US20060046996A1 - Method for treating hyperlipidemia - Google Patents

Method for treating hyperlipidemia Download PDF

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Publication number
US20060046996A1
US20060046996A1 US10/997,878 US99787804A US2006046996A1 US 20060046996 A1 US20060046996 A1 US 20060046996A1 US 99787804 A US99787804 A US 99787804A US 2006046996 A1 US2006046996 A1 US 2006046996A1
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Prior art keywords
ezetimibe
pitavastatin
blood cholesterol
group
cholesterol level
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US10/997,878
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Taro Aoki
Hiroyuki Yamazaki
Takashi Maejima
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Kowa Co Ltd
Nissan Chemical Corp
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Kowa Co Ltd
Nissan Chemical Corp
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Application filed by Kowa Co Ltd, Nissan Chemical Corp filed Critical Kowa Co Ltd
Priority to US10/997,878 priority Critical patent/US20060046996A1/en
Assigned to KOWA CO., LTD., NISSAN CHEMICAL INDUSTRIES, LTD. reassignment KOWA CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MAEJIMA, TAKASHI, AOKI, TARO, YAMAZAKI, HIROYUKI
Priority to PT05777087T priority patent/PT1785137E/en
Priority to ES05777087T priority patent/ES2354366T3/en
Priority to KR1020077001596A priority patent/KR101244508B1/en
Priority to AT05777087T priority patent/ATE489093T1/en
Priority to CN2005800291311A priority patent/CN101010080B/en
Priority to DE602005024981T priority patent/DE602005024981D1/en
Priority to PCT/JP2005/015756 priority patent/WO2006025378A1/en
Priority to EP05777087A priority patent/EP1785137B1/en
Priority to JP2006532716A priority patent/JP4886516B2/en
Priority to PL05777087T priority patent/PL1785137T3/en
Publication of US20060046996A1 publication Critical patent/US20060046996A1/en
Priority to US11/546,248 priority patent/US7459447B2/en
Priority to HK08100666.5A priority patent/HK1110200A1/en
Priority to CY20111100106T priority patent/CY1111150T1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a method for treating hyperlipidemia, which exhibits an excellent blood cholesterol-lowering action.
  • Hyperlipidemia is a symptom characterized by the abnormal elevation of lipoprotein levels in blood, particularly cholesterol levels in blood. Hyperlipidemia is known to be closely linked to diseases such as arteriosclerosis and myocardial infarction and its treatment is considered extremely important.
  • HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin are most commonly used for its treatment.
  • pitavastatin ((3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid) is known to exhibit a potent HMG-CoA reductase inhibitory action and therefore be useful as an antihyperlipidemic agent (Japanese Patent No. 2569746, U.S. Pat. No. 5,102,888, EP No. 304063).
  • the blood cholesterol level of patients with hyperlipidemia is lowered by the administration of an HMG-CoA reductase inhibitor.
  • Many patients suffering from hyperlipidemia have a higher blood cholesterol level and their blood cholesterol level is not always possible to fully be lowered by the administration of an HMG-CoA reductase inhibitor. In such a case, treatment with an increased dose of an HMG-CoA reductase inhibitor is not advisable from the viewpoint of safety.
  • ezetimibe ((3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone) is known as an antihyperlipidemic agent which inhibits absorption of diet-induced and bile-acid-induced cholesterol in the intestinal tract, thus lowering the blood cholesterol level by a mechanism different from that of the HMG-CoA reductase inhibitor (WO95/08532).
  • An object of the present invention is to provide a method for treating hyperlipidemia and hypercholesterolemia, which has an excellent blood cholesterol lowering action.
  • the present inventors have carried out an extensive investigation, and found that the concomitant use of pitavastatin and ezetimibe brings about a remarkably excellent blood cholesterol level lowering action, so it is very useful for the treatment of hyperlipidemia and hypercholesterolemia.
  • the present invention has been accomplished.
