CN105560206A - Preparation of Pradaxa capsule - Google Patents
Preparation of Pradaxa capsule Download PDFInfo
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- CN105560206A CN105560206A CN201410541060.4A CN201410541060A CN105560206A CN 105560206 A CN105560206 A CN 105560206A CN 201410541060 A CN201410541060 A CN 201410541060A CN 105560206 A CN105560206 A CN 105560206A
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Abstract
The invention discloses a capsule containing Pradaxa or its salt. The capsule is composed of drug-containing particles and organic acid particles. The drug-containing particles include active material particles of active ingredient Pradaxa or its pharmaceutically acceptable salt or hydrate and a filler and/or adhesive or optional disintegrating agent; and an isolation layer covering the surfaces of the active material particles. Organic acid particles contain organic acid and/or the filler and/or adhesive and/or disintegrating agent, and the surfaces can be optionally covered with an isolation layer. The organic acid is selected from tartaric acid, succinic acid, citric acid, glutamic acid, fumaric acid, malic acid, aspartic acid or other available organic acid or its hydrate or acid salt. Through screening, the inventor prepares Pradaxa active substance into particles, the surfaces of which are coated with an isolation layer; and the organic acid is made into granules to fill the capsule together with the isolated drug-containing particles. The prepared Pradaxa oral capsule has good solubility, dissolution rate and stability, and can meet the clinical use requirements of Pradaxa.
Description
Technical field
The present invention relates to the capsule of a kind of active substance dabigatran etcxilate and pharmacologically acceptable salt and hydrate, belong to art of pharmacy.
Background technology
The chemical name of the active substance of dabigatran etcxilate of the present invention is 3-[(2-{ [4-(own oxygen carbonylamino-imino-methyl)-phenyl amino]-methyl }-1_ methyl isophthalic acid H-benzimidazole-5-carbonyl)-pyridine-2-base-amino]-ethyl propionate and salt thereof and hydrate.Dabigatran etcxilate chemical constitution is as shown in the formula shown in I.
Dabigatran is first disclosed as WO98/37075, after developed by German Boehringer Ingelheim company, for a kind of novel oral anticoagulation, belong to non-peptide batroxobin inhibitor, this medicine is in April, 2008 first in Germany and Britain's listing, and in October, 2010 for reducing nonvalvular atrial fibrillation patient, apoplexy and systemic embolism risk is occurred by FDA approval again.Dabigatran etcxilate is the prodrug of dabigatran (dabigatran), is mainly used in the prevention of Post operation venous thrombosis.Oral is the main route of administration of dabigatran etcxilate, and it is after gastrointestinal absorption, is converted into the dabigatran with direct anticoagulant active in vivo.Dabigatran is incorporated into the fibrin specific binding site of thrombin, stops Fibrinogen cracking fibrin, thus has blocked final step and the thrombosis of blood coagulation waterfall network.
Dabigatran etcxilate is almost insoluble in the medium of pH>4.0, therefore sour environment is conducive to main active dabigatran etcxilate stripping and body absorption from pharmaceutical preparation.But this active component in acid condition storage stability is not good.Patent (publication number CN100528157C) discloses a kind of dabigatran etcxilate oral pharmaceutical compositions, wherein comprises binding agent and optional interleaving agent and is applied in organic acid core material around the active material layer of core material.Organic acid comprises the materials such as tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid or aspartic acid.It is separate that organic acid core material and active material layer pass through sealing coat.This technique adopts ball core medicine-feeding method, is coated on by active medicine suspension on organic acid ball core.In this method, dose is less, and there is the more difficult control of dose, medicine accommodation layer is uneven, poor reproducibility between batch, and crude drug loss is comparatively large, the problems such as product yield is lower.Patent (publication number CN103127109A) discloses and a kind ofly provides a kind of pharmaceutical compositions containing dabigatran etcxilate or its salt and hydrate.Active substance is prepared into ball core by patent, and then apply organic acidic material layer, the dabigatran etcxilate drug regimen obtained, has better bin stability and dissolution efficiency.But this method relates to multiple coatings, complex process, the problem of official written reply poor stability.
Summary of the invention
The present invention is directed to the relevant nature of dabigatran etcxilate, a kind of preparation method of dabigatran etcxilate capsule is provided.This capsule is in vivo in absorption process, and organic acid particles takes the lead in soluble in water, forms acidic micro-environment, can accelerate the stripping of dabigatran etcxilate, obtain comparatively ideal bioavailability.This active component is in the granule of coated isolation simultaneously, isolates, obtain good bin stability in storage process with organic acid.Present invention process is more simple, is more conducive to industrialized implementation.
Object of the present invention can be reached by following measures:
A kind of dabigatran capsule, it comprises:
1) active material particle containing active component dabigatran etcxilate or its pharmaceutically acceptable salt or hydrate and filler and/or binding agent or optional disintegrating agent, its surface coverage sealing coat.
