous that are Standard in the art, for example, Remington's 5 or non-porous and various inert coverings, e.g., a plastic film Pharmaceutical Sciences, 16th Edition, 1980 and 17th wrap or other non-absorbent film. The term “dressing” also Edition, 1985, both published by Mack Publishing encompasses non-woven or woven coverings, particularly Company, Easton, Pa., the disclosures of which are incor elastomeric coverings, which allow for heat and vapor porated herein by reference in their entireties. transport. These dressings allow for cooling of the treated The topical formulations according to the invention may area, which provides for greater comfort. comprise excipients. Any pharmaceutically acceptable In a preferred embodiment of the current invention, the excipient is Suitable. Examples of excipients that can be topical formulation comprising a local aesthetic and an included in the topical formulation of the invention include, intradermal-penetration agent is contained in a patch that is but are not limited to, preservatives, antioxidants, applied adjacent to the area of Skin to be treated. AS used moisturizers, emollients, buffering agents, Solubilizing 15 herein a "patch” comprises at least a topical formulation and agents, other penetration agents, Skin protectants, a covering layer, Such that, the patch can be placed over the Surfactants, and propellants, conventional Systemic pain area of Skin to be treated. Preferably, the patch is designed relief therapies and analgesics, and pharmaceuticals. to maximize drug delivery through the Stratum corneum and Suitable preservatives include, but are not limited to, into the epidermis or dermis, and to minimize absorption alcohols, quaternary amines, organic acids, parabens, and into the circulatory System, reduce lag time, promote uni phenols. form absorption, and reduce mechanical rub-off. Suitable antioxidants include, but are not limited to, Preferably, the patch components resemble the Viscoelas ascorbic acid and its esters, Sodium bisulfite, butylated tic properties of the skin and conform to the Skin during hydroxytoluene, butylated hydroxyanisole, tocopherols, and movement to prevent undue shear and delamination. chelating agents like EDTA and citric acid. 25 A patch comprising the topical formulation of the inven Suitable moisturizers include, but are not limited to, tion has advantages over conventional methods of adminis glycerine, Sorbitol, polyethylene glycols, urea, and propy tration. One advantage is that the dose is controlled by the lene glycol. patch's Surface area. Other advantages of patches are con Suitable buffering agents for use with the invention Stant rate of administration, longer duration of action (the include, but are not limited to, citric, hydrochloric, and lactic ability of to adhere to the skin for 1, 3, 7 days or longer); acid buffers. improved patient compliance, non-invasive dosing, and Suitable Solubilizing agents include, but are not limited to, reversible action (i.e., the patch can simply be removed). quaternary animonium chlorides, cyclodextrins, benzyl A patch Suitable for use with the invention should contain benzoate, lecithin, and polySorbates. at least: (1) a backing layer and (2) a carrier formulated with Penetration agents for use with the invention include, but 35 a local anesthetic. are not limited to, ethyl alcohol, isopropyl alcohol, Preferred patches include (1) the matrix type patch; (2) octolyphenylpolyethylene glycol, oleic acid, polyethylene the reservoir type patch; (3) the multi-laminate drug-in glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty adhesive type patch; and (4) the monolithic drug-in-adhesive acid esters (e.g., isopropyl myristate, methyl laurate, glyc type patch; and (Ghosh, T. K.; Pfister, W. R.; Yum, S. I. erol monooleate, and propylene glycol monooleate); and 40 Transdermal and Topical Drug Delivery Systems, Inter N-methyl pyrrolidone. pharm Press, Inc. p. 249-297, incorporated herein by Suitable skin protectants that can be used in the topical reference). These patches are well known in the art and formulations of the invention include, but are not limited to, generally available commercially. Vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, For practice of the invention, the matrix type and the and Zinc oxide. 