  • a method for treating hyperlipidemia which comprises administering effective doses of ezetimibe and pitavastatin or a salt or lactone derivative thereof.
  • a method for treating hypercholesterolemia which comprises administering effective doses of ezetimibe and pitavastatin or a salt or lactone derivative thereof.
  • the methods for treating hyperlipidemia and hypercholesterolemia according to the present invention are effective for the treatment of hyperlipidemia and hypercholesterolemia in that these exhibit excellent action in lowering blood cholesterol level.
  • FIG. 1 is a graph showing the blood cholesterol level lowering action brought about by the concomitant use of a calcium salt of pitavastatin and ezetimibe;
  • FIG. 2 is a graph showing the blood cholesterol level lowering action brought about by the concomitant use of a calcium salt of atorvastatin and ezetimibe.
  • Pitavastatin, or salt or lactone derivative thereof (which may hereinafter be called “pitavastatin derivative”) to be used in the invention has cholesterol synthesis inhibitory activity based on HMG-CoA reductase inhibition and is known as an antihyperlipidemic agent.
  • pitavastatin derivatives salts of pitavastatin are preferred, with calcium salt and sodium salt being especially preferred.
  • Ezetimibe to be used in the invention is known as a medicament exhibiting its effects by inhibiting the cholesterol absorption in the intestine.
  • treatment is performed by the coadministration of a pitavastatin derivative and ezetimibe.
  • a pitavastatin derivative and ezetimibe In the evaluation system using guinea pigs, as will be described later in Examples, the blood cholesterol level is lowered significantly by the concomitant use of the pitavastatin derivative and ezetimibe compared with the single administration of each of them.
  • the dosage form of the pitavastatin derivative and ezetimibe can be selected arbitrarily depending on the purpose of the treatment. Any one of powders, granules, dry syrups, tablets, capsules and injections can be used. Such a dosage form can be prepared by incorporating a pharmaceutically acceptable carrier in the pitavastatin derivative and ezetimibe and adopting a formulation method well known and commonly used in the art.
  • An orally administrable solid preparation can be obtained by adding an excipient and optionally, a binder, a disintegrant, a lubricant, a coloring agent, a taste corrigent, a smell corrigent and the like, and processing the resulting mixture into tablets, granules, powders or capsules in a conventional manner.
  • an additive those ordinarily accepted in this field can be used.
  • examples of the excipient include lactose, sodium chloride, glucose, starch, microcrystalline cellulose, and silicic acid;
  • examples of the binder include water, ethanol, propanol, simple syrup, liquefied gelatin, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, and polyvinylpyrrolidone;
  • examples of the disintegrant include agar powder, sodium hydrogencarbonate, sodium lauryl sulfate, and stearic monoglyceride;
  • examples of the lubricant include purified talc, stearate salt, borax, and polyethylene glycol;
  • examples of the coloring agent include ⁇ -carotene, yellow iron sesquioxide, and caramel; and examples of the taste corrigent include sucrose and orange peel.
  • An orally administrable liquid preparation can be obtained by adding a taste corrigent, a buffer, a stabilizer, a preservative and the like and processing the resulting mixture into an internal medicine, syrup, or elixir in a conventional manner.
  • a taste corrigent include sucrose
  • examples of the buffer include sodium citrate
  • examples of the stabilizer include tragacanth
  • examples of the preservative include paraoxybenzoate ester.
  • An injection can be obtained by adding a pH regulator, a stabilizer, or an isotonizing agent, and processing the resulting mixture into a subcutaneous injection, an intramuscular injection, or an intravenous injection in a conventional manner.
  • a pH regulator include sodium phosphate
  • examples of the stabilizer include sodium pyrosulfite
  • examples of the isotonizing agent include sodium chloride.
  • the two medicaments may be administered at certain intervals.
  • the pitavastatin derivative and ezetimibe may be formulated into one medicament or they may be formulated into respective medicaments but provided as a set.
  • their dosage forms are not necessarily the same.
