CN107028906A - A kind of composite tablet containing Ezetimibe and Rosuvastatin and preparation method thereof - Google Patents
A kind of composite tablet containing Ezetimibe and Rosuvastatin and preparation method thereof Download PDFInfo
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- CN107028906A CN107028906A CN201710473352.2A CN201710473352A CN107028906A CN 107028906 A CN107028906 A CN 107028906A CN 201710473352 A CN201710473352 A CN 201710473352A CN 107028906 A CN107028906 A CN 107028906A
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- particle
- ezetimibe
- rosuvastatin
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- disintegrant
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/495—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Abstract
The invention discloses a kind of composite tablet containing Ezetimibe and Rosuvastatin and preparation method thereof, belong to field of pharmaceutical preparations.Described composite tablet is that the Ezetimibe particle and Rosuvastatin particle for obtaining granulation are coated respectively, adds disintegrant afterwards and mix lubricant tabletting is formed；Described Ezetimibe particle is made up of Ezetimibe, filler, solubilizer, adhesive and disintegrant；Described Rosuvastatin particle is made up of Rosuvastatin, filler, stabilizer, disintegrant and adhesive.The present invention separately pelletizes Ezetimibe with Rosuvastatin, effectively interference of the control Ezetimibe to Rosuvastatin, is formed so as to reduce relevant material；Meanwhile, Ezetimibe separately pelletized with Rosuvastatin, it is to avoid interfere, it is ensured that the stabilization of Rosuvastatin.
Description
Technical field
It is specifically a kind of using Ezetimibe and Rosuvastatin as the tool of active component the invention belongs to field of pharmaceutical preparations
There is composite tablet of effect for reducing fat and preparation method thereof.
Background technology
High fat of blood is to cause the one of the main reasons of coronary heart disease and apoplexy, with China human mortality aging and living standard
Improve, high fat of blood patient is also being on the increase.
Ezetimibe and Rosuvastatin Compound Tablet can effectively reduce blood fat, but be due to Ezetimibe solubility it is relatively low,
Rosuvastatin less stable, therefore the two is prepared after Compound Tablet, Ezetimibe is difficult that Fast Stripping, Rosuvastatin are stable
Property is also poor.
CN1002451161A discloses the embodiment of Ezetimibe and Rosuvastatin prepared composition discrete piece, but will be according to
Ezetimibe is separately pelletized with Rosuvastatin causes Ezetimibe to produce influence, relevant material increase on Rosuvastatin.And not
Use stabilizer, it is impossible to ensure the stability of Rosuvastatin.
The compound preparation of Ezetimibe and Rosuvastatin is disclosed in CN102357096A, it is characterised in that first prepare auspicious
Relax and cut down statin particle, then additional Ezetimibe, finally unify tabletting, although the former can effectively control Ezetimibe to Rosuvastain
The interference in spit of fland, but together after tabletting, Rosuvastatin is caused in the case where powerful pressure is acted on, and some enters Ezetimibe layer,
Ezetimibe layer internal environment, such as pH value, adjunct ingredient are different from Rosuvastatin layer so that the part Rosuvastatin is relevant
Material increase is larger.
CN103585157A discloses a kind of using Ezetimibe and Rosuvastatin as the compound preparation of active ingredient, and it is special
Levy and be with Rosuvastatin separately to pelletize the Ezetimibe after micronizing, be pressed into double-layer tablets, it is to avoid interfere.Ensure
The stabilizations of two kinds of medicines, and Ezetimibe is by micronizing, it is easy to dissolution, but this method needs to use special double-deck pressure
Piece machine, the equipment popularity rate is relatively low, and production equipment input is larger, and the place of two layers of handing-over has a certain amount of according to folding in double-layer tablets
Mai Buhui and Rosuvastatin contact, cause relevant material increase.
Therefore, invention one kind can solve Ezetimibe and Rosuvastatin stability problem, the technique being readily produced again
Extremely it is necessary.
The content of the invention
For above-mentioned technical problem, the invention provides a kind of Ezetimibe and the Compound Tablet of Rosuvastatin
Agent, its main advantage is Ezetimibe and Rosuvastatin separating granulating coated, respectively obtains the Ezetimibe after being coated
Particle and Rosuvastatin particle, two kinds of particles are mixed, tabletting obtains Compound Tablet.Two kinds of medicines had so both been avoided mutually to be concerned with
Disturb, be readily produced again.
