CN108156807A - Medicine compound preparation containing Amlodipine, Losartan and Rosuvastatin - Google Patents
Medicine compound preparation containing Amlodipine, Losartan and Rosuvastatin Download PDFInfo
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- CN108156807A CN108156807A CN201680031203.4A CN201680031203A CN108156807A CN 108156807 A CN108156807 A CN 108156807A CN 201680031203 A CN201680031203 A CN 201680031203A CN 108156807 A CN108156807 A CN 108156807A
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- pharmaceutically acceptable
- rosuvastatin
- acceptable salt
- losartan
- amlodipine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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Abstract
Present invention is disclosed a kind of for preventing or treating angiocardiopathy, pharmaceutical composition containing Amlodipine, Rosuvastatin and Losartan, a kind of medicine compound preparation is further disclosed, it includes the first mixture part containing Amlodipine and Rosuvastatin and the second mixture part containing Losartan.The composition closes and compound formulation contains grain size (D90) it is 50 μm or smaller Rosuvastatin, there is excellent dissolution rate, bioavilability, stability, uniformity of dosage units, therefore be useful in pharmaceuticals industry.
Description
Technical field
The present invention relates to a kind of combination of oral medication containing Amlodipine, Losartan and Rosuvastatin and compound systems
Improved dissolution rate, stability and bioavilability is presented in agent, the pharmaceutical composition and compound formulation.
Background technology
About 90 to 95% hypertension case is classified as essential hypertension, and reason is unknown.It is related with hypertension
Risk factor includes psychology and environmental factor such as drinks, smokes, aging, not getting enough athletic exercise, is fat, salinity is excessive in diet, pressure
Deng.In addition, when parent is suffering from hypertension, their offspring just has the possibility of hypertension, and therefore, inherent cause is also recognized
To be a major reason of hypertension.
Due to needing prolonged administration of drugs when treating hypertension, the pharmaceutical composition of different mechanisms compares list in therapeutic effect
Only drug is advantageous.In addition, combination therapy reduces the dosage of single drug, so as to reducing due to taking single drug for a long time
Issuable side effect.Under normal circumstances, it is divided into diuretics, sympathectomy commonly used in treating the drug of hypertension
Agent and vasodilator；Vasodilator is categorized further, as Angiotensin-Converting (ACE) inhibitor, Angiotensin II
Receptor blocker and calcium channel blocker.
Meanwhile hyperlipidemia be due to a kind of imbalance of the excessively high patch caused on blood vessel of lipid levels in blood, it is adjoint
Inflammation eventually becomes angiocardiopathy.In recent years, the lipid in blood is defined as dyslipidemia extremely.
When treating hyperlipidemia, the variation of non-drug therapy such as diet, life style and ideal weight and medicine are kept
Object is used in combination.Statins inhibit the synthesis of cholesterol, reduce plasma low density lipoprotein cholesterol levels and glycerine three
Ester is horizontal.
Amlodipine is 3- ethyl -5- methyl -2- (2- ammonia ethoxymethyl) -4- (2- chlorphenyls) -6- methyl-1s, 4- bis-
Hydrogen -3,5- pyridinedicarboxylic acids (3-ethyl-5-methyl-2- (2-aminoethoxy-methyl) -4- (2-
Chlorophenyl) -6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate) adopted name.Ammonia chlorine
Horizon blocks calcium channel, available for angiocardiopathies such as treatment angina pectoris, hypertension and congestive heart failures.
Losartan is the chloro- 1- of 2- butyl -4- [{ 2'- (1H-TETRAZOLE -5- bases) [1,1'- biphenyl] -4- bases } methyl] -1H- miaows
Azoles -5- methanol (2-butyl-4-chloro-1- [{ 2'- (1H-tetrazol-5-yl) [1,1'-biphenyl] -4-yl }
Methyl] -1H-imidazole-5-methanol) adopted name, in U.S. Patent No. No. 5608075, No. 5138069 and
It is disclosed in No. 5153197.By blocking the interaction of vasoconstrictive Angiotensin II and its receptor, Losartan is main
For treat hypertension, heart failure, ischemic peripheral dyshaemia, myocardial ischemia (angina pectoris), diabetic neuropathy and
Glaucoma, and prevent the generation of heart failure after acute myocardial infarction.
The compound formulation of Amlodipine and Losartan is in terms of prevention and treatment hypertension and angiocardiopathy than single medicine
Object is advantageously.In addition, this dosage form reduces the dosage of single drug, so as to reduce side effect and improve drug compliance.
Rosuvastatin is (E) -7- [4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] pyrimidine -5-
Base]-(3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids ((E) -7- [4- (4-fluorophenyl) -6-isopropyl-2-
[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhep-6-enoic
Acid adopted name).Rosuvastatin is used to treat hypercholesterolemia, hyperlipidemia and atherosclerosis.
