Description
Title of Invention: COMPLEX FORMULATION COMPRISING
LERCANIDIPINE HYDROCHLORIDE AND VALSARTAN AND
METHOD FOR THE PREPARATION THEREOF
Technical Field
[1] The present invention relates to a pharmaceutical composition comprising lercanidipine
hydrochloride and valsartan as active components and method for the
preparation thereof.
[2]
Background Art
[3] Hypertension is a most common cardiovascular disease. Persistent hypertension
damages blood vessels in the kidneys, heart and brain, which increases the occurrence
of renal failure, coronary- artery diseases, heart failure and stroke. Hypertension is
divided into two types—i.e., essential or primary hypertension and secondary hy
pertension. Essential hypertension, the cause of which is unknown, occurs without a
specific underlying disease. Most (95%) of hypertensive patients, especially those over
the age of 40, belong to this type. Even though the cause of essential hypertension
cannot be found since there is no underlying disease, problematic issues may be
genetics, dietary habit of eating salty food, obesity, old age, stress, heavy smoking and
drinking. Secondary hypertension comes from a specific causative disease. About 5%
of hypertensive patients, relatively young people, belong to this type. Secondary hy
pertension is caused by nephritis, endocrine disruption and toxemia during pregnancy,
etc., and blood pressure goes down with treatment of the causative diseases.
[4] Antihypertensive treatment is not for the causative disease and depends on blocking
the normal physiological mechanism of blood pressure regulation. Antihypertensive
treatment is performed on subclinical patients, and it does not affect directly the incon
venience of the patients but prevents the symptom and death from occurring in the
future by lowering blood pressure.
[5] Antihypertensive agents are generally classified according to their regulation site and
mechanism of action into three categories: diuretics, sympatholytic agents and va
sodilators, which are subdivided according to their active sites. Diuretics, which act to
increase the amount of urine to excrete water and salts from the body, lower blood
pressure by reducing water and salts in the body. A sympathetic nerve acts to increase
the frequency and intensity of the heartbeat and to constrict blood vessels. Sympa
tholytic agents suppress the action of the sympathetic nerve to lower blood pressure.
There are three types of sympatholytic agents: a-blocker suppressing the sympathetic
nerves acting to constrict blood vessels; -blocker suppressing the sympathetic nerves
acting on the heartbeat; and central sympatholytics suppressing the sympathetic nerve
acting on the brain. Vasodilators lower blood pressure by dilating blood vessels.
Various vasodilators are known such as ACE inhibitors which inhibit the synthesis of
angiotensin II, a vasoconstrictor, and angiotensin II receptor blockers which inhibit the
action of angiotensin II. A calcium channel blocker, which inhibits the inflow of
calcium into cells to lower blood pressure, is also a vasodilator since high con
centration of intracellular calcium results in vasoconstriction to raise blood pressure.
[6] In case a sufficient antihypertensive effect cannot be obtained due to severe hy
pertension, the dose of the antihypertensive agent is generally increased. However, an
excessively increased dose may cause adverse effects. In this case, the combined use of
medicines having different mechanisms of action, rather than the increased use of a
medicine, can minimize adverse effects while obtaining sufficient effect.
[7] The advantages of a combined use of medicines are as follows:
[8] Firstly, the antihypertensive effect increases synergistically by the concurrent action
of medicines having different mechanisms of action. Furthermore, a homeostasis com
pensatory action of a medicine is suppressed by another medicine, so that more
effective antihypertensive action is obtained. For example, reflexive tachycardia and
retention of salt and water, which are caused by the use of vasodilators, may be
adjusted by the use of -blockers and diuretics, respectively, so that the antihy
pertensive effect increases.
[9] Secondly, sufficient antihypertensive effect can be obtained by the combined use of
medicines, even at low doses, so that a dose-dependent adverse effect may be reduced.
In addition, adverse effects caused by the pharmacological action can be blocked and
reduced.
[10] Thirdly, hypertension is nearly asymptomatic and must be regulated for life, so
patient compliance with the medicine determines the outcome of the treatment. In this
regard, the combined use of effective medicines having low adverse effect can improve
the quality of life and increase patient compliance.
[11] Recently, complex formulations containing at least two medicines in one pill are
commercially available. They are cheap and easy to take. Use of the complex for
mulations can increase patient compliance and prevent or delay damage of the target
organ caused by hypertension.
[12]
Disclosure of Invention
Technical Problem
[13] Considering the current situation, the present inventors have conducted intensive
research to develop a new pharmaceutical composition by the combined use of at least
two antihypertensive agents having different mechanisms of action for increasing the
hypertensive effect synergistically, reducing adverse effects and improving patient
compliance. As a result of such efforts, the present inventors have found that such
purposes can be achieved by the combined use of lercanidipine hydrochloride and
valsartan, especially by the specific complex formulation comprising them, and thus
completed the present invention.
[14] Accordingly, the object of the present invention is to provide a pharmaceutical com
position for the prevention and treatment of cardiovascular diseases which comprises
as active components lercanidipine hydrochloride and valsartan having different
mechanisms of action.
[15] Especially, the present invention provides a complex formulation comprising ler
canidipine hydrochloride and valsartan in a separated form.
[16] Another object of the present invention is to provide a method for preparation of the
complex formulation for the prevention and treatment of cardiovascular diseases which
comprises as active components lercanidipine hydrochloride and valsartan.
