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(12) United States Patent (10) Patent No.: US 8,138,169 B2 Oronsky Et Al

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(12) United States Patent (10) Patent No.: US 8,138,169 B2 Oronsky Et Al USOO8138169B2 (12) United States Patent (10) Patent No.: US 8,138,169 B2 Oronsky et al. (45) Date of Patent: Mar. 20, 2012 (54) COMBINATION THERAPY FOR BIPOLAR 6,863,901 B2 3/2005 Hirsh et al. 7,201.920 B2 4/2007 Kumar et al. DSORDER 2007/0213394 A1 9/2007 Beguin et al. (75) Inventors: Bryan T. Oronsky, Los Altos Hills, CA FOREIGN PATENT DOCUMENTS (US); Neil C. Oronsky, Los Altos Hills, WO WO-200806691.6 A1 6, 2008 CA (US) OTHER PUBLICATIONS (73) Assignee: ComgenRx, Inc., Mountain View, CA Boothby et al. Buprenorphine for the treatment of opioid depen (US) dence. American Journal of Health-System Pharamcy, 2007, 64 (3), pp. 266-272, abstract.* (*) Notice: Subject to any disclaimer, the term of this Brown, et al., “Naltrexone in Patients with Bipolar Disorder and patent is extended or adjusted under 35 Alcohol Dependence.” Depression and Anxiety, 2006, vol. 23, No. 8, pp. 492-495. U.S.C. 154(b) by 424 days. Carlezon, et al., “Kappa-Opioid Ligands in the Study and Treatment of Mood Disorders.” Pharmacology and Therapeutics, (21) Appl. No.: 12/422,156 XP002548302, Sep. 2009, vol. 123, No. 3, pp. 334-343. International Search Report and Written Opinion mailed on Jan. 25. (22) Filed: Apr. 10, 2009 2010, for PCT Application No. PCT/US2009/040272, 17 pages. Kamin, et al., “Extrapyramidal Side Effects in the Psychiatric Emer (65) Prior Publication Data gency Service.” Psychiatric Service, Mar. 2000, vol. 51, No. 3, pp. US 2009/0311347 A1 Dec. 17, 2009 287-289. Levin, et al., "Bipolar Disorder and Substance abuse.” Biological Psychiatry, XP004649079, vol. 56, No. 10, Nov. 2004, pp. 738-748. Related U.S. Application Data Magura, et al., “Outcomes of buprenorphine Maintenance in Office (60) Provisional application No. 61/050,738, filed on May Based Practice,” Journal of Addictive Diseases, vol. 26, No. 2, Jan. 6, 2008, provisional application No. 61/044.312, filed 2007, pp. 13–23. Murphy, et al., “The Effects of Pentazocine, a Kappa Agonist, in on Apr. 11, 2008. Mania.” Neuropsychopharmacology, XP009123535, vol. 31, No. Suppl. 1, Dec. 2006, pp. 243-247. (51) Int. C. Schaffer, et al., “Mood-Elevating Effects of Opioid Analgesics in A6 IK3I/485 (2006.01) Patients with Bipolar Disorder.” Journal Neurophsychiatry, vol. 19. A6 IK3I/496 (2006.01) No. 4, 2007, pp. 449-452. A6 IK3I/53 (2006.01) Tomasiewicz, et al., “The Kappa-Opioid agonist U69.593 Blocks A6 IK3I/554 (2006.01) Cocaine-Induced Enhancement of Brain Stimulation Reward.” (52) U.S. Cl. .............. 514/211.13: 514/242: 514/254.04; XP002548303, Dec. 2008, vol. 64, pp.982-988. 514/282 * cited by examiner (58) Field of Classification Search ............. 514/211.13, 514/242, 254.04, 282 Primary Examiner — Jennifer M Kim See application file for complete search history. (74) Attorney, Agent, or Firm — Goodwin Procter LLP (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Treatment regimens for mood disorders that include admin 4,952.402 A 8/1990 Sparks et al. istration of buprenorphine, alone or in combination with addi 5,500,227 A 3, 1996 OShlack et al. tional pharmacological agents are described. Specifically, 5,900.420 A 5, 1999 Cole treatment regimens that alleviate racing thoughts associated 5,945,416 A 8, 1999 Shannon et al. with bipolar disorder, and pharmaceutical compositions and 5,972.932 A 10/1999 Benvenga et al. 6,294,195 B1 9, 2001 Oshlack et al. kits for use therein are described. Dosing regimens, compo 6,455,536 B1 9, 2002 Brotchie sitions, and kits including buprenorphine for treating mania 6,608.088 B1 8, 2003 Nicolodi et al. associated with opioid withdrawal are also described. 6,716,449 B2 4/2004 OShlack et al. 6,740,659 B2 5, 2004 Brotchie 16 Claims, No Drawings US 8,138,169 B2 1. 2 COMBINATION THERAPY FOR BPOLAR trating, remembering, or making decisions; restlessness or DISORDER irritability; sleeping too much, or difficulty sleeping; change in appetite and/or unintended weight loss or gain; chronic CROSS-REFERENCE TO RELATED pain or other persistent bodily symptoms that are not caused APPLICATIONS by physical illness or injury; and thoughts of death or Suicide, or Suicide attempts. A depressive episode may be diagnosed if This application claims priority to U.S. Provisional Patent five or more of these symptoms last most of the day, nearly Application Ser. No. 61/044.312 filed on Apr. 11, 2008 and every day, for a period of two weeks or longer. U.S. Provisional Patent Application Ser. No. 61/050,738 filed A mild to moderate level of mania is generally referred to on May 6, 2008, each of which is hereby incorporated by 10 as hypomania. Hypomania may feel good to the individual reference in its entirety. who experiences it and may even be associated with good functioning and enhanced productivity. Thus, even when FIELD family and friends learn to recognize the mood Swings as Treatment regimens for mood disorders