CN104394865A - Composite composition having improved stability and containing amlodipine and rozaltan - Google Patents
Composite composition having improved stability and containing amlodipine and rozaltan Download PDFInfo
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Abstract
The present invention relates to a composite composition containing amlodipine and rozaltan, and having improved stability by comprising an antioxidant.
Description
Technical field
The present invention relates to the compositions comprising amlodipine and losartan that a kind of antioxidant is stable.
Background technology
Because hypertension is the Major Risk Factors of life-threatening coronary artery disease (such as apoplexy, heart failure, myocardial infarction etc.) and a reason of cardiovascular complication (such as renal failure), so importantly stably control blood pressure, instead of cure hypertension itself.Therefore, need long term administration depressor, so patient is cautious in selecting medicine.For hypertensive stable treatment, the combination of two or more medicines that therapy mechanism is different can play better preventive effect and therapeutical effect compared to single medicine.In addition, the combined therapy of two or more different pharmaceuticals reduces the dosage of single medicine, and contingent side effect during because this reducing long term administration medicine.
According to mechanism of action, the medicine used in treatment hypertension is classified as usually: diuretic, sympathetic blocking agent and vasodilation.According to mechanism of action, most of vasodilations of current use are divided into again: ACE (Angiotensin-Converting) inhibitor, angiotensin-ii receptor blockers (ARB) and calcium channel blocker.
Amlodipine is dihydropyridines (DHP) calcium channel blocker for reducing blood pressure and treatment angina pectoris chest pain.Once be absorbed, amlodipine then reduces blood pressure by making arterial smooth muscle loosen, and this reduces total peripheral resistance, and therefore reduces blood pressure and increase myocardium blood flow.Amlodipine carries out commercially available as multiple salt, such as benzene sulfonate, maleate, d-camphorsulfonic acid salt etc., and wherein Amlodipine Besylate Tablet is preponderated.
Losartan is one of medicine developed the earliest in ARB (angiotensin-ii receptor blockers) antihypertensive, and is used as angiotensin ii receptor antagonist.
Mechanism calcium channel blocker amlodipine different from each other and ARB losartan, when they together administration time be expected to play synergistically hypertensive therapeutical effect.But, under acceleration conditions, by the non-constant of stability by the compound formulation made by the simple mixtures direct compression of amlodipine and losartan.
Amlodipine formulation substantially by the amlodipine with efficacy of drugs with for activate and the combination of preparing the salt of active component forms.Consider that salt has impact for stabilizing active ingredient amlodipine, amlodipine can be preferably the form of free alkali.But due to the poorly water-soluble of basic salt, amlodipine preferably carries out administration as pharmaceutically acceptable acid-addition salts.At present, amlodipine acid-addition salts and the synergistic compound formulation of other medicines are obtainable.Example comprises: the combination (United States Patent (USP) 6395728) of the combination (United States Patent (USP) 6455574) of Amlodipine Besylate Tablet and atorvastatin calcium, Amlodipine Besylate Tablet and valsartan, and the combination of amlodipine camsylate and simvastatin (Korean Patent 742432).
Because light, heat or water make free alkali tend to instability, amlodipine shows the therapeutic effect of going on business under these conditions.In order to overcome this shortcoming, the multiple hydrochlorate of current amlodipine carries out commercially available with the form of packaging.But the preparation developed so far is still not enough to the stability ensureing amlodipine.
Particularly, when by Amlodipine and losartan physical blending, the bad stability of amlodipine, because losartan and excipient and above-mentioned salt generation chemical reaction.
Generally speaking, losartan uses with the form of potassium salt.Under household condition losartan potassium salt is stable, but when heating in acid condition, losartan potassium salt is degraded.That is, when combining with losartan, amlodipine acid-addition salts makes the stability of losartan reduce.
Such as, the commercially available at present amlodipine comprising amlodipine camsylate and losartan potassium salt/losartan compound formulation (the unexamined open 2008-0052852 of korean patent application) does not have stability enough between guarantee two kinds of compositions.
Summary of the invention
Technical problem
Therefore, keep in mind the above-mentioned problems in the prior art and make the present invention, and the object of this invention is to provide a kind of compositions comprising amlodipine and losartan, wherein, Physical interaction between amlodipine and losartan is minimized, and improves stability by antioxidant and simplify preparation process.
Technical scheme
According to an aspect of the present invention, the invention provides a kind of compositions for prevention and therapy cardiovascular disease, comprise: amlodipine or its pharmaceutically acceptable salt, losartan or its pharmaceutically acceptable salt, and propyl gallate.
