CN103249415A - Complex formulation comprising lercanidipine hydrochloride and valsartan and method for the preparation thereof - Google Patents

Complex formulation comprising lercanidipine hydrochloride and valsartan and method for the preparation thereof Download PDF

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CN103249415A
CN103249415A CN2011800589519A CN201180058951A CN103249415A CN 103249415 A CN103249415 A CN 103249415A CN 2011800589519 A CN2011800589519 A CN 2011800589519A CN 201180058951 A CN201180058951 A CN 201180058951A CN 103249415 A CN103249415 A CN 103249415A
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valsartan
lercanidipine hydrochloride
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lercanidipine
tablet
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CN103249415B (en
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丁荣识
朴秀娥
金利宣
金成一
全宰贤
金烔煃
金由璘
朴熙东
朴圣在
李承学
金周铉
郑珉英
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LG Corp
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Abstract

The present invention relates to a pharmaceutical composition comprising lercanidipine hydrochloride and valsartan as active components and a method for the preparation thereof. 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 the adverse effects of each component. In addition, the present composition comprises lercanidipine hydrochloride and valsartan in a separated form so as to increase the dissolution rates of both components and reduce the adverse effects.

Description

Comprise compound formulation of Lercanidipine hydrochloride and valsartan and preparation method thereof
Technical field
The present invention relates to a kind of Lercanidipine hydrochloride and valsartan of comprising as pharmaceutical composition of active component and preparation method thereof.
Background technology
Hypertension is a kind of modal cardiovascular disease.Lasting hypertension is destroyed the blood vessel in kidney, heart and the brain, and this increases renal failure, coronary heart disease, heart failure and occurrence of stroke.Hypertension is divided into two types, i.e. the special property sent out or essential hypertension and secondary hypertension.The reason of essential hypertension is still unknown, does not have specific potential disease during generation.The hyperpietic of most of (95%), particularly the patient more than 40 years old belongs to this type.Though do not find owing to there is not potential disease essential hypertension, problem reason may be heredity, edible salty food dietary habit, obesity, advanced age, pressure, have a liking for cigarette and excessive drinking.Secondary hypertension then is derived from specifically and induces an illness.About 5% hyperpietic, relatively young people belongs to this type.Secondary hypertension is caused by toxemia of nephritis, endocrine disturbance and pregnancy duration etc., and blood pressure reduces along with the treatment that induces an illness.
Antihypertensive therapy and being not used in induces an illness, and depends on the normal physiological mechanism of blocking-up blood pressure regulating.Antihypertensive therapy is carried out subclinical patient, and its directly do not cause the patient inconvenience but by symptom and death take place after bringing high blood pressure down to prevent.
Hypotensive agent is divided three classes according to its regulatory site and mechanism of action usually: diuretic, sympatholytic and vasodilation, it segments according to action site.The effect of diuretic is to increase the amount of urine and from health discharge water and salt, it brings high blood pressure down by water and the salt that reduces in the health.Orthosympathetic effect is frequency and intensity and the vasoconstrictive that increases heart beating.Sympatholytic then suppresses orthosympathetic being used for and brings high blood pressure down.Three types sympatholytic is arranged: alpha block agent inhibitory action is in vasoconstrictive sympathetic nerve; The beta blocker inhibitory action is in the sympathetic nerve of heart beating; And maincenter sympatholytic inhibitory action is in the sympathetic nerve of brain.Vasodilation brings high blood pressure down by blood vessel dilating.Known have various vasodilations: ACE inhibitor for example, and it suppresses the synthetic of vasoconstrictor Angiotensin II; And angiotensin-ii receptor blockers, it suppresses the effect of Angiotensin II.Calcium channel blocker suppresses to flow in the calcium cell to bring high blood pressure down, and it also is a kind of vasodilation, the rising blood pressure because the intracellular Ca2+ of high concentration causes vasoconstriction.
Obtaining under the situation of abundant resisting hypertension effect owing to serious hypertension, can increase the dosage of hypotensive agent usually.Yet the dosage of excessive increase may cause side effect.In this case, unite and use the medicine with different mechanism of action rather than the use that increases medicine can minimized side effects, obtain effect of sufficient simultaneously.
Unite and use the advantage of medicine as follows:
At first, effect increases the resisting hypertension effect synergistically the medicine by having the different mechanisms of action time.And a kind of homeostasis compensating action of medicine is suppressed by another kind of medicine, thereby obtains more effective antihypertensive function.For example, owing to the reflex tachycardia that uses vasodilation to cause and the retention of salt and water can be regulated by using beta blocker and diuretic respectively, thereby increase the resisting hypertension effect.