  • the dosage of these medicaments in the treatment method of the invention is selected arbitrarily depending on the condition of the patient.
  • the pitavastatin derivative may be administered in an amount of from 0.1 to 50 mg, preferably from 1 to 20 mg a day, while ezetimibe may be administered in an amount of from 0.1 to 500 mg, preferably from 1 to 100 mg a day.
  • the administration may be performed once a day or plural times a day.
  • the blood cholesterol level lowering effect when a calcium salt of pitavastatin and ezetimibe were coadministered was measured by the below-described testing method.
  • a calcium salt of atorvastatin was used instead of the calcium salt of pitavastatin and the effect brought about by the concomitant use of two medicaments was measured in a similar manner.
  • Treatment method The calcium salt of pitavastatin and ezetimibe were suspended in a 0.5 wt. % aqueous solution of carboxymethylcellulose sodium (product of Iwai Chemicals Company) and their concentrations were adjusted to 1 mg/mL and 3 mg/mL, respectively. Since the calcium salt of pitavastatin contained 9.43 wt. % of water, 1.1 times the weight of the dosage was weighed for correction. The suspension was refrigerated (4° C.) in a light resistant bottle and adjustment was conducted every 7 days.
  • Treatment method for comparison In a similar manner to that described above except the use of the calcium salt of atorvastatin instead of the calcium salt of pitavastatin, a calcium salt of atorvastatin for comparison test was prepared.
  • the treatment method according to the present invention Twenty four guinea pigs were classified into four groups (each consisting of 6 guinea pigs), that is, a control group, a single administration group of pitavastatin calcium salt (1 mg/kg), a single administration group of ezetimibe (3 mg/kg), and a coadministration group of pitavastatin calcium salt (1 mg/kg) and ezetimibe (3 mg/kg) so that they differ little in the total blood cholesterol level and blood triglyceride level. These two medicaments were each administered at a dose of 1 mL/kg once a day and this administration was repeated for 14 days. To the control group, a 0.5 wt. % aqueous solution (1 mL/kg) of carboxymethylcellulose sodium was orally administered. In each group, the guinea pigs were fasted for 18 hours after the final administration and then the blood was collected from them to measure the blood cholesterol level.
  • Treatment method for comparison twenty four guinea pigs were tested in a similar manner to the method according to the invention.
  • the dosage of the calcium salt of atorvastatin was 5 mg/kg in each of the group nourished by the single use of atorvastatin calcium salt and the group nourished by the concomitant use of atorvastatin calcium salt and ezetimibe.
  • Multigroup comparison between the control group and the medicament administered group was performed using Bartlett's variance analysis ⁇ Dunnett's multiple comparative assay. A difference with a significance level less than 5% was regarded as significant.
  • a reduction ratio (%) is a value represented by ((total blood cholesterol level of control group on average ⁇ total blood cholesterol level of each group on average)/(total blood cholesterol level of control group on average)) ⁇ 100, while a relative index is a value represented by (total blood cholesterol level of each group on average)/(total blood cholesterol level of control group on average).
  • TABLE 1 Reduction ratio (%) of blood cholesterol level Reduction Relative Administered group ratio index Control group 0 1.0 Group of the single use of ezetimibe 21 0.79 Group of the single use of pitavastatin Ca 29 0.71 Group of the concomitant use of pitavastatin 51 0.49 Ca/ezetimibe
  • the blood cholesterol level lowering action was enhanced greatly (p ⁇ 0.001) compared with that of the group of the single use of each medicament. Its effect was synergistic (relative index of the group of concomitant use (0.49) ⁇ product (0.56) of relative indices of the groups of single use).
  • the blood cholesterol level lowering action of the group of the concomitant use of atorvastatin calcium salt and ezetimibe was enhanced compared with that of each of the groups of single use, but its effect was additive (relative index (0.74) of the group of concomitant use (0.74)>product (0.62) of refractive indices of the groups of single use).