Beneficial effect
Minimized the Physical interaction of amlodipine and losartan by design, and use propyl gallate as antioxidant, the compositions for prevention and therapy cardiovascular disease according to the present invention significantly improves stability and simplifies preparation process.
Accompanying drawing explanation
Fig. 1 shows the stripping curve from the amlodipine in the tablet of embodiment 8 to 17.
Fig. 2 shows the stripping curve from the losartan in the tablet of embodiment 8 to 17.
Detailed description of the invention
Below, detailed description of the present invention will be provided.
The present invention relates to a kind of compositions for prevention and therapy cardiovascular disease, comprise: amlodipine or its pharmaceutically acceptable salt, losartan or its pharmaceutically acceptable salt, and propyl gallate.
Propyl gallate (C
10h
12o
5) be a kind of antioxidant, and, when active component losartan and amlodipine and other pharmaceutically acceptable additive are mixed with mixture, propyl gallate not only plays the effect of the stability improving active component losartan and amlodipine, thus high stability product is provided, and play the effect of thermal induction degraded or the Moisture inducement degraded reducing active component, thus improve the As time goes on resistance changed.Because propyl gallate can not cause skin irritation, propyl gallate is safe compared to other antioxidant.
Said composition can be formulated into: cored tablet, capsule, bilayer tablet, multilayer tablet, and simple tablet.In the present invention, amlodipine or its pharmaceutically acceptable salt and losartan or its pharmaceutically acceptable salt are formulated into the dosage form that active component is physically separated from each other, as far as possible farthest to reduce the contact surface area between active component.It is further preferred that the bilayer tablet that the amlodipine layer be made up of amlodipine or its pharmaceutically acceptable salt is separated from each other with the losartan layer be made up of losartan or its pharmaceutically acceptable salt.Such as, by the upper strata of amlodipine and additive is placed in the sclerosis lower floor of Losartan Potassium and additive, and two layers by obtaining with tablet machine obsession, can bilayer tablet be prepared.
With regard to this respect, propyl gallate can preferably be comprised in the amlodipine layer be made up of amlodipine or its pharmaceutically acceptable salt.
Preferably, based on the gross weight of compositions, the consumption of propyl gallate is 0.001 % by weight to 1 % by weight, is more preferably 0.001 % by weight to 0.5 % by weight, and most preferably is 0.001 % by weight to 0.1 % by weight.When using with above-mentioned content, propyl gallate suitably improves the stability of active component.
In a preferred embodiment of the present invention, based on the gross weight of compositions, the content of amlodipine or its pharmaceutically acceptable salt is 1 % by weight to 6 % by weight, and the content of losartan or its pharmaceutically acceptable salt is 5 % by weight to 30 % by weight.More preferably, the content of amlodipine or its pharmaceutically acceptable salt and the content of losartan or its pharmaceutically acceptable salt can be respectively about 1.2 % by weight to 3.5 % by weight and about 10 % by weight to 20 % by weight.
Based on a tablet of such as compound formulation of the present invention, compound formulation of the present invention preferably can contain the amlodipine of 3mg to 12mg and the losartan of 30mg to 120mg, more preferably containing the amlodipine of 5mg to 10mg and the losartan of 50mg to 100mg.
For use in the present invention, the pharmaceutically acceptable salt of amlodipine can be prepared with the atoxic acid-addition salts containing pharmaceutically acceptable anion, be such as: chloride, hydrobromate, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzene sulfonate, and d-camphorsulfonic acid salt; And most preferably Amlodipine Besylate Tablet and Losartan Potassium.
Most preferably, pharmaceutical composition of the present invention can contain for amlodipine layer: Amlodipine Besylate Tablet, microcrystalline Cellulose, PEARLITOL 25C, sodium starch glycollate, polyvidone, magnesium stearate and propyl gallate; Can contain for losartan layer: Losartan Potassium, microcrystalline Cellulose, polyvinylpolypyrrolidone and magnesium stearate.
In order to ensure long-time stability, pharmaceutical composition of the present invention can comprise coating materials further.As long as this area is normally used, any coating materials can be used.Preferably be selected from by water solublity coating materials, discount interest coatings protect (
protect), Opadry (Opadry), and at least one in the group that forms of hydroxypropyl emthylcellulose (HPMC), above-mentioned water solublity coating materials comprises polyvinyl alcohol derivative, methacrylic acid derivative and polyacrylic acid derivative; Wherein, more preferably discount interest coatings protect.
