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United States Patent (19) 11 Patent Number: 5,939.426 Mccullough (45) Date of Patent: Aug

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United States Patent (19) 11 Patent Number: 5,939.426 Mccullough (45) Date of Patent: Aug US00593.9426A United States Patent (19) 11 Patent Number: 5,939.426 McCullough (45) Date of Patent: Aug. 17, 1999 54 METHODS FORTREATING URINARY Ebert, W., 1977, “Soft Elastic Gelatin Capsules: A Unique INCONTINENCE USING Dosage Form”, Pharmaceutical Technology 1:44-50. DESCARBOETHOXYLORATADINE Goodman and Gilman's, 1996, The Pharmacological Basis of Therapeutics, 9th Ed. pp. 148, 588-592. 75 Inventor: John R. McCullough, Worcester, Mass. Herzog, A.R. et al., 1989, “Urinary Incontinence: Medical and Psychosocial Aspects”, Annu. Rev. Gerontol. Geriatr. 73 Assignee: Sepracor Inc., Marlborough, Mass. 9:74-119. Hilbert, J. et al., 1987, "Pharmacokinetics and Dose Pro 21 Appl. No.: 08/808,116 portionality of Loratadine”, J. Clin. Pharmacol. 27:694-698. 22 Filed: Feb. 28, 1997 Knowles, S., 1992, "Astemizole and Terfenadine-Induced Cardiovascular Effects”, Canadian J. Hospital Pharmacy (51) Int. Cl." ..................................................... A61K 31/44 45:33-34. 52 U.S. Cl. .............................................................. 514/290 Kohl and MacDonald, 1991, “New Pharmacologic 58 Field of Search ............................................... 514/290 Approaches to the Prevention of Space/Motion Sickness”, J. Clin. Pharmacol. 31:934-946. 56) References Cited Kubo, N. et al., 1987, "Antimuscarinic Effects of Antihis U.S. PATENT DOCUMENTS tamines: Quantitative Evaluation by Receptor-Binding Assay”, Japan J. Pharmacol. 43:277-282. 3,536.809 10/1970 Applezweig. 3,598,123 8/1971 Zaffaroni. Lathers, C. et al., 1989, “Pharmacology in Space', TiPS, 3,845,770 11/1974 Theeuwes et al.. 10:243-250. 3,916,899 11/1975 Theeuwes et al.. Levin and Wein, 1982, “Direct Measurement of the Anti 3,940,485 2/1976 Levinson et al. ....................... 424/250 cholinergic Activity of a Series of Pharmacological Com 4,008,796 2/1977 Aylon. pounds on the Canine and Rabbit Urinary Bladder”, J. 4,282,233 8/1981 Vilani. Urology 128:396-398. 4,659,716 4/1987 Villani et al.. 4,777,170 10/1988 Heinrich ............................... 514/226.2 Lunde, I., 1990, “Antihistamines”, Side Effects of Drugs 5,595.997 1/1997 Aberg et al. ............................ 514/290 14:135-138. Massad, C. et al., 1992, “The Pharmokinetics of Intravesical FOREIGN PATENT DOCUMENTS and Oral Oxybutynin Chloride”, J. Urology 148:595-597. WO 92/20377 11/1992 WIPO. McCue, J., 1996, “Safety of Antihistamines in the Treatment WO 96/20708 7/1996 WIPO. of Allergic Rhinitis in Elderly Patients”, Arch. Fam. Med. 5:464–468. OTHER PUBLICATIONS Mirakhur and Dundee, 1983, “Glycopyrrolate: Pharmacol Andersen and Feingold, 1995, “Adverse Drug Interactions ogy and Clinical Use', Anaesthesia 38:1195-1204. Clinically Important for the Dermatologist', Arch. Derma Mitchelson, F., 1992, “Pharmacological Agents Affecting tol. 131:468-473. Emesis', Drugs 43:443-463. Berge, S. et al., 1977, “Pharmaceutical Salts”, J. of Phar Muskat, Y. et al., 1996, “The Use of Scopolamine in the maceutical Sciences 66:1-19. Treatment of Detrusor Instability”, J. Urology Brandes, L. et al., 1992, “Stimulation of Malignant Growth 1.56:1989-1990. in Rodents by Antidepressant Drugs at Clinically Relevant Neiemans, F.A., 1988, “Antiallergic and Antitussive Drugs”, Doses', Cancer