Secondly, by uniting the use medicine, even under low dosage, also can obtain sufficient resisting hypertension effect, thereby can reduce the dose dependent side effect.And, can block and reduce the side effect that pharmacological action causes.
The 3rd, hypertension almost is asymptomatic and must regulates all the life, so patient's compliance of medicine determines the result for the treatment of.In this, unite and use can make the life better quality and increase patient's compliance of the active drug with low side effect.
Recently, can be purchased the compound formulation that in a pill, comprises at least two kinds of medicines.Their low prices and be easy to use.Use compound formulation can increase the target organ damage that patient's compliance and prevention or delay hypertension cause.
Summary of the invention
Technical problem
Consider present situation, the inventor has carried out research widely, to come the developing new drug compositions to be used for the collaborative resisting hypertension effect that increases by uniting the hypotensive agent that at least two kinds of uses have different mechanisms of action, reduce side effect and improve patient's compliance.By these effort, the inventor finds that such purpose can particularly realize by the specific compound formulation that comprises them by uniting use Lercanidipine hydrochloride and valsartan, finishes the present invention thus.
Therefore, the purpose of this invention is to provide a kind of pharmaceutical composition for prevention and treatment cardiovascular disease, it comprises Lercanidipine hydrochloride with different mechanisms of action and valsartan as active component.
Especially, the invention provides a kind of compound formulation, it comprises Lercanidipine hydrochloride and the valsartan of isolated form.
Another object of the present invention provides a kind of method of compound formulation for the preparation of prevention and treatment cardiovascular disease, and described compound formulation comprises Lercanidipine hydrochloride and valsartan as active component.
Solution
Lercanidipine hydrochloride is a kind of dihydropyridine calcium antagonist, and the same with other calcium antagonists, suppresses to flow in the calcium arterial smooth muscle with lax periphery small artery and brings high blood pressure down.Lercanidipine does not cause that faithless flesh shrinks, but can cause slight reflex tachycardia.Lercanidipine has strong affinity to the dihydropyridine subunit of L-type calcium channel and to its competitive antagonism.It is safe that calcium-channel antagonists is considered to, and it is confirmed that for all types of hypertension it is effective.Lercanidipine is a kind of dihydropyridine calcium antagonist, and it is confirmed that to have powerful and long-acting resisting hypertension effect in preclinical test.Lercanidipine advantageously can tolerate under 30mg or lower dosage, and brings high blood pressure down in the dose dependent mode.Calcium antagonist is owing to its resisting hypertension effect is considered to the kidney protectiveness.This probability is confirmed in renal failure that chemotherapy, contrast agent, cyclosporin or aminoglycoside antibiotics are induced and nephrotoxicity.In addition, calcium antagonist has kidney protectiveness effect to the kidney donor in renal transplantation.Lercanidipine is usually with the dosage use of 10-20mg once a day, and the maximal dose of every day is about 30mg.Lercanidipine by fast Absorption, and reaches its maximal plasma concentration in 1.5-3 hour after administration behind oral administration, it carries out first pass metabolism widely.The absorption of lercanidipine highly depends on food intake, and significantly increases (3-4 doubly) by the while dietary intake.Comprise 10 or the oral tablet of 20mg lercanidipine with trade name Sheet " be purchased, by Recordati S.p.A (Milan, Italy) lercanidipine of Xiao Shouing can be according to the preparation of EP0153016 and US4705797 disclosed method, document integral body is quoted adding this paper.And US-A1-2003/0180355 discloses a kind of hyperpietic's for the treatment of method, and it comprises that administration comprises lercanidipine and enalapril as the compound formulation of active component.
Valsartan ((S)-N-valeryl-N-{[2 '-(1H-tetrazolium-5-yl)-diphenyl-4-yl]-methyl }-valine) be a kind of angiotensin ii receptor antagonist, it brings high blood pressure down by vasodilation.Angiotensin II has vasoconstriction and sodium retention effect.Valsartan can be purchased Sheet) and can prepare by known method.For example, the preparation of valsartan is disclosed in US5399578, and its integral body is quoted adding this paper.Valsartan is used for purpose of the present invention with its isolated form or suitable salt form.In the U.S., the predose that valsartan uses is 80-160mg qd, and maximal dose is 320mg qd.In Korea S, valsartan is write a prescription to the patient who suffers from cardiac insufficiency or postmyocardial infarction syndrome, and dosage is 160mg b.i.d.Yet, if patient's blood pressure does not reach expected value under the dosage of 160mg b.i.d, replace valsartan with other drug.The normally used dosage of valsartan is about 40-320mg in a slice, preferably about 80-320mg, most preferably from about 80-160mg.