  • the concomitant use of the pitavastatin calcium salt and ezetimibe according to the invention has a remarkable blood cholesterol level lowering effect, compared with that of the concomitant use of another HMG-CoA reductase inhibitor and ezetimibe.

Abstract

Provided is a method for treating hyperlipidemia or hypercholesterolemia, which comprises administering effective doses of ezetimibe and pitavastatin or a salt or lactone derivative thereof.

Description

    TECHNICAL FIELD
  • The present invention relates to a method for treating hyperlipidemia, which exhibits an excellent blood cholesterol-lowering action.
    • BACKGROUND ART
  • Hyperlipidemia is a symptom characterized by the abnormal elevation of lipoprotein levels in blood, particularly cholesterol levels in blood. Hyperlipidemia is known to be closely linked to diseases such as arteriosclerosis and myocardial infarction and its treatment is considered extremely important.
  • There are a variety of drugs available for the treatment hyperlipidemia or hypercholesterolemia. At present, HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin are most commonly used for its treatment. Of these, pitavastatin ((3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid) is known to exhibit a potent HMG-CoA reductase inhibitory action and therefore be useful as an antihyperlipidemic agent (Japanese Patent No. 2569746, U.S. Pat. No. 5,102,888, EP No. 304063).
  • The blood cholesterol level of patients with hyperlipidemia is lowered by the administration of an HMG-CoA reductase inhibitor. Many patients suffering from hyperlipidemia have a higher blood cholesterol level and their blood cholesterol level is not always possible to fully be lowered by the administration of an HMG-CoA reductase inhibitor. In such a case, treatment with an increased dose of an HMG-CoA reductase inhibitor is not advisable from the viewpoint of safety.
  • On the other hand, ezetimibe ((3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone) is known as an antihyperlipidemic agent which inhibits absorption of diet-induced and bile-acid-induced cholesterol in the intestinal tract, thus lowering the blood cholesterol level by a mechanism different from that of the HMG-CoA reductase inhibitor (WO95/08532).
  • The concomitant use of an HMG-CoA reductase inhibitor and ezetimibe was disclosed to be effective for lowering the blood cholesterol level and treatment of atherosclerosis (WO95/08532). The blood cholesterol level lowering action by the coadministration of an HMG-CoA reductase inhibitor and ezetimibe was also reported (Metab. Clin. Exp., 50(10), 1234-1241 (2001)).
  • The effect brought about by the concomitant use of pitavastatin and ezetimibe on the treatment of hyperlipidemia remains to be seen, however.
    • DISCLOSURE OF THE INVENTION
  • An object of the present invention is to provide a method for treating hyperlipidemia and hypercholesterolemia, which has an excellent blood cholesterol lowering action.
  • With the foregoing in view, the present inventors have carried out an extensive investigation, and found that the concomitant use of pitavastatin and ezetimibe brings about a remarkably excellent blood cholesterol level lowering action, so it is very useful for the treatment of hyperlipidemia and hypercholesterolemia. Thus the present invention has been accomplished.
  • In one aspect of the present invention, there is thus provided a method for treating hyperlipidemia, which comprises administering effective doses of ezetimibe and pitavastatin or a salt or lactone derivative thereof.
  • In another aspect of the present invention, there is also provided a method for treating hypercholesterolemia, which comprises administering effective doses of ezetimibe and pitavastatin or a salt or lactone derivative thereof.
  • The methods for treating hyperlipidemia and hypercholesterolemia according to the present invention are effective for the treatment of hyperlipidemia and hypercholesterolemia in that these exhibit excellent action in lowering blood cholesterol level.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a graph showing the blood cholesterol level lowering action brought about by the concomitant use of a calcium salt of pitavastatin and ezetimibe; and
  • FIG. 2 is a graph showing the blood cholesterol level lowering action brought about by the concomitant use of a calcium salt of atorvastatin and ezetimibe.