The common incidence of hypertension and hyperlipidemia is about 49%, and Amosartan and statins is used in combination
Account for about the 30% of cardiovascular disease medicine treatment.In order to more effectively treat angiocardiopathy, to containing Amlodipine, Losartan
It is increasing with the demand of the compound formulation of Rosuvastatin etc..However, due to this formulation design complexity and activity into
/ interaction lead to the possibility that dissolubility and stability deteriorate, it is difficult to make its commercialization.
The present inventor has found the Rui Shu with specified particle diameter to solve the problems, such as that conventional formulation conducts in-depth research
Cutting down statin has good Dissolution profiles and bioavilability, so as to complete the present invention.
Invention content
It is therefore an object of the present invention to provide a kind of oral drugs containing Amlodipine, Losartan and Rosuvastatin
Composition and compound formulation, the pharmaceutical composition and compound formulation are uniform with excellent bioavilability, stability and content
Property.
It is prepared it is a further object to provide a kind of containing the compound of Amlodipine, Losartan and Rosuvastatin
The method of preparation.
According to an aspect of the present invention, prevention or treatment cardiovascular disease medicine composition are provided, it is including ammonia chlorine
Flat or its pharmaceutically acceptable salt, Rosuvastatin or its pharmaceutically acceptable salt and Losartan or its is pharmaceutically acceptable
Salt, wherein, the grain size (D of the Rosuvastatin or its pharmaceutically acceptable salt90) it is 50 μm or smaller.
According to another aspect of the present invention, the medicine compound preparation for preventing or treating angiocardiopathy is additionally provided,
It includes the first mixture part, which includes Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or its medicine
Acceptable salt and pharmaceutically acceptable additive on；With the second mixture part, which includes Losartan or its medicine
Acceptable salt and pharmaceutically acceptable additive on, wherein mutually dividing on the first and second mixtures part physical
From the grain size (D of the Rosuvastatin or its pharmaceutically acceptable salt90) it is 50 μm or smaller.
According to another aspect of the present invention, a kind of compound system of drug for being used to preventing or treating angiocardiopathy is provided
The preparation method of agent, the method comprising the steps of：A) by Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or its medicine
Acceptable salt and pharmaceutically acceptable additive are mixed on；And b) by Losartan or its pharmaceutically acceptable salt
It is mixed with pharmaceutically acceptable additive, wherein the grain size of the Rosuvastatin or its pharmaceutically acceptable salt
(D90) it is 50 μm or smaller.
Another aspect of the present invention provides a kind of preparation side of double-layer tablets for preventing or treating angiocardiopathy
Method, the method comprising the steps of：A) by Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or its is pharmaceutically acceptable
Salt and pharmaceutically acceptable additive mixed；B) it by Losartan or its pharmaceutically acceptable salt and can pharmaceutically connect
The additive received carries out being mixed to form mixture, and mixture then is made particle；C) the mixture part for preparing step a)
Tabletting is carried out with mixture part prepared by step b) and obtains double-layer tablets, wherein the Rosuvastatin or its is pharmaceutically acceptable
Salt grain size (D90) it is 50 μm or smaller.
Compared with prior art, beneficial effects of the present invention are as follows：
According to an embodiment of the invention, pharmaceutical composition containing Amlodipine, Losartan and Rosuvastatin and compound
Preparation is effectively used for preventing or treating angiocardiopathy.Particularly described pharmaceutical composition and compound formulation have excellent
Dissolution rate, bioavilability, stability and content uniformity.
Description of the drawings
Upon reading the detailed description of non-limiting embodiments with reference to the following drawings, other feature of the invention,
Objects and advantages will become more apparent upon：
Fig. 1 be embodiment 1 to 3, comparing embodiment 1 to 3 tablet in Rosuvastatin dissolution rate variation diagram；
Fig. 2 be embodiment 1 to 3, comparing embodiment 1 to 3 tablet in Amlodipine dissolution rate variation diagram；
Fig. 3 be embodiment 1 to 3, comparing embodiment 1 to 3 tablet in Losartan dissolution rate variation diagram；
Fig. 4 be embodiment 1, embodiment 4 to 10 tablet in Rosuvastatin dissolution rate variation diagram；
Bioavilability variation diagrams of the Fig. 5 for Rosuvastatin in the tablet of embodiment 1 and comparing embodiment 1.
Specific embodiment
According to an aspect of the present invention, prevention is provided or treats the pharmaceutical composition of angiocardiopathy, it includes ammonia chlorine
Horizon or its pharmaceutically acceptable salt, Rosuvastatin or its pharmaceutically acceptable salt and Losartan or its can pharmaceutically connect
The salt received, wherein, the grain size (D of the Rosuvastatin or its pharmaceutically acceptable salt90) it is 50 μm or smaller.
