WO2006011495A1

WO2006011495A1 - Remedy for hypercholesterolemia and/or hypertriglyceridemia

Info

Publication number: WO2006011495A1
Application number: PCT/JP2005/013693
Authority: WO
Inventors: Taro Aoki; Junji Yamaguchi; Yusuke Sasaki
Original assignee: Kowa Company, Ltd.; Nissan Chemical Industries, Ltd.
Priority date: 2004-07-30
Filing date: 2005-07-27
Publication date: 2006-02-02
Also published as: JPWO2006011495A1

Abstract

It is intended to provide a combined drug capable of efficiently lowering both of blood cholesterol level and blood triglyceride level in a small dose. Namely, a remedy for hyperlipidemia and/or hypertriglyceridemia which comprises pitavastatin and fenofibrate as the active ingredients; and a preparation to be used as a remedy for hypdrlipidemia and/or a remedy for hypertriglyceridemia which contains pitavastatin and fenofibrate as the active ingredients.

Description

Specification

Treatment for hypercholesterolemia and z or hypertriglyceridemia

Technical field

[oooi] The present invention relates to a therapeutic agent for hyperlipidemia and Z or hypertriglyceridemia containing pitapastatin and fenofibrate as active ingredients, and a preparation thereof.

Background art

[0002] Hyperlipidemia is a symptom in which lipoproteins in the blood are abnormally increased and is strongly related to diseases such as arteriosclerosis and myocardial infarction. Being

[0003] Various drugs are used for the treatment of hyperlipidemia. Currently, statin-type HMG-CoA reductase inhibitors such as oral pastatin, simpastatin, pravastatin, flupastatin, atorvastatin, rospastatin, pitapastatin, etc. It is the center of the therapeutic agent.

[0004] The main components of blood lipoproteins are cholesterol triglycerides and the like, and hyperlipidemia patients not only have an increase in blood cholesterol but may also have an increase in blood triglycerides. Many. When HMG-CoA reductase inhibitor is administered to hyperlipidemic patients, blood cholesterol can be lowered.

. In hyperlipidemic patients with high levels of both blood cholesterol and blood triglycerides, increasing the dose of HMG-CoA reductase inhibitor to treat both sufficiently is a safety issue. Etc. Not recommended.

[0005] For patients with hyperlipidemia who have high blood cholesterol and blood triglycerides, HMG—CoA reductase inhibitor and fibric acid derivative represented by fenofibrate This combination has been reported.

[0006] Phenofibrate (2- [4 benzoyl) phenoxy] 2-methylpropionic acid (1-methylethyl) is a fibrate antihyperlipidemic agent, and blood cholesterol And has an action of lowering blood triglyceride, and its blood triglyceride lowering action is known to be strong (see Non-patent Document 1).

[0007] In addition, Patent Document 1 describes a specific test example in humans regarding the combined use of cerivastatin and fenofibrate, but the combined use of both drugs reduces blood triglycerides. The effect is said to be additively enhanced. Non-Patent Document 2 states that blood glyceride lowering action is additively enhanced by the combined use of atorvastatin and fenofibrate in diabetic patients.

[0008] As described above, various combinations of HMG-CoA reductase inhibitors and fibrates have been studied, and in particular, both drugs are administered to hyperlipidemic patients with hypertriglyceridemia. Is desired.

Patent Document 1: US Pat. No. 6511985

Non-Patent Document 1: New Current, 7 (6), 9 19 (1996)

Non-Patent Document 2: Diabetes Care, 25, 1198-1202 (2002)

Disclosure of the invention

Problems to be solved by the invention

[0010] The present invention provides a concomitant drug capable of efficiently reducing both blood cholesterol and blood triglycerides.

Means for solving the problem

[0011] As a result of intensive studies in view of such circumstances, the present inventors have found that the combined use of pitapastatin and fenofibrate significantly and synergistically lowers blood triglycerides compared to both administrations alone. It was.

That is, the present invention provides a therapeutic agent for hyperlipidemia or hypertriglyceridemia containing pitapastatin and fenofibrate as active ingredients, and a high fat composition containing pitapastatin and fenofibrate as active ingredients. The present invention relates to a therapeutic agent for blood glucose and hypertriglyceridemia.

