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Wo 2009/095395 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 6 August 2009 (06.08.2009) PCT WO 2009/095395 A2 (51) International Patent Classification: Werner [CA/CA], 39 Harper Street, Waterdown, Ontario A61K 9/32 (2006.01) A61K 31/343 (2006.01) LOR 2H3 (CA). XIAOPIN, Jin [CA/CA], 3805 Peri win A61K 9/36 (2006.01) A61K 31/554 (2006.01) kle Crescent, Mississauga, Ontario L5N 6W8 (CA). A61K 31/137 (2006.01) (74) Agent: DUNNE, Sinead, TOMKINS & CO., 5 Dartmouth (21) International Application Number: Road, Dublin 6 (IE). PCT/EP2009/050924 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: 28 January 2009 (28.01.2009) AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, (25) Filing Language: English CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (26) Publication Language: English IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, (30) Priority Data: LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, 61/023,951 28 January 2008 (28.01.2008) US MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TJ, (71) Applicant (for all designated States except US): BIO- TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, VAIL LABORATORIES INTERNATIONAL SRL ZW [BB/BB], Welches, Barbados, West Indies, Christ Church 17154 (BB). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors; and GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (75) Inventors/Applicants (for US only): WALSH, Edwin ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), [IE/IE], 70 Philipsburgh Terrace, Marino, Dublin 3 (IE). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, JACKSON, Graham [GB/BB], 7, Coral Lane Drive, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, Atlantic Shores, Christ Church (BB). OBEREGGER, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, [Continued on next page] (54) Title: PHARMACEUTICAL COMPOSITIONS FIG. IA — •— Bupropion HBr • Qtalopram HQ ( 5 10 15 20 Time (hrs) (57) Abstract: The present invention relates to a pharmaceutical composition comprising a tablet core comprising a combination of actives selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, bupropion hydrobromide and escitalopram oxalate, and bupropion hydrobromide and quetiapine fumarate, and at least one pharmaceutically acceptable excipient, and a control-releasing coat surrounding the tablet core, wherein said com- position surprisingly provides for a synchronous release of the combination of active agents ιn-vιtro. The once-daily pharmaceutical composition surprisingly also provides for enhanced absorption of bupropion hydrobromide when administered to a subject in need of such administration. CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Published: — without international search report and to be republished upon receipt of that report PHARMACEUTICAL COMPOSITIONS RELATED APPLICATIONS [0001] This application claims priority to U.S. provisional patent application Ser. No. 61/023,951 filed January 28, 2008, the contents of which are hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to novel once daily pharmaceutical compositions comprising combinations of escitalopram and bupropion or citalopram and bupropion and their use for the treatment of central nervous system disorders, such as for example mood disorders (e.g., major depressive disorder (MDD)- also known as major depression, unipolar depression, unipolar disorder, or clinical depression) and anxiety disorders (general anxiety disorder, social anxiety disorder, post traumatic stress disorder, or panic disorder). The present invention also relates to novel once daily pharmaceutical compositions comprising a combination of bupropion and quetiapine fumarate. BACKGROUND OF THE INVENTION [0003] The burden of mental illness and neurological disorders worldwide is significant. According to the World Health Organization, neuropsychiatric disorders account for 31% of the disability in the world, affecting both rich and poor nations alike (World Health Report 2001: Mental Health: New Understanding, New Hope. World Health Organization (WHO). January 2001. Geneva, Switzerland). It is estimated that the incidence of major depression in the general population is around 5% and its lifetime prevalence is about 20% (Weissman, M.M., et al. (1996) Am Med Ass 276: 293-299). Similarly, the incidence of anxiety disorders in the general population is widespread and high, with lifetime prevalence rates ranging between about 14% and 29% in Western countries (Michael, T et al. (2007). Psychiatry, 6 (4): 136-142). This study also found co-morbidity among individuals with an anxiety disorder to be high, with three out of four individuals with a lifetime anxiety disorder experiencing at least one other mental disorder. These FIG.ures, together with the conclusion