    • BEST MODE FOR CARRYING OUT THE INVENTION
  • Pitavastatin, or salt or lactone derivative thereof (which may hereinafter be called “pitavastatin derivative”) to be used in the invention has cholesterol synthesis inhibitory activity based on HMG-CoA reductase inhibition and is known as an antihyperlipidemic agent. Of the pitavastatin derivatives, salts of pitavastatin are preferred, with calcium salt and sodium salt being especially preferred.
  • Ezetimibe to be used in the invention is known as a medicament exhibiting its effects by inhibiting the cholesterol absorption in the intestine.
  • According to the present invention, treatment is performed by the coadministration of a pitavastatin derivative and ezetimibe. In the evaluation system using guinea pigs, as will be described later in Examples, the blood cholesterol level is lowered significantly by the concomitant use of the pitavastatin derivative and ezetimibe compared with the single administration of each of them.
  • In the treatment method of the invention, the dosage form of the pitavastatin derivative and ezetimibe can be selected arbitrarily depending on the purpose of the treatment. Any one of powders, granules, dry syrups, tablets, capsules and injections can be used. Such a dosage form can be prepared by incorporating a pharmaceutically acceptable carrier in the pitavastatin derivative and ezetimibe and adopting a formulation method well known and commonly used in the art.
  • An orally administrable solid preparation can be obtained by adding an excipient and optionally, a binder, a disintegrant, a lubricant, a coloring agent, a taste corrigent, a smell corrigent and the like, and processing the resulting mixture into tablets, granules, powders or capsules in a conventional manner. As such an additive, those ordinarily accepted in this field can be used. Examples of the excipient include lactose, sodium chloride, glucose, starch, microcrystalline cellulose, and silicic acid; examples of the binder include water, ethanol, propanol, simple syrup, liquefied gelatin, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, and polyvinylpyrrolidone; examples of the disintegrant include agar powder, sodium hydrogencarbonate, sodium lauryl sulfate, and stearic monoglyceride; examples of the lubricant include purified talc, stearate salt, borax, and polyethylene glycol; examples of the coloring agent include β-carotene, yellow iron sesquioxide, and caramel; and examples of the taste corrigent include sucrose and orange peel.
  • An orally administrable liquid preparation can be obtained by adding a taste corrigent, a buffer, a stabilizer, a preservative and the like and processing the resulting mixture into an internal medicine, syrup, or elixir in a conventional manner. As such an additive, those ordinarily accepted in this field can be used. Examples of the taste corrigent include sucrose; examples of the buffer include sodium citrate; examples of the stabilizer include tragacanth; and examples of the preservative include paraoxybenzoate ester.
  • An injection can be obtained by adding a pH regulator, a stabilizer, or an isotonizing agent, and processing the resulting mixture into a subcutaneous injection, an intramuscular injection, or an intravenous injection in a conventional manner. As such an additive, those ordinarily accepted in this field can be used. Examples of the pH regulator include sodium phosphate; examples of the stabilizer include sodium pyrosulfite; and examples of the isotonizing agent include sodium chloride.
  • No particular limitation is imposed on the using manner of the medicaments in the treatment method of the present invention. Instead of the simultaneous administration, the two medicaments may be administered at certain intervals. In other words, the pitavastatin derivative and ezetimibe may be formulated into one medicament or they may be formulated into respective medicaments but provided as a set. When they are formulated into respective medicaments, their dosage forms are not necessarily the same.
  • The dosage of these medicaments in the treatment method of the invention is selected arbitrarily depending on the condition of the patient. The pitavastatin derivative may be administered in an amount of from 0.1 to 50 mg, preferably from 1 to 20 mg a day, while ezetimibe may be administered in an amount of from 0.1 to 500 mg, preferably from 1 to 100 mg a day. The administration may be performed once a day or plural times a day.
    • EXAMPLES
  • The present invention will next be described in more detail by Examples. It should be borne in mind that the present invention is not limited to or by them.
