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 sS. ŠsS: w$3-Y Control.Nicardis) S$ 8:SS 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. systolic and diastolic phases of the myocardium, by blocking 0010. However, conventional angiotensin-II-receptor the binding of angiotensin-II, one of fundamental Substances blocker single drugs, which are immediately released in vivo responsible for vasoconstriction, to an AT1 receptor out of after administration thereof, are generally administered in the angiotensin receptors. As the angiotensin-II-receptor blocker, morning or evening mealtime. Administration of the drug at there are about 10 kinds of compound groups that are fre the morning mealtime cannot provide effective inhibitory US 2011/O 1171.94 A1 May 19, 2011
effects on the synthesis of vasoconstriction inducersaldoster metabolite). The active metabolite losartan carboxylic acid one and angiotensin II which occurs during the sleeping exhibits a pharmacological activity 40 times higher than that period of the corresponding day. Further, administration of of losartan. The plasma clearance rate is 600 mL/min for the drug at the evening mealtime cannot provide intensive losartan and 50 mL/min for losartan carboxylic acid (active hypotensive effects up to the early morning time period where metabolite), Suggesting that the active metabolite shows a daily blood pressure on the next day reaches its peak. Accord slower clearance rate, and thus plays an important role in ingly, with the use of an angiotensin-II-receptor blocker maintaining the long-lasting action time. Simvastatin, which single drug exhibiting immediate in Vivo release after admin is used in combination with losartan, is a statin-based lipid istration thereof, it is impossible to achieve maximum reducing agent, which inhibits the conversion of 3-hydroxy hypotensive effects in the early morning time period where 3-methylglutaryl-coenzyme A (HMG-CoA) into mevalonate daily blood pressure reaches its peak. Further, upon night by the action of HMG-CoA reductase, thus showing the administration of the angiotensin-II-receptor blocker single effects of inhibiting the synthesis of cholesterol in the liver drug exhibiting immediate in vivo release in order to admin and reducing low-density lipoprotein cholesterol (LDL-C) ister the drug at a time where maximum hypotensive effects levels Lancet 1995: 346: 750-753, Am J Cardiol 1998: 82: are exerted, the compliance of patients is lowered, thus mak 57T-59T, Am J Cardiol 1995; 76: 107C-1 12C, Hypertens Res ing medication compliance difficult and consequently render 2003; 26: 699-704, Hypertens Res 2003; 26:273-280. Br ing treatment of the disease to be difficult. Med Bull 2001: 59: 3-16, Am J Med 1998: 104 (Suppl 1): 0011 To this end, there is a need for the development of a 6S-8S, Clin Pharmacokinet 2002:41: 343-370. Due to hav formulation which is capable of enhancing the patients’ medi ing such effects, simvastatin is known as a drug which is very cation compliance. effective in the treatment and prevention of composite hyper 0012. The onset of hypertensive diseases is largely in aged lipidemia, atherosclerosis and coronary heart diseases people over the age of 40 and is frequently accompanied by “Scandinavian Simvastatin Survival Study” published in the other secondary diseases. Among drugs which are addition Lancet, vol. 344, (1994), p. 1383-89; Lancet, 1994; 344: ally administered for simultaneous treatment of various dis 1383-1389. Further, simvastatin is inactive in itself, but con eases as well as hypertensive diseases, there are drugs which verts into an active form B-hydroxyacid in the liver and is then are metabolized by hepatic cytochrome. Examples of such metabolized by the hepatic enzyme cytochrome P450 3A4, additional drugs include a lipid inhibitor Such as simvastatin works in the liver and is excreted from the liver. When the oratorvastatin; an antihypertensive agent such as amlodipine, remaining simvastatin, which was not metabolized by cyto felodipine, carvedilol or aliskiren, an antihistamine agent chrome P450 3A4, is present at a high level in blood, this Such as loratadine or azelastine; an analgesic agent such as leads to a further increase in the risk of causing myopathies, acetaminophen or tramadol; an antidepressant such as ami Such as myolysis, which is the adverse side effect of simvas triptyline or imipramine; an anticoagulant such as warfarin; tatin Drug Metab Dispos 1990; 18: 138-145, Drug Metab an anti-emetic agent such as chlorpromazine or granisetron; Dispos 1990; 18: 476-483, Drug Metab Dispos 1997: 25: an anticonvulsant Such as carbamazepine; an anti-acne agent 1191-1199, Clin Pharmacol Ther 1998; 63: 332-341; Clin (retinoid) such as isotretinoin, an antipsychotic agent such as Pharmacol Ther 1998; 64: 177-182; Physicians Desk Refer risperidone; an antidepressant such as propyne or Venlafax ence 2006 (Zocor); J Pharmacol Exp Ther 1997: 282:294 ine; an HIV-antiviral agent (protease inhibitor) Such as fos 300; Pharmacol Exp Ther 1999; 290: 1116-1125; Life Sci amprenavir, an antifungal agent such as itraconazole; a thia 2004; 76: 281-292. Zolidinedione antidiabetic agent Such as pioglitaZone; an anti 0016. As described above, when a drug metabolized by obesity agent Such as Sibutramine; an anti-erectile hepatic cytochrome should be additionally administered con dysfunction agent such as sildenafil; and an anti-incontinence currently with an angiotensin-II-receptor blocker, the angio agent such as tolterodine. tensin-II-receptor blocker and the cytochrome-metabolized 0013 Methods for treating hypertension and accompany drug exhibit competitive action therebetween in vivo, so ing diseases through the administration of an angiotensin-II either of them is not sufficiently metabolized, thus causing the receptor blocker are already known (US Patent Application problem of drug interaction Such as decreased drug efficacy No. 2003-0158244A1, and International Patent Publication or increased adverse side effects. As a consequence, treatment Nos. WO95/26188, WO 97/37688, WO 99/11260, WO of both hypertensive diseases and other diseases by combi 04/062729, WO 06/040085 and WO 2002/40007). nation administration of drugs may be not obtained, and the 0014 For example, an HMG-CoA reductase inhibitor problem of drug interaction may also occur upon concurrent simvastatin, which is one of drugs which are metabolized by administration of drugs. hepatic cytochrome, among drugs which have been used in 0017. Further, in order to address the problem of interac the treatment of hypertensive diseases as well as other dis tions between metabolic enzymes and achieve administration eases, and an angiotensin-II-receptor blocker losartan are of drugs at the time period where maximum pharmacological described to have the following problems. effects of the angiotensin-II-receptor blocker are exerted, 0015 Losartan is absorbed and transported to the liver. when the angiotensin-II-receptor blocker exhibiting immedi Some of losartan is released into blood in the form of an active ate in vivo release is administered 2 to 4 hours after medica losartan molecule, reaching a peak blood concentration tion of a drug metabolized by hepatic cytochrome, the com within 1 hour. However, the remaining portion of losartan is pliance of patients is reduced, thus making it difficult to treat metabolized by two hepatic enzymes, cytochrome P4502C9 the disease of interest. and 3A4 and is therefore converted into losartan carboxylic 0018. In particular, there are large numbers of drugs inhib acid having a higher activity, reaching the highest blood con iting cytochrome P450 enzymes that metabolize and activate centration after 3 to 4hours. That is, the total pharmacological losartan. For instance, co-administration of a cytochrome activity of losartan is the pharmacological action of a mixture P450 3A4-inhibiting drug (such as indinavir, nelfinavir, of losartan and losartan carboxylic acid (losartan’s active ritonavir, clarithromycin, itraconazole, ketoconazole, nefaZ US 2011/O 1171.94 A1 May 19, 2011
odone, saquinavirm tellithromycin, aprepitan, erythromycin, dative action cascade requires antioxidative environment of fluconazole, Verapamil, cimetidine, amiodaronem chloram the coupling system including vitamin E. Vitamin C, glu phenicol, delaviridinem diethyldithiocarbamate, fluvoxam tathione and cysteine. ine, gestodene, imatinib, mibefradil, mifepristone, norfloxa 0023. In addition to the above-stated antioxidants, there cin, norflouxetine, or Voriconazole) or a CYP2C9-inhibiting are oxidative stress-inhibiting ingredients among crude drug drug (such as fluconazole, amiodarone, fenofibratem fluvas ingredients. tatin, fluvoxamine, isoniazid, phenylbutaZone, probenecid, 0024 For example, silymarin or biphenyldimethyldicar Sertraline, Sulfamethoxazole, Sulfaphenazole, teniposide, or boxylate (DDB) is a crude drug which has been well-known Voriconazole) with an angiotensin-II-receptor blocker losar as an ingredient to counteract drug-induced hepatitis by tan leads to inhibition of the losartan activity and conse inhibiting oxidative stress of cell membranes. Further, intra quently desired pharmacological effects of losartan cannot be hepatic biliary atresia, one of pathological symptoms of drug sufficiently exerted. induced hepatitis, is a clinical condition leading to continuous destruction of Surrounding hepatocytes due to no escape of 0019. To this end, there is a need for the development of a cell lysates into the biliary duct. Although ursodeoxycholic formulation which can be freely co-administered with these acid exhibits surface-activating effects, not antioxidative drugs. effects, on Such a drug-induced hepatic disorder, it is an 0020. Further, it is reported that the majority of drugs ingredient having significant hepatic protective effects since undergoing hepatic metabolism may cause inflammation due urSodeoxycholic acid prevents worsening of pathological to destruction of the liver as adverse side effects thereof. In symptoms due to oxidative stress and increases the regenera particular, since the treatment of hypertension is focused on tion capacity of hepatocytes. exertion of drug-induced hypotensive effects and inhibition 0025. As reviewed above, with regard to long-term medi of hypertension-induced complications, not focusing on the cation of an angiotensin-II-receptor blocker or various other treatment of underlying pathological causes, this requires drugs for the treatment of hypertension and prevention of long-term medication and co-administration with other related complications, there is a further need for the develop drugs. Since drug-induced hepatitis is dose-dependent, ment of a formulation which is capable of preventing hepatic administration of several kinds of drugs serves to repeatedly damage. destroy the liver. Further, even though it is administered 0026. As a result of a variety of extensive and intensive alone, long-term medication of an angiotensin-II-receptor studies and experiments to develop a pharmaceutical formu blocker increases the risk of hepatitis. Hepatitis is the destruc lation which is capable of further enhancing drug efficacy tion of hepatic parenchymal cells and lobules. This is referred upon administration of an angiotensin-II-receptor blocker to as oxidative stress, and drug-induced free radicals gener when it is used as a single drug and which is capable of not ated in the liver lead to oxidation of lipids to lipid peroxides only reducing adverse side effects but also further enhancing and the lipid peroxides in turn lead to generation of free drug efficacy when concurrently administered with other radicals in geometric progression, thus resulting in hepatic drugs, the inventors of the present invention have completed destruction. Even though hepatic destruction is prevented if a the present invention. Further, the present inventors have Sufficient amount of an antioxidant is present in the liver, conducted intensive studies and experiments to develop a hypertensive patients are usually deficient in antioxidants pharmaceutical formulation which is excellent in patients throughout all the tissues. compliance and is capable of preventing drug interactions and 0021. The initial pathological symptom caused by oxida preventing hepatic damage which may occur upon long-term tive stress is fatty liver where more than 5% of the hepatocyte administration, and thus the present invention has been com weight turns into lipid peroxides or the like. The fatty liver pleted. quickly degrades into liver-destroying hepatitis, thus result ing in necrosis of hepatocytes. Upon necrosis of hepatocytes, DISCLOSURE OF THE INVENTION enzymes Such as GPT and GOT, playing a role in hepatocytes, are liberated and discharged into blood. Therefore, the state of Technical Problem hepatitis is judged by calculating GPT and GOT values. All types of hepatotoxicity are proportional to sGPT values. For 0027. Therefore, the present invention is intended to pro this reason, lowering of sGPT is fundamental in the treatment vide a formulation which is excellent in patients’ compliance of hepatic diseases Cecil's textbook of medicine. As an upon administration of an angiotensin-II-receptor blocker approach to preventhepatotoxicity of drugs, there is a method and is capable of preventing drug interaction and preventing of lowering sGPT to within a normal range by inhibiting the hepatic damage which may occur upon long-term adminis formation of lipid peroxides through the administration of an tration. antioxidant or the like. 0022. Inhibition of the formation of lipid peroxides in the Technical Solution liver should take place first on the cell membrane. This is because oxidative stress is concentrated on the cell membrane 0028. The present invention provides a pharmaceutical due to localization of lipids on the cell membrane. On the cell formulation containing an angiotensin-II-receptor blocker membrane, Vitamin E removes peroxyl and hydroxyl radi and a release-controlling material. cals, thereby protecting the cell membrane against oxidative 0029. The pharmacologically active ingredient angio stress, and carotenoid which is vitamin A removes singlet tensin-II-receptor blocker in the formulation of the present oxygen. Vitamin E having an antioxidative action is regener invention is released at a level of less than 40% by weight ated by the action of vitamin C, the used vitamin C is regen within 4 hours after oral administration, and preferably a level erated by the action of glutathione, and glutathione is in turn of less than 30% by weight within 4 hours after oral admin regenerated by the action of cysteine. Therefore, the antioxi istration. US 2011/O 1171.94 A1 May 19, 2011
0030. A content of the angiotensin-II-receptor blocker in material is higher than the above-specified range, significant the formulation of the present invention is in the range of 2.5 clinical effects cannot be achieved due to delayed release of to 1200 mg per unit formulation, and preferably 5 to 600 mg. the drug. 0031. The formulation of the present invention further 0035. The enteric polymer refers to a polymer which is contains a hepatitis-preventing and inhibiting agent as a phar insoluble or stable under the acidic conditions of less than pH macologically active ingredient, and a content of the hepati 5, and is dissolved or degraded under the specific pH condi tis-preventing and inhibiting agent in the formulation is in the tions of pH 5 or higher. The enteric polymer that can be used range of 0.01 ug to 1 g, and preferably 0.1 ug to 200 mg. in the present invention is at least one selected from the group consisting of an enteric cellulose derivative, an enteric acrylic 0032 Examples of the hepatitis-preventing and inhibiting acid copolymer, an enteric polymethacrylate copolymer, an agent include vitamins such as B-carotene, riboflavin, ribo enteric maleic acid copolymer, an enteric polyvinyl deriva flavin tetrabutyrate, riboflavin rocoat, riboflavin phosphate tive, and a mixture thereof. Sodium, ascorbic acid, ascorbyl palmitate, calcium ascorbate, 0036 Preferably, the enteric cellulose derivative is at least nicotinamide ascorbate, sodium ascorbate, dehydroascorbic one selected from hydroxypropylmethylcellulose acetate acid, cholecalciferol, cholecalciferolic acid, ergocalciferol, Succinate (or referred to as hypromellose acetate Succinate), tocopherol, tocopherol acetate, tocopherol calcium, toco hydroxypropylmethylcellulose phthalate (or referred to as pherol calcium Succinate, and/or tocopherol Succinate, amino hypromellose phthalate), hydroxymethylethylcellulose acids such as cysteine, cysteine hydrochloride, cysteine phthalate, cellulose acetate phthalate, cellulose acetate Suc malate, methyl cysteine, carboxymethyl cysteine, methyl cinate, cellulose acetate maleate, cellulose benzoate phtha cysteine hydrochloride, N-acetyl-L-cysteine, L-glutathione, late, cellulose propionate phthalate, methylcellulose phtha glutathione disulfide, reduced glutathione, L-glutamine, late, carboxymethylethylcellulose, glutamine hydrochloride, L-glutaminate-L-lysinate, and/or ethylhydroxyethylcellulose phthalate, methylhydroxyethyl N(2)-L-alanine-L-glutamine, C-lipoic acid, selenized yeast, cellulose and a mixture thereof; the enteric acrylic acid Selenium, selenium disulfide, sodium selenate, sodium selen copolymer is at least one selected from a styrenefacrylic acid ite, silymarin, ginko biloba extract, DDB (biphenyldimethyl copolymer, a methyl acrylate/acrylic acid copolymer, a dicarboxylate), urSodeoxycholic acid, chenocholic acid, methyl acrylate/methacrylic acid copolymer, abutyl acrylate/ butylated hydroxyanisole, butylated hydroxytoluene, guai styrenefacrylic acid copolymer, a methyl acrylate/meth acrylic acid/octyl acrylate copolymer and a mixture thereof. acol, erdosteine, resveratrol, pyridoxamine hydrochloride, the enteric polymethacrylate copolymer is at least one pyridoxine hydrochloride, pyridoxal phosphate, agaro-oli selected from a poly(methacrylic acid/methyl methacrylate gosaccharide, fraction flavonoid purifiee micronise, melato copolymer) (e.g., Eudragit L 100 or Eudragit S, Degussa, nin, ubidecarenone, L-ornithine, ornithine aspartate, orni Germany), a poly(methacrylic acid/ethyl acrylate) copoly thine hydrochloride, L-arginine, arginine hydrochloride, mer (e.g., Eudragit L 100-55, Degussa, Germany) and a mix arginine Sodium, L-arginine monoglutamate, protoporphyrin ture thereof; the enteric maleic acid copolymer is at least one disodium, haematoporphyrin, haematoporphyrin hydrochlo selected from a vinyl acetate/maleic anhydride copolymer, a ride, Coriolus versicolor polysaccharide (for example, styrene/maleic anhydride copolymer, a styrene/maleic ATSO: Agents for Liver and Gallbladder (Hepato protec monoester copolymer, a vinyl methyl ether/maleic anhydride tors)), cicloxilic acid, citiolone, oraZamide, azintamide, copolymer, an ethylene/maleic anhydride copolymer, a vinyl hymecromone, and/or C.-naphthyl acetic acid, and the like. butyl ether/maleic anhydride copolymer, an acrylonitrile/me The hepatitis-preventing and inhibiting agent includes phar thyl acrylate/maleic anhydride copolymer, a butyl acrylate/ maceutically acceptable salts thereofand derivatives and ana styrene/maleic anhydride copolymer and a mixture thereof. logs thereofhaving an equivalent pharmacological activity. and the enteric polyvinyl derivative is at least one selected 0033. The angiotensin-II-receptor blocker in the formula from polyvinylalcohol phthalate, polyvinylacetate phthalate, tion of the present invention is at least one selected from polyvinylbutyrate phthalate, polyvinylacetacetal phthalate losartan, Valsartan, telmisartan, irbesartan, candesartan, olm and a mixture thereof. The enteric polymer in the formulation esartan, eprosartan, isomers thereof, pharmaceutically of the present invention is preferably at least one selected acceptable salts thereof, and prodrugs thereof. The prodrug of from hydroxypropylmethylcellulose phthalate and a meth candesartan is decomposed in vivo into an active ingredient acrylic acid/ethyl acrylate copolymer. In the formulation of candesartan and is preferably candesartan cilexetil. The pro the present invention, the enteric polymer is preferably drug of olmesartan is decomposed in vivo into an active hydroxypropylmethylcellulose phthalate or a methyl acry ingredient olmesartan and is preferably olmesartan medox late/methacrylic acid copolymer. omil. 0037. A content of the enteric polymer may be in the range 0034. The release-controlling material in the formulation of 0.1 parts by weight to 20 parts by weight, preferably 0.5 of the present invention is at least one selected from an enteric parts by weight to 10 parts by weight relative to 1 part by polymer, a water-insoluble polymer, a hydrophobic com weight of the active ingredient. If a content of the enteric pound, a hydrophilic polymer and a mixture thereof. The polymer is lower than 0.1 parts by weight, the enteric polymer release-controlling material is preferably at least one selected may be easily dissolved at a pH of less than 5. On the other from a water-insoluble polymer and an enteric polymer. A hand, ifa content of the enteric polymeris higher than 20 parts content of the release-controlling material is in the range of by weight, this may lead to an unnecessary increase in a total 0.05 to 30 parts by weight relative to 1 part by weight of the weight of the formulation or excessively delayed release angiotensin-II-receptor blocker. If a content of the release thereof. controlling material is lower than the above-specified range, it 0038. The water-insoluble polymer refers to a pharmaceu may be difficult to achieve a sufficient delayed-release prop tically acceptable water-insoluble polymer which controls erty. On the other hand, if a content of the release-controlling the release of a drug. The water-insoluble polymer that can be US 2011/O 1171.94 A1 May 19, 2011
