Note: Descriptions are shown in the official language in which they were submitted.
CA 02727957 2011-01-19
ANTIHYPERTENSIVE PHARMACEUTICAL COMPOSITION
BACKGROUND OF THE INVENTION
Field of Invention
The present invention relates to the pharmaceutical field, and more
particularly to
an antihypertensive pharmaceutical composition.
Related Art
In recent years, with the continuous improvement of living standards and the
changes in the dietary structure of Chinese people, the increase of life
stress, and the
increase of the elderly population, the incidence of hypertension is gradually
increased,
and at the same time, hypertension causes lesions to heart, brain, kidneys,
and other
organs, is closely related to sugar and lipid metabolism disorders and
diabetes,
significantly reduces the quality of life of patients, and even threatens the
lives of
patients in serious cases. A large number of international authoritative
clinical studies
on hypertension suggest that increased efforts for depressing the blood
pressure, and
active and sustained depressing of the blood pressure in the hypertension
patients below
130/85 mmHg (optimally below 120/80 mmHg) may effectively mitigate lesions of
target organs such as heart, brain, and kidneys caused by hypertension, reduce
or delay
complications such as stroke, coronary heart disease, angina, myocardial
infarction,
renal failure, atherosclerosis, and aneurysm, reduce the incidence of the
cardiovascular
events, the mortality, and the morbidity, improve the life quality of the
patients, and
prolong the life of the patients. According to the global mortality statistics
of various
diseases of the World Health Organization (WHO), the cardiovascular disease
deaths
represented by hypertension accounts for 36% of the total number of deaths;
therefore,
improving people's awareness on hypertension is of great importance for early-
stage
prevention and timely treatment.
2008 Consensus of Chinese Experts in Diagnosis and Treatment of Elderly
Patients
with Hypertension indicates that, treatment through combined administration
utilizes
multiple different mechanisms for depressing blood pressure, good
antihypertensive
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effect is achieved, adverse reactions are fewer, and thus being more
beneficial for
protection of target organs. Numerous studies show that, in order to achieve
the
purpose of positive and intensive blood pressure depression, 70-100% of the
patients
need to be administrated with two or more antihypertensive drugs in
combination. The
combined administration can not only significantly improve the
antihypertensive effect
due to the additive or synergistic effects of the drugs, but also can reduce
the side effects
of the drugs, and thus the safety and the patient compliance are improved. A
lot of
literatures suggest that, due to reasonable combination of two
antihypertensive drugs,
the adverse effects of the two combined ingredients when administrated
separately may
also be counteracted. Therefore, when a conventional dose of a single medicine
cannot
achieve the desired standard effect, it is recommended to adopt a combined
administration regimen including compound preparations to treat hypertension
patients.
Levamlodipine is an optical pure medicine that is firstly chirally resolved in
China,
an anti hypertensive medicine that is firstly chirally resolved in the world,
and a
long-term basic dihydropyridine calcium antagonists, and may be prepared
through
many methods, see references CN00102701.8 and CN03821593.4. Levamlodipine
functions through a site (N site) attached to dihydropyridine on a cell and
blocks
calcium ions from entering the cardiac and vascular smooth muscle cells in a
transmembrane manner, so as to relax the smooth muscle, decrease the vascular
resistance, and lower the blood pressure. Presently, clinical trial evidences
indicate
that, a therapeutic dose of levamlodipine has very slight or no influence on
cardiac
contractility and atrioventricular conduction, and levamlodipine is a medicine
with the
minimal effect on sympathetic excitation among the calcium antagonists.
Levamlodipine may also be used to treat hypertension associated with heart
failure,
reverse ventricular hypertrophy, improve the relaxation function of the heart
during the
diastolic stage, protect the renal function with mild diuretic function, and
prevent
coronary heart disease, myocardial infarction, and stroke, and may further
partially
reverse abnormal circadian rhythm of blood pressure, and have mild anti-
platelet effect,
anti-myocardial ischemia effect, anti-arrhythmia effect, insulin sensitivity
increasing
effect and a certain anti-atherosclerosis effect. However, in a blood pressure
depressing process, levamlodipine may easily cause sodium and water retention
due to
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the high dosage, thus resulting in edema, so considerable patients withdraw,
and the
clinical application of levamlodipine is limited.