Research 52:3796-3800. Side Effects of Drugs 12:144-147. Brandes, L. et al., 1994, "Enhanced Cancer Growth in Mice Peggs and Shimp, 1995, “Antihistamines: The Old and The Administered Daily Human-Equivalent Doses of Some New', American Family Physician 52:593-600. H-Antihistamines: Predictive In Vitro Correlates”, J. Natl. Quercia and Broisman, 1993, "Focus on Loratadine: A New Cancer Institute 86:770–775. Second-Generation Nonsedating H-Receptor Antagonist”, Carmeliet, 1992, “Voltage- and Time-Dependent Block of Hosp. Formul. 28:137-153. the Delayed K Current in Cardiac Myocytes by Dofetilide', Resnick, N., 1995, “Urinary Incontinence”, The Lancet J. Pharmocol. Exper. Ther. 262:809–817. 346:94-99. Cheung, B.S.K., et al., 1992, “Investigation of Anti-Motion Roman and Danzig, 1993, “Loratadine”, Clinical Reviews in Sickness Drugs in the Squirrel Monkey”, J. Clin. Pharmacol. Allergy 11:89-110. 32:163-175. Clissold et al., 1989, “Loratadine: A Preliminary Reivew of (List continued on next page.) its Pharmacodynamic Properties and Therapeutic Efficacy”, Drugs 37:42–57. Primary Examiner Minna Moezie Cohen, B. et al., 1972, “Meclizine and Placebo in Treating Attorney, Agent, or Firm-Pennie & Edmonds LLP Vertigo of Vestibular Origin”, Arch. Neurol. 27:129-137. 57 ABSTRACT Cooke, R.D., 1983, “Glycopyrrolate in Bladder Dysfunc tion”, S. Afr. Med. J. 63:3. Methods for treating urinary incontinence comprising Craft, T., 1986, "Torsade de Pointes after Astemizole Over administering a therapeutically effective amount of dose”, British Medical Journal 292:660. deScarboethoxyloratadine, or a pharmaceutically acceptable Dörje, F. et al., 1991, “Antagonist Binding Profiles of Five Salt thereof. Cloned Human Muscarinic Receptor Subtypes”, J. Pharma cology and Experimental Therapeutics 256:727-733. 7 Claims, 1 Drawing Sheet 5,939.426 Page 2 OTHER PUBLICATIONS Yarker, Y. et al., 1995, “Oxybutynin', Drugs & Aging 6:243-262. Simons, F.E.R. et al., 1988, “Astemizole-Induced Torsade de Pointes', The Lancet 2:624. M.N.G. Dukes et al., “Side Effects of Drugs Annual 12.” Simons, F.E.R., 1994, “H-Receptor Antagonists”, Drug Elsevier Science Publishers B.V.: 142-143 (1988). Safety 10:350–380. Petrin, A., 1974, "Motion Sickness and its Treatment', Wein, A., 1995, “Pharmacology of Incontinence', Urol. Schweiz. Med. 63:79-81. Clin. N. Am. 22:557-577. Wood, C.D. et al., 1987, "Mechanisms of Antimotion Sick Wood, C., 1979, “Antimotion Sickness and Antiemetic ness Drugs”, Aviation, Space, and Envir. Med. 58 (9, Suppl.) Drugs", Drugs 17:471-479. pp. A262-A265. U.S. Patent Aug. 17, 1999 5,939.426 K RABBT VENTRICULAR CELL (%) (7) (7) E = -50 V 1 OO - -, (7) H 80 period 30s 60 40 Xs = 8.818 EM-6 20 COeff. = 1.836 O ------ 10-7 10-6 10-5 10-4 10-3 conc. loratadine (M) FIG. RABBT VENTRICULAR CELL EH= -50 mV (11) period 30S -6 20 - COeff. = 1.032 O - ---G- 10-7 10-6 10-5 10-4 10-3 Conc. descarboethoxyloratadine (M) FIG. 2 5,939.426 1 2 METHODS FOR TREATING URINARY Muskat et al. State that when the drug is administered by an INCONTINENCE USING oral or Systemic route, it causes Severe side-effects and also DESCARBOETHOXYLORATADNE discuss the contradictory reports regarding the transdermal administration of Scopolamine. Muskat et al. report that FIELD OF THE INVENTION although Scopolamine is known to cause cycloplegia and dryneSS of the mouth, the Side-effects in its Study were not The present invention relates to methods for treating So Severe to require discontinuation of the medication (Id. at urinary incontinence, Vertigo and motion Sickness. 