USOO599433OA United States Patent (19) 11 Patent Number: 5,994,330 El Khoury (45) Date of Patent: Nov.30, 1999 54 TOPICAL APPLICATION OF MUSCARINIC S. Abram, MD et al., Anesth Analg., “Intrathecal Acetyl AGENTS SUCH AS NEOSTIGMNE FOR Cholinesterase Inhibitors Produce Analgesia That is Syner TREATMENT OF ACNE AND OTHER gistic with Morphine and Clonidine in Rats, 81:501-7 NFLAMMATORY CONDITIONS (1995). C. Stein, M.D. et al., New England Journal of Medicine, vol. 76 Inventor: Georges F. El Khoury, 1561 Ramillo 325, No. 16 “Analgesic Effect of Intraarticular Morphine Ave., Long Beach, Calif. 90815 After Arthroscopic Knee Surgery, pp. 1123-1126. T. Yaksh, Ph.D. et al., Anesthesiology, “Studies on the Safety 21 Appl. No.: 09/188,328 of Chronically Administered Intrathecal Neostigmine Meth 22 Filed: Nov. 9, 1998 ylsulfate in Rats and Dogs,” V 82. No. 2, Feb. 1995. “Morphine-A Local Analgesic, International ASSocia (51) Int. Cl." ..................................................... A01N 57/00 tion for the Study of Pain, vol. III. 52 U.S. Cl. .......................... 514/123; 514/123; 514/859; G. Lauretti, MD et al., Anesth Analg “The Effects of 514/855; 514/289; 514/912; 514/78.04; Intrathecal Neostigmine on Somatic and Visceral Pain: 424/401 Improvement by Associate with a Peripheral Anticholin 58 Field of Search ........................... 424/401; 536/55.1; ergic,” 81:615–20 (1996). 514/912, 78.04, 289, 859, 123,855 D. Hood, M.D., et al., Anesthesiology, “Phase I Safety Assessment of Intrathecal Neostigmine Methylsulfate in 56) References Cited Humans,” V 82, No. 2, Feb. 1995 pp. 331-342. U.S. PATENT DOCUMENTS Goodman & Gillman's, The Pharmacological Basis of Therapeutics, 9th Ed., McGraw-Hill pp. 141-175. 3,275,510 9/1966 Magid et al. ........................... 514/946 4,416,886 11/1983 Bernstein ......... ... 424/260 (List continued on next page.) 4,626,539 12/1986 Aungst et al. ... 514/282 4,871,750 10/1989 Roberts ........ ... 514/328 Primary Examiner Keith D. MacMillan 4,897.260 1/1990 Ross et al. ................................ 424/59 ASSistant Examiner Vickie Kim 5,069,909 12/1991 Sharma et al. ... ... 424/499 5,540,918 7/1996 Castillo et al. .. 424/78.04 Attorney, Agent, or Firm Millen, White, Zelano, Branigan, 5,834,480 11/1998 El Khoury .............................. 514/289 P.C. FOREIGN PATENT DOCUMENTS 57 ABSTRACT WO9213540 8/1992 WIPO. Treatment of acne through topical administration is an aspect of the present invention. Specifically, muscarinic OTHER PUBLICATIONS agents may be applied in any therapeutically acceptable J. L. Joris et al., Anesth. Analg., Opioid Analgesia At carrier including gels, creams, lotions, and SprayS. Thera Perhipheral Sites: A Target for Opioids Released During peutic effects observed with the present invention include Stress and Inflammation? 66:1277-81 (1987). decrease in redness, Swelling, and inflammation. Treatment H. Bouaziz, MD et al., Anesth Analg., “Postoperative Anal of other inflammatory conditions is also disclosed. Treat gesia from Intrathecal Neostigmine in Sheep,” 80:1140-4 ment of Suitable conditions in accordance with the present (1995). invention results in Significant improvements in healing of G. Lauretti, MD et al., Anesth Analg., “Dose-Response those conditions. Study of Introthecal Morphine Versus Intrathecal Neostig mine, Their Combination . .” 82:1182-7 (1996). 22 Claims, 1 Drawing Sheet 5,994,330 Page 2 OTHER PUBLICATIONS C. Stein, “Peripheral and Non-Neuronal Opioid Effects,” Tennant et al. Abs. of Int. Pharm. Abs. (Lancet) v. 342 (Oct. Current Scient Ltd., 1–85922-136-X ISSN 0952–7907, pp. 23, 1993) p. 1047-1048. 347-351. Letters to the Editor, The Lancet, vol.342, Oct. 23, 1993, pp. S. Moiniche, et al., “Peripheral Antinociceptive Effects of 1047-1048. Morphine After Burn Injury,” Acta Anaesthesiologica Scan C. Stein, M.D., “The Control of Pain in peripheral Tissue by Opioids,” Mechanisms of Disease, vol. 332, No. 25, pp. dinavica, ISSN 0001–51772, pp. 710–712 (1993). 1685–1690, (1995). C. Stein, “Peripheral Mechanisms of Opioid Analgesia,” C. Williams, Intrasite Gel: A Hyrogel Dressing, Product Anesth Analg 1993; 76:182–92. Focus (3-page article). Remington Pharmaceutical Sciences 18th ed., Chapter 87, C. Stein et al., “Peripheral Opioid Receptors,” Annals of “Medicated Applications,” pp. 1596–1614 (1990). Medicine 17:219–221 (1995). U.S. Patent Nov.30, 1999 5,994,330 5,994,330 1 2 TOPCAL APPLICATION OF MUSCARINC comedones. This agent also decreases the thickness of the AGENTS SUCH AS NEOSTIGMNE FOR Stratum corneum and potentiates the penetration of topical TREATMENT OF ACNE AND OTHER antibiotic agents. Tretinoin therapy comprises once daily NFLAMMATORY CONDITIONS application. Mild redness and peeling are a part of the therapeutic effect of the