The purpose of the present invention can be achieved through the following technical solutions：
A kind of composite tablet containing Ezetimibe and Rosuvastatin, described composite tablet be by pelletize obtain according to folding
Wheat cloth particle and Rosuvastatin particle are coated respectively, add disintegrant afterwards and mix lubricant tabletting is formed；It is described according to
Ezetimibe particle is made up of Ezetimibe, filler, solubilizer, adhesive and disintegrant；Described Rosuvastatin particle by
Rosuvastatin, filler, stabilizer, disintegrant and adhesive composition.
In some technical schemes：Ezetimibe content is 5-20mg, Rosuvastatin content in described composite tablet
For 5-50mg.
In some technical schemes：The composition of auxiliary material used is as follows in Ezetimibe particle and Rosuvastatin particle：
In Ezetimibe particle：Described filler is one or several kinds of groups in lactose, starch, microcrystalline cellulose
Close；Described solubilizer is one or several kinds of groups in lauryl sodium sulfate, polyvinyl alcohol rilanit special, Tween 80
Close；Described adhesive is the one or more in PVP K30, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose
Combination；Described disintegrant is a kind of or several in Ac-Di-Sol, PVPP, sodium carboxymethyl starch
The combination planted；
In Rosuvastatin particle：Described filler includes the one or several kinds in lactose, starch, microcrystalline cellulose
Combination；Described stabilizer is one or several kinds of combinations in calcium phosphate, calcium monohydrogen phosphate, sodium carbonate etc.；Described collapses
Solution agent is one or several kinds of combinations in Ac-Di-Sol, PVPP, sodium carboxymethyl starch；Described
Adhesive is one or more of combinations in PVP K30, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose.
In some technical schemes：The auxiliary material composition of coatings used in Ezetimibe particle and Rosuvastatin particle is such as
Under：
The particle outer layer of Rosuvastatin is surrounded by one layer of coating agent, coating agent be film forming agent, auxiliary film former, antiplastering aid,
One or several kinds of combinations in opacifier；Wherein film forming agent is hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrole
One or more of combinations of alkanone etc.；Auxiliary film former is one or more of combinations of propane diols, polyethylene glycol etc.；It is anti-stick
Agent is one or several kinds of combinations in talcum powder, superfine silica gel powder, magnesium stearate；Opacifier is titanium dioxide；
Ezetimibe particle outer layer is surrounded by one layer of coating agent, and coating agent is film forming agent, auxiliary film former, antiplastering aid, shading
One or several kinds of combinations in agent；Wherein film forming agent is hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone
Deng one or more of combinations；Auxiliary film former is one or more of combinations of propane diols, polyethylene glycol etc.；Antiplastering aid is
One or several kinds of combinations in talcum powder, superfine silica gel powder, magnesium stearate；Opacifier is titanium dioxide.
In some preferred technical schemes：The composition and consumption of contained component are as follows in Ezetimibe particle：
5~20 parts of Ezetimibe；
20~100 parts of filler；
1~20 part of solubilizer；
0.1~5 part of adhesive；
1~10 part of disintegrant；
Further preferably：Described filler is 1 by mass ratio：0.1~1 lactose and microcrystalline cellulose composition；It is described
Solubilizer preferably sodium dodecyl sulfate or Tween 80；The preferred PVP K30 of described adhesive；Described disintegrant is preferred
PVPP；
In some preferred technical schemes：The coating agent composition of Ezetimibe particle is as follows：
Further preferably：Described film forming agent is hydroxypropyl methylcellulose；Described auxiliary film former is propane diols；Described
Antiplastering aid is talcum powder, and described opacifier is titanium dioxide；
More preferably：After each part mixing of above-mentioned coating agent, aqueous dispersion is configured to, for granule coating, bag
Ezetimibe weight gain is 20%-60% after clothing.