[0013] Further, the present invention relates to a preparation for a therapeutic agent for hyperlipidemia or a therapeutic agent for hypertriglyceridemia, comprising pitapastatin and fenofibrate as active ingredients, and pitavastatin and fenofib. The present invention relates to a preparation for a therapeutic agent for hyperlipidemia and a therapeutic agent for hypertriglyceridemia comprising lato as an active ingredient.

[0014] Furthermore, the present invention provides a pharmaceutical thread and composition for the treatment of hyperlipidemia and Z or hypertriglyceridemia, comprising pitapastatin and fenofibrate, and a pharmaceutically acceptable carrier. Is to provide.

[0015] The present invention also provides a method for treating patients with hyperlipidemia and Z or hypertriglyceridemia. Provides a method for the prevention and treatment of hyperlipidemia and z or hypertriglyceridemia, comprising administering an effective amount of phenone and fenofibrate.

[0016] Furthermore, the present invention provides the use of pitapastatin and fenofibrate for the manufacture of a pharmaceutical composition for the treatment of hyperlipidemia and Z or hypertriglyceridemia.

[0017] The hyperlipidemic agent of the present invention is excellent in the effect of lowering blood cholesterol and blood triglycerides, and is also effective in the treatment of lib type and type IV hyperlipidemia.

[0018] Pitapastatin ((3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenol) -3-quinolyl]-3,5-dihydroxy-6-heptenoic acid in the present invention ) Has a strong V, HMG-CoA reductase inhibitory action and is known to be useful as a therapeutic agent for hyperlipidemia (Japanese Patent No. 2569746, US Patent No. 5102888, European Patent) No. 304063). Pitapastatin in the present invention may be a salt such as calcium salt and sodium salt as well as itself. The pitapastatin in the present invention may be in the form of a pitanostatin latatotone or ring-opened form, or may be a prodrug or a salt thereof that can be a precursor of pitapastatin. Furthermore, the pitapastatin in the present invention may be a hydrate or a solvate acceptable as a pharmaceutical product.

[0019] The fenofibrate in the present invention may be a hydrate or a pharmaceutically acceptable solvate as well as itself.

[0020] The present invention relates to a therapeutic agent for hyperlipidemia or hypertriglyceridemia containing pitapastatin and funofibrate as active ingredients, and hyperlipidemia containing pitapastatin and fenofibrate as active ingredients, and In the following, the therapeutic agents (including prophylactic agents) of the present invention will be described as “pharmaceutical compositions”.

[0021] The pharmaceutical composition of the present invention comprises pitapastatin and fenofibrate as active ingredients, but other drugs are further added within a range that does not excessively affect the action and side effects of these drugs. Can be used together.

[0022] As used herein, "combination" refers to hyperlipidemia and Z or hypertriglyceridemia patients who are at risk of developing vascular events in blood vessels such as cardiovascular and cerebrovascular. Above all Hyperlipidemic patients with hypertriglyceridemia are used to prevent and / or treat hyperlipidemia and Z or hypertriglyceridemia in patients at extremely high risk of developing vascular events such as coronary artery disease. Mean that pitapastatin and fenofibrate are administered at the same time.

[0023] Such administration means may include not only a form in which both pitapastatin and fenofibrate are administered as a single preparation, but also a form in which each preparation is administered separately at the same time. In the latter case, each drug is formulated separately and may be from separate products. In addition, in order to make it easier to administer both drugs at the same time, they can be combined into a kit to produce a product.

[0024] The present invention can reduce the dose of each drug by using both "pitapastatin" and "fenofibrate" "in combination" as compared with the case where they are administered alone. It can effectively prevent and treat hyperlipidemia and Z or hypertriglyceridemia. This can improve patient compliance. As long as the effects of the present invention can be exhibited, any formulation or product may be used.

[0025] The pharmaceutical composition of the present invention may be in a dosage form once a day, or in divided dosage forms 2-6 times a day, preferably 3 times a day. Which dosage form is to be used can be appropriately determined according to the patient's condition and symptoms.