2) organic acid particles be made up of the retrievable organic acid such as tartaric acid, succinic acid, citric acid, glutamic acid, fumaric acid, malic acid or aspartic acid and/or filler and/or binding agent and/or disintegrating agent, surface can be selected to cover sealing coat.
3) by the active ingredient particle through isolation of above-mentioned preparation be filled in hard capsule case after having granulates to mix, organic acid and active substance mass ratio are about 0.5 ~ 3.0, and preferably 1.0 ~ 2.0.
Active component of the present invention is dabigatran etcxilate or its pharmaceutically acceptable salt or hydrate, preferred methanesulfonic acid dabigatran etcxilate, the content of active component in active material particle is 20% ~ 80%, the diameter of granule is 0.4 ~ 1.5 millimeter, be preferably 0.6 ~ 1.2 millimeter, most preferably be 0.8 ~ 1.0 millimeter.
Active material particle of the present invention can use slot type method on balling disk(-sc) or standby by squeezing and pressing method/nodularization legal system, fluid bed also can be used to carry an active material layer at celphere surface bag and prepare.When using centrifugal pill or by extruding/spheronization is when preparing active material particle, after active substance mixes with filler, disintegrating agent under binder solution effect in centrifugal type pelleter granulating or by after soft material processed through be suitable for aperture extrude after nodularization in centrifugal type pelleter again.Its filler is selected from microcrystalline Cellulose, sucrose, lactose, mannitol, one or more in calcium phosphate, preferably microcrystalline cellulose.Binding agent is selected from hydroxypropyl cellulose, carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, one or more in polyvinylpyrrolidone, preferred hydroxypropyl cellulose; Binding agent is by appropriate dissolution with solvents, and described solvent comprises isopropyl alcohol, ethanol, in propylene glycol one or more or with combination, preferred isopropyl alcohol and the combination with water thereof of water.Disintegrating agent is selected from cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, one or more in low-substituted hydroxypropyl cellulose, preferred polyvinylpolypyrrolidone.
When using fluid bed medicine carrying, the suspension of active substance and binding agent or solution spray are on celphere surface, and celphere is selected from the one of pharmaceutically acceptable microcrystalline Cellulose ball core, sucrose ball core, starch ball core, preferably microcrystalline cellulose ball core.Binding agent is selected from hydroxypropyl cellulose, carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, one or more in polyvinylpyrrolidone, preferred hydroxypropyl cellulose; Binding agent is by appropriate dissolution with solvents, and described solvent comprises isopropyl alcohol, ethanol, in propylene glycol one or more or with the combination of water, preferred isopropyl alcohol.
In order to increase the bin stability of active substance, and isolating active substance and organic acid, needing at active material particle surface-coated sealing coat.Sealing coat is made up of pharmaceutically acceptable polymer and optional plasticizer, separating medium, defoamer and/or coloring agent, wherein said polymer is selected from hydroxypropyl cellulose, hydroxypropyl emthylcellulose, one or more of polyvinylpyrrolidone and methacrylic acid/methacrylate, preferred hydroxypropyl cellulose.Plasticizer comprises triethyl citrate, tributyl citrate, glycerol triacetate or Polyethylene Glycol.Separating medium comprises Talcum or silicon dioxide.The pigment used can be titanium dioxide or iron oxide pigment.Coating solvent comprises isopropyl alcohol, ethanol, in propylene glycol one or more or with the combination of water, preferred isopropyl alcohol.Sealing coat coating weight gain 1.0 ~ 10.0%, preferably 3.0 ~ 8.0%.
In capsule of the present invention organic acid particles be by organic acid and filler, binding agent and disintegrating agent by slot type method on balling disk(-sc) or standby by squeezing and pressing method/nodularization legal system.Organic acid is selected from the retrievable organic acid such as tartaric acid, succinic acid, citric acid, glutamic acid, fumaric acid, malic acid or aspartic acid or its hydrate or hydrochlorate, preferred tartaric acid.It is filled dosage form and is selected from microcrystalline Cellulose, sucrose, lactose, mannitol, one or more in calcium phosphate, preferably microcrystalline cellulose.Binding agent is selected from hydroxypropyl cellulose, carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, one or more in polyvinylpyrrolidone, preferred hydroxypropyl cellulose; Binding agent is by appropriate dissolution with solvents, and described solvent comprises water, ethanol, isopropyl alcohol, one or more in propylene glycol, preferred isopropyl alcohol.Disintegrating agent is selected from cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, one or more in low-substituted hydroxypropyl cellulose.The content of tartaric acid in organic acid particles is 50 ~ 100%, preferably 60 ~ 80%; The diameter of granule is 0.4 ~ 1.5 millimeter, is preferably 0.6 ~ 1.2 millimeter, most preferably is 0.8 ~ 1.0 millimeter.