The pharmaceutical composition of the present invention has specified particle diameter range due to Rosuvastatin or its pharmaceutically acceptable salt
And higher dissolution rate, bioavilability etc. is presented.Specifically, the grain of Rosuvastatin or its pharmaceutically acceptable salt about
Diameter (D90) it is 50 μm or smaller.In one embodiment of the invention, the grain of Rosuvastatin or its pharmaceutically acceptable salt
Diameter (D90) it is about 25 μm or smaller, it is highly preferred that being about 10 μm or smaller.In one embodiment, Rosuvastatin or pharmacy
Grain size (the D of upper acceptable salt90) may be 50 μm, 47.2 μm, 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 22.5 μm, 20 μm,
15 μm, 10 μm, 8.7 μm, 5 μm, 4 μm, 3 μm, 2 μm, 1 μm, 0.8 μm, 0.5 μm or 0.1 μm.An implementation as the present invention
Grain size (the D of example, Rosuvastatin or pharmaceutically acceptable salt90) can be about 0.8 μm to about 50 μm or about 0.8 μm to about
25 μm or about 0.8 μm Dao about 10 μm.Grain size (the D of Rosuvastatin or pharmaceutically acceptable salt90) it is about 0.8 μm or bigger
When, it is easier to prepare composition.Herein, longest diameter of the size of particle according to particle, D90Mean based on accumulative percentage
Than included in the average diameter of particles of the 90th percentile.Auspicious statin of cutting down can be by wet method or dry pulverization process, such as uses air-flow powder
Broken machine, stream energy pulverizer, micron mill etc., but not limited to this.It using above-mentioned breaking method, can become the grain size of Rosuvastatin
It is small.
As one embodiment of the present of invention, when composition carries out dissolution test according to USP paddle method in water, dissolving out
The dissolution rate of 30 minutes Rosuvastatins measured can be 85% or higher after on-test.It is highly preferred that the composition exists
When carrying out dissolution test using USP paddle method in water, the dissolution rate of 15 minutes Rosuvastatins measured after dissolution test starts
For 85% or higher.Specifically, dissolution rate can be measured according to USP paddle method at a temperature of 30~40 DEG C, more precisely for, 35
It is measured at~38 DEG C, paddle rotating speed is 50~100rpm, more definitely says it is 70~80rpm.According to one embodiment of present invention,
Dissolution rate can 37 DEG C temperature, paddle rotating speed is measures under the conditions of 75rpm.
In addition, the composition of the present invention includes Rosuvastatin, Amlodipine and Rosuvastatin as active constituent, it can
To prevent as oral drug preparation or treat angiocardiopathy.
According to an aspect of the invention, there is provided for preventing or treating the medicine compound preparation of angiocardiopathy, it
Including the first mixture part, which includes Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or its pharmacy
Upper acceptable salt and pharmaceutically acceptable additive；With the second mixture part, which includes Losartan or its pharmacy
Upper acceptable salt and pharmaceutically acceptable additive, wherein mutually dividing on the first and second mixtures part physical
From the grain size (D of the Rosuvastatin or its pharmaceutically acceptable salt90) it is 50 μm or smaller.
The compound formulation of the present invention includes the first and second mixture parts, they are physically detached from each other each other, i.e. ammonia
Preservation is isolated with Losartan for Flordipine and Rosuvastatin.The interaction between ingredient is thus it can be prevented that, so as to show
Improved stability.
In one embodiment of the invention, compound formulation is capsule or double-layer tablets, it includes first layer, which includes ammonia
Flordipine or its pharmaceutically acceptable salt, Rosuvastatin or its pharmaceutically acceptable salt and pharmaceutically acceptable addition
Agent；And the second layer, the layer include Losartan or its pharmaceutically acceptable salt and pharmaceutically acceptable additive.In addition to bilayer
Outside piece, in other the embodiment of the present invention, the compound formulation can be prepared with various forms, wherein the first mixture part
It is separated from each other (for example, nucleocapsid) on the second mixture part physical.
In one embodiment, the grain size (D of Rosuvastatin or its pharmaceutically acceptable salt90) can be 50 μm,
47.2μm、45μm、40μm、35μm、30μm、25μm、22.5μm、20μm、15μm、10μm、8.7μm、5μm、4μm、3μm、2μm、1
μm, 0.8 μm, 0.5 μm or 0.1 μm.In addition, grain size (the D of Rosuvastatin or its pharmaceutically acceptable salt90) can be about 50
μm or smaller, about 0.8 μm to about 50 μm, about 0.8 μm to 25 μm or about 0.8 μm Dao about 10 μm.
The present invention composition or compound formulation include in the first mixture part (or first layer) Amlodipine or its
Pharmaceutically acceptable salt.The pharmaceutically acceptable salt of Amlodipine in the present invention, with containing pharmaceutically acceptable the moon
Prepared by the acid of ion, it can form nontoxic acid-addition salts, such as hydrogen chloride, hydrogen bromide, sulfate, phosphate, acetate, apple
Tartaric acid salt, fumarate, lactate, tartrate, citrate, gluconate, benzene sulfonate or camsilate.It is preferred that
Ground, the pharmaceutically acceptable salt of Amlodipine can be Amlodipine Besylate Tablet or amlodipine camsylate.In addition, this
The Amlodipine of invention includes racemic mixture and (S)-Amlodipine.Amlodipine or its pharmaceutically acceptable salt take daily
It can be about 5 to 10mg Amlodipine with dosage.