The inventor carried out having the above-mentioned mechanism of action and maximum every day dosage Lercanidipine hydrochloride and the various experiments of valsartan to confirm, compare with independent use, unite and use these medicines that prevention and treatment cardiovascular disease are had synergy, reduce and use the side effect that causes separately and improve patient's compliance.Therefore, the pharmaceutical composition that comprises Lercanidipine hydrochloride and valsartan can be used for effectively preventing and treating cardiovascular disease.The example of cardiovascular disease includes but not limited to angina pectoris, hypertension, arteriospasm, arrhythmia, cardiac hypertrophy, cerebral infarction, congestive heart failure, myocardial infarction etc.
Yet, may have some problem that is caused by its intrinsic differences of physical properties by mixing the compound formulation that comprises Lercanidipine hydrochloride and valsartan that two kinds of medicines prepare simply.
First problem is the difference of their pKa value.The pKa value of Lercanidipine hydrochloride is about 6.83, and the pKa value of valsartan is about 3.92.Therefore, Lercanidipine hydrochloride 4.0 or lower pH under have the dissolubility of increase, and valsartan 4.0 or higher pH under have the dissolubility of increase.The dissolubility of so every kind of medicine of pKa differentia influence between two kinds of medicines.
Second problem is the gelling of valsartan.Valsartan 4.0 or lower pH under owing to its low-solubility begins gelling, and dissolving is very slow.The stripping of Yan Chiing makes the absorption delay of valsartan in small intestinal like this.In addition, the gelling of valsartan can postpone the stripping of Lercanidipine hydrochloride.This problem may influence the absorption of Lercanidipine hydrochloride unfriendly, and it is disintegrate and absorption rapidly in gastrointestinal tract.Therefore, must avoid the gelling of valsartan under low pH in the compound formulation.
The 3rd problem is the low stripping of compound formulation.In the preliminary experiment of the compound formulation that the wet granulation of the mixture by Lercanidipine hydrochloride and valsartan prepares, this compound formulation is owing to the interaction between two kinds of components shows low stripping.Low stripping like this has a strong impact on absorption and the bioavailability of two kinds of components.Reduce the effectiveness that ground bioavailability expection also reduces compound formulation.Therefore, need improved preparation method to prevent this problem.
The 4th problem is the difference of disintegration time between the commercially available single medicine preparation, and this makes and is difficult to by using conventional compound method to keep the intrinsic stripping pattern of every kind of medicine.
In order to overcome the problems referred to above, the inventor has designed a kind of compound formulation that comprises Lercanidipine hydrochloride and valsartan, and it physically isolates to minimize contact area and the chance that comes in contact with two kinds of components.According to the present invention, compound formulation can provide the excellent dissolution rate of Lercanidipine hydrochloride and valsartan.
Advantageous effects
The pharmaceutical composition that comprises Lercanidipine hydrochloride and valsartan of the present invention has excellent effect for prevention and treatment cardiovascular disease and concurrent (complex) disease thereof, and reduce the side effect of every kind of component, this is owing to have the synergistic combination of two kinds of components of the different mechanisms of action.In addition, the invention provides a kind of compound formulation, it comprises Lercanidipine hydrochloride and the valsartan of isolated form, thereby can overcome the problem that the simple mixtures by Lercanidipine hydrochloride and valsartan causes, and can increase the dissolution rate of two kinds of components.
Description of drawings
Fig. 1 is the figure that following content is shown: the result of the lercanidipine stripping test that the compound formulation of embodiment 1-4 is compared with comparative example 1.
Fig. 2 is the figure that following content is shown: the result of the lercanidipine stripping test that the compound formulation of embodiment 5-8 is compared with comparative example 1.
Fig. 3 is the figure that following content is shown: the result of the lercanidipine stripping test that the compound formulation of embodiment 1-4 is compared with embodiment 9-12.
Fig. 4 be the figure that following content is shown: embodiment 1 with the result of the lercanidipine stripping test compared with embodiment 13 of compound formulation.
Fig. 5 is the result of the lercanidipine stripping test compared with 3 preparation of compound formulation and the comparative example 2 of the figure that following content is shown: embodiment 1.
