NZ625004B2 - Pharmaceutical composition for preventing or treating hypertriglyceridemia or hypertriglyceridemia-associated diseases - Google Patents

Abstract

Provided is the use of a combination of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-({2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl}methyl)-4-methyl-1,3-oxazolidin-2-one (anacetrapib) and a calcium channel blocker or a fibrate for the prevention or treatment of hypertriglyceridemia or hypertriglyceridemia-associated diseases. A preferred calcium channel blocker is amlodipine. A preferred fibrate is fenofibrate. eridemia or hypertriglyceridemia-associated diseases. A preferred calcium channel blocker is amlodipine. A preferred fibrate is fenofibrate.

Description

Description Title of Invention: PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING HYPERTRIGLYCERIDEMIA OR HYPERTRIGLYCERIDEMIA-ASSOCIATED DISEASES Technical Field The t invention relates to a pharmaceutical ition for preventing or ng hypertriglyceridemia or hypertriglyceridemia—associated disease. More specifically, the present invention relates to a pharmaceutical ition for preventing or treating hypertriglyceridemia or hypertriglyceridemia—associated disease comprising (4S,5R)—5—[3,5—bis(trifluoromethyl)pheny1]—3—({2—[4—fluoro—2—methoxy—5—(propan—2—yl) phenyl]—5—(trifluoromethyl)phenyl}methy1)—4—methy1—1,3—oxazolidin—2—one or its phar— maceutically acceptable salt; and a calcium channel r or a fibrate as active in— gredients.

Background Art Hyperlipidemia involves abnormally elevated levels of any or all lipids and/or lipoproteins in the blood. Hyperlipidemias may be classified according to which types of lipids are ed, that is holesterolemia, hypertriglyceridemia or both in combined hyperlipidemia. Triglycerides are known as one of the independent risk factors of atherosclerosis. Although the relevancy between hypertriglyceridemia and cardiovascular diseases such as atherosclerosis is not still clear, it has been known that hypertriglyceridemia ses the risk of atherosclerosis (Cullen P. Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol 2000; —9; Le NA, Walter MP. The role of hypertriglyceridemia in atherosclerosis.

Curr Atheroscler Rep 2007; 9: 1 10—5; Stalenhoef AF, de Graaf J. Association of fasting and nonfasting serum triglycerides with cardiovascular disease and the role of remnant—like lipoproteins and small dense LDL. Curr Opin Lipidol 2008; 19:355—61).

And also, it has been reported that pancreatitis occurs in people whose triglyceride levels are above 1000 mg/dl or 12 .

Meanwhile, the compound of the following formula 1, whose chemical name is (4S,5R)—5—[3,5—bis(trifluoromethyl)pheny1]—3—({2—[4—fluoro—2—methoxy—5—(propan—2—yl) phenyl]—5—(trifluoromethyl)phenyl}methy1)—4—methy1—1,3—oxazolidin—2—one, has a selective cholesterol ester er protein (CETP) inhibiting activity. The compound is being developed as a drug for preventing or treating atherosclerosis (International Patent Publication No. ). <Formula 1> F s FF FF sure of Invention Technical m The present inventors performed various researches for developing a drug or a drug— combination capable of providing effective therapeutic efficacy against hypertriglyc— eridemia 0r hypertriglyceridemia—associated disease. Surprisingly, the present inventors found that co—administration of the compound of Formula 1 and a calcium channel blocker or a fibrate can remarkably inhibit the concentration of triglycerides in the blood, in comparison with the administration of the compound of Formula 1 alone. ore, it is an object of the present invention to provide a pharmaceutical com— position for preventing or treating hypertriglyceridemia 0r hypertriglyceridemia—as— sociated disease sing the compound of Formula 1 and a m l blocker or a fibrate as active ingredients.

Solution to Problem In accordance with an aspect of the present invention, there is provided a — ceutical composition for preventing or treating hypertriglyceridemia 0r hypertriglyc— eridemia—associated disease comprising a nd of Formula 1 or its pharma— ceutically acceptable salt; and a calcium channel blocker or a fibrate as active in— gredients: <F0rmula l> F s FF FF In the pharmaceutical composition of the present invention, the calcium channel blocker may be amlodipine or its salt. The e may be fenofibrate or its salt.

The ceutical composition of the present invention may be formulated into a dosage form for oral administration. The dosage form for oral stration may comprise the compound of Formula 1 or its pharmaceutically acceptable salt in an amount suitable for administering in a dose g from 10 to 300 mg/day; and/or the calcium channel blocker or the e in an amount suitable for administering in a dose ranging from 5 to 320 mg/day.