[17]
Solution to Problem
[18] Lercanidipine hydrochloride is a dihydropyridine calcium antagonist and, like other
calcium antagonists, inhibits calcium inflow into arterial smooth muscle to relax p e
ripheral arterioles and reduce the blood pressure. Lercanidipine does not cause
negative myocardial contraction but results in slight reflex tachycardia. Lercanidipine
has a strong affinity to the dihydropyridine subunit of L-type calcium channel and
competitively antagonizes thereto. Calcium channel antagonists are considered safe
and are proven to be effective on all types of hypertension. Lercanidipine is a new kind
of dihydropyridine calcium antagonist and has proven to have a strong and long-acting
hypotensive effect in pre-clinical trials. Lercanidipine is favorably tolerable in a dose
of 30 mg or lower and reduces blood pressure in a dose-dependent manner. Calcium
antagonists are considered renal-protective due to their antihypertensive effect. This
potential is proven in the renal failure and nephrotoxicity induced by chemotherapy,
contrast media, cyclosporins or aminoglycoside antibiotics. In addition, calcium an
tagonists have a renal-protective effect on the kidneys of donors in kidney transplants.
Lercanidipine is typically used in a dose of 10 to 20 mg once a day and the maximum
dose is about 30 mg per day. Lercanidipine is rapidly absorbed after oral admin
istration and reaches its maximum plasma concentration in 1.5 to 3 hours after admin
istration, which is subjected to extensive first-pass metabolism. Absorption of ler
canidipine is highly dependent on food intake and increases remarkably (3- to 4-fold)
by simultaneous intake of food. An oral tablet containing 10 or 20 mg of lercanidipine
is commercially available under the trade name "Zanidip ® tablet." Lercanidipine, sold
by Recordati S.p.A (Milan, Italy), can be manufactured according to the method
disclosed in EP 0153016 and US 4705797 of which the whole context is quoted herein.
Furthermore, US-A 1-2003/0 180355 discloses a method of treating hypertensive
patients which comprises administering a complex formulation containing ler
canidipine and enalapril as active components.
[19] Valsartan ((S)-N-valeryl-N-{ [2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]-methyl}-valine),
an angiotensin II receptor antagonist, reduces blood pressure by vasodilation. An
giotensin II has a vasoconstriction and sodium retention effect. Valsartan is com
mercially available (Tareg ® tablet) and also manufactured by a known method. For
example, the preparation of valsartan is disclosed in US 5399578 of which the whole
context is quoted herein. Valsartan is used for the purpose of the present invention in
its isolated form or a suitable salt form. In the U.S., valsartan is used in an initial dose
of 80 to 160 mg qd and the maximum dose is 320 mg qd. In Korea, valsartan is
prescribed for patients with cardiac insufficiency or postmyocardial infarction
syndrome in a dose of 160 mg b.i.d. However, if the blood pressure of the patient does
not reach the desired value with the dose of 160 mg b.i.d, valsartan is replaced with
other drugs. Valsartan is typically used in a dose of about 40 to 320 mg, preferably
about 80 to 320 mg, most preferably about 80 to 160 mg in a tablet.
[20] The present inventors have conducted various experiments of lercanidipine hy
drochloride and valsartan having the above-mentioned mechanisms of action and
maximum daily doses to confirm that the combined use of these drugs has a synergistic
effect on the prevention and treatment of cardiovascular diseases compared with that of
single use, reduces the adverse effects caused by single use, and improves patient
compliance. Accordingly, the pharmaceutical composition comprising lercanidipine
hydrochloride and valsartan can be used effectively for the prevention and treatment of
cardiovascular diseases. Examples of the cardiovascular diseases include angina
pectoris, hypertension, arteriospasm, cardiac arrhythmia, cardiac hypertrophy, cerebral
infarction, congestive heart failure, myocardial infarction, etc., but not limited thereto.
[21] However, a complex formulation comprising lercanidipine hydrochloride and
valsartan prepared by simply mixing the two drugs may have some problems caused
by the difference between their inherent physical properties.
[22] The first problem resides in the difference of their pKa value. Lercanidipine hy
drochloride has a pKa value of about 6.83 and the pKa of valsartan is about 3.92. Ac
cordingly, lercanidipine hydrochloride has an increased solubility at pH 4.0 or lower,
while valsartan has an increased solubility at pH 4.0 or higher. Such a pKa difference
between the two drugs affects the solubility of each drug.
[23] The second problem is gelling of valsartan. Valsartan begins to gel at pH 4.0 or
lower due to its low solubility and dissolves very slowly. Such delayed dissolution
causes delayed absorption of valsartan in the small intestine. In addition, gelling of
valsartan can delay the dissolution of lercanidipine hydrochloride. This trouble can
adversely affect the absorption of lercanidipine hydrochloride which is rapidly disin
tegrated and absorbed in the gastro-intestinal tract. Accordingly, gelling of valsartan at
low pH in a complex formulation must be prevented.
[24] The third problem is low dissolution of the complex formulation. In the preliminary
experiment in which the complex formulation was prepared by wet-granulation of the
mixture of lercanidipine hydrochloride and valsartan, the complex formulation showed
low dissolution due to the interaction between the two components. Such low dis
solution seriously affects the absorption and bioavailability of the two components.
Decreased bioavailability is also expected to decrease the efficacy of the complex for
mulation. Therefore, an improved manufacturing process is required to prevent the
problem.
[25] The fourth problem is the difference of disintegration time between the commercially
available single drug formulations, which makes it difficult to maintain the inherent
dissolution pattern of each drug by using conventional formulation methods.
[26] In order to overcome the above-mentioned problems, the present inventors have
contrived a complex formulation comprising lercanidipine hydrochloride and valsartan
that physically separates the two components to minimize the contact area and chance
of making contact. According to the present invention, the complex formulation can
provide superior dissolution rates of both lercanidipine hydrochloride and valsartan.