The present invention composition or compound formulation include in the first mixture part (or first layer) Rosuvastatin or
Its pharmaceutically acceptable salt.The example of the pharmaceutically acceptable salt of Rosuvastatin can include the inorganic of polycation
Salt, preferably rosuvastain calcium, but not limited to this.Rosuvastatin or its pharmaceutically acceptable salt day taking dose can
Think about 5 to 20mg Rosuvastatin.
The composition or compound formulation of the present invention includes Losartan or its medicine in the second mixture part (or second layer)
Acceptable salt on.The example of the pharmaceutically acceptable salt of Losartan can include Losartan Potassium, but not limited to this.Chlorine is husky
Smooth or its taking dose can be about 50 to 100mg Losartan pharmaceutically acceptable salt day.
In the composition or compound formulation of the present invention, Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or
Its pharmaceutically acceptable salt and Losartan or its pharmaceutically acceptable salt can be according to 1：0.3~4：5~20 weight ratio
Mixing, it is preferable that can be according to 1：1~4：10~20 weight ratio mixing, but not limited to this.
In the composition or compound formulation of the present invention, in the first mixture part or first layer and the second mixture part
Or the pharmaceutically acceptable additive used in the second layer can be pharmaceutically acceptable carrier or excipient.Pharmaceutically
The example of acceptable carrier or excipient includes lactose (lactose hydrous), microcrystalline cellulose, mannitol, sodium citrate, phosphorus
Sour calcium, glycine and starch, disintegrant (such as crospovidone, copolyvidone, croscarmellose sodium, carboxymethyl starch
Sodium, starch, pregelatinized starch and composition silicate) and binding agent (such as polyvinylpyrrolidone, hydroxypropyl methyl cellulose
(HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and Arabic gum).
In one embodiment, composition of the invention or compound formulation contain in the first mixture part or first layer
Lactose hydrous and microcrystalline cellulose are as additive.Lactose hydrous can account for the total weight of the first mixture part or first layer
40~60 weight %.Microcrystalline cellulose can account for 15~35 weight % of the total weight of the first mixture part or first layer.
In another embodiment, lactose hydrous and microcrystalline cellulose can be according to 1 in the first mixture part or first layer:0.2~
1:It is used in 0.9 proportional region.
When using lactose hydration as water-soluble additives in the range, lactose hydrous can form promotion activity
The hydrophilic channel of ingredient dissolving, so as to which ingredient be made quickly to dissolve.Especially, when the lactose hydrous containing 40 weight % or more
Dissolution rate can be improved.If the amount of lactose hydrous is more than the range, it is completely dissolved the time needed for lactose hydrous
Extend, so as to slow down the dissolving of active constituent.If become to hold using avicel cellulose, tableting processes in the range
Easily.However, the amount less than the range may cause to generate some difficulties in tableting processes, and excessively it may result in dosage form
It is oversized.Therefore, Amlodipine is remarkably improved using lactose hydrous and microcrystalline cellulose, Rui Shu is cut down in the range
The dissolution rate of statin and Losartan.
In one embodiment, composition of the invention or compound formulation can be in the first mixture part or first layer
It is used as and collapses comprising crospovidone, croscarmellose sodium, sodium carboxymethyl starch, starch, pregelatinized starch or combination
Solve agent.In one embodiment, composition of the invention or compound formulation can wrap in the first mixture part or first layer
Containing crospovidone, croscarmellose sodium, sodium carboxymethyl starch or combination as disintegrant.Disintegrant can account for
3~10 weight % of the total weight of one mixture part or first layer.If dissolution can be made using disintegrant in the range
Degree improves, and the generation of related substances is reduced, and can ensure enough stability as time goes by under the conditions of heat stress.
In the compound formulation of the present invention, the first mixture part can be deposited in the form of wet granular or dry particl part
.
In one embodiment, the second mixture part of compound formulation of the invention or the second layer can be made with traditional
Grain method is prepared such as tabletting after compacting granulation.In another embodiment, the second mixture part can be prepared into rolling process
The form of particle.Result of the test according to the present invention is by the first mixture portion to being simply mixed when preparing compound formulation
When dividing and being compacted be granulated the second mixture part progress tabletting preparation double-layer tablets prepared, compound formulation shows improved ammonia chlorine
The dissolution rate of Horizon, Rosuvastatin and Losartan, meanwhile, good Dissolution profiles are presented in Amlodipine, Rosuvastatin.
