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(12) Patent Application Publication (10) Pub. No.: US 2011/0117194A1 Kim Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0117194A1 Kim Et Al US 2011 01 17194A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0117194A1 Kim et al. (43) Pub. Date: May 19, 2011 (54) PHARMACEUTICAL FORMULATION A6II 35/66 (2006.01) CONTAINING ANGOTENSIN-RECEPTOR A63L/385 (2006.01) BLOCKER A6IR 36/16 (2006.01) A633/04 (2006.01) (75) Inventors: Sung Wuk Kim, Seongnam-si A6II 3/478 (2006.01) (KR); Sung Soo Jun, Seongnam-si A6II 3/4I (2006.01) (KR); Young Gwan Jo, Daejeon A63L/484 (2006.01) (KR); Ja Seong Koo, Daejeon A6II 47/32 (2006.01) (KR); Ah Ram Lee, Incheon (KR); A6II 47/38 (2006.01) Jae Woon Son, Suwon-si (KR); A6II 47/42 (2006.01) Jeong Taek Kim, Anyang-si (KR) A6II 47/12 (2006.01) A6II 47/4 (2006.01) (73) Assignee: HANALL BIOPHARMA CO., A69/20 (2006.01) LTD., Daejeon (KR) A6IR 9/00 (2006.01) 21) Appl. N 12/9904OO A6IP3L/2 (2006.01) (21) Appl. No.: 9 (52) U.S. Cl. ......... 424/465: 514/763; 514/251; 514/474; (22) PCT Filed: Apr. 28, 2009 514/355; 514/729; 514/458: 514/562; 514/4.3: 424/93.51; 514/440, 424/752; 424/702: 514/381: (86). PCT No.: PCT/KR2O09/002225 514/382: 514/397: 514/772.6; 514/772.4: 514/781: 514/773: 514/784: 514/785; 424/400 S371 (c)(1), (2), (4) Date: Jan. 18, 2011 (57) ABSTRACT The present invention provides a pharmaceutical formulation (30) Foreign Application Priority Data containing an angiotensin-II receptor blocker and a release control material as a pharmacologically active ingredient and Apr. 29, 2008 (KR) ........................ 10-2008-004OOO2 a pharmaceutical formulation comprising an immediate-re lease compartment and an extended-release compartment. Publication Classification The immediate-release compartment contains an agent as a (51) Int. Cl. pharmacologically active ingredient for preventing and inhib A6 IK 9/28 (2006.01) iting hepatitis and the extended-release compartment has an A6 IK3I/05 (2006.01) angiotensin-II receptor blocker as a pharmacologically active A6 IK3I/525 (2006.01) ingredient. The formulation of the present invention maxi A 6LX 3L/375 (2006.01) mizes the effectiveness on pharmacologically and clinically A6 IK 3L/455 (2006.01) lowering blood pressure and preventing complications when A6 IK3I/045 (2006.01) taking the formulation, helps to avoid interaction with a drug A 6LX 3L/355 (2006.01) which is metabolized by the same enzyme in the liver, and A6 IK3I/98 (2006.01) prevents and inhibits the incidence of drug-induced hepatitis A6 IK 38/06 (2006.01) which is caused by drug administration for a long time. Patent Application Publication May 19, 2011 Sheet 1 of 3 US 2011/01171.94 A1 S s.si. sers: s 8 . S. 8 s . SS s s s S.s ŠsS: w$3-Y Control.Nicardis) S$ SS8: s xx Example 1 Telmisartan) S S & S. 8.sys' XXak Sokotokososokokososokost 8.3. SSSS.s Y SS ress Control (COzaar) r&r Example 5LOSarta) S. ---------------------. -------------------------------------------------------a S^k sSS S. SR^s SSS SSR. S. & SSSSyx &X. Example 8 YSSY. Example 9 rr Example 1) ^^ Example 11 s Fig. 4 Patent Application Publication May 19, 2011 Sheet 2 of 3 US 2011/01171.94 A1 the Example O Example 1 Example 13 Ras Example 1 as Control Dio wan) rts Example 32(Walsartan) S - as e SS be -...t-: & YasyYYYYY a - Fig. 6 s WSSS *&^ Control Atacand) ... Example 35Candesartan) Fig. 7 Patent Application Publication May 19, 2011 Sheet 3 of 3 US 2011/01171.94 A1 assas CO trol OneteC) S. Example 40Onesartan) -- SSis setde ---------------------------------------------------------------------- SSS. ." S,S. , SSS&S 8&Xrs SSSSSSSSS X. SRSSSSSS 88s XX. XX v Savsvivyxxxx v' &N *Sir CO troTe Vete) ^ Example 43EproSatan) SS :::SS SSS * COIt OIA proVel) ... Example 45rbeSatan) N xx S SY 'Y',&S sixxxSaxxxx---------- xxxxxxxxx-xx-xxxxxxx --- xxxxxxx xxxx xxxxx xxxx-xxxx xxxxxxxxxxx- xxxxx xxxx xxxx xxxx xxxx 3- xxxxx xxxx xxxxxxx xxxx xxxx 3. xxxxxxxx a Y SY- s Y: AYY kY. SasS. SR s ...S.SS KissSSS US 2011/O 1171.94 A1 May 19, 2011 PHARMACEUTICAL FORMULATION quently clinically applied, including pharmaceutically CONTAINING ANGOTENSIN-RECEPTOR acceptable salts. Further, these compounds are used alone or BLOCKER in combination with an angiotensin converting enzyme inhibitor or the like exhibiting hypotensive effects through a CROSS REFERENCE TO RELATED similar mechanism, on mild to severe patients suffering from APPLICATIONS various symptoms associated with hypertension Angio 0001. This application is a 35 U.S.C. S371 National Phase tensin 2 Receptor Antagonist: An Overview, Am J Health Entry Application from PCT/KR2009/002225, filed on Apr. Syst Pharm 57(13): 1231-1238, 2000). 