Advantageous Effects of Invention It is newly found by the present ion that co—administration of the compound of Formula 1 and a drug such as amlodipine, fenofibrate, etc. can remarkably inhibit the concentration of triglycerides in the blood, in comparison with the administration of the compound of Formula 1 alone. Therefore, the pharmaceutical composition of the present invention can be usefully applied for preventing or treating riglyc— eridemia or riglyceridemia—associated diseases.

Best Mode for Carrying out the Invention The present invention provides a pharmaceutical composition for preventing or treating hypertriglyceridemia or hypertriglyceridemia—associated disease comprising a compound of Formula 1 or its pharmaceutically acceptable salt; and a calcium channel r or a fibrate as active ingredients: <Formula l> FF FF As used herein, the term "hypertriglyceridemia—associated disease" refers to a disease originated from abnormally elevated level of the cerides in the blood. The hyper— ceridemia—associated disease includes combined ipidemia, atherosclerosis, and pancreatitis, but not d thereto. Examples of the hypertriglyceridemia—as— sociated disease include preferably combined hyperlipidemia and atherosclerosis, more preferably combined hyperlipidemia.

The compound of Formula 1 or its pharmaceutically acceptable salt may be prepared according to the disclosures in the International Publication No. .

The International Publication No. is incorporated into the present specification as a reference.

The calcium channel blocker (CCB) includes pine or its salt (e.g., besylate, mesylate, nate, camsylate, maleate, adipate, orotate, etc).

The "fibrate" refers to a 2—phenoxy—2—methylpropanoic acid derivative or its pharma— ceutically acceptable salt, as defined in U82008/0286354. The U82008/0286354 is in— corporated into the present specification as a nce. Examples of the fibrate include drugs such as fenofibrate, bezafibrate, ciprofibrate, vinifibrate, clinofibrate, clofibrate, pirifibrate, etofibrate; and pharmaceutically acceptable salts thereof, but not limited thereto. The fibrate may be preferably brate or its pharmaceutically acceptable salt.

The pharmaceutical composition of the present invention may be formulated into oral or parenteral dosage forms, preferably into a dosage form for oral stration. And also, the pharmaceutical composition of the t invention may have a form obtained by formulating the compound of Formula 1 and a calcium channel blocker or a fibrate into a single unit dosage form. Alternatively, the pharmaceutical ition of the present invention may have a form obtained by formulating the compound of Formula 1 and a m channel blocker or a fibrate into separate dosage forms and then packaging the resulting dosage forms in a single package unit.

The pharmaceutical composition for oral administration having one or two unit dosage form(s) may include a pharmaceutically acceptable carrier, for example, diluents, disintegrating agents, sweeteners, lubricants, and/or flavoring agents, and can be formulated according to conventional methods into tablets, capsules, powders, granules, suspensions, emulsions, syrups, etc. In the case of tablets for oral admin— istration, carriers such as lactose, corn starch, and lubricating agents, e.g. magnesium stearate, are conventionally used. In the case of capsules for oral administration, lactose and/or dried corn starch can be used as a diluent. When an aqueous suspension is required for oral stration, the active ingredient(s) may be combined with emulsifying and/or ding agents. If desired, certain sweetening and/or flavoring agents may be used. For the pharmaceutical composition for parenteral administration (for example, intramuscular, intraperitoneal, aneous and intravenous admin— istration) having one or two unit dosage form(s), e solutions of the active in— gredient are usually prepared, and the pH of the solutions should be suitably ed and buffered with an isotonic agent and/or a ing agent.

The compound of Formula 1 or its pharmaceutically acceptable salt contained in the ceutical composition of the present invention may be stered in a thera— ally effective amount ranging from about 10 mg per day to about 300 mg per day to a subject patient. And also, the calcium channel blocker or the fibrate may be ad— ministered in a therapeutically effective amount ranging from about 5 mg per day to about 320 mg per day to a subject patient. Of course, the dosages may be changed according to the patient's age, weight, susceptibility, symptom, etc. In an embodiment, the pharmaceutical composition of the present invention may be ated into a dosage form for oral administration. The dosage form for oral administration may comprise the nd of Formula 1 or its pharmaceutically acceptable salt in an amount suitable for administering in a dose ranging from 10 to 300 mg/day; and/or the calcium channel blocker or the fibrate in an amount suitable for administering in a dose ranging from 5 to 320 mg/day. Of course, the daily dose of the angiotensin II receptor r depends on the kinds thereof.