In some preferred technical schemes：The composition and consumption of contained component are as follows in the particle of Rosuvastatin：
Further preferably：Described filler preferred mass ratio is 1：0.1~1 lactose and microcrystalline cellulose；Described
Stabilizer preferably phosphoric acid hydrogen calcium, calcium phosphate or sodium carbonate；The preferred Ac-Di-Sol of described disintegrant or crosslinking are poly-
Tie up ketone；The preferred PVP K30 of described adhesive；
In some preferred technical schemes：The coating agent composition of the particle of Rosuvastatin is as follows：
20-80 parts of film forming agent；
0-10 parts of auxiliary film former；
10-60 parts of antiplastering aid；
0-1 parts of opacifier；
Further preferably：Described film forming agent is hydroxypropyl methylcellulose；Described auxiliary film former is propane diols；Described
Antiplastering aid is talcum powder；Described opacifier is titanium dioxide；
More preferably：After each part mixing of above-mentioned coating agent, aqueous dispersion is configured to, for granule coating, bag
Rosuvastatin weight gain is 20%-60% after clothing.
In technical solution of the present invention：The disintegrant added after coating be Ac-Di-Sol, PVPP and
One or several kinds of combinations in sodium carboxymethyl starch；It is preferred that disintegrant is PVPP and/or cross-linked carboxymethyl fiber
Plain sodium；The lubricant added after coating is one or several kinds of combinations in superfine silica gel powder, magnesium stearate and stearic acid；It is preferred that
Lubricant is magnesium stearate.
In some preferred technical schemes：The disintegrant added after coating accounts for Ezetimibe particle and Rosuvastatin
The 0.1%-10% of particle gross weight；The lubricant added after coating accounts for the particle gross weight of Ezetimibe particle and Rosuvastatin
The 0.1%-5% of amount.
A kind of preparation method of the above-mentioned composite tablet containing Ezetimibe and Rosuvastatin, this method includes following step
Suddenly：Ezetimibe particle：Ezetimibe after micronization processes and filler, disintegrant, solubilizer are put into granulator and mixed
Close uniform, adhesive granulation, drying are added afterwards；The particle obtained after drying, which is put into spray into fluid bed, is configured to 5%-20%
The coating agent of aqueous dispersion is coated, the Ezetimibe particle after drying coating；
Rosuvastatin particle：Rosuvastatin and filler, disintegrant, stabilizer are inserted in granulator and mixed
It is even, add binder solution granulation, drying；The particle obtained after drying, which is put into spray into fluid bed, is configured to 5%-20% moisture
The coating agent of granular media is coated, the Rosuvastatin particle after drying coating；
Tabletting：Rosuvastatin particle after Ezetimibe particle after coating and coating is mixed, disintegrant is added
And lubricant, tabletting after mixing, obtain Ezetimibe and Rosuvastatin Compound Tablet.
In the above method：Ezetimibe particle outer layer is surrounded by one layer of coating agent, coating agent be film forming agent, auxiliary film former,
One or several kinds of combinations in antiplastering aid, opacifier；Wherein film forming agent is hydroxypropyl methylcellulose, hydroxypropyl cellulose, gathered
One or more of combinations of vinylpyrrolidone etc.；Auxiliary film former is the one or more of of propane diols, polyethylene glycol etc.
Combination；Antiplastering aid is one or several kinds of combinations in talcum powder, superfine silica gel powder, magnesium stearate；Opacifier is titanium dioxide.
The particle outer layer of Rosuvastatin is surrounded by one layer of coating agent, coating agent be film forming agent, auxiliary film former, antiplastering aid,
One or several kinds of combinations in opacifier；Wherein film forming agent is hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrole
One or more of combinations of alkanone etc.；Auxiliary film former is one or more of combinations of propane diols, polyethylene glycol etc.；It is anti-stick
Agent is one or several kinds of combinations in talcum powder, superfine silica gel powder, magnesium stearate；Opacifier is titanium dioxide；
It is preferred that：The disintegrant added after tabletting is Ac-Di-Sol, PVPP and sodium carboxymethyl starch
In one or several kinds of combinations；It is preferred that disintegrant is PVPP and/or Ac-Di-Sol；Add after tabletting
The lubricant entered is one or several kinds of combinations in superfine silica gel powder, magnesium stearate and stearic acid；Preferred emollient is tristearin
Sour magnesium.