[27]
Advantageous Effects of Invention
[28] The pharmaceutical composition comprising lercanidipine hydrochloride and
valsartan according to the present invention has a superior effect on the prevention and
treatment of cardiovascular diseases and their complex diseases, and reduces adverse
effects of each component due to the synergistic combination of the two components
having different mechanisms of action. In addition, the present invention provides a
complex formulation comprising lercanidipine hydrochloride and valsartan in a
separated form so that the problems caused by simple mixture of lercanidipine hy
drochloride and valsartan may be overcome and the dissolution rates of both
components may increase.
[29]
Brief Description of Drawings
[30] Figure 1 is a graph showing the results of a dissolution test of lercanidipine for the
complex formulations of Examples 1 to 4 compared with that of Comparative Example
1.
[31] Figure 2 is a graph showing the results of a dissolution test of lercanidipine for the
complex formulations of Examples 5 to 8 compared with that of Comparative Example
1.
[32] Figure 3 is a graph showing the results of a dissolution test of lercanidipine for the
complex formulations of Examples 1 to 4 compared with those of Examples 9 to 12.
[33] Figure 4 is a graph showing the results of a dissolution test of lercanidipine for the
complex formulation of Example 1 compared with that of Example 13.
[34] Figure 5 is a graph showing the results of a dissolution test of lercanidipine for the
complex formulation of Example 1 compared with those for the formulations of Com
parative Examples 2 and 3.
[35] Figure 6 is a graph showing the change ( ) of systolic blood pressure (BP) with the
passage of time after the combined administration of lercanidipine hydrochloride 2
mg/kg (Z) and valsartan 16 mg/kg (V) according to Test Example 8 (***p<0.001 (vs.
control), ##p<0.01 (vs. valsartan)).
[36] Figure 7 is a graph showing the change ( ) of mean BP with the passage of time
after the combined administration of lercanidipine hydrochloride 2 mg/kg (Z) and
valsartan 16 mg/kg (V) according to Test Example 8 (***p<0.001 (vs. control), ##p<0.01
(vs. valsartan)).
[37] Figure 8 is a graph showing the change ( ) of diastolic BP with the passage of time
after the combined administration of lercanidipine hydrochloride 2 mg/kg (Z) and
valsartan 16 mg/kg (V) according to Test Example 8 (***p<0.001 (vs. control), ##p<0.01
(vs. valsartan)).
[38] Figure 9 is a graph showing the change ( ) of heart rate with the passage of time
after the combined administration of lercanidipine hydrochloride 2 mg/kg (Z) and
valsartan 16 mg/kg (V) according to Test Example 8 (***p<0.001 (vs. control), ##p<0.01
(vs. valsartan)).
[39]
Mode for the Invention
[40] As a preferred embodiment of the present invention, a complex formulation
comprising lercanidipine hydrochloride and valsartan in a separated form is prepared
by separate granulations of lercanidipine hydrochloride and valsartan.
[41] A method for the preparation of the complex formulation of the present invention
comprises the steps of:
[42] (a) wet-granulating a mixture of lercanidipine hydrochloride and a pharmaceutically
acceptable excipient and drying the granules;
[43] (b) wet-granulating a mixture of valsartan and a pharmaceutically acceptable
excipient and drying the granules; and
[44] (c) mixing the dried granules prepared in steps (a) and (b).
[45] For example, the complex formulation of the present invention is made by preparing
lercanidipine hydrochloride granules and valsartan granules separately, mixing the two
granules and then pressing the mixtures into a tablet. The complex formulations of
Examples 1 to 4 prepared according to the above process show improved dissolution of
lercanidipine hydrochloride without affecting the dissolution of valsartan compared
with the complex formulation of Comparative Example 1 which is prepared by wetgranulation
of an unseparated mixture of lercanidipine hydrochloride and valsartan
(see Figure 1).
[46] Another specified embodiment of the present invention provides a bilayer tablet of
the complex formulation comprising lercanidipine hydrochloride and valsartan. As
described in the following Examples 5 to 8, the bilayer tablet can be prepared by
pressing the valsartan granules into a first tablet layer and then pressing the ler
canidipine hydrochloride granules into a second tablet layer by using a bilayer tablet
press. The bilayer tablet of the present invention shows superior dissolution of ler
canidipine hydrochloride like the complex formulations of Examples 1 to 4 (see Figure
2).
[47] In yet another embodiment of the present invention, the bilayer tablet can comprise a
separation layer between the lercanidipine hydrochloride layer and the valsartan layer
so that a trilayer tablet may be obtained. The separation layer may consist of, for
example, microcrystalline cellulose.
[48] A still further embodiment of the present invention provides a complex formulation
comprising lercanidipine hydrochloride and valsartan in a separated form, wherein a
tablet consisting of valsartan is coated with lercanidipine hydrochloride. Such a for
mulation can be prepared by dissolving or dispersing lercanidipine hydrochloride and
an excipient in a coating solvent to make a coating composition and coating a tablet
consisting of valsartan with the coating composition. Examples of the excipient include
polyvinylpyrrolidone, and ethanol can be used as the coating solvent. If necessary,
another separation layer may be placed between the valsartan tablet and the ler
canidipine hydrochloride coating.
[49] The complex formulation of the present invention may comprise 4 to 32 parts by
weight, preferably 4 to 16 parts by weight of valsartan per 1 part by weight of ler
canidipine hydrochloride. If the amount of valsartan is less than 4 parts by weight per 1
part by weight of lercanidipine hydrochloride, the desired effect cannot be obtained.