1990). Scopolamine is also reported as being used widely for motion SickneSS and as effective for the treatment of Vertigo BACKGROUND OF THE INVENTION (Id.). However, it has also been reported that Scopolamine Urinary incontinence, Such as incontinence caused by has unwanted sedative effects (see Lathers et al., TIPS bladder detrusor muscle instability, is a prevalent problem 10:243–250 (1989)). that affects people of all ages and levels of physical health, Certain first generation H-receptor antihistamines, Such both in healthcare Settings and in the community at large. At as diphenylpyraline and promethazine, have been reported present, urinary incontinence afflicts 15-30% of elderly as having Significant affinity for the muscarinic receptors people living at home, one-third of those living in acute-care 15 (Kubo et al., Japan J. Pharmacol. 43:277–282 (1987)). Settings, and at least one-half of those in long-term care Some first generation H receptor antihistamines, Such as institutions (Resnick, R. M., Lancet 346:94 (1995)). dimenhydrinate, cyclizine and meclizine, have also been Medically, it predisposes perSons to urinary tract infections, found to be effective for treating either vertigo or motion pressure ulcers, perineal rashes, and uro Sepsis. sickness (Id; Wood, C., Drugs 17:471-479 (1979); Cohen et PsychoSocially, urinary incontinence is associated with al., Archives of Neurology 27: 129-135 (1972); see also embarrassment, Social Stigmatization, depression, and with Goodman & Gilman's, The Pharmacological Basis of the risk of institutionalization (Herzo et al., Annu. Rev. Therapeutics, 9th Ed. p. 588, 592 (1996)). Gerontol. Geriatr. 9:74 (1989)). Economically, the costs are Peggs et al. (American Family Physician 52(2):593-600 great; in the United States alone, over S15 billion is spent per (1995)), note that classic antihistamines, which have a annum managing incontinence. 25 greater propensity to croSS the blood-brain barrier, would Treatments for incontinence include drugs with bladder appear to be better indicated for the treatment of these relaxant properties, i.e., which help to control bladder detru conditions. However, the first generation H antihistamines sor muscle overactivity. Such drugs are effective in 80 to have undesirable side-effects, Such as Sedation (see Good 85% of patients with uninhibited bladder contractions. Anti mans & Gilman's, The Pharmacological Basis of cholinergic medications represent the mainstay of this type Therapeutics, 9th Ed. p. 590 (1996). of treatment. The major proportion of the neurohumoral The Second generation H-receptor antihistamines, Such Stimulus for physiologic bladder contraction is as terfenadine, astemizole and loratadine, while having acetylcholine-induced Stimulation of post ganglionic mus fewer Sedative effects, are reported as having weak or no carinic receptor Sites on bladder Smooth muscle. For effect on muscarinic receptors (Goodman & Gilman's, The example, anticholinergicS Such as propantheline bromide 35 Pharmacological Basis of Therapeutics, 9th Ed. p. 588 and glycopyrrolate, and combination Smooth muscle (1996); Simons, F. E., Drugs Safety 10(5):350–380 (1994)). relaxant/anticholinergicS Such as racemic oxybutynin and This is consistent with the findings that Such compounds do dicyclomine, have been used to treat urge incontinence. not possess any significant anticholinergic affects (see (See, e.g., Wein, A. J., Urol.
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