For reducing active substance and organic acid touch opportunity further, increase the bin stability of active substance, the organic acid particles of one of capsule 's content is depending on need at its surface-coated sealing coat.Sealing coat is made up of pharmaceutically acceptable polymer and optional plasticizer, separating medium, defoamer and/or coloring agent, wherein said polymer is selected from: hydroxypropyl cellulose, hydroxypropyl emthylcellulose, one or more of polyvinylpyrrolidone and methacrylic acid/methacrylate.Plasticizer comprises triethyl citrate, tributyl citrate, glycerol triacetate or Polyethylene Glycol.Separating medium comprises Talcum or silicon dioxide.The pigment used can be titanium dioxide or iron oxide pigment.Coating solvent comprises isopropyl alcohol, ethanol, in propylene glycol one or more or with the combination of water.Sealing coat coating weight gain 0.5 ~ 10.0%, preferably 3.0 ~ 8.0%.
By the active ingredient particle through isolation of above-mentioned preparation be filled in hard capsule case after having granulates to mix, organic acid and active substance mass ratio are about 0.5 ~ 3.0, and preferably 1.0 ~ 2.0.
Hard capsules can select gelatine capsule, hydroxy propyl cellulose cellulose capsule or other pharmaceutically acceptable hard capsules, preferred HPMC capsule.
The present invention further discloses the concrete method preparing dabigatran capsule, it is characterized in that comprising the steps:
1) by centrifugal granulation and/or squeezing and pressing method/nodularization method, active substance, filler, binding agent, disintegrating agent are prepared into active material particle, or by fluid bed medicine carrying method, active substance and binding agent are coated on celphere surface and are prepared into active material particle.
2) on active material particle, wrap up pharmaceutically acceptable polymer and arbitrary plasticizer, separating medium with coating device, the sealing coat that defoamer and/or coloring agent are formed, obtain the active material particle of coating.
3) by centrifugal granulation and/or squeezing and pressing method/nodularization method, organic acid, filler, binding agent, disintegrating agent are prepared into organic acid particles.Organic acid particles optionally can isolate suspension or coating solution in surface-coated, carries out coating isolation.
4) be packed into after the active ingredient particle of above-mentioned coating and organic acid particles mixing in hard capsules.
Dabigatran etcxilate active substance, through screening, is prepared into granule by the present inventor, and surface coatings is isolated.Organic acid is made granule, jointly encapsulated with active material particle, prepare dabigatran etcxilate oral capsule, there is good dissolving out capability and good bin stability.
Specific embodiment
embodiment 1
Prescription forms:
*) 75 milligrams of dabigatran etcxilates (active substance matrix) are equivalent to
*) be equivalent to 110 milligrams of dabigatran etcxilates (active substance matrix)
1) preparation of active ingredient particle
Composition:
Active component (methanesulfonic acid dabigatran etcxilate) 126.8 weight portions
Microcrystalline Cellulose ball core 100 weight portion
Hydroxypropyl cellulose 16 weight portion
Make hydroxypropyl cellulose be dissolved in 500 parts by weight of isopropyl alcohol under stirring, then make active substance be dispersed in this solution.
In fluid bed processing unit (plant), under 30 ~ 40 DEG C of inlet air temps by this under spray and spray 100 weight portion particle diameters at 0.4 ~ 0.6 millimeter of microcrystalline Cellulose celphere with the dispersion liquid of this active substance.
Then in fluidized bed drying device, at 35 ~ 45 DEG C, active material particle is made dry 4 hours.
In order to remove agglomerate, using and there is the rotary drum screening machine separation that nominal mesh size is the porous plate of 0.8 and 1.0 millimeter, the granule between 0.8 to 1.0 millimeter is used in other step of this method for making.
2) active ingredient particle coating isolation
Composition:
Active ingredient particle 242.8 weight portion
Hydroxypropyl cellulose 4 weight portion
Pulvis Talci 4 weight portion
Make hydroxypropyl cellulose be dissolved in 80 parts by weight of isopropyl alcohol under stirring, then make Pulvis Talci be dispersed in this solution.
In fluid bed processing unit (plant), to spray 242.8 parts by weight of activated ingredient granules with hydroxypropyl cellulose-talcous dispersion liquid by spraying under this bed under 30 ~ 40 DEG C of inlet air temps.
Then dry 4 hours of the active material particle at 35 ~ 45 DEG C, coating being isolated in fluidized bed drying device.
In order to remove agglomerate, by having the active material particle of the screen cloth screening coating isolation of nominal mesh 1.0 millimeters.The further processed of the material that granular size ﹤ is 1.0 millimeters.
3) preparation of tartaric acid granulate
Composition:
Tartaric acid 130 weight portion
Microcrystalline Cellulose 15 weight portion
Hydroxypropyl cellulose 7.5 weight portion
Adopt extrusion spheronization legal system for tartaric acid granulate, by tartaric acid, microcrystalline Cellulose and hydroxypropyl cellulose mix homogeneously in high shear granulator, adds 40 part of 50% alcoholic solution soft material.
Soft material through hole diameter of sieve (perforated) plate is 0.8 millimeter extrude, round as a ball globulate granule in centrifugal pellet processing machine.