On the other hand, a formulation containing more than 32 parts by weight of valsartan
per 1 part by weight of lercanidipine hydrochloride is not permitted.
[50] The composition of the present invention for the prevention and treatment of cardio
vascular diseases can comprise a pharmaceutically acceptable carrier or excipient in
each of the lercanidipine hydrochloride granules and the valsartan granules. Examples
of the pharmaceutically acceptable carrier or excipient include microcrystalline
cellulose, lactose, low-substituted hydroxypropyl cellulose, disintegrating agents (e.g.,
croscarmellose sodium, crospovidone and sodium starch glycolate) and granulation
binders (e.g., polyvinylpyrrolidone and hydroxypropyl cellulose). In addition, a
lubricant such as colloidal silicon dioxide, hydrous silicon dioxide, magnesium
stearate, sodium stearyl fumarate (Pruv®), glyceryl behenate (Compritol 888®), calcium
stearate, stearic acid and talc may be included.
[51] In the present invention, the lercanidipine hydrochloride granules may comprise 4 to
10 parts by weight of a pharmaceutically acceptable excipient per 1 part by weight of
lercanidipine hydrochloride; and the valsartan granules may comprise 1 to 2 parts by
weight of a pharmaceutically acceptable excipient per 1 part by weight of valsartan.
Such a ratio applies to all the formulations of the present invention including the
separated granules. If the formulation has a ratio out of the above range, it may create
tablets that are too small or too large, and its dissolution may be delayed or increased.
[52] Especially, the ratio of the disintegrating agent used in the present invention is noted.
Conventional super-disintegrating agents, such as croscarmellose sodium,
crospovidone and sodium starch glycolate, are recommended to be used in an amount
of 0.5 to 8.0 wt based on the total amount of excipients. In the present invention,
however, 5 to 20 wt overdose of the super-disintegrating agents is used to prevent
gelling and show inherent dissolution behavior. Conventional formulations coated by
using overdose of a super-disintegrating agent have a problem that coating is difficult
due to rapid moisturizing and the coated layer cracks during storage. However, it is
confirmed that the present invention does not have such troubles.
[53] Examples of coating agents available in film coating layer include conventional ones,
such as hydroxypropylmethyl cellulose, Opadry® series, Eudragit® series, but not
limited thereto.
[54] The present invention is explained in more detail by the following examples.
However, these examples seek to illustrate the present invention only, and the scope of
the present invention is not limited thereto.
[55]
[56] Examples 1 to 4 : Preparation of separated granules
[57] Table 1
[Table 1]
Component Example 1 Example 2 Example 3 Example 4
Lercanidipine hydrochloride granules
Lcrcanidipinc hydrochloride 10.0 mg 20.0 mg 10.0 mg 20 mg
Polyvinyl pyrrolidonc 2.5 mg 2.5 mg 2.5 mg 2.5 mg
Microcrystalline cellulose 20.0 mg 20.0 mg 20.0 mg 20.0 mg
I ctose 26.5 mg 26.5 mg 26.5 mg 26.5 mg
Croscarmellose sodium 20.0 mg 20.0 mg 20.0 mg 20.0 mg
Magnesium stearate 1.0 mg 1.0 mg 1.0 mg 1.0 mg
Sub-total 80.0 mg 90.0 mg 80.0 mg 90.0 mg
Valsartan granules
Valsartan 80.0 mg 80.0 mg 160.0 mg 160.0 g
Low-substituted hydroxypropyl 25.0 mg 25.0 mg 50.0 mg 50.0 mg
cellulose
Crospovidone 15.0 mg 15.0 mg 30.0 mg 30.0 mg
Microcrystalline cellulose 22.5 mg 22.5 mg 45.0 mg 45.0 mg
Croscarmellose sodium 5.0 mg 5.0 mg 10.0 mg 10.0 mg
Hydrous silicon dioxide 5.0 mg 5.0 mg 10.0 mg 10.0 mg
Hydroxypropyl cellulose 6.0 mg 6.0 mg 12.0 mg 12.0 mg
Magnesium stearate 1.5 mg 1.5 mg 3.0 mg 3.0 mg
Sub-total 160.0 mg 160.0 mg 320.0 mg 320.0 mg
Total 240.0 mg 250.0 mg 400.0 mg 410.0 mg
[58]
[59] Lercanidipine hydrochloride granules and valsartan granules having the above com
positions were wet-granulated using distilled water, dried and milled to 25 mesh. The
two granules were mixed and compressed into complex tablets which were then film
coated. Opadry ® II sold by Colorcon as PVPs was used as the film coating material,
and the film coating was carried out in the same manner in all the following examples
and comparative examples. The mixture was combined for a time of 5 minutes or more
so that the super-integrating agent which was added in the process of wet-granulation
was sufficiently wetted. Such a sufficient combination time increases porosity of the
granules, which results in the facilitation of disintegration time to prevent gelation. In
the following examples, all processes of wet-granulation were carried out as above.