used in the present invention is preferably at least one selected hydroxyethylmethylcellulose and a mixture thereof; the gum from the group consisting of polyvinyl acetate, a water-in is at least one selected from guar gum, locust bean gum, soluble polymethacrylate copolymer {e.g. poly(ethyl acry tragacanth, carrageenan, gum acacia, gum arabic, gellan late, methyl methacrylate) copolymer (such as Eudragit gum, Xanthan gum and a mixture thereof; the protein is at NE30D), a poly(ethyl acrylate, methyl methacrylate, trim least one selected from gelatin, casein, Zein and a mixture ethylaminoethyl methacrylate chloride) copolymer (e.g. thereof; the polyvinyl derivative is at least one selected from Eudragit RS PO), etc., ethylcellulose, cellulose ester, cellu polyvinyl alcohol, polyvinyl pyrrolidone, polyvinylacetal lose ether, cellulose acylate, cellulose diacylate, cellulose diethylaminoacetate and a mixture thereof; the hydrophilic triacylate, cellulose acetate, cellulose diacetate, cellulose tri polymethacrylate copolymer is at least one selected from a acetate and a mixture thereof, and more preferably at least one poly(butyl methacrylate, (2-dimethylaminoethyl)methacry selected from polyvinyl acetate, ethylcellulose and cellulose late, methyl methacrylate) copolymer (e.g. Eudragit E 100, acetate. A content of the water-insoluble polymer may be in Evonik, Germany) and a mixture thereof; the polyethylene the range of 0.1 parts by weight to 30 parts by weight, pref derivative is at least one selected from polyethylene glycol, erably 0.5 parts by weight to 20 parts by weight relative to 1 polyethylene oxide and a mixture thereof; and the carboxyvi part by weight of the active ingredient. If a content of the nyl polymer is carbomer. A preferred example of the hydro water-insoluble polymer is lower than 0.1 parts by weight, philic polymer is at least one selected from polyvinylpyrroli release of the drug may be not controlled. On the other hand, done, hydroxypropylcellulose, hypromellose, and a poly if a content of the water-insoluble polymer is higher than 30 (ethyl acrylate, methyl methacrylate, triethylaminoethyl parts by weight, release of the drug may be excessively methacrylate chloride) copolymer. delayed. 0042. A content of the hydrophilic polymer may be in the 0039. The hydrophobic compound refers to a pharmaceu range of 0.05 parts by weight to 30 parts by weight, preferably tically acceptable water-insoluble material which controls the 0.5 to 20 parts by weight relative to 1 part by weight of the release of a drug. The hydrophobic compound that can be active ingredient. If a content of the hydrophilic polymer is used in the present invention may be at least one selected from lower than 0.05 parts by weight, release of the drug may be the group consisting of fatty acid and fatty acid ester, fatty not controlled. On the other hand, if a content of the hydro acid alcohol, wax, inorganic material, and a mixture thereof. philic polymer is higher than 30 parts by weight, release of the Preferably, the fatty acid or fatty acid ester is at least one drug may be excessively delayed. selected from glyceryl palmitostearate, glyceryl Stearate, 0043. The formulation of the present invention may fur glyceryl distearate, glyceryl behenate, cetyl palmitate, glyc ther contain, if necessary, commonly used additives such as eryl monooleate, Stearic acid and a mixture thereof the fatty pharmaceutically acceptable diluent, binder, disintegrant, acid alcohol is at least one selected from cetostearyl alcohol, lubricant, pH-adjusting agent, and solubilizer, within the cetyl alcohol, stearyl alcohol and a mixture thereof; the wax is range where effects of the present invention are not impaired at least one selected from carnauba wax, beeswax, microc and the release of pharmacologically active ingredients is not rystalline wax and a mixture thereof, and the inorganic mate impaired. rial is at least one selected from talc, precipitated calcium 0044. In the formulation of the present invention, a content carbonate, calcium hydrogen phosphate, Zinc oxide, titanium of the additive is in the range of 0.1 to 300 parts by weight, oxide, kaolin, bentonite, montmorillonite, Veegum and a mix relative to 1 part by weight of the active ingredient. ture thereof. More preferred is carnauba wax. 0045 Examples of the diluent that can be used in the 0040. A content of the hydrophobic compound may be in present invention may include starch, microcrystalline cellu the range of 0.1 parts by weight to 20 parts by weight, pref lose, lactose, glucose, mannitol, alginate, an alkaline earth erably 0.5 parts by weight to 10 parts by weight relative to 1 metal salt, clay, polyethylene glycol, dicalcium phosphate, part by weight of the active ingredient. If a content of the and a mixture thereof. hydrophobic compound is lower than 0.1 parts by weight, 0046 Examples of the binder that can be used in the release of the drug may be not controlled. On the other hand, present invention may include starch, microcrystalline cellu if a content of the hydrophobic compound is higher than 20 lose, highly dispersive silica, mannitol. Sucrose, lactose, parts by weight, release of the drug may be excessively polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl delayed. methylcellulose, hydroxypropylcellulose, natural gum, Syn 0041. The hydrophilic polymer refers to a pharmaceuti thetic gum, a polyvinylpyrrolidone copolymer, povidone, cally acceptable water-soluble polymer which controls the gelatin, and a mixture thereof. release of a drug. The hydrophilic polymer that can be used in 0047. Examples of the disintegrant that can be used in the the present invention may be at least one selected from the present invention may include starches or modified Starches group consisting of saccharide, a cellulose derivative, gum, a Such as sodium starch glycolate, corn starch, potato starch, protein, a polyvinyl derivative, a hydrophilic polymethacry and pregelatinized starch; clays such as bentonite, montmo late copolymer, a polyethylene derivative, a carboxyvinyl rillonite, and Veegum; celluloses such as microcrystalline copolymer and a mixture thereof. Preferably, the saccharide cellulose, hydroxypropylcellulose, and carboxymethylcellu is at least one selected from dextrin, polydextrin, dextran, lose; algins such as Sodium alginate, and alginic acid; pectin and a pectin derivative, alginate, polygalacturonic crosslinked celluloses such as croScarmellose sodium; gums acid, Xylan, arabinoxylan, arabinogalactan, starch, hydrox Such as guar gum, and Xanthan gum, crosslinked polymers ypropyl Starch, amylose, amylopectin and a mixture thereof. Such as crosslinked polyvinylpyrrolidone (crospovidone); the cellulose derivative is at least one selected from hydrox effervescent agents such as sodium bicarbonate and citric ypropylmethylcellulose (or referred to as hypromellose), acid, and mixtures thereof. hydroxypropylcellulose, hydroxymethylcellulose, hydroxy 0048 Examples of the lubricant that can be used in the ethylcellulose, methylcellulose, sodium carboxymethylcel present invention may include talc, Stearic acid, magnesium lulose, hydroxypropylmethylcellulose acetate Succinate, Stearate, calcium Stearate, sodium lauryl Sulfate, hydroge US 2011/O 1171.94 A1 May 19, 2011
nated vegetable oil, Sodium benzoate, Sodium Stearyl fuma formulated not so as to contain an angiotensin-II-receptor rate, glyceryl behenate, glyceryl monolaurate, glyceryl blocker. The multi-layered tablet can be compressed in the monostearate, glyceryl palmitostearate, polyethylene glycol, form of a double-layered tablet by adding a particle, granule and mixtures thereof. orpellet coated with a release-controlling material containing 0049. Examples of the stabilizer that can be used in the an angiotensin-II-receptor blocker, a layer containing phar present invention may include ascorbic acid, citric acid, buty maceutically acceptable excipient(s), and a layer (delayed lated hydroxyanisole, butylated hydroxy toluene, and toco release layer) containing pharmaceutically acceptable excipi pherol derivatives. Further examples of the stabilizer may ent(s) together with a release-controlling material, using a include alkalizers such as alkali metal salts, alkaline earth multiple tablet press. If necessary, a triple or more multi metal salts, or mixtures thereof. Preferably, there may be used layered tablet may also be prepared by further adding another calcium carbonate, sodium carbonate, sodium hydrogen car layer on the double-layered tablet. A coated multi-layered bonate, magnesium oxide, magnesium carbonate, and tablet may be prepared by coating the multi-layered tablet. Sodium citrate. Examples of the pH-adjusting agent that can 0058. The press-coated tablet may be a tablet including an be used in the present invention may include acidulants such inner core tablet containing an angiotensin-II-receptor as acetic acid, adipic acid, ascorbic acid, malic acid. Succinic blocker and a release-controlling material and an outer layer acid, tartaric acid, fumaric acid, and citric acid, and basifying containing a release-controlling material enclosing the outer agents such as precipitated calcium carbonate, aqueous surface of the inner core tablet. That is, the press-coated tablet ammonia, and meglumine. may be a tablet including a coating layer enclosing the outer 0050 Examples of the solubilizer that can be used in the Surface of the angiotensin-II-receptor blocker-containing tab present invention may include Sodium lauryl Sulfate, poly let and containing a release-controlling material, and an outer oxyethylene Sorbitan fatty acid ester (Such as polysorbate), layer enclosing the outer Surface of the coating layer and and docusate Sodium. containing a release-controlling material, or may be an 0051. In addition, the formulation of the present invention osmotic press-coated tablet including an osmotic inner core may optionally contain pharmaceutically acceptable addi tablet releasing the drug by means of osmotic pressure, as an tives Such as various additives selected from a colorant and a inner core. fragrance. 0059. The capsule may be of a form where at least one 0052. The range of the additive that can be used in the selected from a particle, a granule, a pellet and a tablet is filled present invention is not limited to the above-mentioned addi in a capsule. The capsule may be prepared by filling a granule tives, and the additive may be used in a conventional dose containing an angiotensin-II-receptor blocker and coated which can be suitably selected by those skilled in the art. with a release-controlling material, or optionally together 0053. The formulation of the present invention can be with a particle or granule containing a pharmaceutically prepared into various formulations. That is, the formulation acceptable excipient and/or a release-controlling material, in of the present invention can be formulated into tablets (such a capsule using a capsule filling machine. as uncoated tablets, film-coated tablets, multi-layered tablets, 0060. Further, the capsule may be prepared by filling a and press-coated tablets), powders, granules, or capsules. pellet coated with a release-controlling material containing 0054 The uncoated tablet may be a tablet which is an angiotensin-II-receptor blocker, or optionally together obtained by compression of granules containing an angio with a particle or granule containing a pharmaceutically tensin-II-receptor blocker and a release-controlling material acceptable excipient and/or a release-controlling material, in using a tablet press or the like. a capsule using a capsule filling machine. 0055. The uncoated tablet can be prepared by coating a 0061 Further, the capsule may be prepared by filling a particle, granule or pellet containing an angiotensin-II-recep film-coated tablet coated with a release-controlling material tor blocker with a release-controlling material, followed by containing an angiotensin-II-receptor blocker, or optionally mixing with a pharmaceutically acceptable excipient(s) and together with a particle or granule containing a pharmaceuti compression into uniform weight. cally acceptable excipient and/or a release-controlling mate 0056. The film-coated tablet may be a tablet in which a rial, in a capsule using a capsule filling machine. tablet containing an angiotensin-II-receptor blocker is coated 0062. The formulation of the present invention may be a with a film-coated layer containing a release-controlling formulation in the form of an uncoated tablet without further material, using a coater or the like. The film-coated tablet can coating, or otherwise, if necessary, may be provided in the be prepared by compressing a particle, granule or pellet con form of a coated tablet further including a coating layer taining an angiotensin-II-receptor blocker into uniform formed on the outside of the formulation. The formation of a weight, thereby preparing a tablet, and coating the resulting coating layer can provide a formulation which is capable of tablet with a release-controlling material, followed by drying further securing stability of pharmacologically active ingre to prepare a film-coated tablet, or coating the resulting film dients. coated tablet with a coating Solution for the purpose of 0063 A method for forming the coating layer may be improving the stability, thereby preparing a film-coated tab Suitably selected by a skilled person in the art, from among let. Further, for the purpose of improving the stability or methods capable of forming a film-like coating layer on the achieving delayed release of drugs, the compressed uncoated surface of the tablet layer, such as a fluidized-bed coating tablet of delayed-release granules may be coated with a coat method and a pan coating method. Preferably, a pan coating ing solution, thereby preparing a film-coated tablet. method may be used. 0057 The multi-layered tablet may be a tablet which is 0064. The coating layer may be formed by using a film formed to have a layered structure of a layer containing an forming agent, a film-forming aid or a mixture thereof. For angiotensin-II-receptor blocker and a release-controlling example, the film-forming agent may be cellulose derivatives material and a layer containing a release-controlling material. Such as hydroxypropylmethylcellulose and hydroxypropyl The layer containing a release-controlling material can be cellulose, saccharide derivatives, polyvinyl derivatives, US 2011/O 1171.94 A1 May 19, 2011
waxes, fats, gelatin and mixtures thereof, and the film-form carvedilol, and aliskiren; an antihistamine agent which is at ing aid may be polyethylene glycol, ethylcellulose, glyceride, least one selected from loratadine, and azelastine; an analge titanium oxide, talc, diethyl phthalate and mixtures thereof. sic agent which is at least one selected from acetaminophen, 0065. A content of the coating layer may be in the range of and tramadol; an antidepressant which is at least one selected 0.5 to 15% by weight (% w/w) based on the total weight of the from amitriptyline, and imipramine; an anticoagulant which tablet. is warfarin; an anti-emetic agent which is at least one selected 0066. If a content of the coating layer is lower than 0.5% from chlorpromazine, and granisetron; an anticonvulsant by weight, it may be difficult to achieve the protection of which is carbamazepine; an anti-acne agent (retinoid) which products, and the stability thereofdepending on formulations. is isotretinoin, an antipsychotic agent which is risperidone; an On the other hand, if a content of the coating layer is higher antidepressant which is at least one selected from propyne, than 15% by weight, release profiles of pharmacologically and Venlafaxine; a human immunodeficiency virus (HIV)- active ingredients may be affected. antiviral agent (protease inhibitor) which is foSamprenavir, 0067. The formulation of the present invention may con an antifungal agent which is itraconazole; a thiazolidinedione tain an osmo-regulator and may be coated with a semi-per antidiabetic agent which is pioglitaZone; an anti-obesity meable membrane coating base. agent which is sibutramine; an anti-erectile dysfunction agent 0068. The osmo-regulator is preferably at least one which is sildenafil; and an anti-incontinence agent which is selected from the group consisting of magnesium Sulfate, tolterodine. magnesium chloride, sodium chloride, lithium chloride, 0075. Further, the present invention provides a pharma potassium Sulfate, sodium sulfate, lithium sulfate and a mix ceutical formulation including a prior-release compartment ture thereof. containing a hepatitis-preventing and inhibiting agent as a 0069. A content of the osmo-regulator may be in the range pharmacologically active ingredient, and a delayed-release of 0.01 parts by weight to 10 parts by weight, preferably 0.05 compartment containing an angiotensin-II-receptor blocker parts by weight to 0.5 parts by weight relative to 1 part by as a pharmacologically active ingredient. weight of the active ingredient. If a content of the osmo 0076 Preferably, the pharmacologically active ingredient regulator is lower than 0.01 parts by weight, it may be difficult contained in the delayed-release compartment is released 1 to to achieve a sufficient chronotherapeutic release. On the other 4 hours after the release of the pharmacologically active hand, ifa content of the osmo-regulatoris higher than 10 parts ingredient contained in the prior-release compartment is ini by weight, it may be difficult to achieve significant clinical tiated. Less than 40% by weight of the pharmacologically effects due to delayed release of the drug. active ingredient contained in the delayed-release compart 0070 The semi-permeable membrane coating base is a ment is released within 4 hours after the release of the phar material which is blended in a coating layer of the pharma macologically active ingredient contained in the prior-release ceutical formulation and refers to a material used to form a compartment is initiated. membrane through which some ingredients can pass but other 0077. Further, preferably, the pharmacologically active ingredients cannot pass. The semi-permeable coating base in ingredient contained in the prior-release compartment is the present invention may employ the above-mentioned released at a level of more than 85% by weight within one water-insoluble polymers. hour after initiation of release thereof. 0071. For example, the semi-permeable membrane coat 0078. A content of the hepatitis-preventing and inhibiting ing base that can be used in the present invention is at least one agent in the formulation of the present invention is in the selected from the group consisting of polyvinyl acetate, a range of 0.01 g to 1 g. polymethacrylate copolymer, poly(ethyl acrylate, methyl 0079 A content of the angiotensin-II-receptor blocker in methacrylate) copolymer, a poly(ethyl acrylate, methyl meth the formulation of the present invention is in the range of 5 to acrylate, trimethylaminoethyl methacrylate chloride) copoly 600 mg. mer, ethylcellulose, cellulose ester, cellulose ether, cellulose 0080 Hereinafter, individual compartments of the formu acylate, cellulose diacylate, cellulose triacylate, cellulose lation in accordance with the present invention will be acetate, cellulose diacetate, cellulose triacetate and a mixture described in more detail. thereof. I0081 1. Prior-Release Compartment 0072 A content of the semi-permeable membrane coating I0082. The “prior-release compartment” refers to a com base may be in the range of 0.01 parts by weight to 10 parts by partment which is released ahead of the “delayed-release weight, preferably 0.05 parts by weight to 1.25 parts by compartment in the pharmaceutical formulation of the weight relative to 1 part by weight of the active ingredient. If present invention. The prior-release compartment may fur a content of the semi-permeable membrane coating base is ther contain “pharmaceutically acceptable additives', if nec lower than 0.01 parts by weight, it may be difficult to achieve essary, in addition to “pharmacologically active ingredients'. a sufficient time-lag. On the other hand, if a content of the I0083 (1) Pharmacologically Active Ingredients semi-permeable membrane coating base is higher than 10 I0084. The pharmacologically active ingredient of the parts by weight, there is a problem associated with no release prior-release compartment is a hepatitis-preventing and of the drug or an excessively long time-lag. inhibiting agent which is the same as described in the phar 0073. The formulation of the present invention may be maceutical formulation containing an angiotensin-II-recep administered once a day, between 5 p.m. and 11 p.m. and may tor blocker and a release-controlling material. be administered in combination with a drug which is metabo I0085 (2) Pharmaceutically Acceptable Additives lized by cytochrome. I0086. The formulation of the present invention may fur 0074 Examples of the drug which is metabolized by cyto ther contain commonly used additives Such as pharmaceuti chrome include a lipid inhibitor which is at least one selected cally acceptable diluent, binder, disintegrant, lubricant, pH from simvastatin, andatorvastatin; an antihypertensive agent adjusting agent, and solubilizer, within the range where which is at least one selected from amlodipine, felodipine, effects of the present invention are not impaired and the US 2011/O 1171.94 A1 May 19, 2011 release of pharmacologically active ingredients is not not impaired and within the range where delayed-release impaired. Details of the pharmaceutically acceptable addi properties are not compromised. tives are the same as those of the pharmaceutical formulation 0099 Details of the pharmaceutically acceptable additives containing an angiotensin-II-receptor blocker and a release are the same as those of the pharmaceutical formulation con controlling material. taining an angiotensin-II-receptor blocker and a release-con 0087 2. Delayed-Release Compartment trolling material. 