28, 2009, and designating the United States, which claims 0007 Among these angiotensin-II-receptor blockers, priority under 35 U.S.C. S 119 to Korean Patent Application losartan, Valsartan, irbesartan, candesartan, telmisartan, epro No. 10-2008-004.0002 filed on Apr. 29, 2008, which is incor Sartan, olmesartan, and the like have been commercialized porated herein in its entirety. and have rapidly grown as anti-hypertension drugs over the past several years. In addition, effects of these drugs are also TECHNICAL FIELD verified through various clinical trials Pharmacologic, Phar macokinetic, and Therapeutic Difference Among angio 0002 The present invention relates to a pharmaceutical tensin-II-receptor Antagonist: Pharmacotherapy 2002): 130 formulation which is capable of further enhancing drug effi 139, 2000. cacy when used as a single drug. Further, the present inven 0008. As demonstrated through such various clinical tri tion relates to a pharmaceutical formulation which is capable als, these angiotensin-II-receptor blockers are equivalent in of reducing adverse side effects and further enhancing drug hypotensive effects on myocardial systolic and diastolic efficacy when concurrently administered with other drugs. phases at an optimum dose, even though they exhibit phar macokinetic differences in in vivo metabolic pathways and BACKGROUND ART half lives. Further, it is also known that these angiotensin-II 0003 Hypertension is a disorder which serves as a pri receptor blockers are similar in effects obtained by the same mary cause of death due to cardiovascular diseases and causes receptor blocker, Such as prevention and treatment of second fatal diseases Such as cerebral stroke, myocardial infarction, ary heart failure associated with various symptoms of hyper congestive heart failure, and peripheral vascular diseases. tension, prevention and treatment of post-myocardial infarc Blood pressure in a human is not constantly maintained day tion arrhythmia and heart failure, prevention and treatment of and night. This is because predictable changes occurring over diabetic complications, prevention and treatment of renal 24 hours in the environment and physiological diversity cre failure, prevention and treatment of cerebral stroke, anti ate circadian biorhythmic patterns of blood pressure and platelet effects, arteriosclerosis-preventive effects, Suppres heartbeat. The blood pressure of non-dippers whose blood sion of harmful effects of aldosterone, reduction of effects of pressure is not reduced in their sleep Suddenly rises when metabolic syndromes, and effects of preventing circulatory getting up in the morning and reaches a peak during a time diseases from becoming worse in a chain-like manner. period where daytime activity is initiated. 0009. With regard to the treatment of hypertension irre 0004. In a renin-angiotensin-aldosterone system which is spective of the type thereof upon taking into consideration the one of various mechanisms responsible for the elevation of nature of disease, maximum effects of medication should be blood pressure, angiotensinogen is converted into angio exerted in the early morning during which daily blood pres tensin I by the action of renin secreted in the kidney, and Sure becomes highest, and more preferably evening adminis angiotensin I is converted into angiotensin II by the action of tration of the drug is recommended so as to keep blood pres an angiotensin converting enzyme. The converted angio Sure-lowering effects for sleeping hours where the synthesis tensin II is involved in vasoconstriction and renal resorption of renin which is a vasoconstriction-inducing fundamental of NaCl and water. The renin-angiotensin-aldosterone system material is performed and from the night to the early morning works primarily in the night and actively produces aldoster during which the synthesis of angiotensin and aldosterone one and angiotensin II which are vasoconstriction-inducing directly responsible for the elevation of blood pressure agents, which consequently contributes to the elevation of reaches the peak Patterns of blood pressure response: Day blood pressure from the night to the morning The cardiovas and night variations: Am J. Hypertens. 2001 April; 14 (4, Part cular continuum and renin-angiotensin-aldosterone system 2) 262A, Preventing increase in early morning blood pres blockade. J Hypertens Suppl. 2005 April; 23(1): S9-17. Sure, heart rate, and the rate-pressure product with controlled 0005 Through the action of such a renin-angiotensin-al onset extended release Verapamil at bedtime versus enalapril, dosterone system, the mortality of hypertensive patients due losartan, and placebo on rising: Am Heart J. 2002 October; to myocardial infarction, cerebrovascular diseases and heart 144 (4): 657-665). The renin-angiotensin-aldosterone sys failure reaches the highest level in the early morning time tem, which is responsible for such elevation of blood pres during which daily activities take place (from 06 a.m. to Sure, works primarily during night to actively produce aldos noon) Morning blood pressure peak, QT intervals, and sym terone and angiotensin II which are vasoconstriction pathetic activity in hypertensive patients. Hypertension 41 inducing agents, so an angiotensin-II-receptor blocker, which (2): 237-243). inhibits the synthesis of aldosterone and selectively blocks an 0006. The angiotensin-II-receptor blocker has been eluci AT1 receptor out of angiotensin receptors, needs to be admin dated up to now as a drug exerting hypotensive effects on both istered at midnight.
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