Fig. 6 is the figure that following content is shown: according to test case 8, behind administering drug combinations Lercanidipine hydrochloride 2mg/kg (Z) and the valsartan 16mg/kg (V), systolic pressure (BP) over time (%) ( * *P＜0.001 (vs. contrast), ##P＜0.01 (vs. valsartan)).
Fig. 7 is the figure that following content is shown: according to test case 8, behind administering drug combinations Lercanidipine hydrochloride 2mg/kg (Z) and the valsartan 16mg/kg (V), average BP over time (%) ( * *P＜0.001 (vs. contrast), ##P＜0.01 (vs. valsartan)).
Fig. 8 is the figure that following content is shown: according to test case 8, behind administering drug combinations Lercanidipine hydrochloride 2mg/kg (Z) and the valsartan 16mg/kg (V), diastole BP over time (%) ( * *P＜0.001 (vs. contrast), ##P＜0.01 (vs. valsartan)).
Fig. 9 is the figure that following content is shown: according to test case 8, behind administering drug combinations Lercanidipine hydrochloride 2mg/kg (Z) and the valsartan 16mg/kg (V), heart rate over time (%) ( * *P＜0.001 (vs. contrast), ##P＜0.01 (vs. valsartan)).
The specific embodiment
As the preferred embodiments of the invention, the compound formulation that comprises the Lercanidipine hydrochloride of isolated form and valsartan prepares by the granulation respectively of Lercanidipine hydrochloride and valsartan.
The method for preparing compound formulation of the present invention may further comprise the steps:
(a) with the mixture wet granulation of Lercanidipine hydrochloride and the acceptable excipient of pharmacy, and with described particle drying;
(b) with the mixture wet granulation of valsartan and the acceptable excipient of pharmacy, and with described particle drying; And
(c) with step (a) and (b) the dried granules mixing of middle preparation.
For example, compound formulation of the present invention mixes two kinds of granules by preparing Lercanidipine hydrochloride granule and valsartan granule respectively, then mixture is pressed into tablet and prepares.Compare with the compound formulation of comparative example 1, show the stripping that Lercanidipine hydrochloride improves and do not influence the stripping of valsartan according to the compound formulation of the embodiment 1-4 of method for preparing, the compound formulation of described comparative example 1 prepares (see figure 1) by the mixture wet granulation that Lercanidipine hydrochloride and valsartan are not isolated.
Another specific embodiments of the present invention provides a kind of bilayer tablet of compound formulation, and it comprises Lercanidipine hydrochloride and valsartan.As described in embodiment 5-8 hereinafter, utilize bi-layer tablet press, bilayer tablet can be pressed into second tablet layer with the Lercanidipine hydrochloride granule and prepare then by the valsartan granule is pressed into first tablet layer.Bilayer tablet of the present invention shows the excellent stripping (see figure 2) of the Lercanidipine hydrochloride the same with embodiment 1-4.
In another embodiment of the present invention, bilayer tablet can comprise the sealing coat between Lercanidipine hydrochloride layer and the valsartan layer, thereby can obtain tri-layer tablets.Sealing coat can for example be made up of microcrystalline Cellulose.
Another embodiment of the present invention provides a kind of compound formulation, and it comprises Lercanidipine hydrochloride and the valsartan of isolated form, wherein the tablet of being made up of valsartan with the Lercanidipine hydrochloride coating.Such preparation can be by being dissolved in Lercanidipine hydrochloride and excipient or be scattered in the coating solvent with the preparation coated composition, and the tablet of being made up of valsartan with this coated composition coating prepares.The example of excipient comprises polyvinylpyrrolidone, and ethanol can be used as the coating solvent.If need, another sealing coat can be placed between valsartan tablet and the Lercanidipine hydrochloride coating.
Compound formulation of the present invention can comprise the valsartan of per 1 weight portion Lercanidipine hydrochloride 4-32 weight portion, preferred 4-16 weight portion.If the amount of valsartan then can't obtain desired effects less than per 1 weight portion Lercanidipine hydrochloride, 4 weight portions.On the other hand, the valsartan that comprises more than per 1 weight portion Lercanidipine hydrochloride, 32 weight portions is unallowed.