0088. In the present invention, the “delayed-release com 0100. The pharmaceutical formulation of the present partment” refers to a compartment whose active ingredient is invention can be prepared into various formulations, for released at a certaintime interval after the release of the active example, tablets (such as uncoated tablets, coated tablets, ingredient of the “prior-release compartment'. The delayed multi-layered tablets, and press-coated tablets), powders, release compartment may contain (1) a “pharmacologically granules, or capsules. active ingredient' and (2-1) a “release-controlling material' 0101 The formulation of the present invention may be in or (2-2) an osmo-regulator and a semi-permeable membrane the form of an uncoated tablet which is obtained by optionally coating base, and (3), if necessary, “pharmaceutically accept Subjecting prior-release compartment-forming granules or able additives'. the like and delayed-release compartment-forming granules 0089 (1) Pharmacologically Active Ingredients or the like to post-mixing with additive(s), followed by com 0090 The pharmacologically active ingredient of the pression, such that the prior-release compartment and the delayed-release compartment is an angiotensin-II-receptor delayed-release compartment are present within a single tab blocker and may further include the hepatitis-preventing and let whereby active ingredients of individual compartments inhibiting agent of the prior-release compartment, if neces are separately released to exhibit the efficacy of each drug. sary. The pharmacologically active ingredient of the delayed 0102 The formulation of the present invention may be in release compartment in the formulation of the present inven the form of a two-phase matrix tablet which is obtained by tion is released at a level of less than 40% by weight of a total uniformly mixing a delayed-release compartment and a prior amount of the active ingredient of the delayed-release com release compartment, followed by compression. partment up to 2 hours after the release of the pharmacologi 0103) Further, the pharmaceutical formulation of the cally active ingredient of the prior-release compartment is present invention may be in the form of a film-coated tablet initiated. Preferably, the pharmacologically active ingredient including a tablet consisting of a delayed-release compart of the delayed-release compartment is released at a level of ment and a film-coated layer consisting of a prior-release less than 20% by weight of a total amount of the pharmaco compartment enclosing the exterior of the tablet, whereby an logically active ingredient of the delayed-release compart active ingredient of the film-coated layer is first released as ment up to 2 hours after the release of the pharmacologically the film-coated layer is dissolved. active ingredient of the prior-release compartment is initi 0104 Further, the pharmaceutical formulation of the ated. present invention may be in the form of a multi-layered tablet 0091) Details of the angiotensin-II-receptor blocker and having a multi-layered structure of a delayed-release com the hepatitis-preventing and inhibiting agent are the same as partment and a prior-release compartment, each compart those of the pharmaceutical formulation containing an angio ment of which is obtained by mixing the granules constituting tensin-II-receptor blocker and a release-controlling material. the delayed-release compartment and the prior-release com 0092 (2-1) Release-Controlling Materials partment with pharmaceutical additives, and compressing the 0093. The delayed-release compartment in the pharma mixture into a double-layered or triple-layered tablet, using a ceutical formulation of the present invention contains a multiple tablet press. The resulting formulation is a tablet for release-controlling material. Details of the release-control oral administration which was formulated to achieve the ling material are the same as those of the pharmaceutical prior-release and delayed-release of drugs according to indi formulation containing an angiotensin-II-receptor blocker vidual layers. and a release-controlling material, provided that there is a 0105. Further, the pharmaceutical formulation of the present invention may be in the form of a press-coated tablet difference in the type of compartments and formulations. including an inner core tablet consisting of a delayed-release 0094 (2-2) Osmo-Regulator and Semi-Permeable Mem compartment and an outer layer consisting of a prior-release brane Coating Base compartment enclosing the outer Surface of the inner core 0095. The delayed-release compartment of the present tablet. The press-coated tablet may be an osmotic press invention may be a compartment which contains an osmo coated tablet. The osmotic press-coated tablet is a formula regulator and is coated by a semi-permeable membrane coat tion wherein the tablet mix is compressed into a tablet in a ing base. manner that an osmo-regulator is incorporated for the 0096. Details of the osmo-regulator and semi-permeable delayed-release of a drug, the tablet surface is coated with a membrane coating base are the same as those of the pharma semi-permeable membrane coating base to prepare an inner ceutical formulation containing an angiotensin-II-receptor core, a granule constituting the prior-release compartment is blocker and a release-controlling material. mixed with pharmaceutical additives to prepare an outer 0097 (3) Pharmaceutically Acceptable Additives layer, followed by compression to form a formulation having 0098. In addition to (2-1) a release-controlling material a delayed-release inner core and a prior-release layer enclos and (2-2) an osmo-regulator and a semi-permeable mem ing the Surface of the inner core. brane coating base, the formulation of the present invention 0106 The pharmaceutical formulation of the present may further contain commonly used additives such as phar invention may be in the form of a capsule containing a par maceutically acceptable diluent, binder, disintegrant, lubri ticle, granule, pellet, or tablet formed of a delayed-release cant, pH-adjusting agent, anti-foaming agent, and solubilizer, compartment and a particle, granule, pellet, or tablet formed within the range where the effects of the present invention are of a prior-release compartment. US 2011/O 1171.94 A1 May 19, 2011
0107 The tablet formed of the delayed-release compart lation or compression, followed by coating with a semi-per ment of the capsule may be an osmotic coated tablet which meable membrane coating base. contains an osmo-regulator inside the tablet and has a semi 0115 Step 2 is a step of obtaining a prior-release granule permeable membrane coating base on the Surface of the tab or tablet by Subjecting a pharmacologically active ingredient let. of the prior-release compartment together with a conven 0108. The base material of the capsule may be one tional pharmaceutically acceptable additive to conventional selected from gelatin, Succinate gelatin, hydroxypropylmeth processes for producing oral Solid formulations, for example, ylcellulose, and a mixture thereof. mixing, kneading, drying, granulation or coating, and com 0109 Further, the pharmaceutical formulation of the pression. present invention may be in the form of a kit including a 0116 Step 3 is a step of obtaining a formulation for oral delayed-release compartment and a prior-release compart administration by mixing the granule or tablet obtained in ment. Specifically, the kit includes (a) prior-release compart each of Steps 1 and 2 with a pharmaceutically acceptable ment; (b) a delayed-release compartment; and (c) a container for filling the prior-release compartment and the delayed excipient and either compressing the mixture into a tablet or release compartment. The kit can be prepared in the form of a filling the mixture in a capsule for oral administration. kit wherein a particle, granule, pellet, or tablet constituting 0117 Step 1 may be carried out after Step 2, or Step 1 may the prior-release compartment is prepared, a granule, pellet, be carried out simultaneously with Step 2. or tablet constituting the delayed-release compartment is 0118. The pharmaceutical formulation of the present separately prepared, and the thus prepared two compartment invention can be prepared according to the above procedure, materials are filled in a foil, blister, or bottle to prepare a and a formulation method of Step 3 will be described in more dosage form for concurrent administration of different drugs. detail hereinafter, but the present invention is not limited 0110. The formulation of the present invention may fur thereto. ther include a coating layer on the outside of the delayed 1. Preparation of Two-Phase Matrix Tablets release compartment and/or the prior-release compartment. 0119) That is, the Surface of particles, granules, pellets, or tablets 0.120. The particles or granules prepared in Step 1 are formed of the delayed-release compartment and/or the prior optionally coated with a release-controlling material and then mixed with the granules prepared in Step 2, followed by release compartment may be coated for the purpose of con compression into uniform weight, thereby preparing tablets. trolled release of drugs or stability of the formulation. The resulting tablets may be film-coated for the purpose of 0111. Further, the formulation of the present invention improving the stability or shape, if necessary. may be a formulation in the form of an uncoated tablet with out further coating, or otherwise, if necessary, may be pro I0121 2. Preparation of Film-Coated Tablets Containing vided in the form of a coated tablet further including a coating Pharmacologically Active Ingredients layer formed on the outside of the formulation. The formation 0.122 The coated tablets or granules prepared in Step 1 are of a coating layer can provide a formulation which is capable optionally coated with a release-controlling material and of further securing the stability of pharmacologically active dried, followed by compression into uniform weight and ingredients. Details of the coating are the same as those of the optionally further coating to prepare tablets. In addition, a pharmaceutical formulation containing an angiotensin-II-re pharmacologically active ingredient of the prior-release com ceptor blocker and a release-controlling material. partment is dissolved and dispersed in a water-soluble film 0112 The formulation of the present invention may be coating solution and is coated on the outer layer of the tablets administered once a day, between 5 p.m. and 11 p.m. and may obtained in Step 1 to thereby prepare oral film-coated tablets be administered in combination with a drug which is metabo containing pharmacologically active ingredients in the film lized by cytochrome. Details thereofare the same as those of coating. the pharmaceutical formulation containing an angiotensin-II (0123 3. Preparation of Multi-Layered Tablets receptor blocker and a release-controlling material. 0.124. The granules prepared in Step 1 are optionally 0113. The pharmaceutical formulation of the present coated with a release-controlling material, and dried. The invention can be preferably formulated into a desired dosage dried granules are compressed with the granules prepared in form depending on individual diseases or ingredients, by an Step 2 by using a multi-layered tablet press, thereby obtaining appropriate method known in the art, for example, using the a double-layered tablet. According to the formulation design principle of the chronotherapy as disclosed in Chronothera or if necessary, a triple or more multi-layered tablet may also peutics (2003, Peter Redfern, PhP), specifically by a method be prepared by further adding a release adjuvant layer on the including the following steps. double-layered tablet. A coated multi-layered tablet may be 0114 Step 1 is a step of obtaining a delayed-release gran prepared by coating the multi-layered tablet. ule or tablet by Subjecting a pharmacologically active ingre 0.125 4. Preparation of Press-Coated Tablets dient of the delayed-release compartment and one or two 0.126 The coated tablets or granules prepared in Step 1 are release-controlling materials selected from the group consist optionally coated with a release-controlling material and ing of an enteric polymer, a water-insoluble polymer, a hydro dried, followed by compression into uniform weight. The phobic compound, and a hydrophilic polymer together with a resulting granules are used as an inner core optionally after pharmaceutically acceptable conventional additive to mix performing further coating, and compressed with the gran ing, kneading, drying, granulation or coating, and compres ules prepared in Step 2 by using a press-coated tablet press, Sion, or of obtaining a delayed-release granule or tablet by thereby providing press-coated tablets where the surface of Subjecting the pharmacologically active ingredient and an the tablet of Step 1 is enclosed by the prior-release layer. osmo-regulator together with a conventional pharmaceuti Coated press-coated tablets may be prepared by coating the cally acceptable additive to mixing, kneading, drying, granu press-coated tablets. US 2011/O 1171.94 A1 May 19, 2011
0127. 5. Preparation of Capsules (Containing Granules or 0.135 FIG. 2 is a graph showing the dissolution profiles for Tablets) a losartan single drug and a formulation of Example 5. 0128. The granules prepared in Step 1 are optionally 0.136 FIG.3 is a graph showing the dissolution profiles for coated with a release-controlling material, and dried. The formulations of Examples 8 to 11. dried granules together with the granules prepared in Step 2 0.137 FIG. 4 is a graph showing the comparative dissolu may be placed in a capsule filling machine, and filled in a tion profiles for formulations of Examples 10, and 12 to 14. capsule having a given size at an effective amount of each 0.138 FIG. 5 is a graph showing the dissolution profiles for main ingredient, thereby preparing a capsule. a Valsartan single drug and a formulation of Example 32. 0129. 6. Preparation of Capsules (Pellets) 0.139 FIG. 6 is a graph showing the dissolution profiles for 0130 (1) A pharmacologically active ingredient of the a candesartan single drug and a formulation of Example 35. delayed-release compartment, a release-controlling material, 0140 FIG. 7 is a graph showing the dissolution profiles for and if necessary, pharmaceutically acceptable additives are an olmesartan medoxomil single drug and a formulation of dissolved or Suspended in water, an organic solvent, or a Example 40. mixed solvent. This solution or Suspension is coated on Sugar 0141 FIG. 8 is a graph showing the dissolution profiles of spheres and dried, and if necessary, coated with one or more an eprosartan single drug and a formulation of Example 43. release-controlling materials dissolved in water, an organic 0.142 FIG.9 is a graph showing the dissolution profiles for solvent, or a mixed solvent, followed by drying. The mixture an irbesartan single drug and a formulation of Example 45. may be mixed with the granules prepared in Step 2 or the tablets obtained in Step 3 and then filled in capsules using a MODE FOR INVENTION capsule filling machine, thereby preparing capsules. 0.143 Now, the present invention will be described in more 0131 (2) A pharmacologically active ingredient of the detail with reference to the following Examples. These prior-release compartment and pharmaceutically acceptable examples are provided only for illustrating the present inven additives may be dissolved or Suspended in water, an organic tion and should not be construed as limiting the scope and Solvent or a mixed solvent, coated on Sugar spheres, followed spirit of the present invention. by drying, and mixed with the controlled-release pellets of Section (1) containing a pharmacologically active ingredient Example 1 of the delayed-release compartment and filled in capsules using a capsule filling machine to prepare capsules. Preparation of Angiotensin-II-Receptor Blocker 0132) The formulation of the present invention is designed Containing Uncoated Tablets based on Chronotherapy taking into consideration the expres 0144. 1) Preparation of Angiotensin-II-Receptor Blocker sion time of pharmacological action in vivo, and maximizes Delayed-Release Granules pharmacological and clinical hypotensive effects and com 0145 According to the ingredient contents shown in Table plication-preventing effects upon administration thereof by 1 below, telmisartan, microcrystalline cellulose, sorbitol, the formulation such that release of the drug is delayed as meglumine, and Sodium hydroxide were sieved through a No. compared to administration of an angiotensin-II-receptor 35 sieve and mixed in a high-speed mixer for 5 minutes to blocker single drug which is immediately released in vivo prepare a mixture. Meanwhile, polyvinylpyrrolidone was dis after administration thereof. Further, the pharmaceutical for solved in purified water (70 mg/tablet) to prepare a binding mulation of the present invention is designed based on Xeno Solution, followed by kneading, granulation and drying. The biotics taking into consideration the metabolic enzyme inter dried material was placed in a fluidized bed coater. Mean action, and maximizes pharmacological and clinical while, polyvinyl acetate was dissolved in a (2:8) mixed sol hypotensive effects and complication-preventing effects and vent of ethanol and methylene chloride (240 mg/tablet) to further reduces adverse side effects by the formulation such prepare a solution which was then coated on the granules in a that release of the drug is delayed as compared to a drug fluidized bed coater (GPCG-1: Glatt, Germany). After metabolized by hepatic cytochrome, thus providing a time completion of the coating process, drying was carried out to lag interval of release between different drugs without caus prepare angiotensin-II-receptor blocker delayed-release ing competitiveness therebetween on the metabolism by the granules. same enzyme cytochrome in the liver. Further, the pharma 0146 2) Compression ceutical formulation of the present invention can prevent and 0147 The angiotensin-II-receptor blocker delayed-re inhibit the onset of drug-induced hepatitis due to long-term lease granules prepared in Section 1) and magnesium Stearate administration or excessive administration. were placed in a double cone mixer, followed by final mixing for 4 minutes. The final mixture was compressed into tablets ADVANTAGEOUSEFFECTS using a rotary tablet press (MRC-33: Sejong, South Korea) to 0133. The formulation of the present invention maximizes prepare delayed-release uncoated tablets of the angiotensin the effectiveness on pharmacologically and clinically lower II-receptor blocker. ing blood pressure and preventing complications when taking Example 2 the formulation, helps to avoid interactions with a drug which is metabolized by the same enzyme in the liver, and prevents Preparation of Angiotensin-II-Receptor Blocker and inhibits the incidence of drug-induced hepatitis which is Containing Uncoated Tablets caused by drug administration for a long time. 0.148. 1) Preparation of Angiotensin-II-Receptor Blocker DESCRIPTION OF THE DRAWINGS Delayed-Release Granules 0149 According to the ingredient contents shown in Table 0134 FIG. 1 is a graph showing the dissolution profiles for 1 below, irbesartan, pregelatinized starch, lactose, and cros a telmisartan single drug and a formulation of Example 1. carmellose sodium were sieved through a No. 35 sieve and US 2011/O 1171.94 A1 May 19, 2011 mixed in a high-speed mixer for 5 minutes to prepare a mix prepare a mixture. Meanwhile, hydroxypropylcellulose was ture. Meanwhile, Poloxamer 188 was dissolved in purified dissolved in purified water (40 mg/tablet) to prepare a binding water (90 mg/tablet) to prepare a binding solution, followed Solution, followed by kneading, granulation and drying. The by kneading, granulation and drying. The dried material was dried material was placed in a fluidized bed coater. Mean placed in a fluidized bed coater. Meanwhile, cellulose acetate while, hypromellosephthalate (HP-55) and polyethylene gly (acetyl group 32.0%) and cellulose acetate (acetyl group col 6000 were dissolved in a (2:8) mixed solvent of ethanol 39.8%) were dissolved in a (2:8) mixed solvent of ethanol and and methylene chloride (1200 mg/tablet) to prepare a solution methylene chloride (800 mg/tablet) to prepare a solution which was then coated on the granules in a fluidized bed which was then coated on the granules in a fluidized bed coater (GPCG-1: Glatt, Germany). After completion of the coater (GPCG-1: Glatt, Germany). After completion of the coating process, drying was carried out. The dried material, coating process, drying was carried out. The dried material microcrystalline cellulose, and colloidal silicon dioxide were and colloidal silicon dioxide were placed in a double cone placed in a double cone mixer, followed by mixing to prepare mixer, followed by mixing to prepare angiotensin-II-receptor angiotensin-II-receptor blocker delayed-release granules. blocker delayed-release granules. 0150. 2) Compression 0158 2) Compression 0151. The angiotensin-II-receptor blocker delayed-re 0159. The angiotensin-II-receptor blocker delayed-re lease granules prepared in Section 1) and magnesium Stearate lease granules prepared in Section 1) and magnesium Stearate were placed in a double cone mixer, followed by final mixing were placed in a double cone mixer, followed by final mixing for 4 minutes. The final mixture was compressed into tablets for 4 minutes. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong, South Korea), using a rotary tablet press (MRC-33: Sejong, South Korea), thereby preparing delayed-release uncoated tablets of the thereby preparing delayed-release uncoated tablets of the angiotensin-II-receptor blocker. angiotensin-II-receptor blocker. Example 3 Example 5 Preparation of Angiotensin-II-Receptor Blocker Containing Uncoated Tablets Preparation of Film-Coated Tablets Containing 0152 1) Preparation of Angiotensin-II-Receptor Blocker Delayed-Release Granules Delayed-Release Granules 0153. According to the ingredient contents shown in Table 0160 1) Preparation of Angiotensin-II-Receptor Blocker 1 below, Valsartan, microcrystalline cellulose, and Delayed-Release Uncoated Tablets crosslinked polyvinylpyrrolidone were sieved through a No. 0.161 Angiotensin-II-receptor blocker delayed-release 35 sieve and mixed in a high-speed mixer for 5 minutes to uncoated tablets were prepared in the same manner as in prepare a mixture. Meanwhile, polyvinylpyrrolidone was dis Sections 1) and 2) of Example 4 and according to the ingre solved in purified water (100 mg/tablet) to prepare a binding dient compositions and contents shown in Table 1 below. Solution, followed by kneading, granulation and drying. The dried material was placed in a fluidized bed coater. Mean (0162 2) Film coating while, a solution of hypromellose in purified water (70 0163 The uncoated tablets prepared in Section 1) were mg/tablet) and a solution of hypromellose phthalate in a (8:2) placed in a Hi-coater (SFC-30N, Sejong Machinery Co., Ltd., mixed solvent of ethanol and purified water (120 mg/tablet) South Korea). According to the ingredient compositions were respectively prepared. The granules were placed in a shown in Table 1 below, hypromellose 2910, hydroxypropy fluidized bed coater (GPCG-1: Glatt, Germany), followed by lcellulose, titanium oxide, and talc were dissolved and dis two-step coating with the prepared solutions. After comple persed in a (8:2) mixed solvent of ethanol and purified water tion of the coating process, drying was carried out to prepare (400 mg/tablet) to prepare a coating solution which was then angiotensin-II-receptor blocker delayed-release granules. coated on the uncoated tablets to prepare angiotensin-II-re 0154 2) Compression ceptor blocker-containing film-coated tablets. 0155 The angiotensin-II-receptor blocker delayed-re lease granules prepared in Section 1) and magnesium Stearate were placed in a double cone mixer, followed by final mixing Example 6 for 4 minutes. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong, South Korea), Preparation of Film-Coated Tablets Containing thereby preparing delayed-release uncoated tablets of the Delayed-Release Granules angiotensin-II-receptor blocker. 0164. 1) Preparation of Angiotensin-II-Receptor Blocker Example 4 Delayed-Release Uncoated Tablets 0.165 Angiotensin-II-receptor blocker delayed-release Preparation of Angiotensin-II-Receptor Blocker uncoated tablets were prepared in the same manner as in Containing Uncoated Tablets Sections 1) and 2) of Example 4 and according to the ingre 0156 1) Preparation of Angiotensin-II-Receptor Blocker dient compositions and contents shown in Table 1 below, Delayed-Release Granules except that eprosartan was used in place of losartan potas 0157 According to the ingredient contents shown in Table S1. 1 below, losartan potassium, microcrystalline cellulose, 0166 2) Film Coating Sodium starch glycolate, and lactose were sieved through a 0.167 Film-coated tablets containing delayed-release No. 35 sieve and mixed in a high-speed mixer for 5 minutes to granules were prepared in the same manner as in the prepa US 2011/O 1171.94 A1 May 19, 2011
ration of a film-coated layer in Section 2) of Example 5 and and contents shown in Table 1 below, thereby preparing film according to the ingredient compositions and contents shown coated tablets containing a delayed-release film. in Table 1 below. Examples 12 to 14 Example 7 Preparation of Film-Coated Tablets Containing a Preparation of Film-Coated Tablets Containing Delayed-Release Film Delayed-Release Granules 0179 1) Preparation of Angiotensin-II-Receptor Blocker 0168 1) Preparation of Angiotensin-II-Receptor Blocker Uncoated Tablets Delayed-Release Uncoated Tablets 0180. In the case of Examples 12 to 14, angiotensin-II 0169. Angiotensin-II-receptor blocker delayed-release receptor blocker uncoated tablets were prepared in the same uncoated tablets were prepared in the same manner as in manner as in Section 1) of Example 8 and according to the Sections 1) and 2) of Example 1 and according to the ingre ingredient compositions and contents shown in Table 2 dient compositions and contents shown in Table 1 below. below. (0170 2) Film Coating 0181 2) Preparation of Angiotensin-II-Receptor Blocker 0171 Film-coated tablets containing delayed-release granules were prepared in the same manner as in the prepa Delayed-Release Film-Coated Tablets ration of a film-coated layer in Section 2) of Example 5 and 0182. In the case of Examples 12 to 14, the uncoated according to the ingredient compositions and contents shown tablets prepared in Section 1) were placed in a Hi-coater in Table 1 below. (SFC-30N, Sejong Machinery Co., Ltd., South Korea). According to the ingredient contents shown in Table 2 below, polyvinylpyrrolidone, ethylcellulose and Acryl-EZE were Examples 8 to 11 dissolved and dispersed in purified water (80 mg/tablet) to Preparation of Film-Coated Tablets Containing a prepare a coating Solution which was then coated thereon to Delayed-Release Film prepare angiotensin-II-receptor blocker delayed-release film coated tablets containing a delayed-release film. (0172 1) Preparation of Angiotensin-II-Receptor Blocker 0183 3) Film Coating Containing a Delayed-Release Uncoated Tablets Film 0173. In the case of Example 8, for the preparation of 0184. In the case of Examples 12 to 14, the delayed-re angiotensin-II-receptor blocker delayed-release film-coated lease film-coated tablets prepared in Section 2) were placed in tablets, according to the ingredient compositions shown in a Hi-coater (SFC-30N, Sejong Machinery Co., Ltd., South Table 2 below, losartan potassium, microcrystalline cellulose, Korea), and coated in the same manner as in the preparation of pregelatinized starch, a polyvinylpyrrolidone copolymer, and a film-coated layer in Section 2) of Example 5 and according colloidal silicon dioxide were sieved through a No. 35 sieve to the ingredient compositions and contents shown in Table 1 and mixed in a double cone mixer for 30 minutes to prepare a below, thereby preparing film-coated tablets containing a mixture. To the mixture was added magnesium Stearate, fol delayed-release film. lowed by mixing for 4 minutes. The final mixture was com pressed into tablets using a rotary tablet press (MRC-33: Sejong, South Korea), thereby preparing angiotensin-II-re Example 15 ceptor blocker uncoated tablets. 0.174. In the case of Examples 9 to 11, angiotensin-II Preparation of Capsules (Granules) receptor blocker uncoated tablets were prepared in the same manner as above and according to the ingredient composi 0185. 1) Preparation of Angiotensin-II-Receptor Blocker tions and contents shown in Table 1 below. Delayed-Release Granules 0175 2) Preparation of Angiotensin-II-Receptor Blocker 0186. According to the ingredient contents shown in Table Delayed-Release Film-Coated Tablets 3 below, olmesartan medoxomil, microcrystalline cellulose, 0176 The uncoated tablets prepared in Section 1) were and pregelatinized starch were sieved through a No. 35 sieve placed in a Hi-coater (SFC-30N, Sejong Machinery Co., Ltd., and mixed in a high-speed mixer for 5 minutes to prepare a South Korea). According to the ingredient contents shown in mixture. Meanwhile, hydroxypropylcellulose was dissolved Table 2 below, ethylcellulose and Acryl-EZE were dissolved in purified water (30 mg/tablet) to prepare a binding solution, and dispersed in purified water (80 mg/tablet) to prepare a followed by kneading, granulation and drying. The dried coating solution which was then coated thereon to prepare material was placed in a fluidized bed coater. Meanwhile, angiotensin-II-receptor blocker delayed-release film-coated polyvinyl acetate was dissolved in a (2:8) mixed solvent of tablets containing a delayed-release film. ethanol and methylene chloride (240 mg/tablet) to prepare a 0177 3) Film Coating Containing a Delayed-Release Solution which was then coated on the granules in a fluidized Film bed coater (GPCG-1: Glatt, Germany) to prepare angio 0.178 The delayed-release film-coated tablets prepared in tensin-II-receptor blocker delayed-release granules. Section 2) were placed in a Hi-coater (SFC-30N, Sejong 0187. 2) Mixing and Capsule Filling Machinery Co., Ltd., South Korea) and coated in the same 0188 To the granules prepared in Section 1) was added manner as in the preparation of a film-coated layer in Section magnesium Stearate, followed by final mixing in a double 2) of Example 5 and according to the ingredient compositions cone mixer. The final mixture was placed in a powder feeder US 2011/O 1171.94 A1 May 19, 2011 and then filled in capsules using a capsule filling machine, sodium hydroxide were dissolved in purified water (70 thereby preparing a delayed-release formulation in the form mg/tablet) to prepare a binding solution, followed by knead of a capsule. ing, granulation and drying. The dried material was placed in a fluidized bed coater. Meanwhile, polyvinyl acetate was Example 16 dissolved in a (2:8) mixed solvent of ethanol and methylene chloride (1200 mg/tablet) to prepare a solution which was Preparation of Capsules (Pellets) then coated on the granules in a fluidized bed coater (GPCG 0189 1) Preparation of Angiotensin-II-Receptor Blocker 1: Glatt, Germany). After completion of the coating process, Delayed-Release Pellets drying was carried out to prepare desired granules. 0190. Sugar seeds (sugar sphere) were sieved through a 0201 2) Compression No. 35 sieve and placed in a fluidized bed granulator (GPCG 0202 The delayed-release granules prepared in Section 1) 1: Glatt). Meanwhile, hypromellose and losartan potassium and magnesium Stearate at the content shown in Table 3 below were dissolved in a (8:2) mixed solvent of ethanol and puri were placed in a double cone mixer, followed by final mixing fied water (750 mg/tablet) to prepare a binding solution which for 4 minutes. The final mixture was compressed into tablets was then sprayed thereon to form angiotensin-II-receptor using a rotary tablet press (MRC-33: Sejong, South Korea), blocker-containing pellets, followed by drying. A solution of thereby preparing uncoated tablets containing C-lipoic acid hypromellose phthalate (HP-55) in a (2:8) mixed solvent of and telmisartan. ethanol and methylene chloride (1200 mg/tablet) was sprayed on the granules to prepare angiotensin-II-receptor blocker Example 19 delayed-release pellets. 0191) 2) Mixing and Capsule Filling Preparation of Uncoated Tablets Containing a Hepa 0.192 To the pellets prepared in Section 1) was added titis-Preventing and Inhibiting Agent and an Angio magnesium Stearate, followed by final mixing in a double tensin-II-Receptor Blocker cone mixer. The final mixture was placed in a powder feeder 0203 1) Preparation of Delayed-Release Granules and then filled in capsules using a capsule filling machine, 0204 According to the ingredient contents shown in Table thereby preparing a formulation in the form of a capsule. 3 below, irbesartan, 13-carotene, microcrystalline cellulose, pregelatinized starch, lactose, and croscarmellose sodium Example 17 were sieved through a No. 35 sieve and mixed in a high-speed Preparation of Capsules (Tablets) mixer for 5 minutes to prepare a mixture. Meanwhile, Polox amer 188 was dissolved in purified water (100 mg/tablet) to 0193 1) Preparation of Angiotensin-II-Receptor Blocker prepare a binding solution, followed by kneading, granula Delayed-Release Uncoated Tablets tion and drying. The dried material was placed in a fluidized 0194 Angiotensin-II-receptor blocker delayed-release bed coater. Meanwhile, cellulose acetate (acetyl group uncoated tablets were prepared in the same manner as in 32.0%) and cellulose acetate (acetyl group 39.8%) were dis Section 1) of Example 8 and according to the ingredient solved in a (2:8) mixed solvent of ethanol and methylene compositions and contents shown in Table 3 below. chloride (800 mg/tablet) to prepare a solution which was then 0.195 2) Film Coating Containing a Delayed-Release coated on the granules in a fluidized bed coater (GPCG-1: Film Glatt, Germany). After completion of the coating process, 0196. The uncoated tablets prepared in Section 1) were drying was carried out to prepare angiotensin-II-receptor placed in a Hi-coater (SFC-30N, Sejong Machinery Co., Ltd., blocker delayed-release granules. South Korea). According to the ingredient contents shown in (0205 2) Compression Table 3 below, hypromellose phthalate (HP-55) and polyeth 0206. The delayed-release granules prepared in Section ylene glycol 6000 were dissolved and dispersed in a (8:2) 1), and colloidal silicon dioxide and magnesium Stearate at mixed solvent of ethanol and purified water (80 mg/tablet) to the contents shown in Table 3 below were placed in a double prepare a coating Solution which was then coated thereon to cone mixer, followed by final mixing for 4 minutes. The final prepare angiotensin-II-receptor blocker film-coated tablets mixture was compressed into tablets using a rotary tablet containing a delayed-release film. press (MRC-33: Sejong, South Korea), thereby preparing (0197) 3) Mixing and Capsule Filling uncoated tablets containing 13-carotene and irbesartan. 0198 The final product of Section 2) was placed in a powder feeder and then filled in capsules using a capsule Example 20 filling machine, thereby preparing a formulation in the form Preparation of Uncoated Tablets Containing a Hepa of a capsule. titis-Preventing and Inhibiting Agent and an Angio Example 18 tensin-II-Receptor Blocker Preparation of Uncoated Tablets Containing a Hepa 0207 1) Preparation of Delayed-Release Granules titis-Preventing and Inhibiting Agent and an Angio 0208 According to the ingredient contents shown in Table tensin-II-Receptor Blocker 3 below, Valsartan, silymarin, microcrystalline cellulose, and crosslinked polyvinylpyrrolidone were sieved through a No. (0199. 1) Preparation of Delayed-Release Granules 35 sieve and mixed in a high-speed mixer for 5 minutes to 0200. According to the ingredient contents shown in Table prepare a mixture. Meanwhile, polyvinylpyrrolidone was dis 3 below, telmisartan, C.-lipoic acid, microcrystalline cellu solved in purified water (70 mg/tablet) to prepare a binding lose, sorbitol, and meglumine were sieved through a No. 35 Solution, followed by kneading, granulation and drying. The sieve and mixed in a high-speed mixer for 5 minutes to pre dried material was placed in a fluidized bed coater. Mean pare a mixture. Meanwhile, polyvinylpyrrolidone and while, a solution of hypromellose in purified water (70 US 2011/O 1171.94 A1 May 19, 2011 mg/tablet) and a solution of hypromellose phthalate (HP-55) shown in Table 3 below, acetylcysteine, hypromellose 2910, in a (8:2) mixed solvent of ethanol and purified water (120 hydroxypropylcellulose, titanium oxide, and talc were dis mg/tablet) were coated on the granules in a fluidized bed solved and dispersed in purified water (260 mg/tablet) to coater (GPCG-1: Glatt, Germany). After completion of the prepare a coating Solution which was then coated thereon to coating process, drying was carried out to prepare delayed prepare film-coated tablets including an acetylcysteine-con release granules. taining prior-release film layer and losartan potassium-con 0209. 2) Compression taining delayed-release granules. 0210. The delayed-release granules prepared in Section 1) Example 23 and magnesium Stearate at the content shown in Table 3 below Preparation of Film-Coated Tablets Containing were placed in a double cone mixer, followed by final mixing Angiotensin-II-Receptor Blocker Delayed-Release for 4 minutes. The final mixture was compressed into tablets Granules and a Hepatitis-Preventing and Inhibiting using a rotary tablet press (MRC-33: Sejong, South Korea), thereby preparing uncoated tablets containing silymarin and Agent Prior-Release Film Valsartan. 0219 1) Preparation of Delayed-Release Uncoated Tab lets Example 21 0220 According to the ingredient contents shown in Table 3 below, eprosartan, selenized yeast, microcrystalline cellu Preparation of Uncoated Tablets Containing a Hepa lose, sodium starch glycolate, and lactose were sieved titis-Preventing and Inhibiting Agent and an Angio through a No. 35 sieve and mixed in a high-speed mixer for 5 tensin-II-Receptor Blocker minutes to prepare a mixture. Meanwhile, hydroxypropylcel lulose was dissolved in purified water (40 mg/tablet) to pre 0211 1) Preparation of Delayed-Release Granules pare a binding solution, followed by kneading, granulation 0212. According to the ingredient contents shown in Table and drying. The dried material was placed in a fluidized bed 3 below, losartan potassium, biphenyldimethyldicarboxylate, coater. Meanwhile, hypromellose phthalate (HP-55) and microcrystalline cellulose, sodium starch glycolate, and lac polyethylene glycol 6000 were dissolved in ethanol (220 tose were sieved through a No. 35 sieve and mixed in a mg/tablet) and methylene chloride (980 mg/tablet) to prepare high-speed mixer for 5 minutes to prepare a mixture. Mean a solution which was then coated on the granules in a fluidized while, hydroxypropylcellulose was dissolved in purified bed coater (GPCG-1: Glatt, Germany). After completion of water (40 mg/tablet) to prepare a binding solution, followed the coating process, drying was carried out. The dried mate by kneading, granulation and drying. The dried material was rial and colloidal silicon dioxide were placed in a double cone placed in a fluidized bed coater. Meanwhile, hypromellose mixer, followed by mixing to prepare delayed-release gran phthalate (HP-55) and polyethylene glycol 6000 were dis ules. solved in a (8:2) mixed solvent of ethanol and purified water 0221) 2) Compression (120 mg/tablet) to prepare a solution which was then coated 0222. The delayed-release granules prepared in Section 1) on the granules in a fluidized bed coater (GPCG-1: Glatt, and magnesium Stearate at the content shown in Table 3 below Germany). After completion of the coating process, drying were placed in a double cone mixer, followed by final mixing was carried out. The dried material and colloidal silicon diox for 4 minutes. The final mixture was compressed into tablets ide were placed in a double cone mixer, followed by mixingto using a rotary tablet press (MRC-33: Sejong, South Korea), prepare delayed-release granules containing biphenyldim thereby preparing uncoated tablets containing selenized yeast ethyldicarboxylate and losartan. and eprosartan. 0213 2) Compression 0223 3) ATSO (Coriolus versicolor Polysaccharide)- 0214. The delayed-release granules prepared in Section 1) Containing Film Coating and magnesium Stearate at the content shown in Table 3 below 0224. The uncoated tablets prepared in Section 1) were were placed, followed by final mixing for 4 minutes. The final placed in a Hi-coater (SFC-30N, Sejong Machinery Co., Ltd., mixture was compressed into tablets using a rotary tablet South Korea). According to the ingredient compositions press (MRC-33: Sejong, South Korea), thereby preparing shown in Table 3 below, ATSO (Coriolus versicolor polysac delayed-release uncoated tablets. charide), hypromellose 2910, hydroxypropylcellulose, tita nium oxide, and talc were dissolved and dispersed in purified Example 22 water (260 mg/tablet) to prepare a coating solution which was Preparation of Film-Coated Tablets Containing then coated thereonto prepare film-coated tablets including a Angiotensin-II-Receptor Blocker Delayed-Release prior-release film layer containing Coriolus versicolor Granules and a Hepatitis-Preventing and Inhibiting polysaccharide (ATSO) and delayed-release granules con Agent Prior-Release Film taining selenized yeast and eprosartan. 0215 1) Preparation of Losartan Potassium-Containing Example 24 Delayed-Release Uncoated Tablets Preparation of Film-Coated Tablets Containing 0216 Delayed-release uncoated tablets were prepared in Angiotensin-II-Receptor Blocker Granules and a the same manner as in Sections 1) and 2) of Example 21 and Hepatitis-Preventing and Inhibiting Agent Prior-Re according to the ingredient compositions and contents shown lease Film in Table 3 below, except that biphenyldimethyldicarboxylate 0225 1) Preparation of Telmisartan-Containing Delayed was not incorporated. Release Uncoated Tablets 0217 2) Acetylcysteine-Containing Film Coating 0226 Delayed-release uncoated tablets were prepared in 0218. The uncoated tablets prepared in Section 1) were the same manner as in Sections 1) and 2) of Example 1 and placed in a Hi-coater (SFC-30N, Sejong Machinery Co., Ltd., according to the ingredient compositions and contents shown South Korea). According to the ingredient compositions in Table 3 below. US 2011/O 1171.94 A1 May 19, 2011
