USOO70O8939B2 (12) United States Patent (10) Patent No.: US 7,008,939 B2 Christoph (45) Date of Patent: Mar. 7, 2006 (54) USE OF WEAK OPIOIDS AND MIXED WO WO 93/15062 8/1993 OPIOIDAGONISTS/ANTAGONISTS FOR WO WO 98/46216 10/1998 TREATMENT OF URINARY INCONTINENCE WO WO 99/22737 5/1999 (75) Inventor: Thomas Christoph, Aachen (DE) OTHER PUBLICATIONS Dray et al., “Meptazinol: Unusual In Vivo Opioid Receptor (73) Assignee: Gruenenthal GmbH, Aachen (DE) Activity at Supraspinal and Spinal Sites”, Neuropharmacol ogy, vol. 25, No. 4 (1986), pp. 343-349. (*) Notice: Subject to any disclaimer, the term of this JP 07053534 A, Patent Abstracts of Japan, no date available. patent is extended or adjusted under 35 Parfitt, Martindale-The Complete Drug Reference- Thirty U.S.C. 154(b) by 0 days. Second Edition, Pharmaceutical Press, 1999, pp. 26-29, 34, 52-53, and 89. (21) Appl. No.: 10/448,322 Murray, “Acute Urinary Retention Associated with Sublingual Buprenorphine”, British Medical Journal, vol. (22) Filed: May 30, 2003 286, No. 6367 (1983), pp. 763-764. Malinovsky et al., “The Urodynamic Effects of Intravenous (65) Prior Publication Data Opioids and Ketoprofen in Humans', Anesthesia and US 2004/0029905 A1 Feb. 12, 2004 Analgesia, vol. 87, No. 2 (1998), pp. 456-461. Fowler et al., “Effects of Liquid Diphenoxylate Related U.S. Application Data Hydrochloride and Atropine Sulfate (Lomotil). Instillations on Dynamics and Function of Continent Cecal Urinary (63) Continuation of application No. PCT/EP01/13911, Reservoirs”, The Journal of Urology, vol. 138, No. 4 (1987), filed on Nov. 28, 2001. pp. 735-738. Aceto et al., “Stereoselective Mu- and Delta-Opioid Recep (30) Foreign Application Priority Data tor-Related Antinociception and Binding with (+)- Nov. 30, 2000 (DE) ................................ 1OO 59 415 Thebaine” (Abstract), PubMed Database, National Library of Medicine, no date available. (51) Int. Cl. Speigel et al., “Meptazinola Novel Mu-1 Selective Opioid A6 IK3I/55 (2006.01) Analgesic’ (Abstract), Biosis Database, no date available. A6 IK3I/44 (2006.01) Elwood, “Sticky Business: Patterns of Procurement and A6 IK3I/24 (2006.01) Misuse of Prescription Cough Syrup in Houston”, Journal of (52) U.S. Cl. .................. 514/212.01; 514/282; 514/538 Psychoactive Drugs, vol. 33, No. 2 (2001), pp. 121-133. (58) Field of Classification Search ........... 514/212.01, 514/282, 538 * cited by examiner See application file for complete Search history. Primary Examiner-Raymond J. Henley, III (74) Attorney, Agent, or Firm-Crowell & Moring LLP (56) References Cited U.S. PATENT DOCUMENTS (57) ABSTRACT 5,354,863 A 10/1994 Dappen et al. A pharmaceutical composition for the treatment of an 5,840,696. A 11/1998 Lippton increased urge to urinate or urinary incontinence, compris 5,859,043 A 1/1999 Kapusta ing an effective amount of at least a compound Selected from RE36,547 E * 2/2000 Crain et al. ................. 514/282 the group consisting of codeine, dihydrocodeine, dextropro 6,159,501 A * 12/2000 Skinho...................... 424/461 poxyphene, meptazinol and tilidine. Also disclosed are 2003/O166670 A1 9/2003 Brooks-Korn .............. 514/282 methods of treatment using the pharmaceutical composi FOREIGN PATENT DOCUMENTS tions and preferred dosages for the treatment methods. DE 1994.7747 4/2001 EP O913152 5/1999 17 Claims, No Drawings US 7,008,939 B2 1 2 USE OF WEAK OPODS AND MIXED propiverine or tolterodine, tricyclic antidepressants, Such as OPIOID AGONISTS/ANTAGONISTS FOR imipramine, or muscle relaxants, Such as flavoxate. Other TREATMENT OF URINARY INCONTINENCE medicaments, which in particular increase the resistance of the urethra or of the neck of the bladder, show affinities for CROSS REFERENCE TO RELATED C.-adrenoreceptors, Such as ephedrine, for B-adrenorecep APPLICATIONS tors, Such as clenbutarol, or are hormones, Such as oestra diol. The present application is a continuation of International Certain diarylmethylpiperazines and -piperidines are also Patent Application No. PCT/EP01/13911, filed Nov. 28, described for this indication in WO 93/15062. For tramadol 2001, designating the United States of America and pub also a positive effect on bladder function has been demon lished in German as WO 02/43713 A2, the entire disclosure Strated in a rat model of rhythmic bladder contractions of which is incorporated herein by reference. Priority is (Nippon-Shinyaku, WO 98/46216). The literature further claimed based on Federal Republic of Germany Patent more contains Studies on characterization of the opioid Side Application No. 10059 415.8, filed Nov. 30, 2000. effect of urine retention, which give Some indications of the 15 influence on bladder functions by weak opioids, Such as FIELD OF THE INVENTION diphenoxylate (Fowler et al., 1987.J. Urol 138:735–738) and meperidine (Doyle and Briscoe, 1976 Br J Urol The invention relates to the use of weak opioids and 48:329-335), by mixed opioid agonists/antagonists, Such as mixed opioid agonists/antagonists for the preparation of a buprenorphine (Malinovsky et al., 1998 Anesth Analg medicament for the treatment of an increased urge to urinate 87:456-461; Drenger and Magora, 1989 Anesth Analg or urinary incontinence, and to corresponding medicaments 69:348-353), pentazocine (Shimizu et al. (2000) Br. J. and methods for treatment of an increased urge to urinate or Pharmacol. 