medication but can result in reduced BACKGROUND OF THE INVENTION patient compliance. Patients should be made aware that The present invention is direction to the treatment of acne improvement may take as long as 6 to 12 weeks, and that and other inflammatory conditions. More Specifically, in flare-ups of acne can occur during the first few weeks of Some embodiments this invention relates to methods for therapy. In addition, it is extremely important that patients treating acne which methods comprise the topical applica avoid excessive exposure to the Sun during treatment. tion of muscarinic agents Such as neoStigmine. Treatment in Mild inflammatory acne lesions can also be treated with accordance with the present invention results in improved topical antibiotics including erythromycin ointment, clinda healing in the treated area. mycin Solution, and meclocycline cream. The primary action Acne is one example of inflammatory conditions which of the antibiotics is to reduce the population of Propioni may be treated in accordance with the present invention. 15 bacterium acnes in the Sebaceous follicle and thereby Sup Acne is a multi factorial disease affecting the Sebaceous press the free fatty acid production. The effectiveness of follicle and characterized by papules, pustules, and Scars. topical antibiotics in the treatment of acne is limited by their Acne affects nearly 90% of 16-year old boys and girls but is low lipid Solubility and Subsequent difficulty in penetrating clearly no longer a problem confined to teenagers. Recently sebum-filled follicles. Topical antibiotics are applied twice for this condition, referral for Specialists’ opinions have daily. Significantly increased among people over the age of 20. It Patients with moderate to severe inflammatory acne often has been realized that simple attention to hygiene is no require oral antibiotics in addition to topical therapy. The longer Sufficient, and antiseptic washes So popular Some most commonly prescribed agents include tetracycline, years ago are now perceived as ineffective by many Sufferers erythromycin, minocycline, and doxycycline. Treatment is and most clinicians. 25 usually maintained for Several months. Side effects include During puberty, elevated androgen levels Stimulate the the overgrowth of nonsusceptible organisms including Sebaceous glands to enlarge and produce increased amounts Candida, which can produce vaginal and oral yeast infec of sebum in the sebaceous follicle. Subsequent abnormal tions. keratinization with hyperkeratosis of the follicular epithe Patients with Severe inflammatory acne unresponsive to lium leads to obstruction of the duct by horny plaque. The other therapy may require treatment with oral isotretinoin. blocked duct becomes clogged with a dense material com Isotretinoin is a compound related to Vitamin A, and is the posed of Sebum and keratinous debris forming a micro only agent that decreases Sebum production and reverses the comedo, a precursor of the acne lesion. The exceSS Sebum in abnormal epithelial formation process. This agent can also decrease the population of Propionibacterium acnes in the the micro comedo also provides an anaerobic growth 35 medium for Propionibacterium acnes. Lipase from the bac Sebaceous follicle. Duration of therapy is usually 20 weeks, teria hydrolyzes Sebum triglycerides into free fatty acids that and the Satisfactory response rate is quite high. Treatment is are both comedogenic and proinflammatory. Propionibacte often accompanied by many Side effects, however, including rium acnes also Secretes chemotactic factors that attract dry skin, pruritus, epistaxis, and photoSensitivity, as well as neutrophils. LySOSomal enzyme released from the neutro hypertriglyceridemia, abnormal liver function tests, electro phils rupture the follicle wall releasing proinflammatory 40 lyte imbalances, and elevated platelet counts. Most Serious mediators including keratin and lipids into the Surrounding though, is the teratogenic effect of isotretinoin. Use of dermis. Inflammatory papules appear as a result. Further isotretinoin during pregnancy is absolutely contraindicated. inflammation with macrophages and foreign body reactions So Serious is the potential for death or teratogenic effects to lead to cysts and nodules. The key features of the patho 45 a fetus, isotretinoin is practically contraindicated in Women genesis of acne can be characterized as 1) increased sebum of child-bearing age. Use of isotretinoin must be accompa production, 2) follicular corynekeratinization, 3) bacterial nied by a guarantee by the patient that conception will be proliferation, and 4) inflammation. avoided at any and all costs. Effective management of acne can be accomplished by Because acne is a multifactorial disease