Then spherical tartaric acid granulate is placed in fluidized bed drying device, under 60 ~ 80 DEG C of inlet air temps, makes tartaric acid granulate dry 4 hours.
In order to remove agglomerate, using and there is the rotary drum screening machine separation that nominal mesh size is the porous plate of 0.8 and 1.0 millimeter, the granule between 0.8 to 1.0 millimeter is used in other step of this method for making.
4) tartaric acid granulate coating isolation
Composition:
Tartaric acid granulate 152.5 weight portion
Hydroxypropyl cellulose 4 weight portion
Pulvis Talci 4 weight portion
Make hydroxypropyl cellulose be dissolved in 80 part of 95% ethanol under stirring, then make Pulvis Talci be dispersed in this solution.
In fluid bed processing unit (plant), to spray 152.5 parts of tartaric acid granulate with hydroxypropyl cellulose-talcous dispersion liquid by spraying under this bed under 40 ~ 50 DEG C of inlet air temps.
Then dry 4 hours of the tartaric acid granulate under 60 ~ 80 DEG C of inlet air temps, coating being isolated in fluidized bed drying device.
In order to remove agglomerate, by having the tartaric acid granulate of the screen cloth screening coating isolation of nominal mesh 1.0 millimeters.The further processed of the material that granular size ﹤ is 1.0 millimeters.
5) filled capsules
Composition:
Coating isolation active ingredient particle 250.8 weight portion
Coating isolation tartaric acid granulate 160.5 weight portion
250.8 weight portion coating isolation active ingredient particles are isolated tartaric acid granulate with 160.5 weight portion coatings mix homogeneously, by capsule-filling machinery, the hybrid particles respectively containing 75 or 110 milligrams of active substances is inserted in 1# or 0#HPMC capsule.
embodiment 2
Prescription forms:
*) 75 milligrams of dabigatran etcxilates (active substance matrix) are equivalent to
*) be equivalent to 110 milligrams of dabigatran etcxilates (active substance matrix)
Coating isolation active ingredient particle prescription and preparation method are with embodiment 1, and tartaric acid granulate preparation method is with embodiment 1.
254.8 weight portion coating isolation active ingredient particles are mixed homogeneously with 164.9 weight portion tartaric acid granulate, by capsule-filling machinery, the hybrid particles respectively containing 75 or 110 milligrams of active substances is inserted in 1# or 0#HPMC capsule.
embodiment 3
Prescription forms:
*) 75 milligrams of dabigatran etcxilates (active substance matrix) are equivalent to
*) be equivalent to 110 milligrams of dabigatran etcxilates (active substance matrix)
Coating isolation active ingredient particle prescription and preparation method are with embodiment 1, and coating tartaric acid granulate preparation method is with embodiment 1.
250.8 weight portion coating isolation active ingredient particles are mixed homogeneously with 178.0 weight portion tartaric acid granulate, by capsule-filling machinery, the hybrid particles respectively containing 75 or 110 milligrams of active substances is inserted in 1# or 0#HPMC capsule.
embodiment 4
Prescription forms:
*) 75 milligrams of dabigatran etcxilates (active substance matrix) are equivalent to
*) be equivalent to 110 milligrams of dabigatran etcxilates (active substance matrix)
Coating isolation active ingredient particle prescription and preparation method are with embodiment 1, and coating tartaric acid granulate preparation method is with embodiment 1.
250.8 weight portion coating isolation active ingredient particles are mixed homogeneously with 173.0 weight portion tartaric acid granulate, by capsule-filling machinery, the hybrid particles respectively containing 75 or 110 milligrams of active substances is inserted in 1# or 0#HPMC capsule.
embodiment 5
Prescription forms:
*) 75 milligrams of dabigatran etcxilates (active substance matrix) are equivalent to
*) be equivalent to 110 milligrams of dabigatran etcxilates (active substance matrix)
Coating isolation active ingredient particle and tartaric acid granulate preparation method are with embodiment 1.
258.8 weight portion coating isolation active ingredient particles are mixed homogeneously with 172.0 weight portion tartaric acid granulate, by capsule-filling machinery, the hybrid particles respectively containing 75 or 110 milligrams of active substances is inserted in 1# or 0#HPMC capsule.
embodiment 6
Prescription forms:
*) 75 milligrams of dabigatran etcxilates (active substance matrix) are equivalent to
*) be equivalent to 110 milligrams of dabigatran etcxilates (active substance matrix)
Coating isolation active ingredient particle and coating tartaric acid granulate preparation method are with embodiment 1.