The present invention also es a use of active ients comprising the compound of Formula 1 (i.e., (4S,5R)—5—[3,5—bis(trifluoromethyl)phenyl]—3—({2—[4—fluoro—2—methoxy—5—(propan—2—yl) phenyl]—5—(trifluoromethyl)phenyl}methyl)—4—methyl—l,3—oxazolidin—2—one) or its phar— ically acceptable salt; and a m channel blocker or a fibrate for the man— ufacture of a medicament for preventing or treating hypertriglyceridemia or hyper— triglyceridemia—associated e. In the use of the present invention, the hypertriglyc— eridemia-associated disease includes combined hyperlipidemia, atherosclerosis and pancreatitis, but not limited thereto. es of the hypertriglyceridemia-associated disease e preferably combined hyperlipidemia and atherosclerosis, more preferably combined hyperlipidemia. In the use of the present invention, the calcium channel blocker may be ably amlodipine or its pharmaceutically acceptable salt; and the fibrate may be preferably fenofibrate or its pharmaceutically acceptable salt.

The present invention comprises, within its scope, a method for treating hypertriglyceridemia or hypertriglyceridemia-associated disease in a patient, which comprises stering a therapeutically effective amount of the compound of Formula 1 (i.e., (4S,5R)[3,5-bis(trifluoromethyl)phenyl]({2-[4-fluoromethoxy(propan yl)phenyl](trifluoromethyl)phenyl}methyl)methyl-1,3-oxazolidinone) or its pharmaceutically acceptable salt; and a therapeutically effective amount of a calcium channel blocker or a fibrate to the patient in need thereof. In the method for treating hypertriglyceridemia or hypertriglyceridemia-associated e of the present invention, the hypertriglyceridemia-associated disease includes combined hyperlipidemia, atherosclerosis and pancreatitis, but not limited thereto. Examples of the hypertriglyceridemia-associated disease include preferably combined hyperlipidemia and atherosclerosis, more preferably combined hyperlipidemia. In the method for treating riglyceridemia or hypertriglyceridemia-associated disease of the present invention, the calcium channel blocker may be preferably amlodipine or its pharmaceutically acceptable salt; and the fibrate may be ably fenofibrate or its pharmaceutically acceptable salt. [028a] In one broad format, there is provided use of active ingredients comprising a compound of a 1 or its pharmaceutically able salt and amlodipine or its salt or a fibrate as active ingredients for the cture of a medicament for preventing or ng riglyceridemia or hypertriglyceridemia-associated disease: <Formula 1> [028b] The present invention will be described in further detail with reference to the following examples. These es are for illustrative purposes only and are not ed to limit the scope of the present invention.

Example 1. Evaluation of triglyceride-inhibitory activities in hypercholesterolemia-induced animals (1) Test Method Male New Zealand White s were used as a test animal. All s, except for the G1 group animals (negative control group, n=4), were fed with an irradiation-sterilized hypercholesterolemia diet, i.e., DYET# 620007 (Purina # 5321 chow with 1% cholesterol, Dyets, Inc., Bethlehem, PA 18017), which was purchased from Central Lab. Animal Inc. In order to induce hypercholesterolemia, the animals were supplied with the diet for more than 8 weeks. After collecting the blood samples from the animals, serum biochemical es were performed thereon. Animals having total cholesterol levels of approximately 870 mg/dL were selected as a hypercholes— terolemia—induced animal. The test materials were dissolved in saline containing 0.5% carboxymethylcellulose sodium and 1% Tween 80 and then administered directly into the stomach using an oral syringe adapted with a latex er, once per day for 4 weeks. The test groups are as in the ing Table 1.

Table 1 [Table 1] Group Animal(nu Dose —_ose(mg/kg/day) /kg/day) _material material al E:II-_-_ “IiFormula 1Formula 1 (”I-“.3“Formula1 The blood samples were collected through the jugular vein, from the animals at the day initiating the hypercholesterolemia diet supply (i.e., before feeding), and from the animals (which were fasted for 12 to 16 hours before collecting the blood) at 2 weeks and at 4 weeks after initiating the administration of the test material(s). (2) Results The triglyceride concentrations in the hypercholesterolemia—induced animals as in the above are presented in the following Table 2. The values in Table 2 ent average triglyceride concentrations (mg/dL) of the respective group.