131 (3):610-616) and nalbuphine (Malinovsky urinary incontinence. et al., 1998, loc. cit.), and by potent opioids, Such as morphine (Malinovsky et al., 1998 loc. cit.; Kontani and BACKGROUND OF THE INVENTION 25 Kawabata, (1988); Jpn J Pharmacol. Sep;48(1):31) and fentanyl (Malinovsky et al., 1998 loc. cit.). However, these Urinary incontinence is the involuntary discharge of Studies were usually conducted in analgesically active con urine. This occurs in an uncontrolled manner when the centrations. preSSure within the urinary bladder exceeds the pressure In the case of the indications in question here, however, it needed to close the ureter. Causes can be on the one hand an should be remembered that it is in general a matter of very increased internal pressure in the bladder (e.g. due to detru long-term uses of medicaments and, in contrast to many sor instability) with the consequence of urgency inconti Situations where analgesics are employed, those affected are nence and on the other hand a reduced Sphincter preSSure faced with a situation which is very unpleasant but not (e.g. following giving birth or Surgical interventions) with intolerable. It is therefore to be ensured here-even more so the consequence of StreSS incontinence. The detrusor is the 35 than with analgesics-that Side effects are avoided if the coarsely bundled multilayered bladder wall musculature, perSon affected does not want to exchange one evil for contraction of which leads to discharge of urine, and the another. Also, analgesic actions are also largely undesirable Sphincter is the closing muscle of the urethra. Mixed forms during permanent treatment of urinary incontinence. of these types of incontinence and So-called overflow incon tinence (e.g. in cases of benign prostate hyperplasia) or 40 DESCRIPTION OF THE INVENTION reflex incontinence (e.g. following damage to the spinal cord) occur. Further details in this respect are to be found in The object of the present invention was therefore to Chutka, D. S. and Takahashi, P. Y., 1998, drugs 560: discover Substances which are helpful for treatment of an 587-595. increased urge to urinate or urinary incontinence and at The urge to urinate is the State, aimed at discharge of urine 45 active doses preferably Simultaneously show fewer Side (miction), of increased bladder muscle tension as the bladder effects and/or analgesic actions. capacity is approached (or exceeded). This tensioning acts Surprisingly, it has now been found that certain weak here as a Stimulus to miction. An increased urge to urinate opioids and mixed opioid agonists/antagonists have an out is understood here as meaning in particular the occurrence of Standing action on bladder function at low concentrations a premature or increased and Sometimes even painful urge to 50 and accordingly are particularly Suitable for treatment of urinate up to So-called Strangury. This consequently leads to corresponding diseases. Significantly more frequent miction. Causes can be, inter The invention accordingly provides the use of one of the alia, inflammations of the urinary bladder and neurogenic following compounds bladder disorders, and bladder tuberculosis. However, all codeine or dihydrocodeine, causes have not yet been clarified. 55 dextropropoxyphene, An increased urge to urinate and urinary incontinence are meptazinol or extremely unpleasant and there is a clear need among perSons afflicted by these conditions to achieve an improve tilidine ment which is as long-term as possible. as free base and/or in the form of physiologically acceptable An increased urge to urinate and in particular urinary 60 Salts for the preparation of a medicament for treatment of an incontinence are conventionally treated with medicaments increased urge to urinate or urinary incontinence. using Substances which are involved in the reflexes of the Surprisingly, it has been found that these compounds lower urinary tract (Wein, A. J., 1998, Urology 51 (suppl. Significantly improve physiological parameters which are of 21): 43–47). These are usually medicaments which have an importance in cases of an increased urge to urinate or urinary inhibiting action on the detrusor muscle,