256.8 weight portion coating isolation active ingredient particles are mixed homogeneously with 178.5 weight portion tartaric acid granulate, by capsule-filling machinery, the hybrid particles respectively containing 75 or 110 milligrams of active substances is inserted in 1# or 0#HPMC capsule.
embodiment 7
Prescription forms:
*) 75 milligrams of dabigatran etcxilates (active substance matrix) are equivalent to
*) be equivalent to 110 milligrams of dabigatran etcxilates (active substance matrix)
1) preparation of active ingredient particle
Composition:
Active component (methanesulfonic acid dabigatran etcxilate) 126.8 weight portions
Microcrystalline Cellulose 50 weight portion
Hydroxypropyl cellulose 5 weight portion
Polyvinylpolypyrrolidone 8 weight portion
Adopt extrusion spheronization legal system for active ingredient particle, by active component, microcrystalline Cellulose, hydroxypropyl cellulose and polyvinylpolypyrrolidone join mix homogeneously in high shear granulator, add appropriate isopropyl alcohol soft material.
Soft material through hole diameter of sieve (perforated) plate is 0.8 millimeter extrude, round as a ball globulate granule in centrifugal pellet processing machine.
Then active material particle is placed in fluidized bed drying device, drying 4 hours under 35 ~ 45 DEG C of inlet air temps.
In order to remove agglomerate, using and there is the rotary drum screening machine separation that nominal mesh size is the porous plate of 0.8 and 1.0 millimeter, the granule between 0.8 to 1.0 millimeter is used in other step of this method for making.
2) active ingredient particle coating isolation
Composition:
Active ingredient particle 189.8 weight portion
Hydroxypropyl cellulose 4 weight portion
Pulvis Talci 4 weight portion
Make 4 parts of hydroxypropyl celluloses be dissolved in 80 parts of isopropyl alcohols under stirring, then make Pulvis Talci be dispersed in this solution.
In fluid bed processing unit (plant), to spray 189.8 parts of active ingredient particles with hydroxypropyl cellulose-talcous dispersion liquid by spraying under this bed under 30 ~ 40 DEG C of inlet air temps.
Then dry 4 hours of the active material particle at 35 ~ 45 DEG C, coating being isolated in fluidized bed drying device.
In order to remove agglomerate, by having the active material particle of the screen cloth screening coating isolation of nominal mesh 1.0 millimeters.The further processed of the material that granular size ﹤ is 1.0 millimeters.
3) preparation of tartaric acid granulate
Composition:
Tartaric acid 130 weight portion
Microcrystalline Cellulose 20 weight portion
Hydroxypropyl cellulose 4 weight portion
Polyvinylpolypyrrolidone 5 weight portion
Adopt extrusion spheronization legal system for tartaric acid granulate, by 130 parts of tartaric acid, 20 parts of microcrystalline Cellulose, 4 parts of hydroxy propyl celluloses and 5 parts of polyvinylpolypyrrolidone mix homogeneously in high shear granulator, add 40 part of 50% alcoholic solution soft material.
Soft material through hole diameter of sieve (perforated) plate is 0.8 millimeter extrude, round as a ball globulate granule in centrifugal pellet processing machine.
Then spherical tartaric acid granulate is placed in fluidized bed drying device, under 60 ~ 80 DEG C of inlet air temps, makes tartaric acid granulate dry 4 hours.
In order to remove agglomerate, using and there is the rotary drum screening machine separation that nominal mesh size is the porous plate of 0.8 and 1.0 millimeter, the granule between 0.8 to 1.0 millimeter is used in other step of this method for making.
4) tartaric acid granulate coating isolation
Composition:
Tartaric acid granulate 159 weight portion
Hydroxypropyl cellulose 4 weight portion
Pulvis Talci 6 weight portion
Make 4 parts of hydroxypropyl celluloses be dissolved in 80 part of 95% ethanol under stirring, then make 6 parts of Pulvis Talci be dispersed in this solution.
In fluid bed processing unit (plant), to spray 159 parts of tartaric acid granulate with hydroxypropyl cellulose-talcous dispersion liquid by spraying under this bed under 40 ~ 50 DEG C of inlet air temps.
Then dry 4 hours of the tartaric acid granulate under 60 ~ 80 DEG C of inlet air temps, coating being isolated in fluidized bed drying device.
In order to remove agglomerate, by having the tartaric acid granulate of the screen cloth screening coating isolation of nominal mesh 1.0 millimeters.The further processed of the material that granular size ﹤ is 1.0 millimeters.
5) filled capsules
Composition:
Coating isolation active ingredient particle 197.8 weight portion
Coating isolation tartaric acid granulate 169.0 weight portion
197.8 weight portion coating isolation active ingredient particles are isolated tartaric acid granulate with 169.0 weight portion coatings mix homogeneously, by capsule-filling machinery, the hybrid particles respectively containing 75 or 110 milligrams of active substances is inserted in 1# or 0#HPMC capsule.
embodiment 8
Prescription forms:
*) 75 milligrams of dabigatran etcxilates (active substance matrix) are equivalent to
*) be equivalent to 110 milligrams of dabigatran etcxilates (active substance matrix)
1) preparation of active ingredient particle
Composition:
Active component (methanesulfonic acid dabigatran etcxilate) 126.8 weight portions
Microcrystalline Cellulose 50 weight portion
Hydroxypropyl cellulose 5 weight portion
Polyvinylpolypyrrolidone 12 weight portion
Adopt extrusion spheronization legal system for active ingredient particle, by active component, microcrystalline Cellulose, hydroxypropyl cellulose and polyvinylpolypyrrolidone join mix homogeneously in high shear granulator, add appropriate isopropyl alcohol soft material.