[60]
[61] Examples 5 to 8 : Preparation of complex bilayer tablets
[62] Table 2
[Table 2]
Component Example 5 Example 6 Example 7 Example 8
Lercanidipine hydrochloride granules
Lercanidipine hydrochloride 10.0 g 20.0 mg lO.O g 20 mg
Polyvinylpyrrolidone 2.5 mg 2.5 mg 2.5 mg 2.5 mg
Microcrystalline cellulose 20.0 mg 20.0 mg 20.0 mg 20.0 mg
Lactose 26.5 mg 26.5 mg 26.5 mg 26.5 mg
Croscarmellose sodium 20.0 mg 20.0 mg 20.0 mg 20.0 mg
Magnesium stearate 1.0 mg 1.0 mg 1.0 mg 1.0 mg
Sub-total 80.0 mg 90.0 mg 80.0 mg 90.0 mg
Valsartan granules
Valsartan 80.0 mg 80.0 mg 160.0 mg 160.0 mg
Low-substituted hydroxypropyl
25.0 mg 25.0 mg 50.0 mg 50.0 mg
cellulose
Crospovidone 15.0 mg 15.0 mg 30.0 mg 30.0 mg
Microcrystalline cellulose 22.5 mg 22.5 mg 45.0 mg 45.0 mg
Croscarmellose sodium 5.0 mg 5.0 mg 1 .0 mg 0.0 mg
Hydrous silicon dioxide 5.0 mg 5.0 mg 10.0 mg 10.0 mg
Hydroxypropyl cellulose 6.0 mg 6.0 mg 12.0 mg 12.0 mg
Magnesium stearate 1.5 mg 1.5 mg 3.0 mg 3.0 mg
Sub-total 160.0 mg 160.0 mg 320.0 mg 320.0 mg
Total 240.0 mg 250.0 mg 400.0 mg 410.0 mg
[63]
[64] Lercanidipine hydrochloride granules and valsartan granules having the above com
positions were wet-granulated using distilled water, dried and milled to 25 mesh. The
two groups of granules were compressed into bilayer solid forms and thus the bilayer
solid forms were film coated.
[65]
[66] Examples 9 to 12: Preparation of complex trilayer tablets
[67] Table 3
[Table 3]
Component Example 9 Example 10 Example 11 Example 12
Lcrcanidipinc hydrochloride granules
Lercanidipine hydrochloride 10.0 mg 20.0 mg 10.0 mg 20 mg
Polyvinylpyrrolidone 2.5 mg 2.5 mg 2.5 mg 2.5 mg
Microcrystalline cellulose 20.0 mg 20.0 mg 20.0 mg 20.0 mg
Lactose 26.5 mg 26.5 mg 26.5 mg 26.5 mg
Croscarmellose sodium 20.0 mg 20.0 mg 20.0 mg 20.0 mg
Magnesium stearate 1.0 mg 1.0 mg 1.0 mg 1.0 mg
Sub-total 80.0 mg 90.0 mg 80.0 mg 90.0 mg
Separation layer
Microcrystalline cellulose 30.0 mg 30.0 mg 60.0 mg 60.0 mg
Valsartan granules
Valsartan 80.0 mg 80.0 mg 160.0 g 160.0 g
Low-substituted hydroxypropyl
25.0 mg 25.0 mg 50.0 mg 50.0 mg
cellulose
Crospovidone 15.0 mg 15.0 mg 30.0 mg 30.0 mg
Microcrystalline cellulose 22.5 mg 22.5 mg 45.0 mg 45.0 mg
Croscarmellose sodium 5.0 mg 5.0 mg 10.0 mg 10.0 mg
Hydrous silicon dioxide 5.0 mg 5.0 mg 10.0 mg 10.0 mg
Hydroxypropyl cellulose 6.0 mg 6.0 mg 12.0 mg 12.0 mg
Magnesium stearate 1.5 mg 1.5 mg 3.0 mg 3.0 mg
Sub-total 160.0 mg 160.0 mg 320.0 mg 320.0 mg
Total 270.0 mg 280.0 mg 460.0 mg 470.0 mg
[68]
[69] Lercanidipine hydrochloride granules and valsartan granules having the above com
positions were wet-granulated using distilled water, dried and milled to 25 mesh. The
valsartan granules were added to make the first tablet part, the separation layer was
added to make the second tablet part, and the lercanidipine hydrochloride granules
were added to make the third tablet part. The complex trilayer tablet was obtained and
film coated.
[70]
[71] Example 13: Preparation of tablets coated with lercanidipine hydrochloride
layer
[72] Table 4
[Table 4]
Valsartan granules
Valsartan 80.0 g
Low-substituted hydroxypropyl cellulose 25.0 mg
Crospovidone 15.0 mg
Microcrystalline cellulose 22.5 mg
Croscarmellose sodium 5.0 mg
Hydrous silicon dioxide 5.0 mg
Hydroxypropyl cellulose 6.0 mg
Magnesium stearate 1.5 mg
Sub-total 160.0 m
Coating layer
Lercanidipine hydrochloride 10.0 mg
Polyvinylpyrrolidone 10.0 mg
Sub-total 20.0 mg
Total 180.0 mg
[73]
[74] The valsartan granules having the above composition were pressed into tablets which
were then introduced into a coating machine. Lercanidipine hydrochloride and
polyvinylpyrrolidone were dissolved and suspended in ethanol to prepare the coating
layer. The valsartan tablet was coated by spraying the coating layer thereon, and then
film coated.
[75]
[76] Comparative Example 1: Preparation of tablets from the mixture of unseparated
lercanidipine hydrochloride and valsartan
[77] Table 5
[Table 5]
Component Amount
Lercanidipine hydrochloride 10.0 mg
Valsartan 80.0 mg
Polyvinylpyrrolidone 2.5 mg
Microcrystalline cellulose 42.5 mg
Lactose 26.5 mg
Croscarmellose sodium 25.0 mg
Low-substituted hydroxypropyl cellulose 25.0 mg
Crospovidone 15.0 mg
Hydrous silicon dioxide 5.0 mg
Hydroxypropyl cellulose 6.0 mg
Magnesium stearate 2.5 mg
Total 240.0 mg
[79] The same amounts of lercanidipine hydrochloride, valsartan and excipients as
Example 1 were mixed altogether, wet-granulated and then pressed into tablets. The
tablets thus obtained were film coated.