0227 2) Citiolone-Containing Film Coating ner as in Section 1) of Example 25 and according to the 0228. The uncoated tablets prepared in Section 1) were ingredient compositions and contents shown in Table 4 placed in a Hi-coater (SFC-30N, Sejong Machinery Co., Ltd., below. South Korea). According to the ingredient compositions 0239 2) Film Coating Containing a Delayed-Release shown in Table 3 below, citiolone, hypromellose 2910, Film hydroxypropylcellulose, titanium oxide, and talc were dis 0240 Delayed-release film-coated tablets containing solved and dispersed in purified water (260 mg/tablet) to cicloxilic acid and losartan potassium were prepared in the prepare a coating Solution which was then coated thereon to same manner as in Section 2) of Example 25 and according to prepare film-coated tablets including a citiolone-containing the ingredient compositions and contents shown in Table 4 prior-release film layer and telmisartan-containing delayed below. release granules. Example 25 Example 28 Preparation of Delayed-Release Film-Coated Tablets Preparation of Film-Coated Tablets Containing a Containing a Hepatitis-Preventing and Inhibiting Hepatitis-Preventing and Inhibiting Agent and an Agent and an Angiotensin-II-Receptor Blocker Angiotensin-II-Receptor Blocker 0229. 1) Preparation of Uncoated Tablets 0230. According to the ingredient compositions shown in 0241 1) Preparation of Uncoated Tablets Table 4 below, losartan potassium, uraZamide, microcrystal 0242 Except that riboflavin tetrabutyrate, ascorbic acid, line cellulose, pregelatinized starch, a polyvinylpyrrolidone and pyridoxamine hydrochloride were contained in place of copolymer, and colloidal silicon dioxide were sieved through uraZamide, uncoated tablets were prepared in the same man a No. 35 sieve and mixed in a double cone mixer for 30 ner as in Section 1) of Example 25 and according to the minutes to prepare a mixture. To the mixture was added ingredient compositions and contents shown in Table 4 magnesium Stearate, followed by mixing for 4 minutes. The below. final mixture was compressed into tablets using a rotary tablet 0243 2) Delayed-Release Film Coating press (MRC-33: Sejong, South Korea), thereby preparing 0244 Delayed-release film-coated tablets containing uncoated tablets containing uraZamide and losartan potas riboflavin tetrabutyrate, ascorbic acid, pyridoxamine hydro sium. chloride and losartan potassium were prepared in the same 0231 2) Delayed-Release Film Coating manner as in Section 2) of Example 25 and according to the 0232. The uncoated tablets prepared in Section 1) were ingredient compositions and contents shown in Table 4 placed in a Hi-coater (SFC-30N, Sejong Machinery Co., Ltd., below. South Korea). Meanwhile, ethylcellulose and Acryl-EZE were dissolved and dispersed in purified water (400 mg/tab Example 29 let) to prepare a coating solution which was then coated thereonto prepare delayed-release film-coated tablets having Preparation of Film-Coated Tablets Containing a a delayed-release film and containing uraZamide and losartan Hepatitis-Preventing and Inhibiting Agent and an potassium. Angiotensin-II-Receptor Blocker Example 26 0245. 1) Preparation of Uncoated Tablets Preparation of Delayed-Release Film-Coated Tablets 0246 Except that agaro-oligosaccharide and melatonin Containing a Hepatitis-Preventing and Inhibiting were contained in place of uraZamide, uncoated tablets were Agent and an Angiotensin-II-Receptor Blocker prepared in the same manner as in Section 1) of Example 25 and according to the ingredient compositions and contents 0233. 1) Preparation of Uncoated Tablets shown in Table 4 below. 0234 Except that fraction flavonoid purifiee micronise 0247. 2) Film Coating Containing a Delayed-Release was contained in place of uraZamide, uncoated tablets were Film The uncoated tablets prepared in Section 1) were placed prepared in the same manner as in Section 1) of Example 25 in a Hi-coater (SFC-30N, Sejong Machinery Co., Ltd., South and according to the ingredient compositions and contents Korea). Meanwhile, polyvinylpyrrolidone, ethylcellulose shown in Table 4 below. and Acryl-EZE were dissolved and dispersed in purified 0235 2) Delayed-Release Film Coating water (400 mg/tablet) to prepare a coating solution which was 0236 Delayed-release film-coated tablets containing frac then coated thereon to prepare delayed-release film-coated tion flavonoid purifiee micronise and losartan potassium were tablets having a delayed-release film and containing agaro prepared in the same manner as in Section 2) of Example 25 and according to the ingredient compositions and contents oligosaccharide, melatonin and losartan potassium. shown in Table 4 below. Example 30 Example 27 Preparation of Delayed-Release Film-Coated Tablets Preparation of Delayed-Release Film-Coated Tablets Containing a Hepatitis-Preventing and Inhibiting Containing a Hepatitis-Preventing and Inhibiting Agent and an Angiotensin-II-Receptor Blocker Agent and an Angiotensin-II-Receptor Blocker 0237 1) Preparation of Uncoated Tablets 0248 1) Preparation of Uncoated Tablets 0238 Except that cicloxilic acid was contained in place of 0249 Except that ursodeoxycholic acid was contained in uraZamide, uncoated tablets were prepared in the same man place of uraZamide, uncoated tablets were prepared in the US 2011/O 1171.94 A1 May 19, 2011 same manner as in Section 1) of Example 25 and according to Solution. The binding solution and the mixture of mainingre the ingredient compositions and contents shown in Table 4 dients were placed in a high-speed mixer, followed by knead below. ing. After completion of the kneading process, the kneaded 0250) 2) Film Coating Containing a Delayed-Release material was granulated using an oscillator with a No. 18 Film sieve, and the granules were dried in a hot-water dryer at 30. 0251 Delayed-release film-coated tablets containing After completion of the drying process, the granules were urSodeoxycholic acid and losartan potassium were prepared sieved again through an F-type grinder equipped with a No. in the same manner as in Section 2) of Example 29 and 20 sieve to prepare ahepatitis-preventing and inhibiting agent according to the ingredient compositions and contents shown prior-release layer. in Table 4 below. 0260 3) Compression 0261 The semi-finished product of Section 1) and mag Example 31 nesium Stearate were mixed and placed in a first powder feeder. The semi-finished product of Section 2) and magne Preparation of Delayed-Release Film-Coated Tablets sium Stearate were mixed and placed in a second powder Containing a Hepatitis-Preventing and Inhibiting feeder. Using a multiple tablet press (MRC-37T. Sejong, Agent and an Angiotensin-II-Receptor Blocker South Korea), the products in the feeders were compressed 0252) 1) Preparation of Uncoated Tablets into tablets under Such conditions that the interlayer incorpo 0253 Except that naphthyl acetic acid and azintamide ration can be minimized, thereby preparing multi-layered were contained in place of uraZamide, uncoated tablets were tablets. prepared in the same manner as in Section 1) of Example 25 and according to the ingredient compositions and contents Example 33 shown in Table 4 below. Preparation of Multi-Layered Tablets Containing a 0254 2) Film Coating Containing a Delayed-Release Hepatitis-Preventing and Inhibiting Agent Prior-Re Film lease Layer and an Angiotensin-II-Receptor Blocker 0255 Delayed-release film-coated tablets containing Delayed-Release Layer naphthyl acetic acid, azintamide and losartan potassium were prepared in the same manner as in Section 2) of Example 29 0262. 1) Preparation of Losartan Delayed-Release Layer and according to the ingredient compositions and contents 0263. According to the ingredient contents shown in Table shown in Table 4 below. 5 below, losartan potassium, microcrystalline cellulose, Sodium starch glycolate, and lactose were sieved through a Example 32 No.35 sieve and mixed in a high-speed mixer for 5 minutes to Preparation of Multi-Layered Tablets Containing a prepare a mixture. Meanwhile, hydroxypropylcellulose was Hepatitis-Preventing and Inhibiting Agent Prior-Re dissolved in purified water (40 mg/tablet) to prepare a binding lease Layer and an Angiotensin-II-Receptor Blocker Solution, followed by kneading, granulation and drying. The Delayed-Release Layer dried material was placed in a fluidized bed coater. Mean while, hypromellose, cellulose acetate (acetyl group 32%) 0256 1) Preparation of Valsartan Delayed-Release Layer and cellulose acetate (acetyl group 39.8%) were dissolved in 0257 According to the ingredient contents shown in Table a (2:8) mixed solvent of ethanol and methylene chloride (820 5 below, Valsartan, microcrystalline cellulose, and mg/tablet) to prepare a solution which was then coated on the crosslinked polyvinylpyrrolidone were sieved through a No. granules in a fluidized bedcoater (GPCG-1: Glatt, Germany). 35 sieve and mixed in a high-speed mixer for 5 minutes to After completion of the coating process, drying was carried prepare a mixture. Meanwhile, polyvinylpyrrolidone was dis out to prepare a losartan delayed-release layer. solved in purified water (80 mg/tablet) to prepare a binding 0264. 2) Preparation of Hepatitis-Preventing and Inhibit Solution, followed by kneading, granulation and drying. The ing Agent Prior-Release Layer dried material was placed in a fluidized bed coater. Mean 0265 According to the ingredient compositions and con while, hypromellose was dissolved in purified water (32 tents shown in Table 5 below, arginine hydrochloride, orni mg/tablet) to prepare a solution which was then coated on the thine hydrochloride, microcrystalline cellulose, pregelati granules in a fluidized bed coater (GPCG-1: Glatt, Germany) nized starch, and corn starch were sieved through a No. 35 (first coating). Meanwhile, cellulose acetate (acetyl group sieve and mixed in a high-speed mixer. Meanwhile, hydrox 32%) and cellulose acetate (acetyl group 39.8%) were dis ypropylcellulose was dissolved in purified water (80 mg/tab solved in a (8:2) mixed solvent of ethanol and purified water let) to prepare a binding solution. The binding solution and (640 mg/tablet) to prepare a solution which was then coated the mixture of main ingredients were placed in a high-speed on the above-coated material in a fluidized bed coater mixer, followed by kneading. After completion of the knead (GPCG-1: Glatt, Germany) (second coating). After comple ing process, the kneaded material was granulated using an tion of the coating process, drying was carried out to prepare oscillator with a No. 18 sieve, and the granules were dried in a Valsartan delayed-release layer. a hot-water dryer at 30. After completion of the drying pro 0258 2) Preparation of Hepatitis-Preventing and Inhibit cess, the granules were sieved again through an F-type ing Agent Prior-Release Layer grinder equipped with a No. 20 sieve to prepare a hepatitis 0259. According to the ingredient compositions and con preventing and inhibiting agent prior-release layer. tents shown in Table 5 below, ubidecarenone, haematopor 0266 3) Compression and Coating phyrin, microcrystalline cellulose, pregelatinized Starch, and 0267. The semi-finished product of Section 1) and mag corn starch were sieved through a No. 35 sieve and mixed in nesium Stearate were mixed and placed in a first powder a high-speed mixer. Meanwhile, hydroxypropylcellulose was feeder. The semi-finished product of Section 2) and magne dissolved in purified water (60 mg/tablet) to prepare a binding sium Stearate were mixed and placed in a second powder US 2011/O 1171.94 A1 May 19, 2011 feeder. Using a multiple tablet press (MRC-37T. Sejong, Example 35 South Korea), the products in the feeders were compressed Preparation of Press-Coated Tablets Containing a into tablets under Such conditions that the interlayer incorpo Hepatitis-Preventing and Inhibiting Agent Prior-Re ration can be minimized, thereby preparing multi-layered lease Layer and an Angiotensin-II-Receptor Blocker tablets. Delayed-Release Layer 0274 1) Preparation of Candesartan Cilexetil Delayed Release Inner Core Tablets Example 34 0275 According to the ingredient compositions and con tents shown in Table 5 below, candesartan cilexetil, lactose, Preparation of Multi-Layered Tablets Containing a corn starch, polyethylene glycol 6000 and carboxymethylcel Hepatitis-Preventing and Inhibiting Agent Prior-Re lulose calcium were sieved through a No. 35 sieve and mixed lease Layer and an Angiotensin-II-Receptor Blocker in a high-speed mixer. Meanwhile, hydroxypropylcellulose Delayed-Release Layer was dissolved in purified water (300 mg/tablet) to prepare a binding Solution. The binding solution and the mixture of 0268 1) Preparation of Losartan Delayed-Release Layer mainingredients were placed in a high-speed mixer, followed by kneading. After completion of the kneading process, the 0269. According to the ingredient contents shown in Table kneaded material was granulated using an oscillator with a 5 below, losartan potassium, microcrystalline cellulose, No. 18 sieve, and the granules were dried in a hot-water dryer Sodium starch glycolate, and lactose were sieved through a at 30. After completion of the drying process, the granules No. 35 sieve and mixed in a high-speed mixer for 5 minutes to were sieved again through an F-type grinder equipped with a prepare a mixture. Meanwhile, hydroxypropylcellulose was No. 20 sieve. The sieved material was placed in a double cone dissolved in purified water (40 mg/tablet) to prepare a binding mixer, and magnesium Stearate was added thereto, followed Solution, followed by kneading, granulation and drying. The by final mixing. The final mixture was compressed into tab dried material was placed in a fluidized bed coater. Mean lets using a rotary tablet press (MRC-33: Sejong, South while, hypromellosephthalate (HP-50) and polyethylene gly Korea). The compressed tablets were placed in a Hi-coater (SFC-30N, Sejong Machinery Co., Ltd., South Korea) and col 6000 were dissolved in a (8:2) mixed solvent of ethanol then coated with a coating Solution of hypromellose acetate and purified water (600mg/tablet) to prepare a solution which succinate in a (8:2) mixed solvent of ethanol and purified was then coated on the granules in a fluidized bed coater water (550 mg/tablet), thereby preparing candesartan cilex (GPCG-1: Glatt, Germany). After completion of the coating etil delayed-release coated inner core tablets. process, drying was carried out to prepare a losartan delayed 0276 2) Preparation of Hepatitis-Preventing and Inhibit release layer. ing Agent Prior-Release Outer Layer Granules 0270. 2) Preparation of Hepatitis-Preventing and Inhibit 0277 According to the ingredient compositions and con ing Agent Prior-Release Layer tents shown in Table 4 below, riboflavin, cholecalciferol, 0271 According to the ingredient compositions and con microcrystalline cellulose, pregelatinized starch, and corn starch were sieved through a No. 35 sieve and mixed in a tents shown in Table 5 below, erdosteine, guaiacol, creatine, high-speed mixer. Meanwhile, hydroxypropylcellulose was microcrystalline cellulose, pregelatinized starch, and corn dissolved in purified water (80 mg/tablet) to prepare a binding starch were sieved through a No. 35 sieve and mixed in a Solution. The binding solution and the mixture of mainingre high-speed mixer. Meanwhile, hydroxypropylcellulose was dients were placed in a high-speed mixer, followed by knead dissolved in purified water (80 mg/tablet) to prepare a binding ing. After completion of the kneading process, the kneaded Solution. The binding solution and the mixture of mainingre material was granulated using an oscillator with a No. 18 dients were placed in a high-speed mixer, followed by knead sieve, and the granules were dried in a hot-water dryer at 30. ing. After completion of the kneading process, the kneaded After completion of the drying process, the granules were material was granulated using an oscillator with a No. 18 sieved again through an F-type grinder equipped with a No. sieve, and the granules were dried in a hot-water dryer at 30. 20 sieve. The sieved material was placed in a double cone After completion of the drying process, the granules were mixer, and magnesium Stearate was added thereto, followed sieved again through an F-type grinder equipped with a No. by final mixing to prepare hepatitis-preventing and inhibiting 20 sieve to prepare hepatitis-preventing and inhibiting agent agent prior-release outer layer granules. prior-release layer. (0278 3) Compression 0272 3) Compression and Coating 0279. Using a press-coated tablet press (RUD-1: Kilian), 0273. The semi-finished product of Section 1) and mag press-coated tablets were prepared such that the candesartan nesium Stearate were mixed and placed in a first powder cilexetil delayed-release uncoated tablets prepared in Section feeder. The semi-finished product of Section 2) and magne 1) were placed inside the tablet, and the hepatitis-preventing sium Stearate were mixed and placed in a second powder and inhibiting agent prior-release granules prepared in Sec feeder. Using a multiple tablet press (MRC-37T. Sejong, tion 2) were placed outside the tablet. South Korea), the products in the feeders were compressed into tablets under Such conditions that the interlayer incorpo Example 36 ration can be minimized. Meanwhile, hypromellose 2910, Preparation of Press-Coated Tablets Containing a hydroxypropylcellulose, titanium oxide, and talc were dis Hepatitis-Preventing and Inhibiting Agent Prior-Re solved and dispersed in a (8:2) mixed solvent of ethanol and lease Layer and an Angiotensin-II-Receptor Blocker purified water (600 mg/tablet) to prepare a coating solution. Delayed-Release Layer The compressed tablets were coated with the coating solution 0280 1) Preparation of Eprosartan Delayed-Release Inner in a Hi-coater (SFC-30N: Sejong Machinery Co., Ltd., South Core Tablets Korea) to form a film-coated layer, thereby preparing multi 0281. According to the ingredient contents shown in Table layered tablets. 5 below, eprosartan, microcrystalline cellulose, sodium US 2011/O 1171.94 A1 May 19, 2011 starch glycolate, and lactose were sieved through a No. 35 thereon (first coating). Then, a coating solution of Acryl-EZE sieve and mixed in a high-speed mixer for 5 minutes to pre in purified water (80 mg/tablet) was coated again on the pare a mixture. Meanwhile, hydroxypropylcellulose was dis granules (second coating), thereby preparing losartan solved in purified water (40 mg/tablet) to prepare a binding delayed-release coated inner core tablets. Solution, followed by kneading, granulation and drying. After 0288 2) Preparation of Hepatitis-Preventing and Inhibit completion of the drying process, the granules were sieved ing Agent Prior-Release Outer Layer Granules again through an F-type grinder equipped with a No. 20 sieve. 0289. According to the ingredient compositions and con The sieved material was placed in a double cone mixer, and tents shown in Table 5 below, sodium selenite, a ginko biloba magnesium Stearate was added thereto, followed by final extract, microcrystalline cellulose, pregelatinized starch, and mixing. The final mixture was compressed into tablets using corn starch were sieved through a No. 35 sieve and mixed in a rotary tablet press (MRC-33: Sejong, South Korea). The a high-speed mixer. Meanwhile, hydroxypropylcellulose was compressed tablets were placed in a Hi-coater (SFC-30N, dissolved in purified water (80 mg/tablet) to prepare a binding Sejong Machinery Co., Ltd., South Korea) and then coated Solution. The binding solution and the mixture of mainingre with a coating solution of hypromellose phthalate (HP-50) dients were placed in a high-speed mixer, followed by knead and polyvinyl acetate in a (8:2) mixed solvent of ethanol and ing. After completion of the kneading process, the kneaded purified water (200 mg/tablet), thereby preparing eprosartan material was granulated using an oscillator with a No. 18 delayed-release coated inner core tablets. sieve, and the granules were dried in a hot-water dryer at 30. 0282) 2) Preparation of Hepatitis-Preventing and Inhibit After completion of the drying process, the granules were ing Agent Prior-Release Outer Layer Granules sieved again through an F-type grinder equipped with a No. 0283 According to the ingredient compositions and con 20 sieve. The sieved material was placed in a double cone tents shown in Table 5 below, L-glutathione, L-glutamine, mixer, and magnesium Stearate was added thereto, followed microcrystalline cellulose, pregelatinized starch, and corn by final mixing to prepare hepatitis-preventing and inhibiting starch were sieved through a No. 35 sieve and mixed in a agent prior-release outer layer granules. high-speed mixer. Meanwhile, hydroxypropylcellulose was 0290 3) Compression and Coating dissolved in purified water (80 mg/tablet) to prepare a binding 0291. Using a press-coated tablet press (RUD-1: Kilian), Solution. The binding solution and the mixture of mainingre press-coated tablets were prepared such that the losartan dients were placed in a high-speed mixer, followed by knead delayed-release uncoated tablets prepared in Section 1) were ing. After completion of the kneading process, the kneaded placed inside the tablet, and the hepatitis-preventing and material was granulated using an oscillator with a No. 18 inhibiting agent prior-release granules prepared in Section 2) sieve, and the granules were dried in a hot-water dryer at 30. were placed outside the tablet. After completion of the drying process, the granules were sieved again through an F-type grinder equipped with a No. Example 38 20 sieve. The sieved material was placed in a double cone mixer, and magnesium Stearate was added thereto, followed Preparation of Press-Coated Tablets Containing a by final mixing to prepare hepatitis-preventing and inhibiting Hepatitis-Preventing and Inhibiting Agent Prior-Re agent prior-release outer layer granules. lease Layer and an Angiotensin-II-Receptor Blocker 0284 3) Compression and Coating Delayed-Release Layer 0285) Using a press-coated tablet press (RUD-1: Kilian), 0292 1) Preparation of Telmisartan Delayed-Release press-coated tablets were prepared such that the eprosartan Inner Core Tablets delayed-release uncoated tablets prepared in Section 1) were 0293 According to the ingredient contents shown in Table placed inside the tablet, and the hepatitis-preventing and 5 below, telmisartan, microcrystalline cellulose, sorbitol, and inhibiting agent prior-release granules prepared in Section 2) meglumine were sieved through a No. 35 sieve and mixed in were placed outside the tablet. Meanwhile, hypromellose a high-speed mixer for 5 minutes to prepare a mixture. Mean 2910, titanium oxide, and talc were dissolved and dispersed in while, polyvinylpyrrolidone and sodium hydroxide were dis a (8:2) mixed solvent of ethanol and purified water (800 solved in purified water (70 mg/tablet) to prepare a binding mg/tablet) to prepare a coating Solution. The press-coated Solution, followed by kneading, granulation and drying. After tablets were placed in a Hi-coater (SFC-30N, Sejong Machin completion of the drying process, the granules were sieved ery Co., Ltd., South Korea) and then coated with the coating again through an F-type grindereduipped with a No. 20 sieve. Solution to prepare coated press-coated tablets. The sieved material was placed in a double cone mixer, and magnesium Stearate was added thereto, followed by final Example 37 mixing. The final mixture was compressed into tablets using Preparation of Press-Coated Tablets Containing a a rotary tablet press (MRC-33: Sejong, South Korea). The Hepatitis-Preventing and Inhibiting Agent Prior-Re compressed tablets were placed in a Hi-coater (SFC-30N, lease Layer and an Angiotensin-II-Receptor Blocker Sejong Machinery Co., Ltd., South Korea). Meanwhile, Delayed-Release Layer hypromellose phthalate (HP-55) and polyethylene glycol 6000 were dissolved in a (8:2) mixed solvent of ethanol and 0286 1) Preparation of Losartan Delayed-Release Inner purified water (80 mg/tablet) to prepare a coating Solution Core Tablets which was then coated thereon to prepare telmisartan 0287 Uncoated tablets were compressed in the same man delayed-release coated inner core tablets. ner as in Section 1) of Example 8 and according to the ingre 0294 2) Preparation of Hepatitis-Preventing and Inhibit dient compositions and contents shown in Table 5 below. The ing Agent Prior-Release Outer Layer Granules compressed tablets were placed in a Hi-coater (SFC-30N, 0295 According to the ingredient compositions and con Sejong Machinery Co., Ltd., South Korea). A solution of tents shown in Table 5 below, butylated hydroxyanisole, orni hypromellose in purified water (10 mg/tablet) was coated thine, microcrystalline cellulose, pregelatinized starch, and US 2011/O 1171.94 A1 May 19, 2011