In addition, pharmaceutical composition of the present invention may further include pharmaceutically acceptable additive.Based on the gross weight of compositions, the consumption of additive can be 5 % by weight to 90 % by weight, and is more preferably 50 % by weight to 90 % by weight.As long as pharmaceutically acceptable, any additive can be used.The example of additive comprises: filler, thickening agent, disintegrating agent, lubricant, antiseptic, antioxidant, isotonic agent, buffer agent, coating materials, sweeting agent, dissolution enhancers, alkali, dispersant, wetting agent, suspending agent, stabilizing agent, coloring agent, aromatic, water-soluble additives, and excipient.In more detail, disintegrating agent can be such as: microcrystalline Cellulose, lactose, mannitol, sodium citrate, calcium phosphate, glycine, starch, sodium starch glycollate, polyvinylpolypyrrolidone, crosslinked poly-sodium carboxymethyl cellulose (Croscamellose sodium), and specific composition silicate; Binding agent can comprise: polyvidone, polyvinylpyrrolidone, hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin, Radix Acaciae senegalis, Polyethylene Glycol, silicate derivative (such as light anhydrous silicic acid, synthetic aluminium silicate, calcium silicates or silicic acid magnesium aluminate), phosphate (such as calcium hydrogen phosphate), carbonate (such as calcium carbonate), and their combination; And, lubricant comprises: stearic acid, Metallic stearates (such as calcium stearate or magnesium stearate), Talcum, silica sol, fructose fatty acid ester, hydrogenated vegetable oil, high melting-point wax, fatty acid glyceride, glycerol two behenate (glycerol divehenate), Talcum, and their mixture.
For use in the present invention, disintegrating agent plays and makes solid preparation be rapidly decomposed into the effect of less fragment in Digestive system, thus promotes that stripping is to enough speed.
In the stripping improving solid preparation particularly tablet, importantly select suitable disintegrating agent, and use the disintegrating agent of appropriate amount.When stripping is postponed to reduce by disintegrate, improve the consumption of disintegrating agent.But excessive disintegrating agent is in the preparation and packaging process of tablet or tablet may be made to lose keep the intensity that is enough to maintain its shape and performance in the transport of tablet and lay up period.Therefore, select suitable disintegrating agent to be very important, and also restricted to the amount of disintegrating agent.
Preferably, based on the gross weight of compositions, the consumption of disintegrating agent can be 1 % by weight to 10 % by weight, and is more preferably 3 % by weight to 7 % by weight.If in the scope of above-mentioned amount, disintegrating agent absorbs water and resolves into less fragment to make preparation, thus promotes the release of active component and reach the effective serum levels of pharmacology of active component.
The present composition can the optional free angina pectoris of cardiovascular disease of prevention and therapy, hypertension, arteriospasm, arrhythmia, cardiac hypertrophy, congestive heart failure, thrombosis, and the group of myocardial infarction composition, but be not limited thereto.
Use usual way, the tablet, capsule, many granules etc. that can be carried out administration by oral, Sublingual or other approach can be formulated into according to solid composite medicament of the present invention.Preferably, compositions of the present invention can be formulated into the tablet of oral administration.Such as, the component of the present composition can be mixed simply, and uses tablet machine and be easily mixed with tablet.It is evident that to those skilled in the art, the doctor in charge can determine suitable every TDD in the scope of rational medical judgment.
By following examples, the present invention may be better understood.Following examples be for illustration of and be suggested, but should not be understood to limit the present invention.
Test example 1: the stability test between amlodipine and losartan
In order to detect with stability change interactional between them between amlodipine and losartan, their physical blendings are being measured their content after being exposed to acceleration environment.
(1) test method
With the amount shown in the comparative example 1 and 2 of table 1 below by amlodipine and losartan physical blending.In comparative example 3, the compositions of comparative example 2 is mixed with tablet, with detect be applied to preparation pressure and heat on the impact of the stability between amlodipine and losartan.In comparative example 3, at the pressure contracting blend of 20kPa.
Table 1
In order to test the stability between amlodipine and losartan, the blend of comparative example 1 and the blend of comparative example 2 and the tablet of comparative example 3 are exposed to accelerating cavity.The content of amlodipine and the content of losartan is measured immediately after preparing blend and tablet; And after being exposed to acceleration environment two weeks and five weeks, measure the content of amlodipine and the content of losartan.