Soft material through hole diameter of sieve (perforated) plate is 0.8 millimeter extrude, round as a ball globulate granule in centrifugal pellet processing machine.
Then active material particle is placed in fluidized bed drying device, drying 4 hours under 35 ~ 45 DEG C of inlet air temps.
In order to remove agglomerate, using and there is the rotary drum screening machine separation that nominal mesh size is the porous plate of 0.8 and 1.0 millimeter, the granule between 0.8 to 1.0 millimeter is used in other step of this method for making.
2) active ingredient particle coating isolation
Composition:
Active ingredient particle 193.8 weight portion
Hydroxypropyl cellulose 4 weight portion
Pulvis Talci 8 weight portion
Make 4 parts of hydroxypropyl celluloses be dissolved in 80 parts of isopropyl alcohols under stirring, then make Pulvis Talci be dispersed in this solution.
In fluid bed processing unit (plant), to spray 193.8 parts of active ingredient particles with hydroxypropyl cellulose-talcous dispersion liquid by spraying under this bed under 30 ~ 40 DEG C of inlet air temps.
Then dry 4 hours of the active material particle at 35 ~ 45 DEG C, coating being isolated in fluidized bed drying device.
In order to remove agglomerate, by having the active material particle of the screen cloth screening coating isolation of nominal mesh 1.0 millimeters.The further processed of the material that granular size ﹤ is 1.0 millimeters.
3) preparation of tartaric acid granulate
Composition:
Tartaric acid 130 weight portion
Microcrystalline Cellulose 30 weight portion
Hydroxypropyl cellulose 5 weight portion
Adopt centrifugal granulation to prepare tartaric acid granulate, be dissolved in 40 part of 50% alcoholic solution in room temperature decline hydroxypropyl cellulose.
By tartaric acid; microcrystalline Cellulose is mix homogeneously in high shear granulator; 60 weight portion mixed-powders are added in centrifugal type pelleter; spray above-mentioned hydroxypropyl cellulose solution; after parent nucleus to be formed, the mixed powder adding tartaric acid and microcrystalline Cellulose at set intervals makes the round as a ball granulating of tartaric acid granulate.
Then spherical tartaric acid granulate is placed in fluidized bed drying device, under 60 ~ 80 DEG C of inlet air temps, makes tartaric acid granulate dry 4 hours.
In order to remove agglomerate, using and there is the rotary drum screening machine separation that nominal mesh size is the porous plate of 0.8 and 1.0 millimeter, the granule between 0.8 to 1.0 millimeter is used in other step of this method for making.
4) filled capsules
Composition:
Coating isolation active ingredient particle 205.8 weight portion
Tartaric acid granulate 165.0 weight portion
205.8 weight portion coating isolation active ingredient particles are mixed homogeneously with 165.0 weight portion tartaric acid granulate, by capsule-filling machinery, the hybrid particles respectively containing 75 or 110 milligrams of active substances is inserted in 1# or 0#HPMC capsule.
embodiment 9
Prescription forms:
*) 75 milligrams of dabigatran etcxilates (active substance matrix) are equivalent to
*) be equivalent to 110 milligrams of dabigatran etcxilates (active substance matrix)
Coating isolation active ingredient particle and coating tartaric acid granulate preparation method, with embodiment 7, use extrusion spheronization legal system to carry out coating isolation for after active component and tartaric acid granulate.
209.8 weight portion coating isolation active ingredient particles are mixed homogeneously with 176.0 weight portion tartaric acid granulate, by capsule-filling machinery, the hybrid particles respectively containing 75 or 110 milligrams of active substances is inserted in 1# or 0#HPMC capsule.
embodiment 10
Prescription forms:
*) 75 milligrams of dabigatran etcxilates (active substance matrix) are equivalent to
*) be equivalent to 110 milligrams of dabigatran etcxilates (active substance matrix)
Coating isolation active ingredient particle preparation method, with embodiment 8, uses extrusion spheronization legal system to carry out coating isolation for after active component and tartaric acid granulate; The preparation method of tartaric acid granulate, with embodiment 8, uses centrifugal granulation.
206.8 weight portion coating isolation active ingredient particles are mixed homogeneously with 172.5 weight portion tartaric acid granulate, by capsule-filling machinery, the hybrid particles respectively containing 75 or 110 milligrams of active substances is inserted in 1# or 0#HPMC capsule.
test case
Dissolution test, the methanesulfonic acid dabigatran etcxilate capsule stripping method of testing with reference to FDA recommends: Rotating shaker, 100rpm, dissolution medium: 0.01NHCl(pH2.0), dissolution medium volume: 900ml, temperature: 37 DEG C, sample time: 10,20,30,45,60min.According to gained stripping data, compare stripping curve.Commercially available dabigatran etcxilate capsule (trade name safe Bi Quan, Pradaxa, specification 110 milligrams) selected by contrast capsule.