corn starch were sieved through a No. 35 sieve and mixed in mixing to prepare hepatitis-preventing and inhibiting agent a high-speed mixer. Meanwhile, hydroxypropylcellulose was prior-release outer layer granules. dissolved in purified water (80 mg/tablet) to prepare a binding 0302) 3) Compression and Coating Solution. The binding solution and the mixture of mainingre dients were placed in a high-speed mixer, followed by knead 0303 Using a press-coated tablet press (RUD-1: Kilian), ing. After completion of the kneading process, the kneaded press-coated tablets were prepared such that the candesartan material was granulated using an oscillator with a No. 18 cilexetil delayed-release osmotic inner core tablets prepared sieve, and the granules were dried in a hot-water dryer at 30. in Section 1) were placed as inner core tablets, and the hepa After completion of the drying process, the granules were titis-preventing and inhibiting agent prior-release outer layer sieved again through an F-type grinder equipped with a No. prepared in Section 2) was placed outside the tablet. Mean 20 sieve. The sieved material was placed in a double cone while, hypromellose 2910, hydroxypropylcellulose, titanium mixer, and magnesium Stearate was added thereto, followed oxide, and talc were dissolved and dispersed in 80% ethanol by final mixing to prepare hepatitis-preventing and inhibiting to prepare a coating Solution. The press-coated tablets were agent prior-release outer layer granules. placed in a Hi-coater (SFC-30N, Sejong Machinery Co., Ltd., 0296 3) Compression and Coating South Korea) and then coated with the coating solution to 0297 Using a press-coated tablet press (RUD-1: Kilian), prepare coated osmotic press-coated tablets. press-coated tablets were prepared such that the telmisartan delayed-release uncoated tablets prepared in Section 1) were Example 40 placed inside the tablet, and the hepatitis-preventing and inhibiting agent prior-release granules prepared in Section 2) Preparation of Capsules (Granules-Granules) were placed outside the tablet. Meanwhile, hypromellose 2910, titanium oxide, and talc were dissolved and dispersed in 0304 1) Preparation of Olmesartan Delayed-Release a (8:2) mixed solvent of ethanol and purified water (350 mg/tablet) to prepare a coating Solution. The press-coated Granules tablets were placed in a Hi-coater (SFC-30N, Sejong Machin 0305 According to the ingredient compositions and con ery Co., Ltd., South Korea) and then coated with the coating tents shown in Table 6 below, olmesartan medoxomil, micro Solution to prepare coated press-coated tablets. crystalline cellulose, and pregelatinized Starch were sieved through a No. 35 sieve and mixed in a high-speed mixer for 5 Example 39 minutes to prepare a mixture. Meanwhile, hydroxypropylcel lulose was dissolved in purified water (40 mg/tablet) to pre Preparation of Osmotic Press-Coated Tablets pare a binding solution, followed by kneading, granulation and drying. The dried material was placed in a fluidized bed 0298. 1) Preparation of Candesartan Cilexetil Delayed coater. Meanwhile, polyvinyl acetate was dissolved in a (2:8) Release Osmotic Inner Core Tablets mixed solvent of ethanol and methylene chloride (240 0299. According to the ingredient compositions and con mg/tablet) to prepare a solution which was then coated on the tents shown in Table 6 below, candesartan cilexetil, microc granules in a fluidized bedcoater (GPCG-1: Glatt, Germany). rystalline cellulose, and sodium chloride were sieved through After completion of the coating process, drying was carried a No. 35 sieve and mixed in a double cone mixer for 30 out to prepare olmesartan delayed-release granules. minutes to prepare a mixture. To the mixture was added magnesium Stearate, followed by mixing for 4 minutes. The 0306 2) Preparation of Hepatitis-Preventing and Inhibit final mixture was compressed into tablets using a rotary tablet ing Agent Prior-Release Granules press (MRC-33: Sejong, South Korea). After completion of 0307 According to the ingredient compositions and con the compression process, ethylcellulose was dispersed in tents shown in Table 6 below, protoporphyrin disodium, purified water (50 mg/tablet) to prepare a dispersion which microcrystalline cellulose, pregelatinized starch, and corn was then coated on the inner core tablets in a Hi-coater (SFC starch were sieved through a No. 35 sieve and mixed in a 3ON, Sejong Machinery Co., Ltd., South Korea), thereby high-speed mixer. Meanwhile, hydroxypropylcellulose was preparing osmotic inner core tablets. dissolved in purified water (80 mg/tablet) to prepare a binding 0300 2) Preparation of Hepatitis-Preventing and Inhibit Solution. The binding solution and the mixture of mainingre ing Agent Prior-Release Outer Layer Granules dients were placed in a high-speed mixer, followed by knead 0301 According to the ingredient compositions and con ing. After completion of the kneading process, the kneaded tents shown in Table 6 below, arginine sodium, microcrystal material was granulated using an oscillator with a No. 18 line cellulose, pregelatinized starch, and corn starch were sieve, and the granules were dried in a hot-water dryer at 30. sieved through a No. 35 sieve and mixed in a high-speed After completion of the drying process, the granules were mixer. Meanwhile, hydroxypropylcellulose was dissolved in sieved again through an F-type grinder equipped with a No. purified water (80 mg/tablet) to prepare a binding solution. 20 sieve to prepare hepatitis-preventing and inhibiting agent The binding Solution and the mixture of main ingredients prior-release granules. were placed in a high-speed mixer, followed by kneading. After completion of the kneading process, the kneaded mate 0308 3) Mixing and Capsule Filling rial was granulated using an oscillator with a No. 18 sieve, and 0309 According to the ingredient compositions and con the granules were dried in a hot-water dryer at 30. After tents shown in Table 6 below, the final compositions of Sec completion of the drying process, the granules were sieved tions 1) and 2) were mixed in a double cone mixer. To the again through an F-type grinder equipped with a No. 20 sieve. mixture was added magnesium Stearate, followed by final The sieved material was placed in a double cone mixer, and mixing in a double cone mixer. The final mixture was placed magnesium Stearate was added thereto, followed by final in a powder feeder and then filled in No. 1 gelatin hard US 2011/O 1171.94 A1 May 19, 2011 20 capsules using a capsule filling machine to prepare a formu 0318 2) Preparation of Hepatitis-Preventing and Inhibit lation in the form of a capsule. ing Agent Prior-Release Pellets 0319. According to the ingredient compositions and con Example 41 tents shown in Table 6 below, Sugar seeds (Sugar sphere) were Preparation of Capsules (Granules-Tablets) sieved through a No. 35 sieve and placed in a fluidized bed granulator (GPCG 1: Glatt). Meanwhile, hydroxypropylcel 0310 1) Preparation of Valsartan Delayed-Release Gran lulose, haematoporphyrin, and a ginko biloba extract were ules 0311. According to the ingredient contents shown in Table dissolved in a (8:2) mixed solution of ethanol and purified 6 below, Valsartan, microcrystalline cellulose, and water (150 mg/tablet) to prepare a binding solution which was crosslinked polyvinylpyrrolidone were sieved through a No. then sprayed thereon to form pellets, followed by drying to 35 sieve and mixed in a high-speed mixer for 5 minutes to prepare hepatitis-preventing and inhibiting agent prior-re prepare a mixture. Meanwhile, polyvinylpyrrolidone was dis lease pellets. solved in purified water (70 mg/tablet) to prepare a binding 0320 3) Mixing and Capsule Filling Solution, followed by kneading, granulation and drying. The 0321. The final compositions of Sections 1) and 2) were dried material was placed in a fluidized bed coater. Mean filled in No. 1 gelatin hard capsules using a capsule filling while, a solution of hypromellose in purified water (70 machine, thereby preparing a formulation in the form of a mg/tablet) and a solution of hypromellose phthalate (HP-55) capsule. in a (8:2) mixed solvent of ethanol and purified water (120 mg/tablet) were prepared and then coated on the granules in a Example 43 fluidized bed coater (GPCG-1: Glatt, Germany). After completion of the coating process, drying was carried out to prepare Valsartan delayed-release granules. Preparation of Capsules (Pellets-Tablets) 0312 2) Preparation of Hepatitis-Preventing and Inhibit 0322, 1) Preparation of Eprosartan Delayed-Release Pel ing Agent Prior-Release Tablets 0313 According to the ingredient compositions and con lets tents shown in Table 6 below, hymecromone, microcrystal 0323 Eprosartan delayed-release pellets were prepared in line cellulose, pregelatinized starch, and corn starch were the same manner as in Section 1) of Example 42 and accord sieved through a No. 35 sieve and mixed in a high-speed ing to the ingredient compositions and contents shown in mixer. Meanwhile, hydroxypropylcellulose was dissolved in Example 43 of Table 6, except that eprosartan was used in purified water (80 mg/tablet) to prepare a binding solution. place of losartan potassium. The binding Solution and the mixture of main ingredients 0324 2) Preparation of Hepatitis-Preventing and Inhibit were placed in a high-speed mixer, followed by kneading. ing Agent Prior-Release Tablets After completion of the kneading process, the kneaded mate 0325 Hepatitis-preventing and inhibiting agent prior-re rial was granulated using an oscillator with a No. 18 sieve, and lease tablets were prepared in the same manner as in Section the granules were dried in a hot-water dryer at 30. After 2) of Example 41 and according to the ingredient composi completion of the drying process, the granules were sieved tions and contents given in Example 43 of Table 6, except that again through an F-type grinder equipped with a No. 20 sieve. guaiacol, cholecalciferol and arginine Sodium were used in The sieved material and magnesium Stearate were placed in a place of hymecromone. double cone mixer, followed by final mixing. The final mix 0326) 3) Mixing and Capsule Filling ture was compressed into tablets using a rotary tablet press (MRC-33, Sejong Machinery Co., Ltd., South Korea), 0327. The final products of Sections 1) and 2) were filled thereby preparing hepatitis-preventing and inhibiting agent in capsules using a capsule filling machine, thereby preparing prior-release tablets. a formulation in the form of a capsule. 0314 3) Mixing and Capsule Filling 0315. The final products of Sections 1) and 2) were filled Example 44 in capsules using a capsule filling machine, thereby preparing a formulation in the form of a capsule. Preparation of Capsules (Tablets-Granules) Example 42 0328 1) Preparation of Losartan Delayed-Release Tablets 0329 Uncoated tablets were prepared in the same manner Preparation of Capsules (Pellets-Pellets) as in Section 1) of Example 8 and according to the ingredient 0316 1) Preparation of Losartan Delayed-Release Pellets compositions and contents shown in Table 6 below. The 0317. According to the ingredient compositions and con uncoated tablets were placed in a Hi-coater (SFC-30N, tents shown in Table 6 below, Sugar seeds (Sugar sphere) were Sejong Machinery Co., Ltd., South Korea). According to the sieved through a No. 35 sieve and placed in a fluidized bed ingredient contents shown in Table 6, hypromellosephthalate granulator (GPCG 1: Glatt). Meanwhile, hypromellose and (HP-55) and polyethylene glycol 6000 were dissolved and losartan potassium were dissolved ina (8:2) mixed solution of dispersed to prepare a coating Solution which was then coated ethanol and purified water (500 mg/tablet) to prepare a bind thereon to prepare losartan-containing delayed-release tab ing Solution which was then sprayed thereon to form pellets, lets. followed by drying. Then, a solution of hypromellose phtha 0330 2) Preparation of Hepatitis-Preventing and Inhibit late (HP-55) in a (2:8) mixed solvent of ethanol and methyl ing Agent Prior-Release Granules ene chloride (1200 mg/tablet) was sprayed on the granules, 0331 According to the ingredient compositions and con thereby preparing losartan delayed-release pellets. tents shown in Table 6 below, L-glutamine, a ginko biloba US 2011/O 1171.94 A1 May 19, 2011 extract, arginine sodium, microcrystalline cellulose, pregela Example 45 tinized starch, and corn starch were sieved through a No. 35 Preparation of Capsules (Tablets-Tablets) sieve and mixed in a high-speed mixer. Meanwhile, hydrox 0334 1) Preparation of Irbesartan Delayed-Release Film ypropylcellulose was dissolved in purified water (80 mg/tab Coated Tablets 0335 Irbesartan-containing film-coated tablets were pre let) to prepare a binding Solution. The binding Solution and pared in the same manner as in Example 2 and according to the mixture of main ingredients were placed in a high-speed the ingredient compositions and contents shown in Example mixer, followed by kneading. After completion of the knead 45 of Table 6 below. ing process, the kneaded material was granulated using an 0336 2) Preparation of Hepatitis-Preventing and Inhibit ing Agent Prior-Release Tablets oscillator with a No. 18 sieve, and the granules were dried in 0337 Hepatitis-preventing and inhibiting agent prior-re a hot-water dryer at 30. After completion of the drying pro lease tablets were prepared in the same manner as in Section cess, the granules were sieved again through an F-type 2) of Example 41 and according to the ingredient composi grinder equipped with a No. 20 sieve to prepare hepatitis tions and contents shown in Example 45 of Table 6 below, preventing and inhibiting agent prior-release granules. except that erdosteine, cholecalciferol and butylated hydroxyanisole were used in place of hymecromone. 3) Mix 0332 3) Mixing and Capsule Filling ing and Capsule Filling 0333. The final products of Sections 1) and 2) were filled 0338. The final products of Sections 1) and 2) were filled in No. 1 capsules using a capsule filling machine, thereby in capsules using a capsule filling machine, thereby preparing preparing a formulation in the form of a capsule. a formulation in the form of a capsule.
TABLE 1. Composition ratio (mg/unit formulation) Example No. Ingredients (product name, manufacturer) 1 2 3 4 5 6 7 Angiotensin- Losartan potassium (Cadilla) 50 50 II-receptor rbesartan (Ranbaxy) 150 blocker Valsartan (Dr. Reddy's) 8O containing Telmisartan (Ranbaxy) 40 40 ingredient Eprosartan (MSN) 600 Microcrystalline cellulose 123 45 60 100 100 100 123 (Vivapur 2, JRS) Pregelatinized starch 45 (Starch 1500, Colorcon) Sodiums arch glycolate 18 18 18 (Explotab, JRS) Polyvinyl pyrrollidone copolymer (PVP VA64Fine, BASF) Hydroxypropylcellulose 4 4 4 (HPC-L, Hercules) Lactose (Lactose 200, DMV) 30 30 30 30 Croscarmellose sodium 15 (Vivasol, JRS PHARMA) Crosslinked 15 polyvinyl pyrrollidone (Kollidon CL, BASF) Poloxamer 188 (Lutrol 9 F68, BAS F) Polyvinyl pyrrollidone 7 10 7 (PVP, BASF) Sorbitol (Sorbitol powder, 10 10 Roquette) NaOH (Duksan) Meglumine (USP. Spectrum 1 1 Chemical&Laboratory Products) Colloidal silicon dioxide 3 2 2 2 (Aerosil pharma 200, Degussa) Polyvinyl acetate 24 24 (Kollicoat SR30D, BASF) Hypromellose (Pharmacoat 7 615, Shin-Etsu) Hypromellose phthalate 12 67.3 67.7 67.6 HP-55 (HPMC-P 55, Shin-Etsu) Polyethylene glycol 6000 6.7 6.7 6.8 (PEG 6000, Duksan) Cellulose acetate (acetyl 40 group 32.0%)(Eastman cellulose acetate, Eastman) US 2011/O 1171.94 A1 May 19, 2011 22
TABLE 1-continued Composition ratio (mg/unit formulation) Example No.
Ingredients (product name, manufacturer) 1 2 3 4 5 6 7 Cellulose acetate (acetyl group 39.8%)(Eastman cellulose acetate, Eastman) Post-mixing Magnesium stearate (Nof) 1 1 1 1 1 1 1 Film-coated Hypromellose 2910 12.4 31.6 9.9 layer (Pharmacoat 603, Shin-Etsu) Hydroxypropylcellulose 12.4 31.6 9.9 (HPC-L, Hercules) Titanium oxide (Fanglian, JHP) 1.8 4.6 1.4 Talc (Nippon Soda) 1 2.8 O.8
Total 209 378 185 279 307 900 231
TABLE 2 Composition ratio (mg/unit formulation) Example No. Ingredients (product name, manufacturer) 8 9 10 11 12 13 14 Angiotensin- Losartan potassium (Cadilla) 50 50 50 50 50 50 50 II-receptor Microcrystalline cellulose 14 14 14 14 14 14 14 blocker- (Vivapur 12, JRS) containing Pregelatinized starch 10 10 10 10 10 10 10 ingredient (Starch 1500, Colorcon) Polyvinylpyrrollidone copolymer 4.5 4.5 4.5 4.5 4.5 4.5 4.5 (PVP VA64Fine, BASF) Colloidal silicon dioxide 1 1 1 1 1 1 1 (Aerosil pharma 200, Degussa) Magnesium stearate (Nof) 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Delayed- Polyvinylpyrrollidone 4 8 12 release (PVP, BASF) coating Ethylcellulose (Ethocel, 8 12 16 2O 16 16 16 layer Colorcon) Acryl-EZE (Colorcon) 8 8 8 8 8 8 8 Film-coated Hypromellose 2910 3.6 3.6 4 4 4 4 4 layer (Pharmacoat 603, Shin-Etsu) Hydroxypropylcellulose 3.6 3.6 4 4 4 4 4 (HPC-L, Hercules) Titanium oxide (Fanglian, JHP) O.S O.S 0.7 0.7 0.7 0.7 0.7 Talc (Nippon Soda) O.3 O.3 O.3 O.3 O.3 O.3 O.3
Total 1 OS 109 114 118 118 122 126
TABLE 3 Composition ratio (mg/unit formulation) Example No. Ingredients (product name, manufacturer) 15 16 17 18 19 2O 21 22 23 24 Angiotensin- Losartan potassium (Cadilla) 50 50 50 50 II-receptor Olmesartan medoxomil (MSN) 2O blocker- Irbesartan (Ranbaxy) 150 containing Valsartan (Dr. Reddy's) 8O ingredient Telmisartan (Ranbaxy) 40 40 Eprosartan (MSN) 600 Alpha lipoic acid (USP. Spectrum Chemical&Laboratory Products) B-carotene (SPECTRUM 10 LABORATORY PRODUCTS INC.) Sillymarin (Alchem 70 International) US 2011/O 1171.94 A1 May 19, 2011 23
TABLE 3-continued Composition ratio (mg/unit formulation) Example No. Ingredients (product name, manufacturer) 15 16 17 18 19 2O 21 22 23 24 Biphenyldimethyldicarboxylate 25 (Daewoong Bio) Selenized yeast (Won Poong 92 Pharmaceutical) Urazamide (Yuhan Chemical) Fraction flavonoid purifiee micronise (Kukjeon Pharmaceutical) Cicloxilic acid (Jisuchem) Riboflavin tetrabutyrate (Hwaduk Pharmaceutical) Ascorbic acid (Roche) Pyridoxamine hydrochloride (Chem-Impex) Agaro-oligosaccharide (Takara Bio) Melatonin (Acros Organics) Ursodeoxycholic acid (Daewoong Bio) Naphthyl acetic acid (Advanced Synthesis) Azintamide (DONGBANG FTL) Macrocrystalline cellulose 123 14 123 45 60 100 100 100 123 (Vivapur 12, JRS) Pregelatinized starch (Starch 2O 10 45 500, Colorcon) Sodium starch glycolate 18 18 18 (Explotab, JRS) Polyvinylpyrrollidone 4.5 copolymer (PVP VA64Fine, BASF) Hydroxypropylcellulose (HPC 3 4 4 L., Hercules) Lactose (Lactose 200, DMV) 30 30 30 30 CroScarmellose sodium 15 (Vivasol, JRS PHARMA) Crosslinked 15 polyvinylpyrrollidone (Kollidon CL, BASF Poloxamer 188 (Lutrol F68, BASF) Polyvinylpyrrollidone (PVP, 7 7 7 BASF) Sorbitol (Sorbitol powder, 10 10 Roquette) NaOH (Duksan) 3 3 Meglumine (USP. Spectrum 1 1 Chemical&Laboratory Products) Sugar seed (Non-pareil 101, 35 Freund) Polyvinyl acetate (Kollicoat 24 24 24 SR3OD, BASF) Hypromellose (Pharmacoat 5 7 615, Shin-Etsu) Hypromellose phthalate HP-55 45 7.2 12 67.3 67.6 67.6 (HPMC-P 55, Shin-Etsu) Polyethylene glycol 6000 O.8 6.7 6.8 6.8 (PEG 6000, Duksan) Cellulose acetate (acetyl group 40 32.0%) (Eastman cellulose acetate, Eastman) Cellulose acetate (acetyl group 40 39.8%)(Eastman cellulose acetate, Eastman) Colloidal silicon dioxide 1 2 (Aerosil pharma 200, Degussa) Magnesium stearate (Nof) 1.5 Post-mixing Colloidal silicon dioxide 2 (Aerosil pharma 200, Degussa) Magnesium stearate (Nof) 1 1 1 1 1 1 1 US 2011/O 1171.94 A1 May 19, 2011 24
TABLE 3-continued
Composition ratio (mg/unit formulation) Example No.