45 drug-in-adhesive type patches are especially preferred. The The topical formulations of the invention may include more preferred drug-in-adhesive patch is the monolithic medicinal agents or their pharmaceutically acceptable Salts, type. for example, but not limited to, antifungals Such as The matrix patch comprises an anesthetic containing ciclopiroX, chloroxylenol, triacetin, Sulconazole, nyStatin, matrix, an adhesive backing film Overlay, and preferably, a undecylenic acid, tolnaftate, miconizole, clotrimazole, 50 release liner. In Some cases, it may be necessary to include Oxiconazole, griseofulvin, econazole, ketoconozole, and a impermeable layer to minimize drug migration into the amphotericin B; antibiotics, Such as mupirocin, erthromycin, backing film (e.g., U.S. Pat. No. 4,336,243, incorporated clindamycin, gentamicin, polymyxin, bacitracin, and Silver herein by reference). The anesthetic containing matrix is Sulfadiazine, antiseptics, Such as iodine, povidine-iodine, held against the Skin by the adhesive overlay. Examples of benzalkonium chloride, benzoic acid, chlorhexidine, 55 Suitable anesthetic matrix materials include but are not nitrofuraZone, benzoyl peroxide, hydrogen peroxide, limited to lipophilic polymers, Such as polyvinyl chloride, hexachlorophene, phenol, resorcinol, and cetylpyridinium polydimethylsiloxane, and hydrophilic polymers like chloride; and anti-inflammatories, Such as hydrocortisone, polyvinylpyrrollidone, polyvinyl alcohol, hydrogels based on prednisone, triamcilolone, betamethasone, dexamethasone. gelatin, or polyvinylpyrrollidone/polyethylene oxide mix In yet another embodiment of the current invention, 60 tureS. agents may be included in the topical formulation to prolong The reservoir type patch design is characterized by a the local anesthetic effect, Such as, a glucocorticosteroid backing film coated with an adhesive, and a reservoir (see, U.S. Pat. No. 5,922,340, incorporated herein by compartment comprising a drug formulation preferably, in reference) or a vasoconstrictor, Such as a catecolamine. the form of a Solution or Suspension, that is separated from The topical formulation of the invention may be applied 65 the skin by a semipermeable membrane (e.g., U.S. Pat. No. to the skin of a Subject via a container adapted for Spraying. 4,615,699, incorporated herein by reference). The adhesive After application of the topical formulation to the epidermis, coated backing layer extends around the reservoir's bound US 6,746,689 B2 9 10 aries to provide a concentric Seal with the skin and hold the Selection of the appropriate dosage for the application site reservoir adjacent to the skin. is an important consideration. The rate of intradermal anes The monolithic drug-in-adhesive patch design is charac thetic administration from the topical formulation or patch is terized by the inclusion of the drug formulation in the skin a function of Skin permeability, and skin permeability has contacting adhesive layer, a backing film and preferably, a been shown to vary between anatomical Sites depending on release liner. The adhesive functions both to release the the thickness of the Stratum corneum. For example, the anesthetic and adhere the anesthetic matrix to the skin. The permeability, in general, increases in order from planter foot drug-in-adhesive System does not require an adhesive over arch, lateral ankle, palm, Ventral forearm, dorsal forearm, lay and thus the patch size is minimized. Also, drug-in back, chest, thigh, abdomen, Scalp, axilla, forehead, and adhesive type patches are thin and comfortable (e.g., U.S. scrotum (Wester, R. C. and Maibach, H. I. (1989) Regional Pat. No. 4,751,087, incorporated herein by reference). variation in Percutaneous Absorption: In Percutaneous The multi-laminate drug-in-adhesive patch design further Absorption, Mechanism, Methodology, Drug Delivery, 2" incorporates an additional Semi-permeable membrane ed., Eds. R. L. Bronaugh and H. I. Maibach, Marcel Dekker, between two distinct drug-in-adhesive layerS or multiple Inc., New York, pp. 111-119 (incorporated herein by drug-in-adhesive layers under a single backing film 15 reference)). Of course, the dosages and dosing frequency (Peterson, T. A. and Dreyer, S. J. Proceed. Intern. Symp. will be determined by a trained medical professional. Control. Rel. Bioact. Mater. 21: 477–478, incorporated The amount of local anesthetic in the topical formulation herein by reference). will generally be of from about 1 percent to about 25 percent Semi permeable membranes, useful with the reservoir or of the total weight of the formulation, preferably, of from multi-laminate patch, include thin non-porous ethylene Vinyl about 2 percent to about 20 percent, more preferably, of from acetate films or thin microporous films of polyethylene about 3 percent to about 6 percent of the total weight of the employed in microlaminate Solid State reservoir patches. formulation. Adhesives for use with the drug-in-adhesive type patches are When a combination of local anesthetics is used, a pre well known in the art and Selection is readily accomplished ferred combination is a eutectic mixture of lidocaine and by an ordinary practitioner. Three basic types commonly 25 prilocaine. In Such a mixture, the amount of lidocaine can used are polyisobutylenes, Silicones, and acrylics. Adhesives range of from about 0.5 percent to about 12 percent, pref useful in the present invention can function under a wide erably of from about 1 percent to about 7 percent, and more range of conditions, Such as, high and low humidity, bathing, preferably