Meanwhile the present invention also provides for preventing or treating the composite dosage form of the fixed dosage of angiocardiopathy, it is wrapped
Include the first mixture part, the part include Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or its pharmaceutically
Acceptable salt and pharmaceutically acceptable additive；With the second mixture part, the part include Losartan or its pharmaceutically
Acceptable salt and pharmaceutically acceptable additive, wherein be separated from each other on the first and second mixtures part physical,
Grain size (the D of the Rosuvastatin or its pharmaceutically acceptable salt90) it is 50 μm or smaller.
In one embodiment of fixed-dose combination type, the amount of Amlodipine or its pharmaceutically acceptable salt turns
The amount for turning to Amlodipine radical form is 5~10mg.In one embodiment of fixed-dose combination type, Rosuvastain
Spit of fland or its pharmaceutically acceptable salt, the amount for being converted into Rosuvastatin free acid form are 5~20mg.In addition, in fixative
In the one embodiment for measuring composite dosage form, Losartan or its pharmaceutically acceptable salt, the amount for being converted into Losartan acid form is
50~100mg.
According to one embodiment of present invention, when the compound formulation according to USP slurry processes in water with about 75rpm slurry speed into
During row dissolution test, the dissolution rate of the Rosuvastatin measured after 30 minutes can be 85% or higher.
In addition, the present invention provides a kind of preparation sides of medicine compound preparation for preventing or treating angiocardiopathy
Method, the method comprising the steps of：A) by Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or its is pharmaceutically acceptable
Salt and pharmaceutically acceptable additive mixed；And b) by Losartan or its pharmaceutically acceptable salt and pharmaceutically may be used
The additive of receiving is mixed, wherein the grain size (D of the Rosuvastatin or its pharmaceutically acceptable salt90) for 50 μm or
Smaller.
The method further includes mixing containing Amlodipine, the mixture part of Rosuvastatin and mixing containing Losartan
The step of polymer portion, is separated from each other on two of which part physical.
In one embodiment, the present invention provides a kind of preparations of double-layer tablets for preventing or treating angiocardiopathy
Method, the method comprising the steps of：A) by Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or its can pharmaceutically connect
The salt and pharmaceutically acceptable additive received are mixed；B) by Losartan or its pharmaceutically acceptable salt and pharmaceutically may be used
The additive of receiving carries out being mixed to form mixture, and mixture then is made particle；C) the mixture portion for preparing step a)
Point and step b) prepare mixture part carry out tabletting obtain double-layer tablets, wherein the Rosuvastatin or its can pharmaceutically connect
Grain size (the D for the salt received90) it is 50 μm or smaller.
In the present invention, angiocardiopathy be selected from angina pectoris, hypertension, arteriospasm, arrhythmia cordis, cardiomegaly,
The group of cerebral infarction, congestive heart failure and myocardial infarction combination.
To the present invention be more specifically described by following embodiment below.However, these embodiments are for illustration purposes only,
And the present invention is not limited thereto.
Embodiment 1：The preparation of pharmaceutical composition containing micronizing Rosuvastatin
Rosuvastatin calcium powder is crushed by airslide disintegrating mill, and preparing has 22.5 μm of grain size (D90) micronizing Rui Shu
Cut down statin calcium.The constituent shown according to the following table 1, by amlodipine camsylate, the rosuvastain calcium of micronizing, lactose
Hydrate, microcrystalline cellulose, crospovidone are mixed, and are crossed 30 mesh sieve, are added in magnesium stearate, finally mixed with blender,
Obtain the mixture part containing Amlodipine, Rosuvastatin.
Meanwhile Losartan Potassium, microcrystalline cellulose, crospovidone are mixed, and cross 30 mesh sieve.Then, sieve powder
With roller type press (roller type press wp200, alexanderwerk) at least pressing force of 20kN with 2 to 10rpm roller speed
Degree compacting, forms it into sheet-like particle.Obtained particle pulverizer (Fitz Mill；BAS 06, Fitzpatrick are beautiful
State) it crushes, 20 mesh sieve is crossed, magnesium stearate is added in, is finally mixed with blender, obtain the particle part containing Losartan.
Then, Composite Double synusia is prepared by tablet press machine (Kilian Synthesis 700, Germany), it includes containing ammonia
Mixture part (the first layer of Flordipine, Rosuvastatin；Upper strata) and the particle part (second layer containing Losartan；Bottom
Layer).
Table 1
Embodiment 2 and 3 and comparing embodiment 1 to 3：Prepare the pharmaceutical composition of the Rosuvastatin containing different-grain diameter
It is as shown in table 2 below, using different-grain diameter Rosuvastatin repeat embodiment 1 the step of, obtain Composite Double synusia.
Table 2
Embodiment 4 to 10：Prepare the pharmaceutical composition for containing different amounts of disintegrant in upper strata
It is as shown in table 3 below, it the step of repeating embodiment 1, is obtained using different amounts of disintegrant according to the total weight on upper strata
Obtain Composite Double synusia.In the embodiment, the grain size (D of Rosuvastatin90) using 22.5 μm.