Ingredients (product name, manufacturer) 15 16 17 18 19 2O 21 22 23 24
Film-coated Acetylcysteine (Apollo 100 layer Scientific) ASTO (Coriolus versicolor 240 polysaccharide, Hwail Pharmaceutical) Citiolone (Facus 200 Pharmaceutical) Hypromellose 2910 13.3 14.8 24.7 (Pharmacoat 603, Shin-Etsu) Hydroxypropylcellulose (HPC- 13.3 14.8 24.7 L., Hercules) Titanium oxide (Fanglian, JHP) 1.8 2.3 3.8 Talc (Nippon Soda) 1.2 1.7 2.8
Total 191 136 89 409 388 252 304 409 1,195 465
TABLE 4 Composition ratio (mg/unit formulation) Example No. Ingredients (product name, manufacturer) 25 26 27 28 29 30 31 Angiotensin- Losartan potassium (Cadilla) 50 50 50 50 50 50 50 II-receptor Urazamide (Yuhan Chemical) 200 blocker- Fraction flavonoid purifiee 100 containing micronise (Kukjeon ingredient Pharmaceutical) Cicloxilic acid (Jisuchem) 40 Riboflavin tetrabutyrate 2O (Hwaduk Pharmaceutical) Ascorbic acid (Roche) 15 Pyridoxamine hydrochloride 25 (Chem-Impex) Agaro-oligosaccharide 100 (Takara Bio) Melatonin (Acros Organics) O.1 Ursodeoxycholic acid 5 (Daewoong Bio) Naphthyl acetic acid 15 (Advanced Synthesis) Azintamide (DONGBANG FTL) 50 Macrocrystalline 14 14 14 14 14 14 14 cellulose (Vivapur 12, JRS) Pregelatinized starch 10 10 10 10 10 10 10 (Starch 1500, Colorcon) Polyvinylpyrrollidone copolymer 4.5 4.5 4.5 4.5 4.5 4.5 4.5 (PVP VA64Fine, BASF) Polyvinylpyrrollidone 4 8 10 (PVP, BASF) Colloidal silicon 1 1 1 1 1 1 1 dioxide (Aerosil pharma 200, Degussa) Magnesium stearate (Nof) 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Film-coated Ethylcellulose 8 12 16 2O 16 16 16 layer (Ethocel, Colorcon) Acryl-EZE (Colorcon) 8 8 8 8 8 8 8
Total 297 201 145 169 209.1 118 18O US 2011/O 1171.94 A1 May 19, 2011 25
TABLE 5 Composition ratio (mg/unit formulation) Example No. Ingredients (product name, manufacturer) 32 33 34 35 36 37 38 Delayed- Losartan potassium (Cadila) SO 100 50 release Valsartan (Dr. Reddy's) 8O compartment Telmisartan (Ranbaxy) 40 Eprosartan (MSN) 600 Candesartan cilexetil 16 (Ranbaxy) (rbesartan (Ranbaxy) Microcrystalline cellulose 40 SO 150 1OO 14 123 (Vivapur 12, JRS) Pregelatinized starch 10 (Starch 1500, Colorcon) Polyvinylpyrrollidone copolymer 4.5 (PVP VA64Fine, BASF) Sodium starch glycolate 5 8 18 (Explotab, JRS) Hydroxypropylcellulose 5 8 2 4 (HPC-L, Hercules) Lactose (Lactose 200, DMV) 25 30 58 30 Corn starch (Duksan) 10 Carboxymethylcellulose calcium 38 (CMC Ca, Hwawon) Crosslinked 8O polyvinylpyrrollidone (Kollidon CL, BASF) Poloxamer 188 (Lutrol F68, BASF) Polyvinylpyrrollidone 8 7 (PVP, BASF) Sorbitol (Sorbitol 10 powder, Roquette) NaOH (Duksan) 3 Meglumine (USP. Spectrum 1 Chemical&Laboratory Products) Polyvinyl acetate 7 (Kollicoat SR30D, BASF) Hypromellose 3.2 2 1 (Pharmacoat 615, Shin-Etsu) Hypromellose phthalate 60 12 HP-50 (HPMC-P50, Shin-Etsu) Hypromellose phthalate 7.2 HP-55 (HPMC-P 55, Shin-Etsu) Polyethylene glycol 6000 6 15 O.8 (PEG 6000, Duksan) Cellulose acetate (acetyl 32 2O group 32.0%)(Eastman cellulose acetate, Eastman) Cellulose acetate (acetyl 32 2O group 39.8%)(Eastman cellulose acetate, Eastman) Hypromellose acetate Succinate 55 (HPMC-AS LF, Shin-Etsu) Acryl-EZE (Colorcon) 8 Colloidal silicon dioxide 1 (Aerosil pharma 200, Degussa) Magnesium stearate (Nof) 1 1 1.5 1 Post-mixing Magnesium Stearate (Nof) 4.8 3 1 Prior-release Haematoporphyrin 3 compartment (Atomole Scientific) Ubidecarenone (Daewoong Bio) 10 Arginine hydrochloride 125 (ILSHIN CHEMICAL) Ornithine hydrochloride 13 (CKD BIO) Erdosteine (Ilsung 150 Pharmaceuticals) Guaiacol (AOKchem) 4 Creatine (Shanghai Orgchem) 50 Riboflavin 5 Cholecalciferol 5 L-glutathione 10 L-glutamine 5 US 2011/O 1171.94 A1 May 19, 2011 26
TABLE 5-continued Composition ratio (mg/unit formulation) Example No. Ingredients (product name, manufacturer) 32 33 34 35 36 37 38 Sodium selenite 2O Ginko bioba extract 10 Butylated hydroxyanisole 3 L-ornithine 12 Macrocrystalline cellulose 1OO 100 100 1OO 100 1OO 100 (Vivapur 12, JRS) Pregelatinized starch 50 50 50 50 50 50 50 (Starch 1500, Colorcon) Corn starch (Duksan) 50 50 50 50 50 50 50 Hydroxypropylcellulose 6 6 6 6 6 6 6 (HPC-L, Hercules) Magnesium stearate (Nof) 1 1 1 1 Post-mixing Magnesium Stearate (Nof) 1 1 1 Coating Hypromellose 2910 30 39.5 17.5 layer (Pharmacoat 603, Shin-Etsu) Hydroxypropylcellulose 30 39.5 17.5 (HPC-L, Hercules) Titanium oxide (Fanglian, JHP) 4.4 5.7 2.5 Talc (Nippon Soda) 2.6 3.3 1.5
Total SOO S2S 841 412 1082 327 454
TABLE 6 Composition ratio (mg/unit formulation) Example No. Ingredients (product name, manufacturer) 39 40 41 42 43 44 45 Delayed- Losartan potassium (Cadila) 50 50 release Valsartan (Dr. Reddy's) 8O compartment Telmisartan (Ranbaxy) Olmesartan medoxomil (MSN) 2O Eprosartan (MSN) 600 Candesartan cilexetil 16 (Ranbaxy) (rbesartan (Ranbaxy) 150 Microcrystalline 2O 123 60 14 45 cellulose (Vivapur 12, JRS) Pregelatinized starch 10 10 45 (Starch 1500, Colorcon) Polyvinylpyrrollidone copolymer 4.5 (PVP VA64Fine, BASF) Hydroxypropylcellulose 4 (HPC-L, Hercules) Lactose (Lactose 200, DMV) 30 CroScarmellose sodium 15 (Vivasol, JRS PHARMA) Crosslinked 15 polyvinylpyrrollidone (Kollidon CL, BASF) Poloxamer 188 (Lutrol 9 F68, BASF) Polyvinylpyrrollidone 7 (PVP, BASF) Sugar seed (Non-pareil 35 35 01, Freund) Polyvinyl acetate (Kollicoat 24 SR3OD, BASF) Hypromellose 7 5 5 (Pharmacoat 615, Shin-Etsu) Hypromellose phthalate 12 45 45 7.2 HP-55 (HPMC-P 55, Shin-Etsu) Polyethylene glycol O.8 6000 (PEG 6000, Duksan) Cellulose acetate (acetyl 40 group 32.0%)(Eastman cellulose acetate, Eastman) US 2011/O 1171.94 A1 May 19, 2011 27
TABLE 6-continued Composition ratio (mg/unit formulation) Example No. Ingredients (product name, manufacturer) 39 40 41 42 43 44 45 Cellulose acetate (acetyl 40 group 39.8%)(Eastman cellulose acetate, Eastman) Ethylcellulose (Ethocel, 5 Colorcon) Sodium chloride 3 Colloidal silicon dioxide 1 3 (Aerosil pharma 200, Degussa) Magnesium stearate (Nof) 1 1.5 1 Prior- Haematoporphyrin 6 release (Atomole Scientific) compartment Erdosteine (Ilsung 5 Pharmaceuticals) Guaiacol (AOKchem) 10 Cholecalciferol 10 3 L-glutathione 15 Ginko bioba extract 5 3 Butylated hydroxyanisole 3 Arginine sodium 10 10 3 Protoporphyrin disodium 10 Hymecromone 2O Sugar seed (Non-pareil 10 01, Freund) Macrocrystalline 100 1OO 100 1OO 100 1OO cellulose (Vivapur 12, JRS) Pregelatinized starch 50 50 50 50 50 50 (Starch 1500, Colorcon) Corn starch 50 50 50 Hydroxypropylcellulose 6 6 6 6 (HPC-L, Hercules) Magnesium stearate (Nof) 1 1 Post-mixing Magnesium Stearate (Nof) 2 Coating Hypromellose 2910 11.7 layer (Pharmacoat 603, Shin-Etsu) Hydroxypropylcellulose 11.7 (HPC-L, Hercules) Titanium oxide (Fanglian, JHP) 1.6 Talc (Nippon Soda) 1
Total 288 399 408 162 922 316 596
Experimental Example 1 slow, unlike dissolution profiles of the telmisartan single drug as a control drug. Therefore, telmisartan can be absorbed Comparative Dissolution Profile Test during the night upon evening administration of the tablet, so 0339. A comparative dissolution profile test was per it can be seen that the inventive tablet is highly effective in the formed using a telmisartan delayed-release uncoated tablet treatment of hypertension. prepared in Example 1 and a control drug (Micardis, Boe 0342 Test Method for angiotensin-II-receptor blocker: hringer Ingelheim: telmisartan single drug). The dissolution Based on the general dissolution test method described in the profile test of the telmisartan ingredient was performed for a Korean Pharmacopoeia (8” revision) total of 480 minutes, in which the dissolution medium was (0343 Test method: Paddle method, 50 rpm changed from a simulated gastric juice to a simulated intes 0344) Dissolution medium: 0.01 M hydrochloric acid tinal juice 120 minutes after the start of the test. Details of the solution 750 mL (simulated gastric juice), pH 6.8 phosphate dissolution profile test of each ingredient are as follows. The buffer 1,000 mL (simulated intestinal juice) results obtained are shown in FIG. 1. In FIG. 1, the X-axis 0345 Analysis method: UV-Vis spectrophotometry represents the time series (min), and the y-axis represents the dissolution rate (Drug Released, '%). Experimental Example 2 0340. As can be seen in FIG. 1, when the dissolution profile test was performed, the telmisartan ingredient of the Comparative Dissolution Profile Test uncoated tablet of Example 1 showed a very slow dissolution 0346 A comparative dissolution profile test was per rate as compared to that of the control drug Micardis, and formed using a losartan-containing film-coated tablet pre showed the drug dissolution of less than 20% up to a total of pared in Example 5 and a control drug (Cozaar, MSD: losa 4 hours. rtan single drug). Details of the dissolution profile test of each 0341. As described above, the initial release of telmisartan ingredient are the same as those of Experimental Example 1. in the telmisartan delayed-release uncoated tablet is very The results obtained are shown in FIG.2. In FIG. 2, the X-axis US 2011/O 1171.94 A1 May 19, 2011 28 represents the time series (min), and the y-axis represents the of 240 minutes and the losartan ingredient was rapidly dissolution rate (Drug Released, '%). released with an increase in the amount of crosslinked poly 0347 As can be seen in FIG. 2, when the dissolution vinylpyrrolidone to be used. profile test was performed under the conditions of Experi 0354. Therefore, the losartan film-coated tablet containing mental Example 1, the losartan ingredient of the delayed a delayed-release film can achieve rapid release of losartan release granule-containing film-coated tablet showed a very after an intended lag time by controlling the content of slow dissolution rate as compared to that of the control drug crosslinked polyvinylpyrrolidone in the ethylcellulose Cozaar, and showed the drug dissolution of less than 20% up coated delayed-release layer. Therefore, losartan can be to a total of 240 minutes. absorbed during the night upon evening administration of the 0348. As described above, the initial release of losartan in tablet, so it can be seen that the inventive tablet is highly the losartan-containing film-coated tablet of the present effective in the treatment of hypertension. invention is significantly slow, unlike dissolution profiles of the losartan single drug as a control drug. Therefore, losartan Experimental Example 5 can be absorbed during the night upon evening administration of the tablet, so it can be seen that the inventive tablet is highly Comparative Dissolution Profile Test effective in the treatment of hypertension. 0355. A comparative dissolution profile test was per formed using a multi-layered tablet containing a Valsartan Experimental Example 3 delayed-release layer prepared in Example 32 and a control drug (Diovan, MSD: Valsartan single drug). Details of the Comparative Dissolution Profile Test dissolution profile test are the same as those of Experimental 0349. A comparative dissolution profile test was per Example 1. The results obtained are shown in FIG. 5. In FIG. formed using film-coated tablets of Examples 8 to 11. Details 5, the X-axis represents the time series (min), and the y-axis of the dissolution profile test are the same as those of Experi represents the dissolution rate (Drug Released, 96). 0356. As can be seen in FIG. 5, when the dissolution mental Example 1. The results obtained are shown in FIG. 3. profile test was performed under the conditions of Experi In FIG. 3, the x-axis represents the time series (min), and the mental Example 1, the Valsartan ingredient of the delayed y-axis represents the dissolution rate (Drug Released, 96). release layer-containing multi-layered tablet of the present 0350. As can be seen in FIG. 3, when the dissolution profile test was performed under the conditions of Experi invention showed a very slow dissolution rate as compared to mental Example 1, the dissolution rate of losartan was less that of the control drug Diovan. In the dissolution profile test than 20% up to a total of 240 minutes in the delayed-release results for the Valsartan ingredient, the dissolution rate of the film-containing film-coated tablet of the present invention, Valsartan ingredient was about 20% up to a total of 240 thus exhibiting a significant decrease in dissolution rate of the minutes in the Valsartan delayed-release layer-containing losartan ingredient in response to an increase in the amount of multi-layered tablet of the present invention, which was far ethylcellulose to be used. That is, coating of the tablet with lower than that of the control drug. ethylcellulose resulted in significantly delayed dissolution of 0357. As described above, the initial release of valsartan in the losartan ingredient. the Valsartan delayed-release layer-containing multi-layered 0351. Therefore, the initial release of losartan in the losa tablet is significantly slow, unlike dissolution profiles of the rtan film-coated tablet containing a delayed-release film can Valsartan single drug as a control drug. Therefore, Valsartan be delayed up to the intended time by controlling the amount can be absorbed during the night upon evening administration of ethylcellulose coated. Therefore, losartan can be absorbed of the tablet, so it can be seen that the inventive tablet is highly during the night upon evening administration of the tablet, so effective in the treatment of hypertension. it can be seen that the inventive tablet is highly effective in the treatment of hypertension. Experimental Example 6 Comparative Dissolution Profile Test Experimental Example 4 0358. A comparative dissolution profile test was per Comparative Dissolution Profile Test formed using a candesartan cilexetil press-coated tablet pre pared in Example 35 and a control drug (Atacand. AstraZen 0352. A comparative dissolution profile test was per eca: candesartan single drug). Details of the dissolution formed using formulations of Examples 10, and 12 to 14. profile test are the same as those of Experimental Example 1. Details of the dissolution profile test are the same as those of The results obtained are shown in FIG. 6. In FIG. 6, the X-axis Experimental Example 1. The results obtained are shown in represents the time series (min), and the y-axis represents the FIG. 4. In FIG. 4, the x-axis represents the time series (min), dissolution rate (Drug Released, 96). and the y-axis represents the dissolution rate (Drug Released, 0359. As can be seen in FIG. 6, when the dissolution %). profile test was performed under the conditions of Experi 0353 As can be seen in FIG. 4, when the dissolution mental Example 1, the candesartan ingredient of the press profile test was performed under the conditions of Experi coated tablet of the present invention showed a very slow mental Example 1, the delayed-release film-containing film dissolution rate of about 20% up to a total of 240 minutes, as coated tablet of the present invention showed relatively rapid compared to that of the control drug Atacand. As described release of the losartan ingredient after an intended lag time above, the initial release of candesartan in the candesartan when crosslinked polyvinylpyrrolidone is incorporated in the cilexetil press-coated tablet is significantly slow, unlike dis ethylcellulose-coated delayed-release layer. The dissolution Solution profiles of the candesartan single drug as a control rate of the losartan ingredient was less than 20% up to a total drug. Therefore, candesartan can be absorbed during the US 2011/O 1171.94 A1 May 19, 2011 29 night upon evening administration of the tablet, so it can be represents the time series (min), and the y-axis represents the seen that the inventive tablet is highly effective in the treat dissolution rate (Drug Released, 96). ment of hypertension. 0365. As can be seen in FIG. 9, when the dissolution profile test was performed under the conditions of Experi Experimental Example 7 mental Example 1, the irbesartan ingredient of the capsule (tablet) of the present invention showed a very slow dissolu Comparative Dissolution Profile Test tion rate, as compared to that of the control drug Aprovel. In 0360. A comparative dissolution profile test was per the dissolution profile test results for the irbesartan ingredi formed using an olmesartan medoxomil capsule (granule) ent, the dissolution rate of theirbesartan ingredient was about prepared in Example 40 and a control drug (Olimetec, Dae 20% up to a total of 240 minutes in the irbesartan capsule woong Pharmaceutical: olmesartan medoxomil single drug). (tablet) of Example 45, which was far lower than that of the Details of the dissolution profile test are the same as those of control drug. As described above, the initial release of irbe Experimental Example 1. The results obtained are shown in Sartan in the irbesartan capsule (tablet) of the present inven FIG. 7. In FIG. 7, the x-axis represents the time series (min), tion is significantly slow, unlike dissolution profiles of the and the y-axis represents the dissolution rate (Drug Released, irbesartan single drug as a control drug. Therefore, irbesartan %). can be absorbed during the night upon evening administration 0361. As can be seen in FIG. 7, when the dissolution of the capsule. So it can be seen that the inventive capsule is profile test was performed under the conditions of Experi highly effective in the treatment of hypertension. mental Example 1, the olmesartan ingredient of the capsule (granule) of the present invention showed a very slow disso INDUSTRIAL APPLICABILITY lution rate of about 20% up to a total of 240 minutes, as 0366. The formulation of the present invention maximizes compared to that of the control drug Olmetec. As described the effectiveness on pharmacologically and clinically lower above, the initial release of olmesartan in the olmesartan ing blood pressure and preventing complications when taking medoxomil capsule (granule) is significantly slow, unlike the formulation, helps to avoid interactions with a drug which dissolution profiles of the olmesartan medoxomil single drug is metabolized by the same enzyme in the liver, and prevents as a control drug. Therefore, olmesartan can be absorbed and inhibits the incidence of drug-induced hepatitis which is during the night upon evening administration of the capsule, caused by drug administration for a long time. so it can be seen that the inventive capsule is highly effective 1. A pharmaceutical formulation comprising an angio in the treatment of hypertension. tensin-II-receptor blocker as a pharmacologically active ingredient and a release-controlling material. Experimental Example 8 2. The pharmaceutical formulation according to claim 1, wherein the angiotensin-II-receptor blocker is released at a Comparative Dissolution Profile Test level of less than 40% by weight within 4 hours after oral 0362. A comparative dissolution profile test was per administration. formed using an eprosartan capsule (pellet) prepared in 3. (canceled) Example 43 and a control drug (Teveten, Abbott: eprosartan 4. The pharmaceutical formulation according to claim 1, single drug). Details of the dissolution profile test are the wherein the formulation further comprises a hepatitis-pre same as those of Experimental Example 1. The results venting and inhibiting agent as a pharmacologically active obtained are shown in FIG.8. In FIG. 8, the x-axis represents ingredient. the time series (min), and the y-axis represents the dissolution 5. (canceled) rate (Drug Released, 96). 