It is preferred that：The disintegrant added after tabletting accounts for the 0.1%- of the particle gross weight of Ezetimibe particle and Rosuvastatin
10%；The lubricant added after tabletting accounts for the 0.1%-5% of the particle gross weight of Ezetimibe particle and Rosuvastatin.
Beneficial effect：
1st, Ezetimibe and Rosuvastatin are separately pelletized, effectively interference of the control Ezetimibe to Rosuvastatin,
Formed so as to reduce relevant material；
2nd, Ezetimibe and Rosuvastatin are separately pelletized, it is to avoid interfere, it is ensured that Rosuvastatin it is steady
It is fixed；
3rd, prepare without using special bi-layer tablet press, production equipment input is smaller.
Embodiment
With reference to embodiment, the present invention will be further described, but protection scope of the present invention not limited to this：
Embodiment 1：It is a kind of to contain Ezetimibe and one of the Compound Tablet of Rosuvastatin and its preparation technology (prescription
Amount：1000)
Prescription：
Technique：
1. Ezetimibe crosses 200 mesh sieves through micronization processes, and remaining supplementary material crosses 80 mesh sieves respectively.
2. it is Ezetimibe 10g, lactose 40g, microcrystalline cellulose 40g, lauryl sodium sulfate 3g and cross-linked carboxymethyl is fine
It is put into after the plain sodium 5g mixing of dimension, the granulation of addition PVP K30 3% aqueous solution, particle drying in fluid bed, penetrating is configured to
The coating agent of 10% aqueous dispersion is coated, drying Ezetimibe layer particle.
3. by Rosuvastatin 20g, lactose 40g, microcrystalline cellulose 40g, calcium monohydrogen phosphate 10g and cross-linked carboxymethyl cellulose
After sodium 5g mixing, add the granulation of PVP K30 3% aqueous solution, particle drying after be put into fluid bed, penetrating is configured to 10%
The coating agent of aqueous dispersion is coated, drying Rosuvastatin particle.
4. Ac-Di-Sol 10g, superfine silica gel powder 2g are added after two kinds of particles is mixed, tabletting after being well mixed
Obtain Compound Tablet.
Embodiment 2：A kind of two (prescriptions containing Ezetimibe and the Compound Tablet of Rosuvastatin and its preparation technology
Amount：1000)
Prescription：
Preparation technology：
1. Ezetimibe crosses 200 mesh sieves through micronization processes, and remaining supplementary material crosses 80 mesh sieves respectively.
2. by Ezetimibe 10g, lactose 40g, microcrystalline cellulose 20g, lauryl sodium sulfate 4g and PVPP 5g
It is put into after mixing, the granulation of addition PVP K30 3% aqueous solution, particle drying in fluid bed, penetrating is configured to 10% moisture and dissipated
The coating agent of body is coated, drying Ezetimibe particle.
After 3. mixing Rosuvastatin 20g, lactose 40g, microcrystalline cellulose 20g, calcium phosphate 5g and PVPP 5g,
It is put into after adding the granulation of PVP K30 solution, particle drying in fluid bed, sprays into the coating agent bag for being configured to 10% aqueous dispersion
Clothing, drying Rosuvastatin particle.
4. PVPP 5g, magnesium stearate 1.5g are added after two kinds of particles is mixed, well mixed rear tabletting is answered
Square piece.
Embodiment 3：A kind of three (prescriptions containing Ezetimibe and the Compound Tablet of Rosuvastatin and its preparation technology
Amount：1000)
Prescription：
Preparation technology：
1. Ezetimibe crosses 200 mesh sieves through micronization processes, and remaining supplementary material crosses 80 mesh sieves respectively.
2. by Ezetimibe 10g, lactose 40g, microcrystalline cellulose 10g, Tween 80 3g and Ac-Di-Sol 5g
It is put into after mixing, the granulation of addition PVP K30 3% aqueous solution, particle drying in fluid bed, penetrating is configured to 10% moisture and dissipated
The coating agent of body is coated, drying Ezetimibe particle.
