(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 28 August 2008 (28.08.2008) WO 2008/103442 Al (51) International Patent Classification: (74) Agent: BORSON, D. Benjamin; Borson Law Group, PC, A61F 6/06 (2006.01) A61F 2/00 (2006.01) 1320 Willow Pass Road, Suite 490, Concord, California 94520 (US). (21) International Application Number: PCT/US2008/002347 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, 22 February 2008 (22.02.2008) CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FT, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (25) Filing Language: English IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, (26) Publication Language: English PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (30) Priority Data: ZA, ZM, ZW 60/891,454 23 February 2007 (23.02.2007) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): URI- kind of regional protection available): ARIPO (BW, GH, GEN PHARMACEUTICALS, INC. [ /US]; 875 GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, Mahler Road, Suite 235, Burlingame, California 94010 ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (US). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, (72) Inventors; and NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, (75) Inventors/Applicants (for US only): FRANKLIN, Amie CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Ellen [US/US]; 653 Sharp Park Road, Pacifica, Califor nia 94044 (US). GIESING, Dennis H. [US/US]; 4421 SW Published: Gull Point Drive, Lee's Summit, Montana 64082 (US). — with international search report (54) Title: URETHRAL SUPPOSITORIES FOR OVERACTIVE BLADDER (57) Abstract: Urethral suppositories containing a mixed-activity anti-cholinergic drug and methods of use for treatment of over active bladder are provided. Buffering drugs to pH near their pKas can result in a desired proportion of uncharged drug and can enhance absorption of the agents into urethral tissues. URETHRAL SUPPOSITORIES FOR OVERACTIVE BLADDER Claim of Priority This application claims priority to United States Provisional Patent Application No: 60/891,454, filed February 23, 2007, entitled "Buffered Urethral Suppositories for Overactive Bladder," Amie E. Franklin and Dennis Giesing, inventors. This application is expressly incorporated fully by reference. Field of the Invention This invention is directed to buffered urethral suppositories for treatment of overactive bladder (OAB), and methods for their use. In particular, this invention relates to suppositories incorporating mixed anti-cholinergic agents and uses thereof to treat symptoms of overactive bladder. BACKGROUND Overactive bladder is defined as urgency with or without urge incontinence, usually with frequency and nocturia. This condition is characterized by involuntary bladder muscle contractions during the bladder-filling phase. The muscle contractions may be spontaneous or provoked with patients frequently unable to suppress them, resulting in involuntary expression of urine. Overactive bladder is a fairly common malady as approximately 17 million individuals in the United States and more than 100 million worldwide are afflicted. Importantly, the condition worsens as people age with one in four women and one in ten men aged 65 or older presenting with the disease. Although not life-threatening for the affected individual, overactive bladder is inconvenient, potentially embarrassing, and may disrupt sleep, while significantly impacting quality of life. Frequently these individuals are afraid to leave their home, or are unable to participate in a lengthy meeting, dinner, or social event. Unfortunately, many of these people hesitate to seek treatment because they think their symptoms are a normal part of aging. This view is incorrect because an overactive bladder is not normal, is treatable, and treatment can significantly ease symptoms and improve quality of life. SUMMARY We have realized a new problem with conventional treatments of overactive bladder, namely that overactive bladder is not simply due to dysfunctional bladder detrusor smooth muscle, but rather, is a complex disorder involving an interplay between sensory and motor nerves. Thus, although the use of anti-muscarinic agents alone can be useful in some patients, we discovered that therapy using agents that have mixed-activity anti-cholinergic activity can be especially useful. Further, because absorption of a drug across cell layers is affected by the lipid solubility of the drug, this invention also optionally includes adjusting the pH of the suppository to affect the relative concentrations of charged (polar) and uncharged (non-polar) forms of the drug. Thus, certain aspects of the present invention include a urethral suppository comprising: (1) a carrier base material; (2) a therapeutically effective amount of an agent selected from the group consisting of a mixed-activity anti-cholinergic agent; and optionally (3) a buffering agent in a sufficient quantity to ensure that an effective amount of the therapeutic agent is in an uncharged state for dissolution in the urethra; wherein the suppository is formed into a solid structure configured for insertion into the urethra of a patient. Additional aspects of this invention include use of urethral suppositories to treat symptoms of overactive bladder. DETAILED DESCRIPTION The distal portion of the urinary tract includes the bladder and urethra. The bladder stores urine produced by the kidneys until voiding becomes necessary. The bladder is under control of the autonomic nervous system, including sensory (afferent) nerves and parasympathetic (efferent) nerves. The urethra is a hollow tubular tissue structure that connects to and provides an external outlet of urine from the bladder. In women the urethra is rather short, approximately 1.5-2 inches, whereas in men the length is considerably longer and traverses the prostate before connecting to the bladder. At one end of the urethra, at the base of the bladder is the internal sphincter which is under involuntary reflex control and opens in response to pressure from the bladder when abdominal muscles bear down on the bladder. The external sphincter is closer to the urinary exit and is under voluntary control thereby allowing urine evacuation under voluntary control. Urethral sphincter control is involved in one of the symptoms of overactive bladder, incontinence. One type of incontinence is called urge incontinence when muscle spasms of the bladder result in sensory urgency and leakage from the internal urethral sphincter which opens up in response to increased bladder pressure. Of note, the internal urethral sphincter muscle is unusual in that in its normal state the smooth muscle is contracted and to open up the sphincter the smooth muscle needs to relax. Since the urethra controls incontinence at two of its sphincters and incontinence is often associated with overactive bladder, the urethra is an important part of overactive bladder. Poor systemic perfusion of the urethra makes oral or systemic delivery of drugs poor routes of administration to treat overactive bladder and associated urethral disorders since the drug would have difficulty in gaining access and may have to be administered at such a high dose that systemic or other side-effects make the drug less tolerable. However the alternative, local delivery of drug to the urethra poses its own special problem due to the periodic flushing of urine through the urethra which would wash away any unabsorbed drug on the epithelium of the urethra. Furthermore, the urine can vary significantly in pH from 4.5 to 8 which would dramatically change the absorbability of charged molecules whose charge is pH dependent resulting in unpredictable drug absorption from the urethra. Consequently, there is a need to treat overactive bladder via the urethra locally, but solve the problem of the drug being washed away prematurely before being absorbed by urine flow and to allow rapid absorption in spite of the tremendous variability in the pH of the local environment due to remnant urine on the internal surface of the urethra. Although overactive bladder is considered a disease of the bladder, researchers have described a urethral component to the disease. This is not surprising as many neural and systemic networks are shared by the bladder and urethra. Unlike the bladder, the urethra is a collapsed tube in its resting stage and open to allow urine to pass out of the bladder. Therefore, any liquid or gel material placed in the urethra would be pushed out of the urethra into the bladder or out of the body. To treat the urethra, a medication can be incorporated into a structure that is retained in the urethra for a period of minutes to hours. Embodiments of a drug delivery system include a suppository base as a means to expose the urethra to medication for periods of time from minutes to hours. The formulation of the delivery system including the type of base materials used as a delivery vehicle, the concentration of drug, and the ratio of drug to buffering agent can be chosen so as to produce an efficient mechanism for delivering the therapeutic agent. Size can be an important aspect for the performance of a urethral suppository and for patient tolerance of the suppository, and thus is a consideration in any suppository formulation.