Compositions for prevention and treatment cardiovascular disease of the present invention can comprise pharmaceutically acceptable carrier or excipient separately at Lercanidipine hydrochloride granule and valsartan granule.The example of pharmaceutically acceptable carrier or excipient comprises microcrystalline Cellulose, lactose, low-substituted hydroxypropyl cellulose, disintegrating agent (as cross-linking sodium carboxymethyl cellulose, crospovidone and carboxymethyl starch sodium) and granulation binders (as polyvinylpyrrolidone and hydroxypropyl cellulose).In addition, can comprise lubricant, as silica sol, hydrated SiO 2, magnesium stearate, sodium stearyl fumarate
Figure BDA00003316628800071
Glyceryl behenate
Figure BDA00003316628800072
Calcium stearate, stearic acid and Talcum.
In the present invention, the Lercanidipine hydrochloride granule can comprise the acceptable excipient of pharmacy of per 1 weight portion Lercanidipine hydrochloride 4-10 weight portion; And the valsartan granule can comprise the acceptable excipient of pharmacy of per 1 weight portion valsartan 1-2 weight portion.Such ratio is applicable to the preparation that the present invention is all, comprises the granule of isolation.If preparation has the ratio that exceeds above-mentioned scope, then may produce too small or excessive tablet, and its stripping may be delayed or increase.
Should pay special attention to the ratio of used disintegrating agent among the present invention.The amount that conventional superdisintegrant such as cross-linking sodium carboxymethyl cellulose, crospovidone and carboxymethyl starch sodium recommendation are used is the 0.5-8.0wt% based on the excipient total amount.Yet, in the present invention, use the superdisintegrant of overdose of 5-20wt% preventing gelling, and show intrinsic stripping behavior.Utilize the problem of conventional formulation of the superdisintegrant coating of overdose to be to be difficult to coating and coatings is broken at memory period owing to moistening fast.Yet, it is confirmed that there is not such problem in the present invention.
The example that can be used for the coating materials in the film coatings comprises conventional coating materials, for example hydroxypropyl emthylcellulose,
Figure BDA00003316628800073
Series, Series, but be not limited to this.
Embodiment by hereinafter explains the present invention in more detail.Yet these embodiment only are used for example the present invention, and scope of the present invention is not limited.
Embodiment
Embodiment 1-4: the granule that preparation is isolated
[table 1]
Figure BDA00003316628800081
Utilize distilled water will have Lercanidipine hydrochloride granule and the valsartan granule wet granulation of above-mentioned composition, drying also grinds to form 25 orders.Two kinds of granules are mixed and be pressed into complex tablet, then with its film coating.Colorcon is sold as PVP
Figure BDA00003316628800082
II is used as the film coating material, and carries out the film coating in all following embodiment and comparative example in an identical manner.Mixture is mixed 5 minutes or longer time, thereby make the superdisintegrant (super-integrating agent) that in wet-granulation process, adds fully moistening.Abundant incorporation time like this increases the porosity of granule, helps disintegration time to prevent gelling.Among the embodiment hereinafter, the wet granulation that carries out as indicated above.
Embodiment 5-8: preparation composite double layer tablet
[table 2]
Figure BDA00003316628800091
Utilize distilled water will have Lercanidipine hydrochloride granule and the valsartan granule wet granulation of above-mentioned composition, drying also grinds to form 25 orders.Two groups of granules are pressed into double-deck solid form, thus with double-deck solid form film coating.
Embodiment 9-12: preparation composite three-layer tablet
[table 3]
Figure BDA00003316628800101
Utilize distilled water will have Lercanidipine hydrochloride granule and the valsartan granule wet granulation of above-mentioned composition, drying also grinds to form 25 orders.Add the valsartan granule to prepare the first tablet part, add sealing coat preparing the second tablet part, and add the Lercanidipine hydrochloride granule to prepare the 3rd tablet part.Obtain the composite three-layer tablet and with its film coating.
Embodiment 13: the preparation tablet of Lercanidipine hydrochloride layer coating
[table 4]
Figure BDA00003316628800111
The valsartan granule that will have above-mentioned composition is pressed into tablet, introduces then in the coating machine.Lercanidipine hydrochloride and polyvinylpyrrolidone are dissolved in and are scattered in the ethanol with the preparation coatings.By coatings being sprayed at the valsartan tablet its coating, film coating then.
Comparative example 1: never the mixture of the Lercanidipine hydrochloride of Ge Liing and valsartan prepares tablet
[table 5]
Figure BDA00003316628800121
To mix jointly with Lercanidipine hydrochloride, valsartan and the excipient of embodiment 1 same amount, wet granulation is pressed into tablet then.With thus obtained tablet film coating.
Comparative example 2: the tablet that obtains from the simple mixtures of commercially available granule
[table 6]
Figure BDA00003316628800122
Preparation has and commercially available Lercanidipine hydrochloride Sheet) and valsartan
Figure BDA00003316628800132
Sheet) granule of same composition simply mixes it and is pressed into tablet, film coating then.