[80]
[81] Comparative Example 2 : Tablets obtained from simple mixture of commercially
available granules
[82] Table 6
[Table 6]
Lercanidipine hydrochloride granules
Lercanidipine hydrochloride 10.0 g
Polyvinylpyrrolidone 4.5 mg
Macrocrystalline cellulose 39.0 mg
Lactose 30.0 mg
Sodium starch glycolate 15.5 mg
Magnesium stearate 1.0 mg
Sub-total 100.0 mg
Valsartan granules
Valsartan 80.0 mg
Microcrystalline cellulose 54.0 mg
Crospovidone 15.0 mg
Colloidal anhydrous silicic acid 1.5 mg
Magne sium stearate 4.5 mg
Sub-total 155.0 mg
Total 255.0 mg
[83]
[84] Granules having the same compositions as the commercially available lercanidipine
hydrochloride (Zanidip® tablet) and valsartan (Tareg® tablet) were prepared, simply
mixed and pressed into tablets and then film coated.
[85]
[86] Comparative Example 3 : Commercially available preparation of lercanidipine
hydrochloride
[87] Table 7
[Table 7]
Commercially available preparation of
lercanidipine hydrochloride
Lercanidipine hydrochloride lO.O g
Polyvinylpyrrolidone 4.5 mg
Microcrystalline cellulose 39.0 g
Lactose 30.0 mg
Sodium starch glycolate 15.5 mg
Magnesium stearate 1.0 mg
Opadry OY-S-6497 3.0 mg
Sub-total 103.0 mg
[88]
[89] Tablets were prepared according to the same prescription and process as the com
mercially available lercanidipine hydrochloride (Zanidip ® tablet).
[90]
[91] Test Example 1: Dissolution test of lercanidipine hydrochloride for preparations
according to Examples 1 to 4
[92] For the complex tablets of Examples 1 to 4 prepared from the separated granules and
the complex tablets of Comparative Example 1 prepared from the unseparated mixture,
a dissolution test was performed and compared under the following conditions.
[93]
[94]
[95] Eluate: pH 1.2 (900 mL)
[96] Instrument: USP Paddle Method, 50 rpm
[97] Temperature: 37°C
[98]
[99]
[100] Column: Stainless steel column which has an inner diameter of about 4.6 mm and a
length of 15 cm and which is filled with octadecylsilylated silica gel of 5 for liquid
chromatography
[101] Mobile phase: acetonitrile/pH 3.0 sodium perchlorate buffer (60/40)
[102] Flow rate: About 1.0 mL/min
[103] Detector: UV spectrophotometer (Wavelength 240 nm)
[104]
[105]
[106] As is confirmed by Figure 1, the lercanidipine hydrochloride- valsartan complex
tablets of Examples 1 to 4 prepared from the separated granules showed a higher level
of dissolution rate at the beginning stage, when compared with the tablets of Com
parative Example 1.
[107]
[108] Test Example 2 : Dissolution test of lercanidipine hydrochloride for preparations
according to Examples 5 to 8
[109] For the complex bilayer tablets of Examples 5 to 8 prepared from the separated
granules and the wet complex tablet of Comparative Example 1 prepared from the unseparated
mixture, a dissolution test was performed and compared under the same
conditions as Test Example 1.
[110] As is confirmed by Figure 2, the lercanidipine hydrochloride- valsartan complex
tablets of Examples 5 to 8 prepared from the separated granules showed a higher level
of dissolution rate, when compared with the tablets of Comparative Example 1.
[Ill]
[112] Test Example 3 : Dissolution test of lercanidipine hydrochloride for preparations
according to Examples 9 to 12
[113] For the complex trilayer tablets of Examples 9 to 12 prepared from the separated
granules and the wet complex tablets of Examples 1 to 4 prepared from the separated
granules, adissolution test was performed and compared under the same conditions as
Test Example 1.
[114] As is confirmed by Figure 3, the complex trilayer tablets prepared from the separated
granules and the wet complex tablets prepared from the separated granules showed
similar dissolution rates.
[115]
[116] Test Example 4 : Dissolution test of lercanidipine hydrochloride for preparation
according to Example 13
[117] For the separated coating tablet of Example 13 and the wet complex tablet of
Example 1, a dissolution test was performed and compared under the same conditions
as Test Example 1.
[118] As is confirmed by Figure 4, the separated coating tablet and the wet complex tablet
showed similar dissolution rates.
[119]
[120] Test Example 5 : Comparative dissolution test for preparations according to
Example 1, and Comparative Examples 2 and 3
[121] For the complex tablet of Example 1 prepared from the separated granules, the tablet
of Comparative Example 2 obtained from a simple mixture of commercial granules
and the commercial preparation of Comparative Example 3, a dissolution test was
performed and compared under the same conditions as Test Example 1.
[122] As is confirmed by Figure 5, the complex tableta according to Example 1 showed the
same dissolution pattern of lercanidipine hydrochloride as the commercial preparation
of lercanidipine hydrochloride according to Comparative Example 3. On the other
hand, the tablet of Comparative Example 2 which was obtained by simply mixing the
commercially available lercanidipine hydrochloride granules and valsartan granules
and pressing them into tablets showed a very low dissolution of lercanidipine hy
drochloride, which seems to be caused by the gelation of valsartan.
[123]
[124] Test Example 6 : Clinical effect by combination therapy of lercanidipine hy¬
drochloride and valsartan
[125] The following tests were performed to evaluate the efficacy and safety of the com
bination therapies of lercanidipine hydrochloride and valsartan in comparison with
each component administered alone in patients with essential hypertension.
