U.S. patent application number 10/997878 was filed with the patent office on 2006-03-02 for method for treating hyperlipidemia.
This patent application is currently assigned to KOWA CO., LTD.. Invention is credited to Taro Aoki, Takashi Maejima, Hiroyuki Yamazaki.
Application Number | 20060046996 10/997878 |
Document ID | / |
Family ID | 35944235 |
Filed Date | 2006-03-02 |
United States Patent
Application |
20060046996 |
Kind Code |
A1 |
Aoki; Taro ; et al. |
March 2, 2006 |
Method for treating hyperlipidemia
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.
Inventors: |
Aoki; Taro; (Tokorozawa-shi,
JP) ; Yamazaki; Hiroyuki; (Higashimurayama-shi,
JP) ; Maejima; Takashi; (Higashimurayama-shi,
JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
KOWA CO., LTD.
Nagoya-shi
JP
460-8625
Nissan Chemical Industries, Ltd.
Tokyo
JP
101-0054
|
Family ID: |
35944235 |
Appl. No.: |
10/997878 |
Filed: |
November 29, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60605525 |
Aug 31, 2004 |
|
|
|
Current U.S.
Class: |
514/311 ;
514/460; 514/548 |
Current CPC
Class: |
A61K 31/47 20130101;
A61K 31/4709 20130101; A61K 31/4709 20130101; A61P 9/10 20180101;
A61K 31/47 20130101; A61K 31/397 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/397 20130101;
A61P 3/06 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/311 ;
514/460; 514/548 |
International
Class: |
A61K 31/47 20060101
A61K031/47; A61K 31/366 20060101 A61K031/366; A61K 31/225 20060101
A61K031/225 |
Claims
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.
Description
TECHNICAL FIELD
[0001] The present invention relates to a method for treating
hyperlipidemia, which exhibits an excellent blood
cholesterol-lowering action.
BACKGROUND ART
[0002] 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.
[0003] 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).
[0004] 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.
[0005] 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).
[0006] 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)).
[0007] 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
[0008] An object of the present invention is to provide a method
for treating hyperlipidemia and hypercholesterolemia, which has an
excellent blood cholesterol lowering action.
[0009] 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.
[0010] 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.
[0011] 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.
[0012] 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
[0013] 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
[0014] 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
[0015] 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.
[0016] Ezetimibe to be used in the invention is known as a
medicament exhibiting its effects by inhibiting the cholesterol
absorption in the intestine.
[0017] 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.
[0018] 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.
[0019] 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 .beta.-carotene, yellow iron
sesquioxide, and caramel; and examples of the taste corrigent
include sucrose and orange peel.
[0020] 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.
[0021] 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.
[0022] 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.
[0023] 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
[0024] 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
[0025] 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
[0026] 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.degree. 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
[0027] 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.degree. C.) in a light resistant bottle and
adjustment was conducted every 7 days.
[0028] 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
[0029] 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.
[0030] 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
[0031] 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
[0032] The measurement results are shown in Tables 1 and 2, and
FIGS. 1 and 2.
[0033] 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)).times.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-US-00001 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
[0034] TABLE-US-00002 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
[0035] 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).
[0036] 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).
[0037] 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.
* * * * *