After 3. mixing Rosuvastatin 40g, lactose 40g, microcrystalline cellulose 10g, sodium carbonate 7g and PVPP 5g,
It is put into after adding the granulation of the aqueous solution of PVP K30 3%, particle drying in fluid bed, sprays into the bag for being configured to 10% aqueous dispersion
Clothing agent is coated, drying Rosuvastatin particle.
4. PVPP 5g, magnesium stearate 1g are added after two kinds of particles is mixed, well mixed rear tabletting obtains compound
Piece.
Embodiment 4：Study on the stability
By obtained Compound Tablet in embodiment 1,2,3, carry out accelerating six months (40 DEG C ± 2 DEG C of temperature, relative humidity 75%
± 5%) stability test, testing result see the table below.
The sample of embodiment 1 accelerates six months result of the tests
The sample of embodiment 2 accelerates six months result of the tests
The sample of embodiment 3 accelerates six months result of the tests
As a result showing the prescription of embodiment 1,2,3 can keep stable in June in accelerated stability test.
Embodiment 5：Long-term stable experiment
By obtained Compound Tablet in embodiment 1,2,3, carry out 24 months long-term stable experiment (25 DEG C ± 2 DEG C of temperature,
± 10%) the stability test of relative humidity 60%, testing result see the table below.
Embodiment 1 sample, 24 months long-term stable experiment results
Embodiment 2 sample, 24 months long-term stable experiment results
Embodiment 3 sample, 24 months long-term stable experiment results
As a result showing the prescription of embodiment 1 can keep stable in 24 months long-term stable experiments.
In addition, inventor has found through overtesting, pelletizing press sheet after Ezetimibe and Rosuvastatin mixing, because Rui Shu is cut down
Statin less stable, can cause relevant material increase, it is therefore desirable to isolate two kinds of raw materials after being contacted with Ezetimibe, conventional
Method has a compacting double-layer tablets, and each layer contains a kind of material, but the place of two layers of handing-over of double-layer tablets, has a certain amount of according to folding
Wheat cloth is contacted with Rosuvastatin, causes relevant material increase, and double-layer tablets need bi-layer tablet press, general factory in production
Without this equipment；Another method is that Ezetimibe and Rosuvastatin are pelletized respectively, then mixed pressuring plate, although the technique energy
Allow most Ezetimibe to be separated with Rosuvastatin, but still suffer from tabletting the Ezetimibe of a part and easypro cut down with auspicious
Statin is contacted, and causes relevant material increase；And the innovative use of the present invention pelletizes Ezetimibe and Rosuvastatin respectively
After being coated again, mixing adds additional auxiliary material, and then the method for tabletting isolates Ezetimibe and Rosuvastatin in the formulation,
Because two kinds of particles outer layer there are the coatings that can play buffer action, therefore Ezetimibe and Rosuvastain can be avoided in tabletting
Spit of fland is contacted, so as to reduce the generation about material, the toxic side effect that reduction Drug-related Substances are produced improves drug effect, and this hair
Bright method is without bi-layer tablet press, technique simple possible.Shown according to stability test result：As granule coating weightening 20%-
When 60%, obtained Ezetimibe is preferable with Rosuvastatin compound tablet stability, and steady quality is reliable, when coating weight gain is small
When 20%, coating membrane coating membrane cracky in tabletting, it is impossible to completely isolate two kinds of medicines；And when coating weight gain is more than
When 60%, the release of medicine can be influenceed.
Experiment：Granule coating is to the influence about material
(1) test method：The Compound Tablet containing Ezetimibe and Rosuvastatin prepared according to embodiment 1, obtains sample
Product A；
Prepare in accordance with the following methods, prescription be the same as Example 1, specific implementation step is as follows：
1. Ezetimibe crosses 200 mesh sieves through micronization processes, and remaining supplementary material crosses 80 mesh sieves respectively.
2. it is Ezetimibe 10g, lactose 40g, microcrystalline cellulose 40g, lauryl sodium sulfate 3g and cross-linked carboxymethyl is fine
The plain sodium 5g mixing of dimension, the granulation of addition PVP K30 3% aqueous solution, drying.