Table 3
Test example 1：According to the different-grain diameter (D of Rosuvastatin90), take orally the variation of compound formulation dissolution rate
To tablet prepared by embodiment 1 to 3, comparing embodiment 1 to 3, drug-eluting examination is carried out under the following conditions respectively
It tests, the dissolution rate variation for changing over time Rosuvastatin, Amlodipine and Losartan is measured with this.
Experimental condition-
Dissolving medium：Water 900mL
Instrument:USP slurry processes, 75rpm
Temperature:37℃
Dissolution time:5th, 10,15 and 30 minutes
Analysis condition-
Column：For liquid chromatography, fill up the stainless steel column (internal diameter of 3 μm of octadecylsilylated silica gel：About 4.6mm,
Length：15cm)
Mobile phase：* sodium hexanesulfonate/0.05% (v/v) phosphoric acid of 6mM：Acetonitrile (60:40, v/v)
(* 6mM sodium hexanesulfonate/0.05% (v/v) phosphoric acid：The sodium hexanesulfonate hydrate of 1.24g is added to 1L flasks,
The phosphoric acid of 0.5mL is carefully added again.Pure water is added in, is thoroughly stirred evenly.)
Detector：Ultraviolet specrophotometer (absorbance at 254nm)
Flow：1.3mL/ minute
Volume injected：10μL
Column temperature：45℃
Acceptance criteria-
At 30 minutes, dissolution rate is 85% or higher
Dissolution results are shown in Fig. 1~Fig. 3.As shown in Figures 2 and 3, the grain size (D of Rosuvastatin90) size difference
The dissolution rate of Amlodipine and Losartan is not influenced.Two kinds of substance dissolution rates meet acceptance criteria.
At the same time, as shown in Figure 1, according to Rosuvastatin grain size (D90) size, the dissolution rate performance of Rosuvastatin
Go out significant difference.The tablet containing micronizing Rosuvastatin prepared in Examples 1 to 3, initial stage show quickly molten
Out-degree, and meet acceptance criteria.But the piece of the Rosuvastatin containing greater particle size prepared by comparing embodiment 1~3
Agent, initial stage shows relatively low dissolution rate, and does not meet acceptance criteria.
The above result shows that dissolution rate can be by Rosuvastatin grain size (D90) a certain range is adjusted to improve.
Test example 2：Oral administered compound closes formulation content uniformity testing
In order to evaluate the grain size according to different Rosuvastatins, the variation of the uniformity of dosage units of composition has carried out South Korea
The uniformity of dosage units test of pharmacopeia.
To the tablet prepared in Examples 1 to 3, comparing embodiment 1~3, retouch in the general test of Pharmacopoeia Coreana
The content range pattern stated.High performance liquid chromatography (HPLC) of the content in test example 1 calculates acceptance value to determine.Knot
Fruit such as table 4.
Table 4
As shown in table 4 above, it is being prepared in Examples 1 to 3, containing grain size be (D90) 50 μm or smaller Rosuvastatin
Tablet, with it is being prepared in comparing embodiment 1~3, containing grain size be more than (D90) 50 μm of the tablet of Rosuvastatin compares, it is preceding
Person's acceptance value significantly improves.This result shows that, the Rosuvastatin of certain particle size range can be used for preparing mixed with what is improved
Close the preparation of uniformity and content uniformity.
Test example 3：According to the different amounts of the disintegrant on upper strata, the variation of compound formulation dissolution rate is taken orally
To the tablet prepared in embodiment 1 and embodiment 4~10, with the condition identical with test example 1, to Rosuvastatin
Dissolution rate be determined with time change.As a result such as Fig. 4.As shown in figure 4, the tablet of embodiment 4 and 5 dissolves out in the early stage
It spends relatively low, does not meet acceptance criteria.However, the tablet of embodiment 1 and embodiment 6 to 10 show in the early stage it is fast instant
Solution, and meet acceptance criteria.
Test example 4：The oral compound preparation for containing different content disintegrant on upper strata is steady under heat stress storage requirement
Qualitative test
To the tablet prepared in embodiment 1 and embodiment 4 to 10, stability test is carried out under heat stress storage requirement,
The stability of tablet is evaluated by analyzing the changes of contents of related substances derived from Rosuvastatin.It the results are shown in Table 5.
Stability test room condition (thermal stress conditions)-
(1) temperature and humidity：50℃±2℃
(2) sample：It is stored in high-density polyethylene bottle
(3) testing time：After initial and storage 28 days
Analysis condition-
Column：For liquid chromatography, fill up the stainless steel column (internal diameter of 5 μm of octadecylsilylated silica gel：About 4.6mm,
Length：25cm)
Mobile phase：* sodium hexanesulfonate/0.05% (v/v) phosphoric acid of 6mM：Acetonitrile (6:4, v/v)
Detector：Ultraviolet specrophotometer (absorbance at 239nm)
Flow：1.0mL/ minute
Volume injected：10μL
Column temperature：45℃
Table 5
As shown in table 5, the tablet of embodiment 1 and embodiment 6~8 shows very high stability under the conditions of heat stress,
Generate a small amount of Amlodipine, Rosuvastatin and Losartan related substances simultaneously.On the other hand, the tablet of embodiment 9 and 10
The Amlodipine of generation and Rosuvastatin related substances, than embodiment 1 tablet more than 5~8 times.