Comparative example 3: the commercially available preparation of Lercanidipine hydrochloride
[table 7]
Figure BDA00003316628800133
According to commercially available Lercanidipine hydrochloride
Figure BDA00003316628800134
Sheet) identical prescription and method prepare tablet.
Test case 1: the stripping test of the Lercanidipine hydrochloride of the preparation of embodiment 1-4
For the complex tablet of the embodiment 1-4 for preparing from spacer particles and the complex tablet of never isolating the comparative example 1 of mixture preparation, carry out stripping under the following conditions and test and compare.
＜leaching condition 〉
Eluent: pH1.2 (900mL)
Instrument: USP starches method, 50rpm
Temperature: 37 ℃
＜analysis condition 〉
Post: stainless steel column, internal diameter are about 4.6mm, and length is 15cm, are filled with 5 μ m octadecyl silicyl silica gel for liquid chromatograph
Mobile phase: acetonitrile/pH3.0 sodium perchlorate buffer (60/40)
Flow velocity: about 1.0mL/min
Detector: UV spectrophotometer (wavelength 240nm)
＜result 〉
Confirm as Fig. 1, compare with the tablet of comparative example 1, show higher levels of dissolution rate from Lercanidipine hydrochloride-valsartan complex tablet of the embodiment 1-4 of spacer particles preparation in the incipient stage.
Test case 2: the stripping test of the Lercanidipine hydrochloride of the preparation of embodiment 5-8
For the wet complex tablet from the comparative example 1 of the composite double layer tablet of the embodiment 5-8 of spacer particles preparation and the mixture preparation never isolated, under the condition identical with test case 1, carry out the stripping test and compare.
Confirm as Fig. 2, compare with the tablet of comparative example 1, show higher levels of dissolution rate from Lercanidipine hydrochloride-valsartan complex tablet of the embodiment 5-8 of spacer particles preparation.
Test case 3: the stripping test of the Lercanidipine hydrochloride of the preparation of embodiment 9-12
For from the composite three-layer tablet of the embodiment 9-12 of spacer particles preparation and from the wet complex tablet of the embodiment 1-4 of spacer particles preparation, under the condition identical with test case 1, carry out the stripping test and compare.
Confirm as Fig. 3, show similar dissolution rate from the composite three-layer tablet of spacer particles preparation and the wet complex tablet for preparing from spacer particles.
The stripping test of the Lercanidipine hydrochloride of the preparation of test case 4: embodiment 13
For the isolation coat tablet of embodiment 13 and the wet complex tablet of embodiment 1, under the condition identical with test case 1, carry out the stripping test and compare.
Confirm that as Fig. 4 isolation coat tablet and wet complex tablet show similar dissolution rate.
Test case 5: embodiment 1 tests with the comparison stripping of the preparation of comparative example 2 and 3
For the tablet of the comparative example 2 that obtains from the complex tablet of the embodiment 1 of spacer particles preparation, from the simple mixtures of commercial granule and the commercial formulation of comparative example 3, under the condition identical with test case 1, carry out the stripping test and compare.
Confirm that as Fig. 5 the complex tablet of embodiment 1 shows the stripping pattern of the Lercanidipine hydrochloride identical with the commercial formulation of the Lercanidipine hydrochloride of comparative example 3.On the other hand, by mixing commercially available Lercanidipine hydrochloride granule and valsartan granule simply and its tablet that is pressed into the comparative example 2 that tablet obtains is shown low-down Lercanidipine hydrochloride stripping, this looks like because the gelling of valsartan causes.
Test case 6: the clinical effectiveness of the conjoint therapy of Lercanidipine hydrochloride and valsartan
Carry out following test to estimate effectiveness and the safety with the conjoint therapy of the Lercanidipine hydrochloride of comparing to every kind of component of patient's administration of suffering from essential hypertension separately and valsartan.
The experimenter is the patient who suffers from essential hypertension in 20-75 year, and it is at the blood pressure that shows 90mmHg≤DBP (diastolic pressure)≤109mmHg administration placebo the 0th after 2 weeks when week measures.For the interference effect of the antihypertensive drug that uses before eliminating and improve drug compliance, tried the patient just 2 all break-ins (run-in) after the drug holiday in 0～1 week in the phase with single-blind fashion use placebo.The experimenter with identical probability random assortment be by 1 placebo group, 4 monotherapy groups and 4 conjoint therapy groups form altogether after 4 groups, they use medicine according to the group in the following table, measurement point and medicine-feeding period in the double blinding mode.In this case, commercially available
Figure BDA00003316628800151
Sheet 10mg is used as Lercanidipine hydrochloride, and commercially available Sheet 80mg is as valsartan.