[126] The subjects were 20- to 75-year-old patients suffering from essential hypertension,
who showed the blood pressure of 90 mmHg < DBP (diastolic blood pressure) < 109
mmHg when measured in Week 0 after the administration of placebo for 2 weeks. In
order to remove the interference effect with the antihypertensive drug previously taken
and to improve drug compliance, the subject patients took a placebo in a single blind
during the run-in period of 2 weeks right after the drug holiday of 0 ~ 1 week. After
the subjects were randomly assigned to a total of four groups consisting of one placebo
group, four monotherapy groups and four combination therapy groups in the same
probability, they took the drug in a double blind according to the group, measuring
point and administration period in the following table. In this case, the commercially
available Zanidip ® tablet 10 mg was used as lercanidipine hydrochloride, and the com
mercially available Tareg® tablet 80 mg was used as valsartan.
[127] Table 8
[Table 8]
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5
(Day -21) (Day -14) (Day 0) (Day 28) (Day 5 )
Screening Run-in Double- blind Treatment
Period Period
(Single-blind
Placebo)
Placebo Group 1: Placebo
Group 2 : Lercanidipine hydrochloride (L) 10 mg
Group 3: Lercanidipine hydrochloride (L) 20 mg
Group 4 : Valsartan(V) 80 mg
Group 5: Valsartan(V) 1 0 mg
Group 6 : Lercanidipine hydrochloride (L)
Valsartan (V) 80 mg
Group 7 : Lercanidipine hydrochloride (L) 10 mg +
Valsartan (V) 60 mg
Group 8 : Lercanidipine hydrochloride (L) 20 mg +
Valsartan (V) 80 mg
Group 9 : Lercanidipine hydrochloride (L) 20 mg
Valsartan (V) 60 mg
[128]
[129] At each measuring point, the blood pressure of the subject patients was measured
according to the blood pressure monitoring guidelines provided by the Korean Society
of Hypertension to calculate the changes of DBP and SBP (systolic blood pressure)
from the baselines after 8 weeks (values after 8 weeks - baseline). The effects of the
combination therapies were compared with that of the monotherapy to evaluate the su
periority.
[130] 130 patients satisfying the criteria of 100 mmHg < DBP < 109 mmHg on Visit 3
(Day 0) were tested, and the results are summarized in the following Table 9. It was
demonstrated that the patients taking the combination therapy of lercanidipine hy
drochloride 20 mg + valsartan 80 mg showed a statistically significant superiority both
in the changes of DBP and SBP in comparison to those taking placebo or
monotherapy.
[131] In the following Table 9, "Diff." represents the differences in the blood pressure
change of monotherapy in comparison to that of combination therapy (i.e., blood
pressure change of monotherapy - blood pressure change of combination therapy), and
Two-sided 95% CI is two-sided 95% confidence interval, which means that a sig
nificant difference can be recognized when the lower limit of the confidence interval is
greater than 0. The terms are used hereinafter as having the same meaning.
[132] Table 9
[Table 9]
[133]
[134] Furthermore, on Visit 3 (Day 0), 368 patients who satisfied the criteria of 90 mmHg
< DBP < 109 mmHg and whose blood pressures were measured at trough time (22-26
hours after drug administration) on Visit 5 (Day 56) were tested. As a result, it was
demonstrated that the patients taking the combination therapy of lercanidipine hy
drochloride 10 mg + valsartan 160 mg or lercanidipine hydrochloride 20 mg +
valsartan 160 mg showed a statistically significant superiority to those taking placebo
or monotherapies both in the changes of DBP and SBP. In the case of the patients
taking the combination therapy of lercanidipine hydrochloride 20 mg + valsartan 80
mg, it was demonstrated that they show superiority to those taking placebo or
monotherapy of lercanidipine hydrochloride 20 mg only, both in the changes of DBP
and SBP (see Tables 10 to 12).
[135] Table 10
[Table 10]
Combination DBP SBP
Monotherapy
Therapy Diff. Two-sided 95% CI Diff. Two-sided 95% CI
Placebo L 10 + V 160 7.72 4.82, 10.62 .04 5.6, 16.47
L10 L10 + V160 7.08 4.11, 10.05 8.62 3.76, 13 .47
V160 L10 + V160 3.45 0.7, 6.2 5.3 1 0.28, 10.34
[136]
[137] Table 1 1
[Table 11]
Table 12
[Table 12]
[140]
[141] Test Example 7 : Clinical effect by combination therapy of lercanidipine hy¬
drochloride and valsartan
[142] The following test was performed to evaluate the efficacy and safety of the com
bination therapy of lercanidipine hydrochloride and valsartan in comparison with each
component administered alone ton patients with essential hypertension.
[143] The subjects were 20- to 75-year-old patients suffering from essential hypertension,
who showed the blood pressure of 95 mmHg < DBP < 114 mmHg when measured in
Week 0 after the administration of placebo for 2-4 weeks. In order to remove the in
terference effect with the antihypertensive drug previously taken and to improve drug
compliance, the subject patients took a placebo in a single blind during the run-in
period of 2-4 weeks right after the drug holiday of 1 week. After the subjects were
randomly assigned to a total of four groups consisting of one placebo group, two
monotherapy groups and one combination therapy group in the same probability, they
took the drug in a double blind according to the group, measuring point and admin
istration period in the following table. In this case, the commercially available Zanidip
® tablet 10 mg was used as lercanidipine hydrochloride, and the commercially
available Tareg® tablet 80 mg was used as valsartan.
