JPWO2006011495A1 - Treatment for hypercholesterolemia and / or hypertriglyceridemia - Google Patents

Abstract

The present invention provides a concomitant drug that can efficiently reduce both blood cholesterol and blood triglycerides at a low dose. The present invention relates to a therapeutic agent for hyperlipidemia and / or hypertriglyceridemia containing pitavastatin and fenofibrate as active ingredients. The present invention also relates to a preparation for a therapeutic agent for hyperlipidemia and / or a therapeutic agent for hypertriglyceridemia, comprising pitavastatin and fenofibrate as active ingredients.

Description

  The present invention relates to a therapeutic agent for hyperlipidemia and / or hypertriglyceridemia containing pitavastatin and fenofibrate as active ingredients, and a preparation thereof.

  Hyperlipidemia is a symptom in which lipoproteins in the blood are abnormally increased, and is strongly associated with diseases such as arteriosclerosis and myocardial infarction, so that treatment is considered important.

  Various drugs are used to treat hyperlipidemia, and statins such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin, etc. are the main therapeutic agents ing.

  The main components of blood lipoproteins are cholesterol, triglycerides and the like, and patients with hyperlipidemia are often accompanied by an increase in blood triglycerides as well as an increase in blood cholesterol. When an HMG-CoA reductase inhibitor is administered to a hyperlipidemic patient, blood cholesterol is lowered, but the blood triglyceride lowering action is not sufficient. In hyperlipidemic patients with high blood cholesterol and blood triglycerides, in order to sufficiently reduce both, the method of increasing the dose of HMG-CoA reductase inhibitor is a safety issue. Not recommended.

  A combination of HMG-CoA reductase inhibitor and a fibric acid derivative typified by fenofibrate has been reported to hyperlipidemic patients with high levels of both blood cholesterol and blood triglycerides. Yes.

  Fenofibrate (2- [4- (4-chlorobenzoyl) phenoxy] -2-methylpropionic acid (1-methylethyl)) is a fibrate antihyperlipidemic agent and is used in blood cholesterol and blood It has an action of lowering triglycerides, and its blood triglyceride lowering action is known to be strong (see Non-Patent Document 1).

  Further, 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 is supposed to enhance the blood triglyceride lowering action additively. Non-Patent Document 2 states that blood triglyceride lowering action is additively enhanced by the combined use of atorvastatin and fenofibrate in diabetic patients.

  As described above, various combinations of HMG-CoA reductase inhibitors and fibrate drugs have been studied. Particularly, hyperlipidemia patients with hypertriglyceridemia are desired to be administered in combination with both drugs. Yes.

US Pat. No. 6511985 New Current, 7 (6), 9-19 (1996) Diabetes Care, 25, 1198-1202 (2002)

  The present invention provides a concomitant drug that can efficiently reduce both blood cholesterol and blood triglycerides.

  As a result of intensive studies in view of such circumstances, the present inventors have found that when pitavastatin and fenofibrate are used in combination, blood triglycerides are significantly and synergistically lower than both administrations alone.

  That is, the present invention relates to a therapeutic agent for hyperlipidemia or hypertriglyceridemia containing pitavastatin and fenofibrate as active ingredients, and hyperlipidemia and hypertriglyceridemia containing pitavastatin and fenofibrate as active ingredients. It relates to a therapeutic agent.

  The present invention also provides a preparation for treating hyperlipidemia or therapeutic agent for hypertriglyceridemia containing pitavastatin and fenofibrate as active ingredients, and a high preparation containing pitavastatin and fenofibrate as active ingredients. The present invention relates to a preparation for a therapeutic agent for lipemia and a therapeutic agent for hypertriglyceridemia.

  Furthermore, the present invention provides a pharmaceutical composition for treating hyperlipidemia and / or hypertriglyceridemia, comprising pitavastatin and fenofibrate, and a pharmaceutically acceptable carrier.

  The present invention also relates to prevention / treatment of hyperlipidemia and / or hypertriglyceridemia, comprising administering an effective amount of pitavastatin and fenofibrate to a patient with hyperlipidemia and / or hypertriglyceridemia. It provides a way to

  Furthermore, the present invention provides the use of pitavastatin and fenofibrate for the manufacture of a pharmaceutical composition for the treatment of hyperlipidemia and / or hypertriglyceridemia.

  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 type IIb and type IV hyperlipidemia.