[0026] The dosage of the pharmaceutical composition of the present invention is selected as pitanostatin in the range of 0.1 to 50 mg per day for adults, usually 1 to 20 mg, and 1 to 10 mg per day for adults as fenofibrate. Usually, it is selected in the range of 100 to 300 mg. However, this effective amount is not necessarily limited and will be determined by the attending physician depending on factors such as the patient's age, weight, health status and symptoms.

[0027] The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier. Such pharmaceutically acceptable carriers include various known excipients, binders (eg, starch), disintegrants, buffers, preservatives, antioxidants, lubricants, fragrances, thickeners. , Coloring agents, milking agents and the like. The amount of these carriers added is preferably selected in the range of about 0.1 to about 95% by weight and about 10 to 90% by weight of the total weight of the pharmaceutical composition of the present invention. [0028] The pharmaceutical composition of the present invention can be formulated into various dosage forms for oral administration and parenteral administration. For example, capsules, tablets, powders, suspensions, solutions, etc. can be formulated as needed. These preparations can be prepared by conventional preparation techniques in pharmacy.

[0029] Therefore, the present invention provides a pharmaceutical preparation for hyperlipidemia and a therapeutic agent for Z or hypertriglyceridemia comprising pitapastatin and fenofibrate as active ingredients, thus formulated. Is to provide.

[0030] With regard to the expression of a drug effect in the combination of pitapastatin and fenofibrate, which is the drug of the present invention, the present inventors have found a synergistic effect for the first time in comparison with the prior art. The present inventors examined the combined use of pitapastatin calcium salt and fenofibrate. As shown in the examples below, the details are as follows. In the evaluation using rats, as shown in Table 1 and FIG. 1, compared with the case where pitapastatin calcium salt and fenofibrate were each administered alone, It had the effect of significantly lowering blood triglycerides, and the effect was synergistic.

[0031] That is, the rate of decrease in blood triglyceride was 14.7% in the group administered with pitapastatin calcium salt alone, and 23.8% in the group administered with fenofibrate alone, whereas it was 23.8%. When salt and fenofibrate were used in combination, it was 37.3%, and there was a significant difference in the p <0.01 test. When this result is expressed as a relative index when the non-administration group is 1.0, the pitapastatin calcium salt single administration group is 0.853, the fenofibrate single administration group is 0.762, and pitapastatin When calcium salt and fenofibrate are used in combination, it is 0.627. Relative index force when administered in combination The product of the relative indices of each group in the single administration group (see Bulge's formula (Keijiro Takagi et al., “Pharmacology”, published by Nanzan Hall, 1987)), Good! ] 0.853x0. 762 = 0. 650 / J, which was determined to be a synergistic effect by concomitant administration.

[0032] Therefore, it has been found that the drug of the present invention is extremely effective in the treatment of symptoms accompanied by a high triglyceride state by the combined use of not only the treatment of hyperlipidemia with pitapastatin. In addition, by using both in combination, there is a synergistic effect, and the doses of pitapastatin and fenofibrate can be reduced compared to each drug alone. became.

The invention's effect

[0033] The present invention enhances the blood triglyceride-lowering action of pitapastatin and enables treatment of hyperlipidemic patients with high levels of both blood cholesterol and triglycerides. In other words, the combined use of pitapastatin and fenofibrate has been found to have a synergistic effect on the reduction of blood tridalylide, and in a smaller amount, not only treatment and prevention of hyperlipidemia but also hypertriglyceridemia Therefore, the present invention provides a combination therapy of extremely effective drugs and a preparation for the same.

Brief Description of Drawings

[0034] FIG. 1 is a graph showing the effect of reducing blood triglycerides by the combined administration of pitapastatin calcium salt and fenofibrate. The vertical axis in FIG. 1 shows blood triglyceride concentration (mgZ dL), and the horizontal axis shows, from the left, the control, the pitanostatin calcium salt alone administration group, the fenofibrate alone administration group, and the combination administration group of both.

[0035] Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Example 1

[0036] A lowering effect on blood triglycerides by the combined administration of pitapastatin calcium salt and fenofibrate.