Table 2
| Temperature | 40±2℃ |
| Relative humidity | 75±5％ |
The following content of measurement amlodipine and the content of losartan.
1. the method for the content of amlodipine is measured
Accurate weighing and powdered are carried out to three tablets of comparative example 3.Take out the comparative example 1 of respective amount and the powder of comparative example 2 respectively.
Weigh each sample being equivalent to the amount of the amlodipine of 5mg, and be placed in the brown volumetric flask of 100mL.Then, mobile phase is added in the brown volumetric flask of this 100mL to produce the volume of 100mL.Take out the solution of 25mL, and be placed in the brown volumetric flask of 50mL.Mobile phase is toppled over so far in bottle to make the surface of mobile phase accurately align with graticule.Then, filtered by the film filter of 0.45 μm.Content is measured with HPLC under condition in the following Table 3.
2. the method for the content of losartan is measured
Accurate weighing and powdered are carried out to three tablets of comparative example 3.Take out the comparative example 1 of respective amount and the powder of comparative example 2 respectively.
Weigh each sample being equivalent to the amount of the Losartan Potassium of 50mg, and be placed in the volumetric flask of 200mL, then, mobile phase A (phosphate buffer: acetonitrile (85:15, v/v%)) is added in the volumetric flask of this 200mL to produce the volume of 100mL.In ultrasonic extraction after 10 minutes, add mobile phase A to produce the volume of accurate 200mL.Filtered by the film filter of 0.45 μm.Content is measured with HPLC under condition in the following Table 3.
Table 3
(2) result of the test
The result obtained by said method is summarized in table 4 below.
With regard to this respect, measure the content of amlodipine and the content of losartan respectively by according to the calculating of mathematical expression 1 and 2 below.
[mathematical expression 1]
A
s: the peak area of amlodipine in standard solution
A
t: the peak area of amlodipine in testing liquid
W
s: the weight (mg) of the standard specimen of the amlodipine camsylate got
W
t: the weight of the test sample of getting
T: the average quality (mg) of test sample
C: the indicated weight (indicated weight) (mg) of the amlodipine of every tablet
D: extension rate
P: the purity (%) of the standard specimen of amlodipine camsylate
[mathematical expression 2]
A
t: the peak area of Losartan Potassium in testing liquid
A
s: the peak area of Losartan Potassium in standard solution
W
s: the weight (mg) of the standard specimen of the Losartan Potassium got
W
t: the weight of the test sample of getting
T: the average weight (mg) of test sample
C: the indicated weight (mg) of the Losartan Potassium of every tablet
P: the purity (%) of the standard specimen of Losartan Potassium
Table 4
From table 4, even if when only making amlodipine and losartan carries out physical contact, also reduce the content of amlodipine to a great extent.From only in 5 weeks the content of amlodipine reduce greatly to 20% observation, Losartan Potassium affects amlodipine widely.As for the tablet prepared by physical blending thing in comparative example 3, As time goes on the content of amlodipine is with larger rate reduction, and this shows that heat or the stability of pressure to amlodipine also have a great impact.
Test example 2: the test of antioxidant effect
When blended together, observe: due to the physical contact between amlodipine and losartan, heat and pressure, their As time goes on stability reduce.As the strategy improving stability, use antioxidant.With regard to this respect, have selected as the obtainable two kinds of different oxidants of medicated premix, and detect the impact of these two kinds different oxidants on the stability of amlodipine and losartan.
Have selected BHA (butylated hydroxyanisole (BHA), it plays to be bonded to oxygen to form the representative synthetized oxidation preventive agent of Free Radical) and citric acid (to be chelated to the representative cheating agents antioxidants of feature).
(1) test method
As shown in the comparative example 4 and 6 of table 5 below, amlodipine is carried out physical blending with losartan together with antioxidant.The blend of comparative example 4 and 6 is mixed with the tablet in comparative example 5 and 7 respectively.Be 5.10mm under the pressure of 10kPa and with thickness, use rotary tablet machine to prepare.
Accelerating cavity under condition shown in blend and tablet being exposed in table 2.After preparing blend and tablet, measure the content of amlodipine and the content of losartan immediately, and measure the content of amlodipine and the content of losartan after being exposed to acceleration environment two weeks and five weeks.
The method identical with test example 1 is used to measure the content of amlodipine and the content of losartan.With regard to this respect, calculate the content of amlodipine and the content of losartan according to mathematical expression 1 and 2 respectively.
Table 5
(2) result of the test
Summarize in table 6 below by testing the result obtained.