of from about 2.5 percent to about 5 percent and Sweating etc. Preferably the adhesive is a composition based the amount ofprilocaine can range of from about 0.5 percent on natural or Synthetic rubber, a polyacrylate Such as, to about 12 percent, preferably of from about 1 percent to polybutylacrylate, polymethylacrylate, poly-2-ethylhexyl about 7 percent, and more preferably of from about 2.5 acrylate; polyvinylacetate; polydimethylsiloxane, or and percent to about 5 percent. Preferably, the mixture is for hydrogels (e.g., high molecular Weight polyvinylpyrrollidone mulated as an oil in Water emulsion. and oligomeric polyethylene oxide). The most preferred Another preferred local aesthetic combination is a mixture adhesive is a pressure Sensitive acrylic adhesive, for 35 of lidocaine and tetracaine. In Such a mixture, the amount of example Durotak(R) adhesives (e.g., Durotak(R 2052, lidocaine can range of from about 0.5 percent to about 12 National Starch and Chemicals). The adhesive may contain percent, preferably of from about 1 percent to about 7 a thickener, Such as a Silica thickener (e.g., Aerosil, Degussa, percent, and more preferably of from about 2.5 percent to Ridgefield Park, N.J.) or a crosslinker Such as, aluminu about 5 percent and the amount of tetracaine can range of macetylacetonate. 40 from about 0.5 percent to about 12 percent, preferably of Suitable release liners include but are not limited to from about 1 percent to about 7 percent, and more preferably occlusive, opaque, or clear polyester films with a thin of from about 2.5 percent to about 5 percent. Preferably the coating of pressure Sensitive release liner (e.g., Silicone mixture is formulated as an oil in water emulsion. fluorsilicone, and perfluorcarbon based polymers. The amount of intradermal-penetration agent in the topi Backing films may be occlusive or permeable and are 45 cal formulation will generally be of from about 1 percent to derived from synthetic polymers like polyolefin oils about 90 percent of the total weight of the formulation, polyester, polyethylene, polyvinylidine chloride, and poly preferably, of from about 2 percent to about 50 percent, more urethane or from natural materials like cotton, wool, etc. preferably, of from about 3 percent to about 10 percent of the Occlusive backing films, Such as Synthetic polyesters, result total weight of the formulation. in hydration of the outer layers of the stratum corneum while 50 The intradermal-dermal penetration agent present in the non-occlusive backings allow the area to breath (i.e., pro topical formulation of the invention can comprise a mixture mote water vapor transmission from the skin Surface). More of a triglyceride, (e.g., Soybean oil) and an aloe composition preferably the backing film is an occlusive polyolefin foil (e.g., aloe-Vera gel). When Such a mixture is used, the (Alevo, Dreieich, Germany). The polyolefin foil is prefer triglyceride can be present in an amount of from about of ably about 0.6 to about 1 mm thick. 55 from about 0.5 percent to about 45 percent of the total A particularly preferred patch design comprises a poly weight of the formulation, preferably, of from about 1 olefin foil and a preSSure Sensitive acrylic adhesive com percent to about 25 percent, more preferably, of from about prising the active agents and any excipients. 1.5 percent to about 5 percent of the total weight of the Additionally, in order to make the present therapy Safer, formulation and the aloe composition can be present in an use-Specific, and more manageable overall, the present patch 60 amount of from about 0.5 percent to about 45 percent of the may have Such a geometric shape Such that it corresponds to total weight of the formulation, preferably, of from about 1 the Special conditions of the application field. Thus, the percent to about 25 percent, more preferably, of from about shape of the patch can be flat or three-dimensional, round, 1.5 percent to about 5 percent of the total weight of the oval, Square, and have concave or convex outer shapes, or formulation. the patch or bandage can also be segmented by the user into 65 With gels, creams, or ointments, typically 1 to 4 applica corresponding shapes with or without additional auxiliary tions are required per day. Generally, about 0.5 g/cm to CS. about 5 g/cm, preferably 1 g/cm to about 2 g/cm of the US 6,746,689 B2 11 12 topical formulation is applied to the epidermis. Preferably, minor skin abrasions and cuts, insect bites, headaches, back the formulation is applied to the skin area in an amount of pain, or any pain or condition caused by Stimulation of from about 1 g/cm to about 2 g/cm. Preferably, after Sub-dermal sensory nerve receptors (i.e., nociceptors) or that application, the treated area is covered with a dressing. can be treated by regional blockage of nociceptive pathways When a patch is used to achieve a local anesthetic effect, (afferent and/or efferent). The