3. by Rosuvastatin 20g, lactose 40g, microcrystalline cellulose 40g, calcium monohydrogen phosphate 10g and cross-linked carboxymethyl cellulose
After sodium 5g mixing, add the granulation of the aqueous solution of PVP K30 3%, drying.
4. Ac-Di-Sol 10g, superfine silica gel powder 2g are added after two kinds of particles is mixed, tabletting after being well mixed
Obtain sample B；
(2) result of the test：
Sample A and sample B is subjected to stability test (accelerated test and long term test), result of the test is as follows：
As seen from the experiment, Ezetimibe rosuvastain calcium Compound Tablet made from the inventive method is total miscellaneous less.
Claims (10)
1. a kind of composite tablet containing Ezetimibe and Rosuvastatin, it is characterised in that：Described composite tablet is to pelletize
Obtained Ezetimibe particle and Rosuvastatin particle is coated respectively, add disintegrant and mix lubricant tabletting afterwards and
Into；Described Ezetimibe particle is made up of Ezetimibe, filler, solubilizer, adhesive and disintegrant；Described Rui Shu is cut down
Statin particle is made up of Rosuvastatin, filler, stabilizer, disintegrant and adhesive.
2. composite tablet according to claim 1, it is characterised in that：Ezetimibe content is 5- in described composite tablet
20mg, Rosuvastatin content is 5-50mg.
3. composite tablet according to claim 1, it is characterised in that：Institute in Ezetimibe particle and Rosuvastatin particle
It is as follows with the composition of auxiliary material：
In Ezetimibe particle：Described filler is one or several kinds of combinations in lactose, starch, microcrystalline cellulose；
Described solubilizer is one or several kinds of combinations in lauryl sodium sulfate, polyvinyl alcohol rilanit special, Tween 80；
Described adhesive is one or more of in PVP K30, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose
Combination；Described disintegrant is the one or several kinds in Ac-Di-Sol, PVPP, sodium carboxymethyl starch
Combination；
In Rosuvastatin particle：Described filler includes one or several kinds of groups in lactose, starch, microcrystalline cellulose
Close；Described stabilizer is one or several kinds of combinations in calcium phosphate, calcium monohydrogen phosphate, sodium carbonate etc.；Described disintegrant
For one or several kinds of combinations in Ac-Di-Sol, PVPP, sodium carboxymethyl starch；Described bonding
Agent is one or more of combinations in PVP K30, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose.
4. composite tablet according to claim 1, it is characterised in that：Used in Ezetimibe particle and Rosuvastatin particle
The auxiliary material composition of coatings is as follows：
The particle outer layer of Rosuvastatin is surrounded by one layer of coating agent, and coating agent is film forming agent, auxiliary film former, antiplastering aid, shading
One or several kinds of combinations in agent；Wherein film forming agent is hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone
Deng one or more of combinations；Auxiliary film former is one or more of combinations of propane diols, polyethylene glycol etc.；Antiplastering aid is
One or several kinds of combinations in talcum powder, superfine silica gel powder, magnesium stearate；Opacifier is titanium dioxide；
Ezetimibe particle outer layer is surrounded by one layer of coating agent, and coating agent is in film forming agent, auxiliary film former, antiplastering aid, opacifier
One or several kinds of combinations；Wherein film forming agent is hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone etc.
One or more of combinations；Auxiliary film former is one or more of combinations of propane diols, polyethylene glycol etc.；Antiplastering aid is talcum
One or several kinds of combinations in powder, superfine silica gel powder, magnesium stearate；Opacifier is titanium dioxide.
5. composite tablet according to claim 1, it is characterised in that：The composition and use of contained component in Ezetimibe particle
Amount is as follows：
5~20 parts of Ezetimibe；
20~100 parts of filler；
1~20 part of solubilizer；
0.1~5 part of adhesive；
1~10 part of disintegrant；
It is preferred that：Described filler is 1 by mass ratio：0.1~1 lactose and microcrystalline cellulose composition；Described solubilizer is excellent
Select lauryl sodium sulfate or Tween 80；The preferred PVP K30 of described adhesive；The poly- dimension of the preferred crosslinking of described disintegrant
Ketone；
The coating agent composition of Ezetimibe particle is as follows：
It is preferred that：Described film forming agent is hydroxypropyl methylcellulose；Described auxiliary film former is propane diols；Described antiplastering aid is cunning
Stone flour, described opacifier is titanium dioxide；
After the mixing of above-mentioned coating agent each part, aqueous dispersion is configured to, for granule coating, Ezetimibe after coating
Weight gain is 20%-60%.