  Pitavastatin ((3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] -3,5-dihydroxy-6-heptenoic acid) in the present invention is a strong HMG -It has been known that it has a CoA reductase inhibitory action and is useful as a therapeutic agent for hyperlipidemia (Japanese Patent No. 2567746, US Pat. No. 5,102,888, European Patent No. 304063). The pitavastatin in the present invention may be not only itself but also its salt such as calcium salt and sodium salt. The pitavastatin in the present invention may be in the form of a lactone or ring-opened form of pitavastatin, or may be a prodrug that can be a precursor of pitavastatin or a salt thereof. Furthermore, pitavastatin in the present invention may be a hydrate or pharmaceutically acceptable solvate thereof.

  Further, the fenofibrate in the present invention is not limited to itself, and may be a hydrate or a pharmaceutically acceptable solvate.

  The present invention relates to a therapeutic agent for hyperlipidemia or hypertriglyceridemia containing pitavastatin and fenofibrate as active ingredients, and a therapeutic agent for hyperlipidemia and hypertriglyceridemia containing pitavastatin and fenofibrate as active ingredients In the following, the therapeutic agent (including a prophylactic agent) of the present invention will be described as a “pharmaceutical composition”.

  The pharmaceutical composition of the present invention comprises pitavastatin and fenofibrate as active ingredients, but other drugs can be further used in combination as long as the effects and side effects of these drugs are not excessively affected.

  As used herein, “combination” refers to hyperlipidemia and / or hypertriglyceridemia patients, particularly hypertriglyceridemia, who are at risk of developing vascular events in blood vessels such as cardiovascular and cerebrovascular For the prevention and / or treatment of hyperlipidemia and / or hypertriglyceridemia in patients at extremely high risk of developing vascular events such as coronary artery disease. It means that fenofibrate is administered at the same time.

  As such administration means, not only a form in which both pitavastatin and fenofibrate are administered as one preparation, but also a form in which each preparation is separately administered at the same time may be employed. In the latter case, each drug is separately formulated and may be based on separate products. Moreover, both preparations can be combined into a kit to produce a product so that administration of both drugs at the same time can be performed more easily.

  In the present invention, by using both pitavastatin and fenofibrate “in combination”, it is possible to reduce the dosage of individual drugs as compared with the case where they are administered alone. Triglyceridemia can be efficiently prevented and treated. This can improve patient compliance. As long as the effects of the present invention can be exhibited, any formulation or product may be used.

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

  The dosage of the pharmaceutical composition of the present invention is selected as pitavastatin in the range of 0.1 to 50 mg per day for adults, usually 1 to 20 mg, and for fenofibrate in the range of 1 to 1000 mg per day for adults, usually 100 to 300 mg. Selected. However, this effective amount is not necessarily limited, and is determined by the attending physician depending on factors such as the age, weight, health status and symptoms of the patient.

  The pharmaceutical composition of the present invention can 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, emulsifiers and the like can be mentioned. The amount of these carriers to be 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.

  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, and the like can be formulated as necessary. These formulations can be prepared by conventional formulation techniques in pharmacy.

  Therefore, the present invention provides a preparation for a therapeutic agent for hyperlipidemia and / or a therapeutic agent for hypertriglyceridemia, which contains pitavastatin and fenofibrate as active ingredients, thus formulated. It is.

  The expression of drug efficacy in the combination of pitavastatin and fenofibrate, which is the drug of the present invention, is not found in the prior art, and the present inventors have found a synergistic effect for the first time. The present inventors examined the combined use of pitavastatin calcium salt and fenofibrate. As shown in the examples below, the details thereof are notable in the evaluation using rats, as shown in Table 1 and FIG. 1, compared with the case where pitavastatin calcium salt and fenofibrate were each administered alone. It had the effect of lowering blood triglycerides, and the effect was synergistic.

  That is, the reduction rate of blood triglycerides was 14.7% in the pitavastatin calcium salt single administration group and 23.8% in the fenofibrate single administration group, but pitavastatin calcium salt and fenofibrate were used in combination. The result was 37.3%, and there was a significant difference in the test of p <0.01. When this result is expressed as a relative index when the non-administration group is 1.0, the pitavastatin calcium salt single administration group is 0.853, the fenofibrate single administration group is 0.762, and the pitavastatin calcium salt When fenofibrate is used in combination, 0.627 is obtained. The relative index when administered in combination is the product of the relative indices of each group (see Bulge's formula (Keijiro Takagi et al., “Pharmacology”, Nanzando, published in 1987)), that is, 0.853 × 0. Since it was smaller than .762 = 0.650, it was determined that the combined administration had a synergistic effect.

  Therefore, it was found that the drug of the present invention is extremely effective not only for treatment of hyperlipidemia with pitavastatin but also for treatment of symptoms accompanied by a high triglyceride state by the combined use of both. Moreover, by using both together, a synergistic effect was observed, and it was possible to reduce the doses of pitavastatin and fenofibrate compared to the case of each drug alone.