invention may also be used to the local anesthetic required is determined by the active for local anesthetization of skin prior to a minor Surgical Surface area of the medicated portion of the patch in direct procedure Such as an injection. Fresh patches may be applied contact with the skin. Several dosage Strengths are advan multiple times per day, depending on the condition treated tageous depending upon the condition to be treated. In general, a physician may begin dosing with a low or and a physician's recommendation. In general, a fresh patch intermediate Strength patch and then, depending upon the is applied about every 18 to about every 48 hours. More effectiveness, adjust the dosage up or down by prescribing preferably, the patch is applied daily. a patch of higher or lower anesthetic concentration or a patch Although the present invention has been described in of larger or Smaller Surface area, or, in Some cases, multiple considerable detail with reference to certain preferred patches. 15 embodiments, other embodiments are possible. Therefore, Preferably, the local anesthetic in the patch will comprise the Spirit and Scope of the appended claims should not be of from about 0.5 percent to about 40 percent by weight of limited to the description of the preferred embodiments the patch's total weight, preferably of from about 10 percent contained herein. to about 30 percent, more preferably of from about 15 percent to about 25 percent, and most preferably of from EXAMPLES about 18 percent to about 22 percent by weight of the patch's total weight. The following examples are provided for illustrative When a combination of local anesthetics is used in the purposes only and are not to be construed as limiting the patch, a preferred combination is a eutectic mixture of invention's Scope in any manner. lidocaine and prilocaine. In Such a mixture, the amount of 25 lidocaine can range of from about 0.25 percent to about 20 Example 1 percent, preferably of from about 1 percent to about 15 Comparison of Aloe-Vera Gel with Propylene Glycol as an percent, and more preferably of from about 2 percent to Intradermal-Penetration Agent about 10 percent and the amount of prilocaine can range of The study was conducted with a 10 cm matrix patch from about 0.25 percent to about 20 percent, preferably of composed of 1 mm thick polyolefin foam (as an occlusive from about 1 percent to about 15 percent, and more prefer backing) coated with an acrylate matrix, the matrix com ably of from about 2 percent to about 10 percent. prising a mixture of lidocaine and intradermal-penetration Another preferred local aesthetic combination for use in a agent in an acrylate polymer. patch is a mixture of lidocaine and tetracaine. In Such a 35 mixture, the amount of lidocaine can range of from about The matrix was prepared by mixing lidocaine (20 weight 0.25 percent to about 20 percent, preferably of from about 1 percent); acrylate polymer (DurotakB 387-2052, 75 weight percent to about 15 percent, and more preferably of from percent); intradermal-penetration agent, aluminumacetylac about 2 percent to about 10 percent and the amount of etonate (Al(ACAC), 0.4 weight percent, as a crosslinker); tetracaine can range of from about 0.25 percent to about 20 40 and ethanol until homogeneous. Note, that a greater weight percent, preferably of from about 1 percent to about 15 of propylene glycol than aloe-Vera gel accounts for propy percent, and more preferably of from about 2 percent to about 10 percent. lene glycols higher evaporation rate. The homogeneous In general, the intradermal-penetration agent will com mixture was then coated on polyolefin foil with a hand prise of from about 0.5 percent to about 40 percent by weight 45 coater machine to an average thickness of about 270 um. The of the patch's total weight, preferably of from about 2 coated foil was dried for about 1 hour at about 50 C. to percent to about 20 percent, more preferably of from about evaporate the ethanol giving the patch. The average patch 3 percent to about 6 percent by weight of the patch's total weight was 50 g/m dry. The amounts of lidocaine and weight. intradermal-penetration agent in each patch are given in the The intradermal-dermal penetration agent present in patch 50 Table I below as the percentage of the total patch weight. of the invention can comprise a mixture of a triglyceride, (e.g., Soybean oil) and an aloe composition (e.g., aloe-Vera The matrix patch was applied to the forearm of 8 volun gel). When Such a mixture is used, the triglyceride can be teers. The Volunteers assumed normal activities including present in an amount of from about of from about 0.25 bathing during which all of the patches adhered reliably percent to about 25 percent of the total weight of the patch, 55 throughout the Study. After 24 hours, the patches were preferably, of from about 0.5 percent to about 12 percent, removed. All eight Volunteers reported a