Table 6
Before this, observe: even if amlodipine also shows huge changes of contents when contacting with losartan simple physical.Under the existence of antioxidant, as shown in table 6, keep the content of amlodipine for a long time always.Any one in two kinds of antioxidants improves the stability of amlodipine under the existence of losartan, and vice versa.In addition, even if antioxidant also ensure that amlodipine stability As time goes on, so amlodipine maintains its initial content after tabletting under conditions of heat and pressure.Further, when using together with antioxidant, the content of Losartan Potassium does not change significantly, even and if be also held stably under heat or pressure condition.
Test example 3: the test selecting antioxidant
3.1 antioxidant dependency stability tests
Based on the effect of above-mentioned confirmed antioxidant to stability, carry out testing to select best one to 12 kinds of different antioxidants.
(1) preparation of compound formulation
As shown in table 7 to the embodiment 1 of table 10 and comparative example 8 to 21, prepare the physical blending thing comprising 12 kinds of different antioxidants.Use the combination of two kinds of antioxidants to demonstrate synergism.In comparative example 13, employ the combination of BHA and BHT, and in comparative example 14, employ the combination of citric acid and BHA.Be provided with in comparative example 8 not containing the compound formulation of antioxidant.
Will often kind of compositions physical blending, and use tablet machine to be mixed with tablet.Accelerating cavity under condition shown in blend and tablet being exposed in table 2.After preparing blend and tablet, measure the content of amlodipine and the content of losartan immediately, and measure the content of amlodipine and the content of losartan after two weeks and five weeks being exposed under acceleration environment.Under the pressure of 10kPa, blend is mixed with single tablet.
The content of amlodipine and the content of losartan is measured with the method identical with test example 1.
Table 7
Table 8
Table 9
(2) result of the test
Summarize by testing the result obtained in table 10 below and table 11.
Table 10
Table 11
From the data of table 10 and table 11,12 kinds of different antioxidants and their combination demonstrate the impact of the stability on amlodipine and losartan.But citric acid, sodium sulfite and edetate sodium tend to the content reducing losartan, and zinc oxide, ascorbic acid, tocopherol acetate, tocopherol and sodium pyrosulfite reduce the content of amlodipine.Observe: other antioxidant, BHA, BHT and propyl gallate keep the content of amlodipine and the content of losartan to stablize.Therefore, the combination of BHT, propyl gallate and BHT and BHA is selected to stablize to make amlodipine and losartan.
the test of 3.2 selection antioxidants
In test example 3.1, demonstrate three kinds of antioxidant substances (BHT, propyl gallate, BHT+BHA) of the stability ensureing amlodipine and losartan, determine the best one that best stabilized effect is shown as follows.
(1) test method
As shown in the embodiment 2 of table 12 below and comparative example 22 and 23, by amlodipine and losartan physical blending together with three kinds of antioxidant substances.
Blend is mixed with the bilayer tablet be made up of amlodipine layer and losartan layer, each layer is all containing antioxidant.Bi-layer tablet press is used with the pressure of 12.5kPa, bilayer tablet to be fabricated to the thickness with 5.30mm.Each tablet is exposed to the accelerating cavity under the condition of table 2.After preparing tablet, measure the content of amlodipine and the content of losartan immediately, and being exposed under acceleration environment two weeks, surrounding and measure the content of amlodipine and the content of losartan after eight weeks.
1. the method for amlodipine content is measured
Three tablets of each sample of accurate weighing, and powdered.Weigh each sample being equivalent to the amount of the amlodipine of 5mg, and be placed in the brown volumetric flask of 100mL, then, mobile phase is added in the brown volumetric flask of this 100mL to produce the volume of 100mL.Take out the solution of 25mL, and be placed in the brown volumetric flask of 50mL.Mobile phase is toppled over so far in bottle to make the surface of mobile phase accurately align with graticule, then filtered by the film filter of 0.45 μm.Content is measured with HPLC under condition in table 3.
2. the method for losartan content is measured
Three tablets of each sample of accurate weighing, and powdered.Weigh each sample being equivalent to the amount of 50mg Losartan Potassium, and be placed in the volumetric flask of 200mL, then, mobile phase A is added in the volumetric flask of this 200mL to produce the volume of 100mL.In ultrasonic extraction after 10 minutes, add mobile phase A to produce the volume of accurate 200mL.Filtered by the film filter of 0.45 μm.Content is measured with HPLC under condition in table 3.
