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 * 9/20029/2000 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 3/19914/1990 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.