Meanwhile compared with the tablet of embodiment 1 and embodiment 6 to 8, the tablet of the smaller embodiment 4 and 5 of disintegrant content
The related substances of generation are near or below embodiment 1.Should the result shows that, on the basis of the total weight of upper strata, when the disintegration in tablet
When agent dosage is more than 10 weight %, under the conditions of heat stress, over time, it is highly difficult to ensure enough stability
's.
Test example 5：The Evaluation On The Bioavailability of Rosuvastatin
The composition prepared with embodiment 1 and comparing embodiment 1 carries out Evaluation On The Bioavailability to beasle dog.Experiment is logical
It crosses and random crossing research is carried out to six beasle dogs to carry out.As a result as shown in table 6 and Fig. 5.Fig. 5 describes Rosuvastatin blood
Starch linear list of the arithmetic mean of instantaneous value to time (HR) of concentration (ng/mL).
Table 6
It is (D containing grain size as shown in table 6 and Fig. 590) 22.5 μm of the composition of Rosuvastatin (makes in embodiment 1
It is standby) with being (D containing grain size90) 60 μm of the composition (being prepared in comparing embodiment 1) of Rosuvastatin compares, biological utilisation
Spend higher.The result is related with improved solubility property, as shown in Figure 1.It therefore, should be the result shows that the Rosuvastatin of micronizing
Its dissolution rate can be improved, and finally improves its bioavilability.
Claims (16)
1. a kind of for preventing or treating the medicine composition of cardiovascular disease, it includes Amlodipine or its is pharmaceutically acceptable
Salt, Rosuvastatin or its pharmaceutically acceptable salt and Losartan or its pharmaceutically acceptable salt, wherein, it is described auspicious to relax
Cut down statin or the grain size (D of its pharmaceutically acceptable salt90) it is 50 μm or smaller.
2. according to the pharmaceutical composition described in claim the 1, which is characterized in that the Rosuvastatin or its pharmaceutically may be used
Grain size (the D of the salt of receiving90) it is 0.8 to 50 μm.
3. according to the pharmaceutical composition described in claim the 2, which is characterized in that described, the Rosuvastatin or its medicine
Grain size (the D of acceptable salt on90) it is 0.8 to 25 μm.
4. according to the pharmaceutical composition described in claim the 3, which is characterized in that the Rosuvastatin or its pharmaceutically may be used
Grain size (the D of the salt of receiving90) it is 0.8 to 10 μm.
5. according to the pharmaceutical composition described in claim the 1, which is characterized in that when composition according to USP paddle method in water
When carrying out dissolution test, the dissolution rate of the Rosuvastatin measured in 30 minutes after dissolution test starts is 85% or higher.
6. according to the pharmaceutical composition described in claim the 5, which is characterized in that when composition according to USP paddle method in water
When carrying out dissolution test, the dissolution rate of the Rosuvastatin measured in 15 minutes after dissolution test starts is 85% or higher.
7. it is a kind of for preventing or treating the medicine compound preparation of angiocardiopathy, including：
First mixture part, the part include Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or its pharmacy
Upper acceptable salt and pharmaceutically acceptable additive；With
Second mixture part, the part include Losartan or its pharmaceutically acceptable salt and pharmaceutically acceptable addition
Agent,
It is separated from each other on wherein described first and second mixtures part physical,
Grain size (the D of the Rosuvastatin or its pharmaceutically acceptable salt90) it is 50 μm or smaller.
8. according to the medicine compound preparation described in claim the 7, which is characterized in that the medicine compound preparation is bilayer
Piece, including：
First layer, including Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or its pharmaceutically acceptable salt and
Pharmaceutically acceptable additive；
The second layer, including Losartan or its pharmaceutically acceptable salt and pharmaceutically acceptable additive.
9. according to the medicine compound preparation described in claim the 7, which is characterized in that the first mixture part, which includes, to collapse
Agent is solved as additive.
10. according to the medicine compound preparation described in claim the 9, which is characterized in that the disintegrant accounts for the first mixture
3~10 weight % of partial total weight.
11. according to the medicine compound preparation described in claim the 9, which is characterized in that the disintegrant is crospovidone,
Croscarmellose sodium, sodium carboxymethyl starch, starch, pregelatinized starch or combination.
12. according to the medicine compound preparation described in claim the 7, which is characterized in that contain the first mixture part
Lactose hydrous and microcrystalline cellulose are as additive.