    • Example 1 Blood cholesterol Level Lowering Effect Brought About by the Concomitant use of pitavastatin calcium Salt and ezetimibe
  • The blood cholesterol level lowering effect when a calcium salt of pitavastatin and ezetimibe were coadministered was measured by the below-described testing method. For comparison, a calcium salt of atorvastatin was used instead of the calcium salt of pitavastatin and the effect brought about by the concomitant use of two medicaments was measured in a similar manner.
  • 1. Animals Provided for the Test and their Breeding Environment
  • Six-week-old Hartley male guinea pigs (purchased from Nippon SLC) were provided for the test. Throughout the test period, they were bred in a breeding room maintained at a light-dark cycle (a light term by a room light: from 7:00 am to 7:00 pm), a temperature of 23±3° C. and a humidity of 55±15% and fed with a solid feedstuff (“RC-4”, product of Oriental Yeast Industry) and tap water ad libitum.
  • 2. Preparation of Medicament
  • Treatment method according to the invention: The calcium salt of pitavastatin and ezetimibe were suspended in a 0.5 wt. % aqueous solution of carboxymethylcellulose sodium (product of Iwai Chemicals Company) and their concentrations were adjusted to 1 mg/mL and 3 mg/mL, respectively. Since the calcium salt of pitavastatin contained 9.43 wt. % of water, 1.1 times the weight of the dosage was weighed for correction. The suspension was refrigerated (4° C.) in a light resistant bottle and adjustment was conducted every 7 days.
  • Treatment method for comparison: In a similar manner to that described above except the use of the calcium salt of atorvastatin instead of the calcium salt of pitavastatin, a calcium salt of atorvastatin for comparison test was prepared.
  • 3. Testing Method
  • The treatment method according to the present invention: Twenty four guinea pigs were classified into four groups (each consisting of 6 guinea pigs), that is, a control group, a single administration group of pitavastatin calcium salt (1 mg/kg), a single administration group of ezetimibe (3 mg/kg), and a coadministration group of pitavastatin calcium salt (1 mg/kg) and ezetimibe (3 mg/kg) so that they differ little in the total blood cholesterol level and blood triglyceride level. These two medicaments were each administered at a dose of 1 mL/kg once a day and this administration was repeated for 14 days. To the control group, a 0.5 wt. % aqueous solution (1 mL/kg) of carboxymethylcellulose sodium was orally administered. In each group, the guinea pigs were fasted for 18 hours after the final administration and then the blood was collected from them to measure the blood cholesterol level.
  • Treatment method for comparison: twenty four guinea pigs were tested in a similar manner to the method according to the invention. The dosage of the calcium salt of atorvastatin was 5 mg/kg in each of the group nourished by the single use of atorvastatin calcium salt and the group nourished by the concomitant use of atorvastatin calcium salt and ezetimibe.
  • 4. Static Analysis and Data Processing Method
  • Multigroup comparison between the control group and the medicament administered group was performed using Bartlett's variance analysis−Dunnett's multiple comparative assay. A difference with a significance level less than 5% was regarded as significant.
  • 5. Results
  • The measurement results are shown in Tables 1 and 2, and FIGS. 1 and 2.
  • A reduction ratio (%) is a value represented by ((total blood cholesterol level of control group on average−total blood cholesterol level of each group on average)/(total blood cholesterol level of control group on average))×100, while a relative index is a value represented by (total blood cholesterol level of each group on average)/(total blood cholesterol level of control group on average).
    TABLE 1
    Reduction ratio (%) of blood cholesterol level
    Reduction Relative
    Administered group ratio index
    Control group 0 1.0
    Group of the single use of ezetimibe 21 0.79
    Group of the single use of pitavastatin Ca 29 0.71
    Group of the concomitant use of pitavastatin 51 0.49
    Ca/ezetimibe
  • TABLE 2
    Reduction ratio (%) of blood cholesterol level
    Reduction Relative
    Administered group ratio index
    Control group 0 1.0
    Group of the single use of ezetimibe 19 0.81
    Group of the single use of atorvastatin Ca 23 0.77
    Group of the concomitant use of atorvastatin 26 0.74
    Ca/ezetimibe
  • In the group of the concomitant use of pitavastatin calcium salt and ezetimibe according to the method of the invention, the blood cholesterol level lowering action was enhanced greatly (p<0.001) compared with that of the group of the single use of each medicament. Its effect was synergistic (relative index of the group of concomitant use (0.49)<product (0.56) of relative indices of the groups of single use).