6. composite tablet according to claim 1, it is characterised in that：The composition of contained component in the particle of Rosuvastatin
And consumption is as follows：
It is preferred that：Described filler preferred mass ratio is 1：0.1~1 lactose and microcrystalline cellulose；Described stabilizer is preferred
Calcium monohydrogen phosphate, calcium phosphate or sodium carbonate；The preferred Ac-Di-Sol of described disintegrant or PVPP；Described
The preferred PVP K30 of adhesive；
The coating agent composition of the particle of Rosuvastatin is as follows：
20-80 parts of film forming agent；
0-10 parts of auxiliary film former；
10-60 parts of antiplastering aid；
0-1 parts of opacifier；
It is preferred that：Described film forming agent is hydroxypropyl methylcellulose；Described auxiliary film former is propane diols；Described antiplastering aid is cunning
Stone flour；Described opacifier is titanium dioxide；
After the mixing of above-mentioned coating agent each part, aqueous dispersion is configured to, for granule coating, Rosuvastain after coating
Spit of fland weight gain is 20%-60%.
7. composite tablet according to claim 1, it is characterised in that：The disintegrant added after coating is that cross-linked carboxymethyl is fine
One or several kinds of combinations in the plain sodium of dimension, PVPP and sodium carboxymethyl starch；It is preferred that disintegrant is PVPP
And/or Ac-Di-Sol；The lubricant added after coating is one kind in superfine silica gel powder, magnesium stearate and stearic acid
Or several combinations；Preferred emollient is magnesium stearate.
8. composite tablet according to claim 7, it is characterised in that：The disintegrant added after coating accounts for Ezetimibe particle
With the 0.1%-10% of the particle gross weight of Rosuvastatin；The lubricant added after coating accounts for Ezetimibe particle and Rui Shu is cut down
The 0.1%-5% of the particle gross weight of statin.
9. a kind of preparation method of the composite tablet containing Ezetimibe and Rosuvastatin described in claim 1, its feature exists
In：The method includes the steps of：
Ezetimibe particle：Ezetimibe after micronization processes and filler, disintegrant, solubilizer are put into granulator and mixed
Close uniform, adhesive granulation, drying are added afterwards；The particle obtained after drying, which is put into spray into fluid bed, is configured to 5%-20%
The coating agent of aqueous dispersion is coated, the Ezetimibe particle after drying coating；
Rosuvastatin particle：Rosuvastatin is inserted in granulator and is well mixed with filler, disintegrant, stabilizer, plus
Enter binder solution granulation, drying；The particle obtained after drying, which is put into spray into fluid bed, is configured to 5%-20% aqueous dispersions
Coating agent be coated, drying be coated after Rosuvastatin particle；
Tabletting：Rosuvastatin particle after Ezetimibe particle after coating and coating is mixed, disintegrant and profit is added
Tabletting after lubrication prescription, mixing, obtains Ezetimibe and Rosuvastatin Compound Tablet.
10. preparation method according to claim 9, it is characterised in that：Ezetimibe particle outer layer is surrounded by one layer of coating agent,
Coating agent is one or several kinds of combinations in film forming agent, auxiliary film former, antiplastering aid, opacifier；Wherein film forming agent is hydroxyl
One or more of combinations of third methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone etc.；Auxiliary film former is the third two
One or more of combinations of alcohol, polyethylene glycol etc.；Antiplastering aid be talcum powder, superfine silica gel powder, magnesium stearate in one kind or
Several combinations；Opacifier is titanium dioxide.