  The present invention enhances the blood triglyceride-lowering effect of pitavastatin and enables treatment of hyperlipidemic patients with high blood cholesterol and triglycerides. That is, by using pitavastatin and fenofibrate in combination, it was found that there is a synergistic effect on the reduction of blood triglyceride, and treatment and prevention of hypertriglyceridemia as well as treatment and prevention of hyperlipidemia in a smaller amount The present invention provides a highly effective combination therapy of drugs and a preparation for the same.

FIG. 1 is a graph showing the effect of reducing blood triglycerides by the combined administration of pitavastatin calcium salt and fenofibrate. The vertical axis in FIG. 1 shows blood triglyceride concentration (mg / dL), and the horizontal axis shows the control, the pitavastatin calcium salt single administration group, the fenofibrate single administration group, and the combination administration group of both from the left.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited at all by these Examples.

  Decreased effect on blood triglycerides by combined administration of pitavastatin calcium salt and fenofibrate.

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, it was raised in a breeding room maintained at a temperature of 23 ± 3 ° C. and a humidity of 55 ± 15% during the light / dark cycle (bright period by room light: 7 am to 7 pm), and solid feed (CE-2; Nippon Claire Co., Ltd.) and tap water were given freely.

2. Preparation of drug Pitavastatin calcium salt and fenofibrate were suspended in a 0.5% mass aqueous solution of sodium carboxymethylcellulose (Iwai Chemicals Co., Ltd.) and the dosage was adjusted to 2 mL / kg. Since pitavastatin calcium salt contains 9.43% by mass of water, it was corrected by weighing 1.1 mass times the dose. The suspension was stored refrigerated (4 ° C.) in a light-shielding bottle, and preparation was performed every 7 days.

3. Test Method Thirty-two rats were divided into the following 4 groups (8 patients in each group), namely, a control group, a pitavastatin calcium salt alone (10 mg / kg) group, a fenofibrate alone (10 mg / kg) group, and a pitavastatin calcium salt (10 mg / kg). kg) and fenofibrate (10 mg / kg) combined groups were grouped so that blood total cholesterol and triglycerides were averaged. Both drugs were orally administered once a day (4 pm) for 14 days, and the control group was orally administered with 2 mL / kg of a 0.5% by weight aqueous solution of sodium carboxymethylcellulose. In any group, blood was collected after fasting for 18 hours from the final administration, and blood triglyceride concentration was measured.

4). Statistical analysis and data processing method Multi-group comparison between the control group and the drug administration group was performed using Bartlett's analysis of variance-Dunnett's multiple comparison test, and a risk rate of less than 5% was determined to be significant.

5. Test result It shows in the following Table 1 and FIG. The blood triglyceride reduction rate (%) is ((control blood triglyceride average value-blood triglyceride average value in each group) / (control group blood triglyceride average value)) x 100, and the relative index is ((each Group blood triglyceride average value) / (control group blood triglyceride average value))). Blood triglycerides tended to decrease in the pitavastatin calcium salt and fenofibrate alone group compared to the control group. On the other hand, in both drug combination groups, blood triglycerides significantly decreased and the action was synergistic (relative index of combination group (0.627) <product of relative index of each single administration group (0.853 × 0.762 = 0.650 (Bulge's formula (Keijiro Takagi et al .: Pharmacology, 1987, Nanzan-do))) (p <0.01).

Table 1 Effects of combined use with pitavastatin calcium salt and fenofibrate

  Thus, the combined use of both drugs confirmed a synergistic lowering effect on blood triglycerides, not only preventing and treating hyperlipidemia of pitavastatin, but also extremely effective prevention and treatment of hypertriglyceridemia at the same time. The therapeutic effect was confirmed.

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

Claims (5)

  A therapeutic agent for hyperlipidemia and / or hypertriglyceridemia, comprising pitavastatin and fenofibrate as active ingredients.   A pharmaceutical composition for the treatment of hyperlipidemia and / or hypertriglyceridemia, comprising pitavastatin and fenofibrate, and a pharmaceutically acceptable carrier.   A preparation for a therapeutic agent for hyperlipidemia and / or a therapeutic agent for hypertriglyceridemia, comprising pitavastatin and fenofibrate as active ingredients.   Use of pitavastatin and fenofibrate for the manufacture of a pharmaceutical composition for the treatment of hyperlipidemia and / or hypertriglyceridemia. A method for preventing or treating hyperlipidemia and / or hypertriglyceridemia, comprising administering an effective amount of pitavastatin and fenofibrate to a patient with hyperlipidemia and / or hypertriglyceridemia.

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