Table 12
(2) result of the test
Summarize in table 13 below by testing the result obtained.
Table 13
From table 13, for said composition, the stage is similar with the content of losartan to the amlodipine after accelerated test 4 weeks with 8 weeks in early days.But, be used alone the tablet of the comparative example 22 of BHT and use the tablet of the comparative example 23 of the combination of BHT and BHA to occur brown in accelerated test after 4 weeks and 8 weeks respectively.Therefore, the antioxidant propyl gallate used in embodiment 2 is measured as has strong anti-oxidation potentiality, has the minimum physics and chemistry impact of tablet.
test example 4: the test ensureing complex stabilities
In order to minimize the interaction between amlodipine and losartan, manufacture the preparation that coating has the coating materials of potent waterproof.The stability depending on coating is measured to them.
The comparison of 4.1 preparations
As in afore-mentioned test prove, when amlodipine and losartan contact with each other, amlodipine and losartan are due to the interaction between them or with the interaction of excipient and bad stability.Stability between the single tablet bilayer tablet be made up of amlodipine layer and losartan layer (designing for the contact area minimized between amlodipine and losartan) and amlodipine and losartan being carried out to physical blending compares.
(1) test method
As shown in the embodiment 3 and 4 of table 14, by amlodipine and losartan blended, and the bilayer tablet being mixed with monolayer tablet respectively and being made up of amlodipine layer and losartan layer.Each tablet is exposed to the accelerating cavity under the condition of table 2.After preparing tablet, measure the content of amlodipine and the content of losartan immediately, and measure the content of amlodipine and the content of losartan after 2 weeks, 4 weeks and 8 weeks being exposed to accelerating cavity.
The content of amlodipine and the content of losartan is measured in the mode identical with test example 1.
Table 14
(2) result of the test
Give in table 15 by testing the result obtained.
Table 15
From the data of table 15, observe: even if the tablet of embodiment 3 and 4 still stably kept the content of amlodipine and the content of losartan after 8 weeks.But the tablet of embodiment 3 is not inclined to and As time goes on reduces content.Therefore, with regard to stability, bilayer tablet is better than monolayer tablet, and this is considered to owing to minimum contact between two kinds of active constituents of medicine thus the interaction blocked between them.
4.2 coating tests
In order to detect long-time stability, carrying out coating combination drug of the present invention with three kinds of different coating materials, and monitoring its stability change of passing in time.
(1) prepare
As shown in table 16 below, amlodipine and losartan are mixed with the bilayer tablet be made up of amlodipine layer and losartan layer.The above-mentioned tablet of coating is carried out by the one in three kinds of coating materials (discount interest coatings protect (BASF), Opadry, hydroxypropyl emthylcellulose (HPMC)).Tablet is exposed to the accelerating cavity under the condition of table 2.Measure the content of amlodipine and the content of losartan in tablet after the production immediately, and measure the content of amlodipine and the content of losartan in tablet after 2 weeks, 4 weeks and 8 weeks being exposed under acceleration environment.
1. the method for amlodipine content is measured
Three tablets of each sample of accurate weighing, and powdered.Weigh each sample being equivalent to the amount of 5mg amlodipine, and be placed in the brown volumetric flask of 100mL, then, mobile phase is added in the brown volumetric flask of this 100mL to produce the volume of 100mL.Take out the solution of 25mL, and be placed in the brown volumetric flask of 50mL.Mobile phase is toppled over so far in bottle to make the surface of mobile phase accurately align with graticule, then, filtered by the film filter of 0.45 μm.Content is measured with HPLC under condition in table 3.
2. the method for losartan content is measured
Three tablets of accurate weighing comparative example 3, and powdered.Weigh each sample being equivalent to the amount of 50mg Losartan Potassium, and be placed in the volumetric flask of 200mL, then, mobile phase A is added in the volumetric flask of this 200mL to produce the volume of 100mL.In ultrasonic extraction after 10 minutes, add mobile phase A to produce the volume of accurate 200mL.Filtered by the film filter of 0.45 μm.Content is measured with HPLC under condition in table 3.
Table 16
(2) result of the test
Summarize in table 17 by testing the result obtained.
Table 17
Shown in table 17, the content measured immediately after the production and the content measured after being exposed under acceleration environment 2 weeks, 4 weeks and 8 weeks show: the tablet of the discount interest coatings protect coating of embodiment 5 has the highest stability.Be designed to the contact of blocking drugs and water, discount interest coatings protect can prevent drug hydrolysis effectively.Also observe: the HPMC used respectively in embodiment 6 and 7 and Opadry improve the stability of medicine, but lower than the efficiency of discount interest coatings protect.