[144] Table 13
[Table 13]
[145]
[146] At each measuring point, the blood pressure of the subject patients was measured
according to the blood pressure monitoring guidelines provided by the Korean Society
of Hypertension to calculate the changes of DBP and SBP from the baselines after 8
weeks (values after 8 weeks - baseline). The effect of the combination therapy was
compared with that of the monotherapy to evaluate the superiority.
[147] 193 patients satisfying the criteria of 95 mmHg < DBP < 114 mmHg on Visit 3 (Day
0) were tested, and the results are summarized in the following Table 14. It was
demonstrated that the patients taking the combination therapy of lercanidipine hy
drochloride 10 mg + valsartan 80 mg showed a statistically significant superiority both
in the changes of DBP and SBP to those taking the placebo. It was also demonstrated
that the patients taking the combination therapy of lercanidipine hydrochloride 10 mg
+ valsartan 80 mg showed a statistically significant superiority in the change of SBP to
those taking the monotherapy of lercanidipine hydrochloride 10 mg.
[148] Table 14
[Table 14]
[149]
[150] Test Example 8 : Effect from combination therapy of lercanidipine hy¬
drochloride and valsartan in rats
[151] Male SHRs (Spontaneous Hypertensive Rats, Orient), 13 weeks old, were acclimated
and bred for 1 week while maintaining the temperature range of 22~24°C and humidity
of 50-70% in a 12-hour light-dark cycle. Feed and beverage in standard diet were
provided ad libitum.
[152] One day before the drug administration, the blood pressure and heart rate of the test
animals were measured using BP-2000 Blood Pressure Analysis System (Visitech).
After the measurement, the animals were fasted for about 12 hours, during which
beverage was provided ad libitum. The respective test drugs were orally administered
to the fasted test animals in a volume of 5 ml/kg. The same volume of medium was
orally administered to the negative control group. The test drugs lercanidipine hy
drochloride and valsartan were used after being dissolved in 20%
2-hydroxypropyl-beta-cyclodextrin (HPCD). To increase the solubility, 0.5 ml of IN
HC1 was added to lercanidipine hydrochloride and 0.5 ml of 0.05% NaOH was added
to valsartan, and then thoroughly dissolved. The test groups, one of which was the
combination therapy group (N=10) administered 2 mg/kg of lercanidipine hy
drochloride and 16 mg/kg of valsartan and the other of which was the monotherapy
group (N=10) administered 16 mg/kg of valsartan, were compared with the control
group in the changes of blood pressure and heart rate, and then statistically calculated.
The statistical calculation was performed in a one-way ANOVA to analyze the sig
nificant differences between the test group and the control group, and the combination
therapy group and the monotherapy group.
[153] As can be seen from the results of Figures 6 to 9, the combination therapy group ad
ministered 2 mg/kg of lercanidipine hydrochloride and 16 mg/kg of valsartan showed
significant blood pressure decrease and heart rate increase in comparison with both the
monotherapy group administered 16 mg/kg of valsartan and the control group 1 hour
after administration in SHR. On the other hand, the monotherapy group administered
16 mg/kg of valsartan showed no significant blood pressure decrease or heart rate
increase in comparison with the control group.
Claims
A pharmaceutical composition for the prevention and treatment of a
cardiovascular disease which comprises lercanidipine hydrochloride
and valsartan as active components.
The composition according to claim 1, wherein the lercanidipine hy
drochloride and valsartan are in a separated form.
The composition according to claim 2, which is prepared by separate
granulations of the lercanidipine hydrochloride and valsartan.
The composition according to claim 3, wherein each of the ler
canidipine hydrochloride granules and valsartan granules further
comprise a pharmaceutically acceptable excipient.
The composition according to claim 4, wherein the lercanidipine hy
drochloride granules comprise 4 to 10 parts by weight of a pharma
ceutically acceptable excipient per 1 part by weight of lercanidipine hy
drochloride.
The composition according to claim 4, wherein the valsartan granules
comprise 1 to 2 parts by weight of a pharmaceutically acceptable
excipient per 1 part by weight of valsartan.
The composition according to claim 4, which comprises the com
bination of 10 mg of lercanidipine hydrochloride and 80 mg of
valsartan, 10 mg of lercanidipine hydrochloride and 160 mg of
valsartan, 20 mg of lercanidipine hydrochloride and 80 mg of valsartan,
or 20 mg of lercanidipine hydrochloride and 160 mg of valsartan.
The composition according to claim 2, wherein each of the ler
canidipine hydrochloride and valsartan is included in a separated layer.
The composition according to claim 8, wherein a separation layer is
placed between the lercanidipine hydrochloride layer and the valsartan
layer.
The composition according to claim 2, which is prepared by coating a
valsartan-containing tablet with a lercanidipine hydrochloridecontaining
layer.
The composition according to claim 10, wherein a separation layer is
placed between the valsartan-containing tablet and the lercanidipine hydrochloride-
containing layer.
The composition according to claim 1, wherein the cardiovascular
disease is at least one selected from the group consisting of angina
pectoris, hypertension, arteriospasm, cardiac arrhythmia, cardiac hypertrophy,
cerebral infarction, congestive heart failure and myocardial
infarction.
[Claim 13] A method for the preparation of the composition according to claim 3,
which comprises the steps of:
(a) wet-granulating a mixture of lercanidipine hydrochloride and a
pharmaceutically acceptable excipient and drying the granules;
(b) wet-granulating a mixture of valsartan and a pharmaceutically ac
ceptable excipient and drying the granules; and
(c) mixing the dried granules prepared in steps (a) and (b).