Indapamide is a non-thiazide diuretic antihypertensive medicine and a
sulfonamide
derivative, has a half-life of 17 h, and the metabolites thereof still have
antihypertensive
effect, so indapamide is a diuretic having a certain calcium antagonism. The
antihypertensive mechanism of indapamide is complicated and includes that: I']
through
the influence on the prostate substances, PG12 (prostaglandin 12) and PGE2
(prostaglandin E2) are increased, and PCF2a (prostaglandin F2a) and TXA2
(thromboxane A2) are decreased, such that the hemorheology is improved, in
which
PGE2 and PG12 have the function of dilating the coronary artery and peripheral
vessels;
:.I through reduction of the response of the vascular wall to sodium ion, the
calcium
channels of the vascular wall cells are inhibited, and the sodium re-
absorption of renal
distal tubular is slightly inhibited, to relax the smooth muscle, dilate the
vessels, and
achieve the effects of diuresis and natriuresis, thus achieving the
antihypertensive effects.
The diuretic may mitigate the edema due to sodium and water retention caused
by CCB,
but indapamide has the side effect of glucose metabolism interference, so use
of
indapamide at high dose in long term may cause hypokalemia.
SUMMARY OF THE INVENTION
In view of the technical problems existing in depressing the blood pressure in
the
prior art of the edema side effect due to sodium and water retention caused
when
levamlodipine is administrated alone and the side effect of glucose metabolism
interference caused when indapamide is administrated alone, the present
invention is
directed to an antihypertensive pharmaceutical composition.
The antihypertensive pharmaceutical composition of the present invention
includes
levamlodipine or a pharmaceutically acceptable salt thereof, and indapamide.
In the present invention, as levamlodipine and indapamide are administrated in
combination, the dosages of levamlodipine and indapamide in the treatment
process are
reduced, and the same or even better antihypertensive effect is achieved.
Moreover, as
levamlodipine and indapamide are administrated at a low dose, the edema side
effect
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due to sodium and water retention caused by levamlodipine and the side effect
of
glucose metabolism interference caused by indapamide are decreased.
Furthermore,
the edema side effect due to sodium and water retention caused by
levamlodipine may
be further decreased due to the diuretic property of indapamide.
In the present invention, a weight ratio of levamlodipine to indapamide is
1:0.04-1,
and preferably 1:0.2-1.
The pharmaceutically acceptable salt is one or more selected from
levamlodipine
benzenesulfonate, levamlodipine mesylate, levamlodipine acetate, levamlodipine
aspartate, levamlodipine tartrate, levamlodipine maleate, levamlodipine
sulfate,
levamlodipine hydrochloride, and levamlodipine hydrobromide.
The antihypertensive pharmaceutical composition of the present invention
further
includes a pharmaceutically acceptable adjuvant.
In the antihypertensive pharmaceutical composition of the present invention, a
content of levamlodipine is preferably 0.1-30 wt%, more preferably 0.25-5 wt%;
and a
content of indapamide is preferably 0.01-5 wt%, and more preferably 0.05-2.5
wt%.
The pharmaceutically acceptable adjuvant is one or more selected from
microcrystalline cellulose, pregelatinized starch, lactose, hydroxymethyl
starch sodium,
magnesium stearate, talc, and polyvinylpyrrolidone (referred to as PVP-k30).
The antihypertensive pharmaceutical composition of the present invention
further
includes a pharmaceutically acceptable diluent, adhesive, disintegrant,
lubricant,
coloring agent and/or flavoring agent.
The antihypertensive pharmaceutical composition of the present invention may
be
prepared into an oral preparation, such as, a tablet or a capsule, in which
the tablet may
be coated with a sugar coat or a film coat, or be not coated.
The present invention has the following effective and active effects. As
levamlodipine and indapamide are administrated in combination, a good
synergistic
antihypertensive effect is achieved. The dosage of levamlodipine and
indapamide is
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decreased, while the same or even better anti hypertensive effect is achieved.
Moreover,
low dose of levamlodipine may also decrease the edema side effect due to
sodium and
water retention caused by levamlodipine, and the diuretic property of
indapamide may
further decrease the edema side effect due to sodium and water retention
caused by
levamlodipine. Furthermore, low dose of indapamide may also decrease the side
effect
of glucose metabolism interference caused by indapamide.
BRIEF DESCRIPTION OF THE DRAWINGS
No drawings
DETAILED DESCRIPTION OF THE INVENTION
Embodiments 1-2 Compound tablets
Table I Compositions and doses of compound tablets of Embodiments 1-2
Compositions Embodiment I Embodiment 2
Levarnlodipine 2.5 (based on levamlodipine) 0.2 (based on levamlodipine)
benzenesulfonate (g)
Indapamide(g) 0.1 0.02
Microcrystalline 30 40
cellulose (g)
Pregelatinized starch (g) 77.4 105.78
Lactose (g) 30 40
Hydroxymethyl starch 9 12
sodium (g)
Magnesium stearate (g) 1 2
95% ethanol suitable amount suitable amount
In total (tablets) 1000 1000
Preparation process: Levamlodipine benzenesulfonate, indapamide,
microcrystalline cellulose, pregelatinized starch, lactose, and hydroxymethyl
starch
sodium were placed in a mortar, and uniformly mixed by grinding, screened with
a
20-mesh sieve, added into a suitable amount of 95% ethanol to obtain a soft
material,
screened with a 20-mesh sieve, granulated, and air dried at 40 C. The dried
granules
were finished with a 16-mesh sieve, added with magnesium stearate, uniformly
mixed
and then tableted.