As can be seen from above dissolution data, drug regimen of the present invention has good dissolved corrosion, can meet clinical needs.
Claims (10)
1. contain a capsule for dabigatran etcxilate or its salt, it comprises:
1) active material particle containing active component dabigatran etcxilate or its pharmaceutically acceptable salt or hydrate and filler and/or binding agent or optional disintegrating agent, its surface coverage sealing coat;
2) organic acid particles be made up of the retrievable organic acid such as tartaric acid, succinic acid, citric acid, glutamic acid, fumaric acid, malic acid or aspartic acid or its hydrate or hydrochlorate and/or filler and/or binding agent and/or disintegrating agent, surface can be selected to cover sealing coat.
2. the capsule according to right 1, it is characterized in that described active component is dabigatran etcxilate or its pharmaceutically acceptable salt, the content of active component in medicine-containing particle is 20% ~ 80%, and the diameter of granule is 0.4 ~ 1.5 millimeter, is preferably 0.8 ~ 1.0 millimeter.
3. capsule according to claim 1, it is characterized in that the medicine-containing particle of one of described content, by slot type method on balling disk(-sc) or standby by squeezing and pressing method/nodularization legal system, its filler is selected from: one or more in microcrystalline Cellulose, sucrose, lactose, mannitol, calcium phosphate; Binding agent is selected from: one or more in hydroxypropyl cellulose, carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, polyvinylpyrrolidone, binding agent by appropriate dissolution with solvents, described solvent comprise in isopropyl alcohol, ethanol, propylene glycol one or more or with the combination of water; Disintegrating agent is selected from: one or more in cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose; And the mass ratio of active component, filler, binding agent, bonding solvent and disintegrating agent is during preparation: (20 ~ 80): (10 ~ 60): (1 ~ 10): (5 ~ 50): (0 ~ 10).
4. capsule according to claim 1, it is characterized in that the medicine-containing particle of one of described content, standby by fluid bed medicine carrying legal system, at celphere surface-coated drug-loaded layer, wherein celphere is selected from the one of pharmaceutically acceptable microcrystalline Cellulose ball core, sucrose ball core, starch ball core; Binding agent is selected from one or more in hydroxypropyl cellulose, carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, polyvinylpyrrolidone, binding agent by appropriate dissolution with solvents, described solvent comprise in isopropyl alcohol, ethanol, propylene glycol one or more or with the combination of water; During preparation, the granulation of active component, celphere, binding agent and bonding solvent is than being (20 ~ 80): (10 ~ 80): (1 ~ 10): (5 ~ 50).
5. according to the capsule in claim 2 to 4, it is characterized in that the active material particle surface coverage of one of content has sealing coat: sealing coat is made up of pharmaceutically acceptable polymer and optional plasticizer, separating medium, defoamer and/or coloring agent, and wherein said polymer is selected from: one or more of hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone and methacrylic acid/methacrylate; Plasticizer comprises triethyl citrate, tributyl citrate, glycerol triacetate or Polyethylene Glycol; Separating medium comprises Talcum or silicon dioxide; The pigment used can be titanium dioxide or iron oxide pigment; Coating solvent comprise in isopropyl alcohol, ethanol, propylene glycol one or more or with the combination of water; Sealing coat coating weight gain 1.0 ~ 10.0%, preferably 3.0 ~ 8.0%.
6. capsule according to claim 1, is characterized in that the organic acid particles of one of described content, the preferred tartaric acid of organic acid, and the content of tartaric acid in organic acid particles is 50 ~ 100%, preferably 60 ~ 80%; The diameter of granule is 0.4 ~ 1.5 millimeter, preferably 0.8 ~ 1.0 millimeter.
7. the organic acid particles in the capsule according to claim 1 or 6, by slot type method on balling disk(-sc) or by squeezing and pressing method/nodularization legal system for time, it fills dosage form is selected from microcrystalline Cellulose, sucrose, lactose, mannitol, calcium phosphate one or more; Binding agent is selected from hydroxypropyl cellulose, carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, one or more in polyvinylpyrrolidone; Binding agent by appropriate dissolution with solvents, described solvent comprise in isopropyl alcohol, ethanol, propylene glycol one or more or with the combination of water; Disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose; And the mass ratio of tartaric acid, filler, binding agent, binder solution and disintegrating agent is: (20 ~ 80): (10 ~ 60): (1 ~ 10): (5 ~ 50): (0 ~ 10).