[table 8]
Figure BDA00003316628800153
At each measurement point, the monitoring of blood pressure that provides according to Korea S hypertension association (Korean Society of Hypertension) instructs, and measurement is tried patient's blood pressure to calculate 8 all backs with respect to the change (value-baselines after 8 weeks) of DBP and the SBP (systolic pressure) of baseline.The effect of conjoint therapy is compared to estimate superiority with the effect of monotherapy.
130 patients that satisfy 100mmHg≤DBP≤109mmHg standard of test when 3 (the 0th days) are examined in visit, and the results are summarized in the following table 9.It confirms, compares with the patient who uses placebo or monotherapy, uses the patient of Lercanidipine hydrochloride 20mg+ valsartan 80mg conjoint therapy all to show significant superiority in the change of DBP and SBP.
In following table 9, the difference (being the blood pressure change of the blood pressure change-conjoint therapy of monotherapy) of the blood pressure change of monotherapy is compared in " Diff. " expression with conjoint therapy, and bilateral 95%CI is bilateral 95% confidence interval, its expression when the lower limit of confidence interval greater than 0 the time, can think significant difference.Hereinafter used term has identical implication.
[table 9]
Figure BDA00003316628800161
And 368 patients that satisfy 90mmHg≤DBP≤109mmHg standard that measured blood pressure in the trough phase (after the administration 22～26 hours) when examining 3 (the 0th days) in visit examine 5 (the 56th day) time in visit and test.The result confirms, uses the patient of Lercanidipine hydrochloride 10mg+ valsartan 160mg or Lercanidipine hydrochloride 20mg+ valsartan 160mg to change the patient who compares use placebo or monotherapy at DBP with SBP, all shows the significant superiority of statistics.Under the patient's of the conjoint therapy that uses Lercanidipine hydrochloride 20mg+ valsartan 80mg situation, it is confirmed that they in DBP and SBP change with respect to using placebo or the patient of the monotherapy of Lercanidipine hydrochloride 20mg only, show superiority (seeing Table 10-12).
[table 10]
Figure BDA00003316628800171
[table 11]
Figure BDA00003316628800172
[table 12]
Figure BDA00003316628800173
Test case 7: the clinical effectiveness of the conjoint therapy of Lercanidipine hydrochloride and valsartan
Carry out following test to estimate effectiveness and the safety with the conjoint therapy of the Lercanidipine hydrochloride of comparing to every kind of component of patient's administration of suffering from essential hypertension separately and valsartan.
The experimenter is the patient who suffers from essential hypertension in 20-75 year, and it is at the blood pressure that shows 95mmHg≤DBP≤114mmHg administration placebo the 0th after 2～4 weeks when week measures.For the interference effect of the antihypertensive drug that uses before eliminating and improve drug compliance, tried the patient just in running-in period in 2～4 weeks after the drug holiday in 1 week with single-blind fashion use placebo.The experimenter with identical probability random assortment be by 1 placebo group, 2 monotherapy groups and 1 conjoint therapy group form altogether after 4 groups, they use medicine according to the group in the following table, measurement point and medicine-feeding period in the double blinding mode.In this case, commercially available
Figure BDA00003316628800174
Sheet 10mg is used as Lercanidipine hydrochloride, and commercially available
Figure BDA00003316628800175
Sheet 80mg is as valsartan.
[table 13]
At each measurement point, the monitoring of blood pressure that provides according to Korea S hypertension association instructs measurement to be tried patient's blood pressure to calculate 8 all backs with respect to the change (value-baselines after 8 weeks) of DBP and the SBP of baseline.The effect of conjoint therapy is compared to estimate superiority with the effect of monotherapy.
193 patients that satisfy 95mmHg≤DBP≤114mmHg standard of test when 3 (the 0th days) are examined in visit, and the results are summarized in the following table 14.It confirms, compares with the patient who uses placebo, uses the patient of Lercanidipine hydrochloride 10mg+ valsartan 80mg conjoint therapy all to show the significant superiority of statistics in the change of DBP and SBP.It also confirms, uses the patient of the conjoint therapy of Lercanidipine hydrochloride 10mg+ valsartan 80mg to compare with the patient of the monotherapy that uses Lercanidipine hydrochloride 10mg, shows the significant superiority of statistics that SBP changes.