Embodiments 3-4 Compound capsules
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Table 2 Compositions and doses of compound capsules of Embodiments 3-4
Compositions_ Embodiment 3 Embodiment 4
Levamlodipine 2.5 (based on 60 (based on
benzenesulfonate (g) levamlodipine) levamlodipine)
Indapamide (g) 2.5 10
Microcrystalline cellulose (g) 135 120
Talc (g) 4 5.4
0.5% solution of PVP-k30 in suitable amount suitable amount
ethanol
In total (capsules) 1000 1000
Preparation process: levamlodipine benzenesulfonate, indapamide, and
microcrystalline cellulose were placed in a mortar, and uniformly mixed by
grinding,
screened with a 20-mesh sieve, added into a suitable amount of 0.5% solution
of
PVP-k30 in ethanol to obtain a soft material, screened with a 20-mesh sieve,
granulated, and air dried at 40 C. The dried granules were finished with a 16-
mesh
sieve, added with talc, uniformly mixed, and then capsulated.
Effect Embodiment I Blood pressure depressing test in rats
Experiment method: 50 health spontaneous hypertension SHR rats (female to male
1:1, weight 200-240 g) were equally divided into 5 groups according to the
level of the
hypertension (the specific grouping method is as shown in Table 3), and
intragastrically
administrated with the medicine. For the blood pressure of the rate, the
systolic
pressure at the tail artery of the rat when being wake and quite was
indirectly measured
by an electronic blood pressure meter through the tail volume method
respectively
before administration and at the end of one, two, three, and four weeks after
administration.
Table 3 Grouping of SHR rats
Group Number Administrated drug and dose
of rats
Blank model group 10 Equal volume of 0.9% saline
Levamlodipine 10 5 mg levamlodipine benzenesulfonate/kg=d
group
Indapamide group 10 5 mg indapamide/kg-d
Compound 10 2.5 mg levamlodipine benzenesulfonate/kg-d +0.5 mg
low-dose group indapamide/kg-d
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Compound 10 2.5 mg levamlodipine benzenesulfonate/kg=d +2.5 mg
high-dose group indapamide/kg-d
Note: 2.5 mg levamlodipine benzenesulfonate/kg-d in Table I is calculated
based on
levamlodipine
Experimental results: the levamlodipine group, the indapamide group, the
compound low-dose group, the compound high-dose group have significant
antihypertensive effect, compared with the blank model group; the compound low-
dose
group, and the compound high-dose group have significant anti hypertensive
effect,
compared with the levamlodipine group and the indapamide group. The specific
experimental results are as shown in Table 4. In view of the edema side
effect, no
edema occurred in the blank model group, the indapamide group, the compound
low-dose group, and the compound high-dose group, while edema occurred at an
incidence rate of 10% in the levamlodipine group.
Table 4 Influence on blood pressure of SHR rats of administration of
levamlodipine,
indapamide, and compound preparations thereof
Group Before I week 2 weeks after 3 weeks after 4 weeks after
administrat after administration administration administration
ion administrat (KPa) (KPa) (KPa)
(KPa) ion
(Kpa)
Blank 27.09 1.24 27.23 1.11 26.81. 1.25 26.96 1.44 27.14 1.34
model
group
Levamiodip 26.96 1.29 26.79 1.31 25.33 1.26# 24.55 1.28# 23.87 1.28"
ine group
lndapamide 27.02 1.39 26.88 1.38 25.85 1.38# 25.56 1.35" 25.36 1.36#
group
Compound 26.72 1.78 26.55 1.82 24.79 1.69"' 23.73 1.56#' 22.68 1.53""
low-dose
group
Compound 26.79 1.44 26.61 1.45 24.78 1.39#A' 23.67 1.32#A' 22.51 1.14"'
high-dose
group
Note: # compared with the blank model group, p<0.01, = compared with the
levamlodipine group, p<0.05, A compared with the levamlodipine group, p<0.01,
^
compared with the indapamide group, p<0.01.
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Conclusions: the compound preparations of levamlodipine and indapamide have a
better antihypertensive effect than levamlodipine and indapamide, and there is
significantly difference in the anti-hypertensive effects. The combined
administration
of levamlodipine and indapamide has a certain synergistic effect on the
spontaneous
hypertension rats, and has a therapeutic effect superior to those of the two
medicines
administrated alone, and the combined administration does not induce the edema
side
effect due to sodium and water retention.
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