that include 15 possible bipolar disorder, the individual may deny that any administration of buprenorphine, alone or in combination thing is wrong. Without proper treatment, however, hypoma with additional pharmacological agents are described. Spe nia can become severe mania or can Switch into depression. cifically, treatment regimens that alleviate racing thoughts Sometimes severe episodes of mania or depression include associated with bipolar disorder, and pharmaceutical compo symptoms of psychosis. Common psychotic symptoms are sitions and kits for use therein are described. The buprenor hallucinations (hearing, seeing, or otherwiseSensing the pres phine and other pharmacological agents can be administered ence of things not actually there) and delusions (false, at therapeutic or subtherapeutic doses to treat the racing strongly held beliefs not influenced by logical reasoning or thoughts. Dosing regimens, compositions, and kits including explained by an individuals usual cultural concepts). Psy buprenorphine for treating mania associated with opioid chotic symptoms in bipolar disorder tend to reflect the withdrawal are also described. 25 extreme mood state at the time. For example, delusions of grandiosity, Such as believing one is the President or has BACKGROUND special powers or wealth, may occur during mania; delusions of guilt or worthlessness, such as believing that one is ruined Bipolar disorder, also known as manic-depressive illness, and penniless or has committed some terrible crime, may is a disorder that causes unusual shifts in a individual’s mood, 30 appear during depression. energy, and ability to function. Different from the normal ups It may be helpful to think of the various mood states in and downs that people experience, the symptoms of bipolar bipolar disorder as a spectrum or continuous range. At one disorder are generally severe. They can result in damaged end is severe depression, above which is moderate depression relationships, poor job or School performance, and even Sui and then mild low mood, which many people call “the blues' cide. 35 when it is short-lived but is termed “dysthymia' when it is Bipolar disorder typically develops in late adolescence or chronic. Then there is normal or balanced mood, above which early adulthood. However, some people have their first symp comes hypomania (mild to moderate mania), and then severe toms during childhood, and Some develop them late in life. mania. Bipolar disorder is a long-term illness that usually requires In some people, however, symptoms of mania and depres management throughout an individual’s life. 40 sion may occur together in what is called a mixed bipolar Bipolar disorder typically causes dramatic mood Swings, state. Symptoms of a mixed State often include agitation, from overly elated (“high) and/or irritable to sad and hope trouble sleeping, a significant change in appetite, psychosis, less, and then back again, often with periods of normal mood and Suicidal thinking. An individual may have a very sad, in between. Severe changes in energy and behavior often hopeless mood while at the same time feeling extremely times are experienced with these changes in mood. The peri 45 energized. ods of highs and lows are referred to as episodes of mania and Bipolar disorder may also initially present as a problem depression. other than mental illness. For instance, it may surface as Signs and symptoms of mania (or a manic episode) may alcohol or drug abuse, poor School or work performance, or include the following: increased energy, activity, and restless strained interpersonal relationships. Such problems in fact ness; excessively “high overly good, euphoric mood; 50 may be signs of an underlying bipolar disorder. extreme irritability; racing thoughts and talking very fast, The classic form of the illness, which involves recurrent jumping from one idea to another, distractibility (e.g., diffi episodes of mania and depression, is called bipolar I disorder. culty concentrating); decreased need for sleep; unrealistic Some individuals, however, never develop severe mania but belief in one’s abilities and powers; poor judgment; spending instead experience milder episodes of hypomania that alter sprees; a lasting period of behavior that is different from 55 nate with depression; this form of the illness is called bipolar usual; increased sexual drive; abuse of drugs (particularly II disorder. When four or more episodes of illness occur cocaine, alcohol, and sleeping medications); and provocative, within a 12-month period, an individual is said to have rapid intrusive, or aggressive behavior. A manic episode may be cycling bipolar disorder. Some individuals experience mul diagnosed if elevated mood occurs with three or more of the tiple episodes within a single week, or even within a single other symptoms most of the day, nearly every day, for one 60 day. week or longer. Bipolar disorder may be treated with medication and psy Signs and symptoms of depression (or a depressive epi chosocial therapy.
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