[table 14]
Figure BDA00003316628800182
Test case 8: the effect of the conjoint therapy of Lercanidipine hydrochloride and valsartan in the rat
(spontaneous hypertensive rat Orient) adapts to and raises and train a week, keeps 22～24 ℃ temperature range and 50～70% humidity range simultaneously, and illumination-dark cycle is 12 hours to make the male SHR in 13 ages in week.Food and the drinking-water of standard diet arbitrarily are provided.
In the previous day of administration, utilize BP-2000 analysis of blood pressure system (Visitech) to measure blood pressure and the heart rate of test animal.After the measurement, with about 12 hours of animal fasting, during drinking-water arbitrarily is provided.With the volume of the 5ml/kg various testing drugs of test animal oral administration to fasting.Medium to negative control group oral administration equal volume.After being dissolved in 20% 2-HP-(HPCD), use test medicine Lercanidipine hydrochloride and valsartan.In order to increase dissolubility, to the 1N HCl of Lercanidipine hydrochloride adding 0.5ml, to the 0.05%NaOH of valsartan adding 0.5ml, dissolving fully then.(one of them is conjoint therapy group (N=10), the Lercanidipine hydrochloride of administration 2mg/kg and the valsartan of 16mg/kg with the test group; Another is monotherapy group (N=10), the valsartan of administration 16mg/kg) with the relatively change of blood pressure and heart rate of matched group, carry out statistical calculations then.Carry out statistical calculations with unidirectional ANOVA, with the significant difference between analytical test group and matched group and conjoint therapy group and the monotherapy group.
From the result of Fig. 6-9 as seen, the conjoint therapy group of the Lercanidipine hydrochloride of administration 2mg/kg and the valsartan of 16mg/kg is compared with monotherapy group and the matched group of the valsartan of administration 16mg/kg, administration is after 1 hour in SHR, and showing significant blood pressure reduction and heart rate increases.On the other hand, the monotherapy group of the valsartan of administration 16mg/kg is compared with matched group and is not shown significant blood pressure reduction or heart rate increase.

Claims (13)

1. pharmaceutical composition that is used for prevention and treatment cardiovascular disease, it comprises Lercanidipine hydrochloride and valsartan as active component.
2. the compositions of claim 1, wherein said Lercanidipine hydrochloride and valsartan are isolated form.
3. the compositions of claim 2, it is by granulating described Lercanidipine hydrochloride and valsartan respectively to prepare.
4. the compositions of claim 3, wherein said Lercanidipine hydrochloride granule and valsartan granule also comprise the acceptable excipient of pharmacy separately.
5. the compositions of claim 4, wherein said Lercanidipine hydrochloride granule comprises the acceptable excipient of pharmacy of per 1 weight portion Lercanidipine hydrochloride 4-10 weight portion.
6. the compositions of claim 4, wherein said valsartan granule comprises the acceptable excipient of pharmacy of per 1 weight portion valsartan 1-2 weight portion.
7. the compositions of claim 4, it comprises the combination of the valsartan of the Lercanidipine hydrochloride of the valsartan of the Lercanidipine hydrochloride of valsartan, 20mg of the Lercanidipine hydrochloride of valsartan, 10mg of the Lercanidipine hydrochloride of 10mg and 80mg and 160mg and 80mg or 20mg and 160mg.
8. the compositions of claim 2, wherein said Lercanidipine hydrochloride and valsartan are included in the layer of isolation separately.
9. the compositions of claim 8, wherein sealing coat is placed between Lercanidipine hydrochloride layer and the valsartan layer.
10. the compositions of claim 2, it prepares by the tablet that the layer coating with hydrochloric lercanidipine contains valsartan.
11. the compositions of claim 10, wherein sealing coat is placed between the layer of the described tablet that contains valsartan and described hydrochloric lercanidipine.
12. the compositions of claim 10, wherein said cardiovascular disease are to be selected from least a in following group: angina pectoris, hypertension, arteriospasm, arrhythmia, cardiac hypertrophy, cerebral infarction, congestive heart failure and myocardial infarction.
13. a method for compositions for preparing claim 3, it may further comprise the steps:
(a) with the mixture wet granulation of Lercanidipine hydrochloride and the acceptable excipient of pharmacy, and with described particle drying;
(b) with the mixture wet granulation of valsartan and the acceptable excipient of pharmacy, and with described particle drying; And
(c) with step (a) and (b) the dried granules mixing of middle preparation.
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