  • In the treatment method for comparison by using the atorvastatin calcium salt having the most potent blood cholesterol level lowering action among the HMG-CoA reductase inhibitors, on the other hand, the blood cholesterol level lowering action of the group of the concomitant use of atorvastatin calcium salt and ezetimibe was enhanced compared with that of each of the groups of single use, but its effect was additive (relative index (0.74) of the group of concomitant use (0.74)>product (0.62) of refractive indices of the groups of single use).
  • The concomitant use of the pitavastatin calcium salt and ezetimibe according to the invention has a remarkable blood cholesterol level lowering effect, compared with that of the concomitant use of another HMG-CoA reductase inhibitor and ezetimibe.

Claims (2)

1. A method for treating hyperlipidemia, which comprises administering effective doses of ezetimibe and pitavastatin or a salt or lactone derivative thereof.
2. A method for treating hypercholesterolemia, which comprises administering effective doses of ezetimibe and pitavastatin or a salt or lactone derivative thereof.
US10/997,878 2004-08-31 2004-11-29 Method for treating hyperlipidemia Abandoned US20060046996A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
US10/997,878 US20060046996A1 (en) 2004-08-31 2004-11-29 Method for treating hyperlipidemia
JP2006532716A JP4886516B2 (en) 2004-08-31 2005-08-30 Antihyperlipidemic agent
PL05777087T PL1785137T3 (en) 2004-08-31 2005-08-30 Remedy for hyperlipemia
CN2005800291311A CN101010080B (en) 2004-08-31 2005-08-30 Remedy for hyperlipemia
EP05777087A EP1785137B1 (en) 2004-08-31 2005-08-30 Remedy for hyperlipemia
KR1020077001596A KR101244508B1 (en) 2004-08-31 2005-08-30 Remedy for hyperlipemia
AT05777087T ATE489093T1 (en) 2004-08-31 2005-08-30 REMEDIES FOR HYPERLIPIDEMIA
PT05777087T PT1785137E (en) 2004-08-31 2005-08-30 Remedy for hyperlipemia
DE602005024981T DE602005024981D1 (en) 2004-08-31 2005-08-30 CURE FOR HYPERLIPIDEMIA
PCT/JP2005/015756 WO2006025378A1 (en) 2004-08-31 2005-08-30 Remedy for hyperlipemia
ES05777087T ES2354366T3 (en) 2004-08-31 2005-08-30 MEDICATION FOR HYPERLIPEMIA.