[0037] 1. Test animals and rearing environment

Wistar male rats (Nippon Medical Science Experimental Animal Co., Ltd.) 6 weeks old were used. Throughout the experimental period, the light-dark cycle (bright period with room light: 7 am to 7 pm), temperature 23 ± 3 ° C, humidity 55 persons, maintained at 15%, solid feed (CE— 2; Nippon Claire Co., Ltd.) and tap water were given freely.

[0038] 2. Preparation of drug

Pitapastatin calcium salt and fenofibrate were suspended in a 0.5% mass aqueous solution of carboxymethyl cellulose sodium (Iwai Chemicals Co., Ltd.) and the dosage was adjusted to 2 mL / kg. Since pitapastatin calcium salt contains 9.43% by mass of water, 1.1 mass times the dose was weighed and corrected. Store the suspension in a light-shielding bottle in a refrigerator (4 ° C). Production was carried out every 7 days.

[0039] 3. Test method

32 rats were divided into the following 4 groups (8 patients in each group): control group, pitapastatin calcium salt alone (10 mg / kg) group, fenofibrate alone (10 mg / kg) group, and pitapastatin strength lucum salt (1 Omg / kg) and fenofibrate (1 Omg / kg) combined groups were grouped so that total cholesterol and triglycerides were averaged. Both drugs were orally administered once a day (4 pm) repeatedly for 14 days, and the control group was orally administered 2 mL / kg of a 0.5% by weight aqueous solution of sodium carboxymethylcellulose. In all groups, blood was collected after fasting for 18 hours from the final administration, and blood triglyceride concentration was measured.

[0040] 4. Statistical analysis and data processing methods

A multigroup comparison between the control group and the drug-administered group was performed using Bartlett's analysis of variance—Dmrnett's multiple comparison test, and a risk rate of less than 5% was determined to be significant.

[0041] 5. Test results

It is shown in Table 1 and Figure 1 below. The blood triglyceride reduction rate (%) is ((control blood triglyceride average value in each group blood triglyceride average value) / (control group blood triglyceride average value)) X 100, relative index is ((each Mean blood triglyceride value) Z (control blood triglyceride average value))). Blood triglycerides tended to decrease in the pitapastatin calcium salt and fenofibrate alone group compared to the control group. On the other hand, blood triglycerides were significantly decreased in both drug groups, and their effects were synergistic (relative index in combination group (0.627) and product of relative index in each single administration group (0. 853 X 0. 762 = 0. 650 (Bulge's formula (Keijiro Takagi et al .: Pharmacology, 1987, Nanzan-do))) (p <0. 01).

[0042] Table 1 Effect of combined use with pitano-statin calcium salt and fenofibrate

[table 1]

[0043] Thus, the combined use of both drugs confirmed a synergistic blood triglyceride lowering effect. In addition to the preventive and therapeutic effects of pitapastatin on hyperlipidemia, it was confirmed that it was extremely effective in preventing and treating hypertriglyceridemia.

Industrial applicability

The present invention provides a therapeutic agent for hyperlipidemia and Z or hypertriglyceridemia containing pitapastatin and fenofibrate as active ingredients, and a preparation for the same. In addition to hyperlipidemia, hypertriglyceridemia can be treated or prevented at the same time, and the use of both can be reduced by the synergistic effect of the combination of both. is there. Therefore, the present invention is extremely useful not only in the medical field but also in the pharmaceutical field and has industrial applicability.

Claims

The scope of the claims

[1] A therapeutic agent for hyperlipidemia and Z or hypertriglyceridemia, comprising pitapastatin and fenofibrate as active ingredients.

[2] A pharmaceutical thread composition for the treatment of hyperlipidemia and Z or hypertriglyceridemia, comprising pitapastatin and fenofibrate, and a pharmaceutically acceptable carrier.

[3] A preparation for treating hyperlipidemia and for treating Z or hypertriglyceridemia, comprising pitapastatin and fenofibrate as active ingredients.

[4] Use of pitapastatin and fenofibrate for the manufacture of a pharmaceutical composition for the treatment of hyperlipidemia and Z or hypertriglyceridemia.

[5] A method for the prevention and treatment of hyperlipidemia and Z or hypertriglyceridemia comprising administering an effective amount of pitapastatin and fenofibrate to a patient with hyperlipidemia and Z or hypertriglyceridemia .