Test example 5: dissolution test
5.1 dissolution test
In order to the stripping curve of seeking of ideal, guaranteed for the stability comprising amlodipine and losartan complex tablet and multiple excipient are prepared.
(1) prepare
Amlodipine is become with table 18 the coating bilayer tablet be made up of amlodipine layer and losartan layer with losartan with the excipient shown in table 19.
Table 18
Table 19
Make the preparation experience dissolution test under the following conditions of embodiment 8 to 17.
1. amlodipine
Weigh the Amlodipine Besylate Tablet reference material of 34.7mg, and be placed in the brown volumetric flask of 250mL, then, the hydrochloric acid solution of 0.001mol/L is poured onto in the brown volumetric flask of this 250mL to produce the volume of 250mL.Take out the solution of 10mL, and be placed in the brown volumetric flask of 100mL.The HCl solution of 0.01mol/L is toppled over so far in bottle to make the surface of mobile phase accurately align with graticule, then, filtered by the film filter of 0.45 μm, to produce the filtered solution as reference material.
Three tablets of each sample of accurate weighing respectively, and make it under the condition of table 20, experience dissolution test.In stripping after 5 minutes, 10 minutes, 15 minutes, 30 minutes and 45 minutes, take out the solvent soln of 10mL, and by the film filter of 0.45 μm, it is filtered.Filtered solution is used as testing liquid.
With HPLC analytical test solution and reference material under the condition of table 3.
Table 20
| Device | Pharmacopoeia Coreana, the 2nd dissolution test defined of GENERAL EXPERIMENTATION |
| Test(ing) liquid | 0.01mol/L，HCl 500mL |
| Leaching temperature | 37±0.5℃ |
| Rotation number | 100±5rpm |
2. losartan
The Losartan Potassium reference material of accurate weighing 50mg, and be placed in the volumetric flask of 100mL, then, mobile phase A is poured in the volumetric flask of this 100mL to graticule.Take out the solution of 10mL, and be placed in the volumetric flask of 100mL.Add pure water to graticule, filtered by the film filter of 0.45 μm subsequently, to produce the filtered solution as reference material.
Three tablets of each sample of accurate weighing respectively, and make it under the condition of table 21, experience dissolution test.Take out the solvent soln of 10mL in stripping after 5 minutes, 10 minutes, 15 minutes, 30 minutes and 45 minutes, and by the film filter of 0.45 μm, it is filtered.Filtered solution is used as testing liquid.
With HPLC analytical test solution and reference material under the condition of table 3.
Table 21
| Device | Pharmacopoeia Coreana, the 2nd dissolution test defined of GENERAL EXPERIMENTATION |
| Test(ing) liquid | Purified water, 900mL |
| Leaching temperature | 37±0.5℃ |
| Rotation number | 75±5rpm |
(2) result of dissolution test
Fig. 1 and Fig. 2 describes the result of dissolution test.
Fig. 1 shows the stripping curve from the amlodipine in the tablet of embodiment 8 to 17, and Fig. 2 shows the stripping curve from the losartan in the tablet of embodiment 8 to 17.
As seen from Figure 1, the stage all demonstrates the dissolution rate of high amlodipine to all preparations in early days, but only the preparation of embodiment 9 and embodiment 10 meets the dissolution rate of in 5 minutes 85% or higher.For losartan, only the preparation of embodiment 9 and embodiment 10 demonstrates the dissolution rate of in 5 minutes 85% or higher.Therefore, best amlodipine and the stability-enhanced tablet of losartan is measured as according to the preparation comprising amlodipine and losartan of embodiment 9.
Claims (11)
1. for a compositions for prevention and therapy cardiovascular disease, comprise: amlodipine or its pharmaceutically acceptable salt, losartan or its pharmaceutically acceptable salt, and propyl gallate.
2. compositions according to claim 1, described compositions is the form of bilayer tablet, and described bilayer tablet has the independent layer of two of being made up of the amlodipine layer containing amlodipine or its pharmaceutically acceptable salt and the losartan layer containing losartan or its pharmaceutically acceptable salt.
3. compositions according to claim 2, wherein, described propyl gallate is included in the described amlodipine layer containing amlodipine or its pharmaceutically acceptable salt.
4. compositions according to claim 1, wherein, based on the gross weight of described compositions, the content of described propyl gallate is 0.001 % by weight to 1 % by weight.