The particle outer layer of Rosuvastatin is surrounded by one layer of coating agent, and coating agent is film forming agent, auxiliary film former, antiplastering aid, shading
One or several kinds of combinations in agent；Wherein film forming agent is hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone
Deng one or more of combinations；Auxiliary film former is one or more of combinations of propane diols, polyethylene glycol etc.；Antiplastering aid is
One or several kinds of combinations in talcum powder, superfine silica gel powder, magnesium stearate；Opacifier is titanium dioxide；
It is preferred that：The disintegrant added after tabletting is in Ac-Di-Sol, PVPP and sodium carboxymethyl starch
One or several kinds of combinations；It is preferred that disintegrant is PVPP and/or Ac-Di-Sol；Added after tabletting
Lubricant is one or several kinds of combinations in superfine silica gel powder, magnesium stearate and stearic acid；Preferred emollient is magnesium stearate.
It is preferred that：The disintegrant added after tabletting accounts for the 0.1%- of the particle gross weight of Ezetimibe particle and Rosuvastatin
10%；The lubricant added after tabletting accounts for the 0.1%-5% of the particle gross weight of Ezetimibe particle and Rosuvastatin.
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| CN201710473352.2A CN107028906A (en) | 2017-06-21 | 2017-06-21 | A kind of composite tablet containing Ezetimibe and Rosuvastatin and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021019499A1 (en) | 2019-07-31 | 2021-02-04 | TECNIMEDE - Sociedade Técnico-medicinal, SA | Solid oral multiple-unit immediate release compositions, methods and uses thereof |
| CN112451495A (en) * | 2020-11-25 | 2021-03-09 | 江苏阿尔法药业有限公司 | Rosuvastatin calcium tablet and preparation method thereof |
| CN112451498A (en) * | 2020-11-24 | 2021-03-09 | 江苏阿尔法药业有限公司 | Atorvastatin calcium tablet and preparation method thereof |
| CN112999178A (en) * | 2021-03-01 | 2021-06-22 | 乐普制药科技有限公司 | Ezetimibe pitavastatin calcium compound double-layer tablet |
| CN115227659A (en) * | 2022-08-19 | 2022-10-25 | 北京百奥药业有限责任公司 | Ezetimibe simvastatin composition and preparation method thereof |
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| CN103505460A (en) * | 2012-06-19 | 2014-01-15 | 北京万生药业有限责任公司 | Method for preparing losartan potassium and hydrochlorothiazide composition |
| CN103585157A (en) * | 2013-11-13 | 2014-02-19 | 武汉武药科技有限公司 | Double-layer tablet containing ezetimibe and rosuvastatin and preparation method thereof |
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| CN103505460A (en) * | 2012-06-19 | 2014-01-15 | 北京万生药业有限责任公司 | Method for preparing losartan potassium and hydrochlorothiazide composition |
| CN103585157A (en) * | 2013-11-13 | 2014-02-19 | 武汉武药科技有限公司 | Double-layer tablet containing ezetimibe and rosuvastatin and preparation method thereof |
Cited By (5)
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| WO2021019499A1 (en) | 2019-07-31 | 2021-02-04 | TECNIMEDE - Sociedade Técnico-medicinal, SA | Solid oral multiple-unit immediate release compositions, methods and uses thereof |
| CN112451498A (en) * | 2020-11-24 | 2021-03-09 | 江苏阿尔法药业有限公司 | Atorvastatin calcium tablet and preparation method thereof |
| CN112451495A (en) * | 2020-11-25 | 2021-03-09 | 江苏阿尔法药业有限公司 | Rosuvastatin calcium tablet and preparation method thereof |
| CN112999178A (en) * | 2021-03-01 | 2021-06-22 | 乐普制药科技有限公司 | Ezetimibe pitavastatin calcium compound double-layer tablet |
| CN115227659A (en) * | 2022-08-19 | 2022-10-25 | 北京百奥药业有限责任公司 | Ezetimibe simvastatin composition and preparation method thereof |
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Effective date of registration: 20190613 Address after: 224553 Binhai County, Yancheng City, Jiangsu Province 799-6 Xin'an Avenue, Binhai Medical Industrial Park, Yancheng City, Binhai County, Jiangsu Province Applicant after: Jiangsu Ogge Pharmaceutical Co., Ltd. Address before: 210 042 32 blocks, 699-18 Xuanwu Avenue, Nanjing, Jiangsu Province Applicant before: Jiangsu Fu Rui biological medicine company limited |
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Application publication date: 20170811 |