Table 2 [Table 2] 192.6 315.1 544.1 167.4 255.8 356.7 164.6 170.4 209.0 As shown in Table 2, when the compound of Formula 1 and/or amlodipine or fenofibrate were orally administered repeatedly for 4 weeks, the co—administration groups (G4 and G5) showed remarkably high triglyceride—inhibitory activities, in comparison with the group administered with the compound of a 1 alone (G3, 356.7 mg/dL at the 4 weeks after initiating the administration). Therefore, it is expected that the combination of the nd of Formula 1 and the m channel blocker or the fibrate such as amlodipine or brate can be usefully applied for preventing or treating hypertriglyceridemia or hypertriglyceridemia—associated diseases.

Example 2. Evaluation of triglyceride-inhibitory activities in hypertriglyc- eridemia and hypercholesterolemia-induced animals (1) Test Method Male New Zealand White rabbits were used as a test animal. All animals, except for the G1 group animals (negative l group), were fed with an irradiation—sterilized riglyceridemia and hypercholesterolemia diet, i.e., DYET# 621082 (Purina# 5321 chow with 0.5% cholesterol, 14% coconut oil & 2% e Dextrin, Dyets, Inc., Bethlehem, PA 18017), which was purchased from Saeronbio Inc. In order to induce hypertriglyceridemia and hypercholesterolemia, the animals were supplied with the diet for more than 4 weeks. After collecting the blood samples from the animals, serum biochemical es were performed thereon. Animals showing significant changes in total cholesterol levels and triglyceride levels were selected, in comparison with the non—treated control group. The selected s were divided into 4 groups on the basis of the total cholesterol levels and triglyceride levels, thereby all the groups having substantially equal average values in the total cholesterol levels and ceride levels. The test materials were dissolved in saline containing 0.5% carboxymethyl— cellulose sodium and 1% Tween 80 and then administered directly into the stomach using an oral syringe adapted with a latex catheter, once per day for 4 weeks. The test groups are as in the ing Table 3.

Table 3 [Table 3] (mL/kg/day) First material Second —SecondFirst material al I“_rnaterial __ G-__ __ Formula 1 -_ _- I-Compound of Amlodipine a 1 .- The blood samples were collected through the jugular vein, from the animals at the day initiating the administration of the test material(s) (i.e., at the time of group— dividing, 0 week), and from the animals (which were fasted for 12 to 16 hours before collecting the blood) at 4 weeks after initiating the administration of the test material(s) (n=4—7). (2) Results The triglyceride concentrations in the hypertriglyceridemia and hypercholes— terolemia—induced animals as in the above are presented in the following Table 4. The values in Table 4 ent average triglyceride concentrations (mg/dL) of the re— spective group.

Table 4 [Table 4] Percent inhibition of triglyceride in the blood (%) As shown in Table 4, when the compound of Formula 1 and/or pine were orally administered repeatedly for 4 weeks, the groups administered with the compound of Formula 1 alone (G3) or amlodipine alone (G4) respectively showed .2% and 17.9% inhibitions in the triglyceride levels, in comparison with the G2 group. However, the co—administration groups (G5) showed 33.1% inhibition in the triglyceride level in comparison with the G2 group. The triglyceride—inhibitory activity (i.e., 33.1% tion) of G5 was more potent in comparison with the sum of triglyceride—inhibitory activities of G3 and G4 (i.e., 28.1% tion). Therefore, it can be acknowledged that the combination of the compound of Formula 1 and the calcium channel blocker such as amlodipine provides synergistic effect in ting triglyceride levels.

Claims (6)

What is claimed is:

1. Use of active ingredients comprising a compound of a 1 or its pharmaceutically acceptable salt and amlodipine or its salt or a fibrate as active ingredients for the manufacture of a medicament for preventing or treating hypertriglyceridemia or hypertriglyceridemia-associated disease: <Formula 1>

2. The use according to claim 1, n the fibrate is fenofibrate or its salt.

3. The use according to claim 1 or claim 2, n the medicament is formulated into a dosage form for oral administration.

4. The use according to claim 3, wherein the dosage form for oral administration comprises the compound of Formula 1 or its pharmaceutically acceptable salt in an amount suitable for administering in a dose ranging from 10 to 300 mg/day.

5. The use according to claim 3, n the dosage form for oral administration comprises amlodipine or its salt or the fibrate in an amount suitable for administering in a dose ranging from 5 to 320 mg/day.

6. The use ing to any one of claims 1 to 5, wherein the hypertriglyceridemia-associated disease is combined hyperlipidemia, atherosclerosis, or pancreatitis. Daewoong Pharmaceutical Co., Ltd. By the patent attorneys for the applicant CULLENS