5. compositions according to claim 1, wherein, based on the gross weight of described compositions, the content of amlodipine or its pharmaceutically acceptable salt is 1 % by weight to 6 % by weight, and the content of losartan or its pharmaceutically acceptable salt is 5 % by weight to 30 % by weight.
6. compositions according to claim 1, comprises coating materials further.
7. compositions according to claim 6; wherein; described coating materials is selected from by water solublity coating materials, discount interest coatings protect, Opadry; with the group that hydroxypropyl emthylcellulose (HPMC) forms, described water solublity coating materials comprises polyvinyl alcohol derivative, methacrylic acid derivative and polyacrylic acid derivative.
8. compositions according to claim 1, wherein, the pharmaceutically acceptable salt of amlodipine is Amlodipine Besylate Tablet, and the pharmaceutically acceptable salt of losartan is Losartan Potassium.
9. compositions according to claim 1, comprises pharmaceutically acceptable additive further.
10. compositions according to claim 9, wherein, based on the gross weight of described compositions, the content of described additive is 5 % by weight to 90 % by weight.
11. compositionss according to claim 1, wherein, described cardiovascular disease is selected from by angina pectoris, hypertension, arteriospasm, arrhythmia, cerebral infarction, cardiac hypertrophy, congestive heart failure, thrombosis, and the group of myocardial infarction composition.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2012-0039708 | 2012-04-17 | ||
| KR1020120039708A KR101392364B1 (en) | 2012-04-17 | 2012-04-17 | Pharmaceutical composition comprising amlodipine and losartan having an improved stability |
| PCT/KR2013/003231 WO2013157840A1 (en) | 2012-04-17 | 2013-04-17 | Composite composition having improved stability and containing amlodipine and rozaltan |
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| KR (1) | KR101392364B1 (en) |
| CN (1) | CN104394865B (en) |
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| TWI714560B (en) * | 2015-03-31 | 2021-01-01 | 南韓商韓美藥品股份有限公司 | Pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone |
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| KR102369607B1 (en) * | 2014-09-30 | 2022-03-03 | 한미약품 주식회사 | Solid Pharmaceutical Composition Comprising Amlodipine and Losartan |
| KR20200143914A (en) * | 2019-06-17 | 2020-12-28 | 주식회사유한양행 | A pharmaceutical composition in a multi-layered tablet form comprising amlodipine or its salt and chlorthalidone its salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101708159A (en) * | 2009-12-04 | 2010-05-19 | 中牧实业股份有限公司 | Preparation method for heat-sensitive medicament suspension |
| CN102292070A (en) * | 2009-01-23 | 2011-12-21 | 韩美控股株式会社 | Solid pharmaceutical composition comprising amlodipine and losartan with improved stability |
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| US20050209288A1 (en) * | 2004-01-12 | 2005-09-22 | Grogan Donna R | Compositions comprising (S)-amlodipine malate and an angiotensin receptor blocker and methods of their use |
| KR101247583B1 (en) * | 2006-12-08 | 2013-03-26 | 한미사이언스 주식회사 | Pharmaceutical composition comprising amlodipine or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof |
| KR101270751B1 (en) * | 2010-05-06 | 2013-06-07 | (주)비씨월드제약 | Composition for the gastric retention and controlled release of therapeutic agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102292070A (en) * | 2009-01-23 | 2011-12-21 | 韩美控股株式会社 | Solid pharmaceutical composition comprising amlodipine and losartan with improved stability |
| CN102292084A (en) * | 2009-01-23 | 2011-12-21 | 韩美控股株式会社 | solid pharmaceutical composition comprising amlodipine and losartan |
| CN101708159A (en) * | 2009-12-04 | 2010-05-19 | 中牧实业股份有限公司 | Preparation method for heat-sensitive medicament suspension |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| TWI714560B (en) * | 2015-03-31 | 2021-01-01 | 南韓商韓美藥品股份有限公司 | Pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone |
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| KR101392364B1 (en) | 2014-05-07 |
| RU2628538C2 (en) | 2017-08-18 |
| KR20130117048A (en) | 2013-10-25 |
| CN104394865B (en) | 2016-11-09 |
| BR112014025956B1 (en) | 2019-10-29 |
| PH12014502326A1 (en) | 2015-01-12 |
| RU2014145827A (en) | 2016-06-10 |
| PH12014502326B1 (en) | 2015-01-12 |
| WO2013157840A1 (en) | 2013-10-24 |
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