8. the capsule according to right 6-7, the organic acid particles of one of its content is if necessary in its surface-coated sealing coat, sealing coat is made up of pharmaceutically acceptable polymer and optional plasticizer, separating medium, defoamer and/or coloring agent, and wherein said polymer is selected from: one or more of hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone and methacrylic acid/methacrylate; Plasticizer comprises triethyl citrate, tributyl citrate, glycerol triacetate or Polyethylene Glycol; Separating medium comprises Talcum or silicon dioxide; The pigment used can be titanium dioxide or iron oxide pigment; Coating solvent comprise in isopropyl alcohol, ethanol, propylene glycol one or more or with the combination of water; And sealing coat coating weight gain 0.5 ~ 10.0%, preferably 3.0 ~ 8.0%.
9. capsule according to claim 1, will insert in hard capsule after the medicine-containing particle and organic acid particles mixing of isolation, organic acid and active substance mass ratio be about 0.5 ~ 3.0, and preferably 1.0 ~ 2.0; In every capsules, the content of active substance dabigatran etcxilate is 50 ~ 200 milligrams, preferably 75 ~ 150 milligrams.
10. prepare a capsule according to claim 1, it is characterized in that comprising the steps:
1) by centrifugal granulation and/or squeezing and pressing method/nodularization method, active substance, filler, binding agent, disintegrating agent are prepared into active material particle, or by fluid bed medicine carrying method, active substance and binding agent are coated on celphere surface and are prepared into active material particle;
2) on active material particle, wrap up pharmaceutically acceptable polymer and arbitrary plasticizer, separating medium with coating device, the sealing coat that defoamer and/or coloring agent are formed, obtain the active material particle of coating;
3) by centrifugal granulation and/or squeezing and pressing method/nodularization method, organic acid, filler, binding agent, disintegrating agent are prepared into organic acid particles; Organic acid particles optionally can isolate suspension or coating solution in surface-coated, carries out coating isolation;
4) be packed into after the active ingredient particle of above-mentioned coating and organic acid particles mixing in hard capsules.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410541060.4A CN105560206A (en) | 2014-10-13 | 2014-10-13 | Preparation of Pradaxa capsule |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410541060.4A CN105560206A (en) | 2014-10-13 | 2014-10-13 | Preparation of Pradaxa capsule |
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| CN105560206A true CN105560206A (en) | 2016-05-11 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201410541060.4A Pending CN105560206A (en) | 2014-10-13 | 2014-10-13 | Preparation of Pradaxa capsule |
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Cited By (6)
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| CN108261409A (en) * | 2017-01-02 | 2018-07-10 | 齐鲁制药有限公司 | A kind of combination of oral medication of dabigatran etcxilate and preparation method thereof |
| WO2019004979A3 (en) * | 2017-05-10 | 2019-04-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| WO2019004980A3 (en) * | 2017-05-10 | 2019-04-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| CN113577067A (en) * | 2021-06-03 | 2021-11-02 | 北京福元医药股份有限公司 | Dabigatran etexilate mesylate pharmaceutical preparation |
| EP3787624A4 (en) * | 2018-05-04 | 2022-03-30 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Capsule-in-capsule compositions of dabigatran etexilate |
| CN115227663A (en) * | 2021-04-22 | 2022-10-25 | 石药集团恩必普药业有限公司 | Dabigatran etexilate mesylate capsule and preparation method thereof |
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| CN103127109A (en) * | 2013-02-05 | 2013-06-05 | 南京华威医药科技开发有限公司 | Pharmaceutical composition containing dabigatran etexilate or salt and hydrate thereof |
| WO2013124340A1 (en) * | 2012-02-21 | 2013-08-29 | Laboratorios Del Dr. Esteve, S.A. | Oral pharmaceutical compositions of dabigatran etexilate |
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| WO2013124340A1 (en) * | 2012-02-21 | 2013-08-29 | Laboratorios Del Dr. Esteve, S.A. | Oral pharmaceutical compositions of dabigatran etexilate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108261409A (en) * | 2017-01-02 | 2018-07-10 | 齐鲁制药有限公司 | A kind of combination of oral medication of dabigatran etcxilate and preparation method thereof |
| WO2019004979A3 (en) * | 2017-05-10 | 2019-04-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| WO2019004980A3 (en) * | 2017-05-10 | 2019-04-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| AU2018293361B2 (en) * | 2017-05-10 | 2021-09-16 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| EP3787624A4 (en) * | 2018-05-04 | 2022-03-30 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Capsule-in-capsule compositions of dabigatran etexilate |
| CN115227663A (en) * | 2021-04-22 | 2022-10-25 | 石药集团恩必普药业有限公司 | Dabigatran etexilate mesylate capsule and preparation method thereof |
| CN115227663B (en) * | 2021-04-22 | 2023-12-12 | 石药集团恩必普药业有限公司 | Dabigatran etexilate mesylate capsule and preparation method thereof |
| CN113577067A (en) * | 2021-06-03 | 2021-11-02 | 北京福元医药股份有限公司 | Dabigatran etexilate mesylate pharmaceutical preparation |
| CN113577067B (en) * | 2021-06-03 | 2023-08-15 | 北京福元医药股份有限公司 | Dabigatran etexilate mesylate pharmaceutical preparation |
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Application publication date: 20160511 |