13. according to the medicine compound preparation described in claim the 7, which is characterized in that the second mixture part roller
Pressure technique is prepared into the form of particle.
14. a kind of preparation method of medicine compound preparation for preventing or treating angiocardiopathy,
The method comprising the steps of：
A) by Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or its pharmaceutically acceptable salt and pharmaceutically may be used
The additive of receiving is mixed；With
B) Losartan or its pharmaceutically acceptable salt and pharmaceutically acceptable additive are mixed；
Grain size (the D of wherein described Rosuvastatin or its pharmaceutically acceptable salt90) it is 50 μm or smaller.
15. according to the preparation method of the medicine compound preparation described in claim the 14, which is characterized in that the compound formulation
It is tablet or capsule.
16. a kind of preparation method of double-layer tablets for preventing or treating angiocardiopathy, the method comprising the steps of：
A) by Amlodipine or its pharmaceutically acceptable salt, Rosuvastatin or its pharmaceutically acceptable salt and pharmaceutically may be used
The additive of receiving is mixed；
B) Losartan or its pharmaceutically acceptable salt and pharmaceutically acceptable additive are carried out being mixed to form mixture, so
Particle is made in the mixture afterwards；
C) mixture part prepared by step a) the mixture parts prepared and step b) is subjected to tabletting and obtains double-layer tablets；
Grain size (the D of wherein described Rosuvastatin or its pharmaceutically acceptable salt90) it is 50 μm or smaller.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110171819.4A CN112933093A (en) | 2015-06-30 | 2016-06-29 | Pharmaceutical composite preparation containing amlodipine, losartan and rosuvastatin |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20150093714 | 2015-06-30 | ||
| KR10-2015-0093714 | 2015-06-30 | ||
| PCT/KR2016/006977 WO2017003186A1 (en) | 2015-06-30 | 2016-06-29 | Pharmaceutical complex formulation comprising amlodipine, losartan and rosuvastatin |
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| CN202110171819.4A Division CN112933093A (en) | 2015-06-30 | 2016-06-29 | Pharmaceutical composite preparation containing amlodipine, losartan and rosuvastatin |
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| CN108156807A true CN108156807A (en) | 2018-06-12 |
Family
ID=57608904
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| CN201680031203.4A Pending CN108156807A (en) | 2015-06-30 | 2016-06-29 | Medicine compound preparation containing Amlodipine, Losartan and Rosuvastatin |
| CN202110171819.4A Pending CN112933093A (en) | 2015-06-30 | 2016-06-29 | Pharmaceutical composite preparation containing amlodipine, losartan and rosuvastatin |
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| Country | Link |
|---|---|
| KR (2) | KR20170003459A (en) |
| CN (2) | CN108156807A (en) |
| MX (2) | MX2017014311A (en) |
| PH (1) | PH12017501986A1 (en) |
| RU (1) | RU2724338C2 (en) |
| WO (1) | WO2017003186A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113747885A (en) * | 2019-04-18 | 2021-12-03 | 韩美药品株式会社 | Pharmaceutical combination preparation comprising ezetimibe and losartan |
| CN116018137A (en) * | 2020-08-25 | 2023-04-25 | 株式会社大熊制药 | Pharmaceutical composition in single dosage form for treating or preventing hypertension and hyperlipidemia |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019022436A2 (en) * | 2017-07-27 | 2019-01-31 | 에리슨제약(주) | Pharmaceutical composition comprising nep inhibitor and beta-blocker |
| KR20190043076A (en) * | 2017-10-17 | 2019-04-25 | 한미약품 주식회사 | Pharmaceutical composition comprising amlodipine, losartan and rosuvastatin for prevention and treatment of cardiovascular diseases accompanied by diabetes and formulated combination including the same |
| CN108245516B (en) * | 2017-11-09 | 2019-04-12 | 浙江京新药业股份有限公司 | A kind of pharmaceutical composition and preparation method thereof containing rosuvastain calcium |
| CN109464407A (en) * | 2018-12-27 | 2019-03-15 | 成都恒瑞制药有限公司 | Rosuvastain calcium quick-release formulation and preparation method thereof |
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| CN116018137A (en) * | 2020-08-25 | 2023-04-25 | 株式会社大熊制药 | Pharmaceutical composition in single dosage form for treating or preventing hypertension and hyperlipidemia |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112933093A (en) | 2021-06-11 |
| PH12017501986A1 (en) | 2018-03-19 |
| MX2021005210A (en) | 2021-06-18 |
| WO2017003186A1 (en) | 2017-01-05 |
| RU2724338C2 (en) | 2020-06-23 |
| RU2018103213A (en) | 2019-07-31 |
| RU2018103213A3 (en) | 2019-12-09 |
| KR20170003459A (en) | 2017-01-09 |
| KR20180044873A (en) | 2018-05-03 |
| MX2017014311A (en) | 2018-03-07 |
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Application publication date: 20180612 |