US11/546,248 US7459447B2 (en) 2004-08-31 2006-10-12 Method for treating hyperlipidemia
HK08100666.5A HK1110200A1 (en) 2004-08-31 2008-01-18 Remedy for hyperlipemia
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US20090275595A1 (en) * 2004-12-10 2009-11-05 Kowa Co., Ltd. Method for reduction, stabilization and prevention of rupture of lipid rich plaque
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US20100048529A1 (en) * 2005-06-22 2010-02-25 Astrazeneca Ab New 2-Azetidinone Derivatives Useful In The Treatment Of Hyperlipidaemic Conditions
US20100137273A1 (en) * 2005-06-22 2010-06-03 Astrazeneca Ab Novel 2-Azetidinone Derivatives As Cholesterol Absorption Inhibitors For The Treatment Of Hyperlipidaemic Conditions
US20100152156A1 (en) * 2005-06-22 2010-06-17 Astrazeneca Ab 2-Azetidinone Derivatives For The Treatment Of Hyperlipidaemic Diseases
US20100168039A1 (en) * 2005-06-22 2010-07-01 Astrazeneca Ab Novel 2-Azetidinone Derivatives As Cholesterol Absorption Inhibitors For The Treatment Of Hyperlipidaemic Conditions
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US7470678B2 (en) 2002-07-05 2008-12-30 Astrazeneca Ab Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
US20050239766A1 (en) * 2002-07-05 2005-10-27 Astrazeneca Ab Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
US20060276486A1 (en) * 2003-04-17 2006-12-07 Kowa Co., Ktd. Lklf/klf2 gene expression promoter
US20070142304A1 (en) * 2003-12-23 2007-06-21 Susanne Alenfalk Diphenylazetidinone derivatives possessing chloesterol absorption inhibitory activity
US20080064676A1 (en) * 2003-12-23 2008-03-13 Astrazeneca Ab Diphenylazetidinone Derivatives Possessing Cholesterol Absorption Inhibitory Activity
US7871998B2 (en) 2003-12-23 2011-01-18 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
US20100099657A2 (en) * 2003-12-23 2010-04-22 Astrazeneca Ab Diphenylazetidinone Derivatives Possessing Cholesterol Absorption Inhibitory Activity
US20110207742A1 (en) * 2004-12-10 2011-08-25 Kowa Co., Ltd. Method for reduction, stabilization and prevention of rupture of lipid rich plaque
US20090275595A1 (en) * 2004-12-10 2009-11-05 Kowa Co., Ltd. Method for reduction, stabilization and prevention of rupture of lipid rich plaque
US20100216759A1 (en) * 2005-06-20 2010-08-26 Astrazeneca Ab Novel 2-Azetidinone Derivatives And Their Use As Cholesterol Absorption Inhibitors For The Treatment Of Hyperlipidaemia
US7863265B2 (en) 2005-06-20 2011-01-04 Astrazeneca Ab 2-azetidinone derivatives and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia
US20100137273A1 (en) * 2005-06-22 2010-06-03 Astrazeneca Ab Novel 2-Azetidinone Derivatives As Cholesterol Absorption Inhibitors For The Treatment Of Hyperlipidaemic Conditions
US20100168039A1 (en) * 2005-06-22 2010-07-01 Astrazeneca Ab Novel 2-Azetidinone Derivatives As Cholesterol Absorption Inhibitors For The Treatment Of Hyperlipidaemic Conditions
US20100152156A1 (en) * 2005-06-22 2010-06-17 Astrazeneca Ab 2-Azetidinone Derivatives For The Treatment Of Hyperlipidaemic Diseases
US20100048529A1 (en) * 2005-06-22 2010-02-25 Astrazeneca Ab New 2-Azetidinone Derivatives Useful In The Treatment Of Hyperlipidaemic Conditions
US20100048530A1 (en) * 2005-06-22 2010-02-25 Astrazeneca Ab New 2-Azetidinone Derivatives As Cholesterol Absorption Inhibitors For The Treatment Of Hyperlipidaemic Conditions
US7893048B2 (en) 2005-06-22 2011-02-22 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US7906502B2 (en) 2005-06-22 2011-03-15 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US7842684B2 (en) 2006-04-27 2010-11-30 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity
US20090069285A1 (en) * 2006-04-27 2009-03-12 Astrazeneca Ab Diphenylazetidinone Derivatives Possessing Cholesterol Absorption Inhibitor Activity

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PT1785137E (en) 2010-12-23
DE602005024981D1 (en) 2011-01-05
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ATE489093T1 (en) 2010-12-15
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PL1785137T3 (en) 2011-04-29
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JPWO2006025378A1 (en) 2008-05-08
CY1111150T1 (en) 2015-06-11
KR101244508B1 (en) 2013-03-18
KR20070047766A (en) 2007-05-07
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US7459447B2 (en) 2008-12-02
EP1785137B1 (en) 2010-11-24

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