that unipolar depression accounted for the fourth leading cause of worldwide Disability Adjusted Life Years (Murray CJ. et al. (1997). Lancet 349: 1436-1442), makes neuropsychiatric disorders, particularly MDD, a significant global health issue, which needs to be treated. [0004] Today, physicians have about 20 FDA approved medications as effective options for treating depressed patients. However, no one treatment is universally effective. While some patients respond to one antidepressant, others respond to another, and some patients may require a combination of medications. [0005] The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the largest and longest study conducted to date, assessed the effectiveness of antidepressant treatments in patients diagnosed with MDD (Rush A.J. et al. (2006). Am J Psychiatry 163: 1905- 191 7). STAR*D was divided into four levels, each of which assessed the effectiveness of a different medication or combination of medications. [0006] Patients who did not become symptom free in one level of treatment moved on to the next level. Level 1 evaluated the effectiveness of the antidepressant citalopram alone. Citalopram and escitalopram (the s-enantiomer of citalopram) currently marketed in the United States as Celexa® and Lexapro®respectively, belong to the class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs). Citalopram was chosen as the first line of treatment because of its superior efficacy, ease of administration (once-a-day), and safety profile in older patients. Patients who did not become symptom free over a 12 to 14 week period after being treated with Celexa® moved on to level 2. [0007] Level 2 patients had the option of switching to a different medication or adding on to the existing Celexa® treatment. Patients who opted for the "add-on" group were prescribed either bupropion-SR (Wellbutrin® SR), or buspirone (BuSpar®). Buspirone itself is not an antidepressant, but enhances the action of antidepressants. Bupropion, on the other hand, is an antidepressant belonging to the chemical class of aminoketones. Bupropion, marketed in the U.S. as Wellbutrin®, Wellbutrin® SR, or Wellbutrin® XL, is classified as an atypical antidepressant. Bupropion was chosen as the antidepressant of choice in Level 2 possibly for several reasons. For one, clinical studies have confirmed the efficacy of bupropion for MDD. (Fava M. et al. (2005). Prim Care Companion J Clin Psychiatry 7(3): 106-113). For another, bupropion, in contrast to nearly all other antidepressants, does not cause weight gain or sexual dysfunction (Zimmerman M. et al. (2005). J Clin Psychiatry 66(10): 1336-1339; Clayton AH. (2003). Primary Psychiatry 10(1): 55-61) and is more effective than SSRIs at improving symptoms of hypersomnia and fatigue in depressed patients (Baldwin et al. (2006). J Clin Psychiatry 67(suppl 6): 9-15). Further, a survey of clinicians found bupropion to be the preferred "add-on" antidepressant for patients not responding to SSRIs as the first line of treatment (Zisook S et al. (2006). Biol Psychiatry 59(3): 203-210; Lam R.W. (2004). J Clin Psychiatry 65(3): 337-340). [0008] One of the conclusions of the STAR*D study is that patients resistant to citalopram and subsequently treated with a combination of citalopram and bupropion faired much better than patients on citalopram or bupropion alone. The study also indicated a possibility of a higher remission rate in citalopram non-responders when bupropion was added on to the existing citalopram treatment rather than when switched to bupropion (30% vs. 20%). [0009] One of the major problems in treating depression with SSRIs is the two to three week delay in onset of their action. This is believed to be a consequence of the mechanism of action of SSRIs (Pineyro G. andBlierP. (1999) Pharmacol Rev 51(3): 533-591). Citalopram, primarily through its S-enantiomer, escitalopram, mediates its antidepressant effects by inhibiting re-uptake of serotonin (5-hydroxytryptamine [5-HT]) released into the synaptic cleft {Brcestrup C. and Sanchez C. (2004). Int J Psychiatry Clin Practice 8 (suppl 1): 11-13). A result of the inhibition of this uptake is that 5-HT persists in the synaptic cleft thereby stimulating receptors of postsynaptic neurons for an extended period in patients suffering from MDD. [0010] Current research suggests that early in the SSRI antidepressant response, 5-HT1A autoreceptors, located at the cell body of neurons, exert a negative feedback response on the firing activity of serotonergic (5-HT) neurons by binding to excess 5-HT. These autoreceptors, after a period of time of treatment with the SSRI, become desensitized and allow 5-HT neurons to regain their normal firing rate in the presence of sustained reuptake inhibition (Blier, P.
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