6. The pharmaceutical formulation according to claim 4. 0363 As can be seen in FIG. 8, when the dissolution wherein the hepatitis-preventing and inhibiting agent is at profile test was performed under the conditions of Experi least one selected from B-carotene, riboflavin, riboflavin tet mental Example 1, the eprosartan ingredient of the capsule rabutyrate, riboflavin rocoat, riboflavin phosphate sodium, (pellet) of the present invention showed a very slow dissolu ascorbic acid, ascorbyl palmitate, calcium ascorbate, nicoti tion rate, as compared to that of the control drug Teveten. As namide ascorbate, Sodium ascorbate, dehydroascorbic acid, described above, the initial release of eprosartan in the epro cholecalciferol, cholecalciferolic acid, ergocalciferol, toco Sartan capsule (pellet) is significantly slow, unlike dissolution pherol, tocopherol acetate, tocopherol calcium, tocopherol profiles of the eprosartan single drug as a control drug. There calcium Succinate, tocopherol Succinate, cysteine, cysteine fore, eprosartan can be absorbed during the night upon hydrochloride, cysteine malate, methyl cysteine, carboxym evening administration of the capsule, so it can be seen that ethyl cysteine, methyl cysteine hydrochloride, N-acetyl-L- the inventive capsule is highly effective in the treatment of cysteine, L-glutathione, glutathione disulfide, reduced glu hypertension. tathione, L-glutamine, glutamine hydrochloride, L-glutaminate-L-lysinate, L-glutamine, N(2)-L-alanine-L- Experimental Example 9 glutamine, C-lipoic acid, selenized yeast, selenium, Selenium disulfide, Sodium selenate, sodium selenite, silymarin, ginko Comparative Dissolution Profile Test biloba extract, biphenyldimethyldicarboxylate, ursodeoxy cholic acid, chenocholic acid, butylated hydroxyanisole, 0364. A comparative dissolution profile test was per butylated hydroxytoluene, guaiacol, erdosteine, resveratrol, formed using an irbesartan capsule (tablet) prepared in pyridoxamine hydrochloride, pyridoxine hydrochloride, Example 45 and a control drug (Aprovel, MSD: irbesartan pyridoxal phosphate, agaro-oligosaccharide, fraction fla single drug). Details of the dissolution profile test of each vonoid purifiee micronise, melatonin, ubidecarenone, L-or ingredient are the same as those of Experimental Example 1. nithine, ornithine aspartate, ornithine hydrochloride, L-argi The results obtained are shown in FIG.9. In FIG.9, the X-axis nine, arginine hydrochloride, arginine sodium, L-arginine US 2011/O 1171.94 A1 May 19, 2011 30 monoglutamate, protoporphyrin disodium, haematoporphy 12-18. (canceled) rin, haematoporphyrin hydrochloride, Coriolus versicolor 19. The pharmaceutical formulation according to claim 10, polysaccharide, cicloxilic acid, citiolone, uraZamide, azinta wherein the fatty acidor fatty acid ester is at least one selected mide, hymecromone, and C-naphthyl acetic acid. from glyceryl palmitostearate, glyceryl Stearate, glyceryl 7. The pharmaceutical formulation according to claim 1, behenate, cetyl palmitate, glyceryl monooleate, Stearic acid wherein the angiotensin-II-receptor blocker is at least one and a mixture thereof; the fatty acid alcohol is at least one selected from losartan, Valsartan, telmisartan, irbesartan, can selected from cetostearyl alcohol, cetyl alcohol, Stearyl alco desartan, olmesartan, eprosartan, isomers thereof, pharma hol and a mixture thereof; the wax is at least one selected from ceutically acceptable salts thereof, and prodrugs thereof. carnauba wax, beeswax, microcrystalline wax and a mixture 8. The pharmaceutical formulation according to claim 1, thereof, and the inorganic material is at least one selected wherein the release-controlling material is at least one from talc, precipitated calcium carbonate, calcium hydrogen selected from an enteric polymer, a water-insoluble polymer, phosphate, Zinc oxide, titanium oxide, kaolin, bentonite, a hydrophobic compound, a hydrophilic polymer and a mix montmorillonite, Veegum and a mixture thereof. ture thereof. 20-21. (canceled) 9. (canceled) 22. The pharmaceutical formulation according to claim 10, 10. The pharmaceutical formulation according to claim 8, wherein the saccharide is at least one selected from dextrin, wherein the enteric polymer is at least one selected from the polydextrin, dextran, pectin and a pectin derivative, alginate, group consisting of an enteric cellulose derivative, an enteric polygalacturonic acid, Xylan, arabinoxylan, arabinogalactan, acrylic acid copolymer, an enteric polymethacrylate copoly starch, hydroxypropyl Starch, amylose, amylopectin and a mer, an enteric maleic acid copolymer, an enteric polyvinyl mixture thereof, the cellulose derivative is at least one derivative, and a mixture thereof; the water-insoluble poly selected from hydroxypropylmethylcellulose, hydroxypro mer is at least one selected from the group consisting of pylcellulose, hydroxymethylcellulose, hydroxyethylcellu polyvinyl acetate, a water-insoluble polymethacrylate lose, methylcellulose, sodium carboxymethylcellulose, copolymer, ethylcellulose, cellulose ester, cellulose ether, hydroxypropylmethylcellulose acetate Succinate, hydroxy cellulose acylate, cellulose diacylate, cellulose triacylate, cel ethylmethylcellulose and a mixture thereof; the gum is at least lulose acetate, cellulose diacetate, cellulose triacetate and a one selected from guar gum, locust bean gum, tragacanth, mixture thereof; the hydrophobic compound is at least one carrageenan, gum acacia, gum arabic, gellan gum, Xanthan selected from a fatty acid or fatty acid ester, a fatty acid gum and a mixture thereof; the protein is at least one selected alcohol, a wax, an inorganic material, and a mixture thereof; from gelatin, casein, Zein and a mixture thereof; the polyvinyl and the hydrophilic polymer is at least one selected from a derivative is at least one selected from polyvinyl alcohol, saccharide, a cellulose derivative, a gum, a protein, a polyvi polyvinyl pyrrolidone, polyvinylacetal diethylaminoacetate nyl derivative, a hydrophilic polymethacrylate copolymer, a and a mixture thereof; the hydrophilic polymethacrylate polyethylene derivative, a carboxyvinyl copolymer and a copolymer is at least one selected from a poly(butyl meth mixture thereof. acrylate, (2-dimethylaminoethyl) methacrylate, methyl 11. The pharmaceutical formulation according to claim 10, methacrylate) copolymer, a poly(methacrylic acid, methyl wherein the enteric cellulose derivative is at least one selected methacrylate) copolymer, a poly(methacrylic acid, ethyl from hydroxypropylmethylcellulose acetate Succinate, acrylate) copolymer and a mixture thereof; the polyethylene hydroxypropylmethylcellulose phthalate, hydroxymethyl derivative is at least one selected from polyethylene glycol, ethylcellulose phthalate, cellulose acetate phthalate, cellu polyethylene oxide and a mixture thereof; and the carboxyvi lose acetate Succinate, cellulose acetate maleate, cellulose nyl polymer is carbomer. benzoate phthalate, cellulose propionate phthalate, methyl 23. (canceled) cellulose phthalate, carboxymethylethylcellulose, ethylhy 24. The pharmaceutical formulation according to claim 1, droxyethylcellulose phthalate, methylhydroxyethylcellulose wherein the pharmaceutical formulation is an uncoated tab and a mixture thereof; the enteric acrylic acid copolymer is at let, a film-coated tablet, a multi-layered tablet, a press-coated least one selected from a styrene? acrylic acid copolymer, a tablet, or a capsule. methyl acrylate/acrylic acid copolymer, a methyl acrylate/ 25. The pharmaceutical formulation according to claim 24, methacrylic acid copolymer, a butyl acrylate/styrene? acrylic wherein the uncoated tablet is a tablet obtained by compres acid copolymer, a methyl acrylate/methacrylic acid/octyl sion of granules containing an angiotensin-II-receptor acrylate copolymer and a mixture thereof; the enteric poly blocker and a release-controlling material; the film-coated methacrylate copolymer is at least one selected from a poly tablet is a tablet in which a tablet containing an angiotensin (methacrylic acid/methyl methacrylate) copolymer, a poly II-receptor blocker is coated with a film-coated layer contain (methacrylic acid/ethyl acrylate) copolymer and a mixture ing a release-controlling material; the multi-layered tablet is thereof the enteric maleic acid copolymer is at least one a tablet having a layered structure of a layer containing an selected from a vinyl acetate/maleic anhydride copolymer, a angiotensin-II-receptor blocker and a release-controlling styrene? maleic anhydride copolymer, a styrene/maleic material and a layer containing a release-controlling material; monoester copolymer, a vinyl methyl ether/maleic anhydride the press-coated tablet is a tablet including an inner core tablet copolymer, an ethylene/maleic anhydride copolymer, a vinyl containing an angiotensin-II-receptor blocker and a release butyl ether/maleic anhydride copolymer, an acrylonitrile/me controlling material and an outer layer containing a release thyl acrylate/maleic anhydride copolymer, a butyl acrylate/ controlling material enclosing the outer Surface of the inner styrene? maleic anhydride copolymer and a mixture thereof. core tablet, or a tablet including a coating layer enclosing the and the enteric polyvinyl derivative is at least one selected outer Surface of an angiotensin-II-receptor blocker-contain from polyvinylalcohol phthalate, polyvinylacetate phthalate, ing tablet and containing a release-controlling material, and polyvinylbutyrate phthalate, polyvinylacetacetal phthalate an outer layer enclosing the outer Surface of the coating layer and a mixture thereof. and containing a release-controlling material or an osmotic US 2011/O 1171.94 A1 May 19, 2011 press-coated tablet, and the capsule is of a form where at least the prior-release compartment is released at a level of more one selected from a particle, a granule, a pellet and a tablet is than 85% by weight within one hour after initiation of release filled in a capsule. thereof. 26-31. (canceled) 42. The pharmaceutical formulation according to claim39, 32. The pharmaceutical formulation according to claim 1, wherein less than 40% by weight of the pharmacologically wherein the formulation further comprises a coating layer on active ingredient contained in the delayed-release compart the outside thereof. ment is released within 4 hours after the release of the phar 33. The pharmaceutical formulation according to claim 1, macologically active ingredient contained in the prior-release wherein the formulation contains an osmo-regulator and is compartment is initiated. coated by a semi-permeable membrane coating base. 43-44. (canceled) 34. The pharmaceutical formulation according to claim 33, 45. The pharmaceutical formulation according to claim39, wherein the osmo-regulator is at least one selected from the wherein the delayed-release compartment further comprises group consisting of magnesium sulfate, magnesium chloride, a hepatitis-preventing and inhibiting agent as a pharmaco Sodium chloride, lithium chloride, potassium Sulfate, sodium logically active ingredient. sulfate, lithium sulfate and a mixture thereof, and the semi 46-47. (canceled) permeable membrane coating base is at least one selected 48. The pharmaceutical formulation according to claim39, from the group consisting of polyvinyl acetate, a poly wherein the delayed-release compartment further comprises methacrylate copolymer, a poly(ethyl acrylate, methyl meth at least one release-controlling material selected from an acrylate) copolymer, a poly(ethyl acrylate, methyl methacry enteric polymer, a water-insoluble polymer, a hydrophobic late, trimethylaminoethyl methacrylate chloride) copolymer, compound, a hydrophilic polymer and a mixture thereof, in ethylcellulose, cellulose ester, cellulose ether, cellulose acy addition to pharmacologically active ingredients. late, cellulose diacylate, cellulose triacylate, cellulose 49-75. (canceled) acetate, cellulose diacetate, cellulose triacetate and a mixture 76. The pharmaceutical formulation according to claim39, thereof. wherein the formulation is for evening administration. 35. (canceled) 77. The pharmaceutical formulation according to claim39, 36. The pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation is for administration wherein the formulation is for evening administration. in combination with a drug which is metabolized by cyto 37. The pharmaceutical formulation according to claim 1, chrome. wherein the pharmaceutical formulation is for administration 78. (canceled) in combination with a drug which is metabolized by cyto 79. The pharmaceutical formulation according to claim 2, chrome. wherein the formulation further comprises a hepatitis-pre 38. The pharmaceutical formulation according to claim 37, venting and inhibiting agent as a pharmacologically active wherein the drug metabolized by cytochrome is at least one ingredient. selected from a lipid inhibitor which is at least one selected from simvastatin, andatorvastatin; an antihypertensive agent 80. The pharmaceutical formulation according to claim 2, which is at least one selected from amlodipine, felodipine, wherein the angiotensin-II-receptor blocker is at least one carvedilol, and aliskiren; an antihistamine agent which is at selected from losartan, Valsartan, telmisartan, irbesartan, can least one selected from loratadine, and azelastine; an analge desartan, olmesartan, eprosartan, isomers thereof, pharma sic agent which is at least one selected from acetaminophen, ceutically acceptable salts thereof, and prodrugs thereof. and tramadol; an antidepressant which is at least one selected 81. The pharmaceutical formulation according to claim 2, from amitriptyline, and imipramine; an anticoagulant which wherein the release-controlling material is at least one is warfarin; an anti-emetic agent which is at least one selected selected from an enteric polymer, a water-insoluble polymer, from chlorpromazine, and granisetron; an anticonvulsant a hydrophobic compound, a hydrophilic polymer and a mix which is carbamazepine; an anti-acne agent which is isotret ture thereof. inoin, an antipsychotic agent which is risperidone; an antide 82. The pharmaceutical formulation according to claim 2, pressant which is at least one selected from propyne, and wherein the pharmaceutical formulation is an uncoated tab venlafaxine; an HIV-antiviral agent which is fosamprenavir, let, a film-coated tablet, a multi-layered tablet, a press-coated an antifungal agent which is itraconazole; a thiazolidinedione tablet, or a capsule. antidiabetic agent which is pioglitaZone; an anti-obesity 83. The pharmaceutical formulation according to claim 2, agent which is sibutramine; an anti-erectile dysfunction agent wherein the formulation further comprises a coating layer on which is sildenafil; and an anti-incontinence agent which is the outside thereof. tolterodine. 84. The pharmaceutical formulation according to claim 2, 39. A pharmaceutical formulation comprising a prior-re wherein the formulation contains an osmo-regulator and is lease compartment containing a hepatitis-preventing and coated by a semi-permeable membrane coating base. inhibiting agent as a pharmacologically active ingredient, and 85. The pharmaceutical formulation according to claim 2, a delayed-release compartment containing an angiotensin-II wherein the formulation is for evening administration. receptor blocker as a pharmacologically active ingredient. 86. The pharmaceutical formulation according to claim 2, 40. The pharmaceutical formulation according to claim39, wherein the pharmaceutical formulation is for administration wherein the pharmacologically active ingredient contained in in combination with a drug which is metabolized by cyto the delayed-release compartment is released 1 to 4 hours after chrome. the release of the pharmacologically active ingredient con 87. The pharmaceutical formulation according to claim 40, tained in the prior-release compartment is initiated. wherein the delayed-release compartment further comprises 41. The pharmaceutical formulation according to claim39, a hepatitis-preventing and inhibiting agent as a pharmaco wherein the pharmacologically active ingredient contained in logically active ingredient. US 2011/O 1171.94 A1 May 19, 2011 32
88. The pharmaceutical formulation according to claim 41, enteric polymer, a water-insoluble polymer, a hydrophobic wherein the delayed-release compartment further comprises compound, a hydrophilic polymer and a mixture thereof, in a hepatitis-preventing and inhibiting agent as a pharmaco addition to pharmacologically active ingredients. logically active ingredient. 93. The pharmaceutical formulation according to claim 40, 89. The pharmaceutical formulation according to claim 42, wherein the formulation is for evening administration. wherein the delayed-release compartment further comprises 94. The pharmaceutical formulation according to claim 41, a hepatitis-preventing and inhibiting agent as a pharmaco wherein the formulation is for evening administration. logically active ingredient. 95. The pharmaceutical formulation according to claim 42, 90. The pharmaceutical formulation according to claim 40, wherein the formulation is for evening administration. wherein the delayed-release compartment further comprises 96. The pharmaceutical formulation according to claim 40, at least one release-controlling material selected from an wherein the pharmaceutical formulation is for administration enteric polymer, a water-insoluble polymer, a hydrophobic in combination with a drug which is metabolized by cyto compound, a hydrophilic polymer and a mixture thereof, in chrome. addition to pharmacologically active ingredients. 97. The pharmaceutical formulation according to claim 41, 91. The pharmaceutical formulation according to claim 41, wherein the pharmaceutical formulation is for administration wherein the delayed-release compartment further comprises in combination with a drug which is metabolized by cyto at least one release-controlling material selected from an chrome. enteric polymer, a water-insoluble polymer, a hydrophobic 98. The pharmaceutical formulation according to claim 42, compound, a hydrophilic polymer and a mixture thereof, in wherein the pharmaceutical formulation is for administration addition to pharmacologically active ingredients. in combination with a drug which is metabolized by 92. The pharmaceutical formulation according to claim 42, cytochrome. wherein the delayed-release compartment further comprises at least one release-controlling material selected from an