local anesthetic more preferably, of from about 1 percent to about 5 percent effect up to 5 hours from the patch removal time. Immedi of the total weight of the patch and the aloe composition can ately after patch removal, each of the eight Volunteers be present in an amount of from about 0.25 percent to about patches was extracted with an organic Solvent to extract the 25 percent of the total weight of the patch, preferably, of 60 from about 0.5 percent to about 12 percent, more preferably, residual lidocaine and the weight of lidocaine remaining in of from about 1 percent to about 5 percent of the total weight each patch was measured by HPLC analysis. The mean rate of the patch. of intradermal lidocaine penetration into the Volunteers The intradermal-penetration agent/local anesthetic com forearms was calculated in mg/day as the initial lidocaine bination of the invention may be used to treat conditions 65 weight less the weight of lidocaine remaining in the patch conventionally treated by topical application of local anes after the study, as determined by HPLC, averaged over the thetics. For example, the invention is useful for treating 8 volunteers. US 6,746,689 B2 13 14

TABLE I Amounts of lidocaine and intradermal-penetration agent in each patch and penetration data intradermal- intradermal-penetration Mean intradermal skin weight % of penetration agent penetration rate No. lidocaine agent concentration (mg/day) 1. 20% aloe-veragel 10% 26 2 24% aloe-veragel 7.5% 28 3 20% propylene glycol 20% 18

The penetration-rate data in Table I above indicates that What is claimed is: aloe-Vera gel is Superior to propylene glycol as a 15 1. A patch comprising a backing and an adhesive, which intradermal-penetration agent. adhesive comprises a penetration enhancing amount of Example 2 Soybean oil and a therapeutically effective amount of a local Comparison of Soybean Oil with Propylene Glycol as an anesthetic. Intradermal-Penetration Agent. 2. The patch of claim 1, wherein the local anesthetic is one A 10 cm matrix patch composed of 1 mm thick poly or more of lidocaine, tetracaine, bupivacaine, prilocaine, olefin foam coated with an acrylate matrix, the matrix mepivacaine, procaine, chloroprocaine, ropivacaine, comprising a mixture of lidocaine and intradermal dibucaine, etidocaine, benzocaine, and a pharmaceutically penetration agent in an acrylate polymer was prepared as in acceptable Salt thereof. Example 1. A thickener (3 weight percent Aerosil) was 25 3. The patch of claim 1, further comprising an aloe included in formulation 1. The amounts of lidocaine and composition. intradermal-penetration agent in each patch are given in the 4. The patch of claim 2, wherein the aloe composition is Table II below as the percentage of the total patch weight. aloe Vera gel. The patch was placed on a piece of nude mouse skin, with 5. The patch of claim 1, wherein the backing comprises a a larger area than the patch's area, and the lower Surface of polyolefin, polyester, polyvinylidine chloride, polyurethane, the mouse Skin was contacted with physiologic phosphate cotton, or wool. buffer for 24 hours. The weight of lidocaine in the buffer 6. The patch of claim 1, wherein the backing comprises a solution was determined by quantitative HPLC analysis as polyolefin foil. above. The intradermal rate of absorption per unit area was 35 7. The patch of claim 6, wherein the polyolefin foil has a then calculated as the weight of lidocaine in the buffer thickness of from about 0.6 mm to about 1.0 mm. Solution divided by the patch's Surface area. Three measure 8. The patch of claim 1, wherein the adhesive comprises ments were determined for each formulation and the values a polyisobutylene, a Silicone, an acrylic, or a mixture averaged. thereof.

TABLE II Amounts of lidocaine and intradermal-penetration agent in each patch and penetration data intradermal intradermal- penetration Intradermal skin wt.% penetration agent penetration ug/cm/24 Adhesive formulation lidocaine agent concentration hours properties 1. 20% Propylene 2O not detected too high glycol 2 20% soybean oil 5 1OOO good

The penetration-rate data in Table II above indicates that 9. The patch of claim 8, wherein the adhesive comprises Soybean oil is Superior to propylene glycol as a intradermal a pressure Sensitive acrylic. penetration agent. 10. The patch of claim 8, wherein the adhesive comprises The foregoing has outlined rather broadly the more per 60 a polyacrylate. tinent and important features of the present invention. While it is apparent that the invention disclosed herein is well 11. The patch of claim 10, wherein the polyacrylate is calculated to fulfill the objects stated above, it will be polybutylacrylate, poly methylacrylate, or poly-2- appreciated that numerous modifications and embodiments ethylhexylacrylate. may be devised by those skilled in the art. Therefore, it is 65 intended that the appended claims cover all Such modifica tions.