CN100333727C - Budesonide target-direction microball and preparation thereof - Google Patents
Budesonide target-direction microball and preparation thereof Download PDFInfo
- Publication number
- CN100333727C CN100333727C CNB2004100728710A CN200410072871A CN100333727C CN 100333727 C CN100333727 C CN 100333727C CN B2004100728710 A CNB2004100728710 A CN B2004100728710A CN 200410072871 A CN200410072871 A CN 200410072871A CN 100333727 C CN100333727 C CN 100333727C
- Authority
- CN
- China
- Prior art keywords
- budesonide
- weight
- coating layer
- acrylate copolymer
- methyl acrylate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 title claims abstract description 45
- 229960004436 budesonide Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000011806 microball Substances 0.000 title abstract description 6
- 238000000576 coating method Methods 0.000 claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000011248 coating agent Substances 0.000 claims abstract description 28
- 239000000463 material Substances 0.000 claims abstract description 24
- 239000000725 suspension Substances 0.000 claims description 54
- 238000005303 weighing Methods 0.000 claims description 30
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 28
- 239000011247 coating layer Substances 0.000 claims description 27
- 229920001577 copolymer Polymers 0.000 claims description 25
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 23
- 238000013019 agitation Methods 0.000 claims description 23
- 239000010410 layer Substances 0.000 claims description 22
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical group O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 20
- 239000006185 dispersion Substances 0.000 claims description 19
- 239000008188 pellet Substances 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- 239000004014 plasticizer Substances 0.000 claims description 14
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical group CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 13
- 239000001069 triethyl citrate Substances 0.000 claims description 12
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 12
- 235000013769 triethyl citrate Nutrition 0.000 claims description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 235000010603 pastilles Nutrition 0.000 claims description 4
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 4
- ONKUXPIBXRRIDU-UHFFFAOYSA-N Diethyl decanedioate Chemical compound CCOC(=O)CCCCCCCCC(=O)OCC ONKUXPIBXRRIDU-UHFFFAOYSA-N 0.000 claims description 3
- 239000007921 spray Substances 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- MOVRNJGDXREIBM-UHFFFAOYSA-N aid-1 Chemical compound O=C1NC(=O)C(C)=CN1C1OC(COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)CO)C(O)C1 MOVRNJGDXREIBM-UHFFFAOYSA-N 0.000 claims description 2
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 claims description 2
- 229960004793 sucrose Drugs 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 12
- 238000000034 method Methods 0.000 abstract description 8
- 238000005516 engineering process Methods 0.000 abstract description 7
- 239000003960 organic solvent Substances 0.000 abstract description 6
- 229920000858 Cyclodextrin Polymers 0.000 abstract description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 abstract description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 239000002243 precursor Substances 0.000 abstract 1
- 239000007788 liquid Substances 0.000 description 23
- 229920003134 Eudragit® polymer Polymers 0.000 description 21
- 210000001072 colon Anatomy 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000002156 mixing Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229960003511 macrogol Drugs 0.000 description 3
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 229940050549 fiber Drugs 0.000 description 2
- 229960005343 ondansetron Drugs 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 239000011805 ball Substances 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
Images
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a Budesonide target-direction microball and a preparation method. The present invention adopts a method that the Budesonide of activity components of water-insoluble medicine is prepared into hydrophilic precursor medicine by supplementary materials, such as Beta-cyclodextrins, etc. Accordingly, the Budesonide microball is prepared by the adoption of production technology of an aqueous coating. Since the disperse phases in the technology of the budesonide microball prepared by the present invention are totally water, any organic solvent is not used; production devices do not need to adopt explosion-proof devices or explosion-proof measures in the production process; the production safety is greatly improved, and simultaneously, the production technology is simplified, and the production cost is reduced.
Description
Technical field
The present invention relates to round shaped grain colon-targeted pellets of budesonide and preparation method thereof.Especially relate to and prepare colon-targeted pellets in the fluidized-bed spraying mode after adopting customization agent means to be converted into hydrophilic the water-insoluble budesonide.
Background technology
Budesonide (budesonide) is a kind of steroidal corticosteroids medicine, its character is for water-soluble hardly, thereby, be the preparation of active constituents of medicine with the budesonide at present, all adopting polarity organic solvent (being generally ethanol) in producing preparation is decentralized photo.
October 2 calendar year 2001, U.S. food and FAD FDA have ratified the development of AstraZeneca company a kind ofly is used for the treatment of budesonide oral solid formulation light, the moderate regional enteritis, this product is prepared from by budesonide and ethyl cellulose, and this product is the commodity on the market " Entocort EC " by name abroad.But do not see the relevant patent of this product or other bibliographical informations.
Domestic literature Journal of China Pharmaceutical University 2003, reported a kind of preparation method of budesonide conlon targeting micropill at 34 (5): 419～422, the method is to adopt pan coating to prepare the medicine carrying micropill, and carries out coating of ethyl cellulose organic solution and EUDRAGIT
FS30D aqueous dispersion coating.
People such as Rodriguez are at Chemical Abstracts 63-Pharmaceuticals Vol.130, NO.9, reported a kind of novel ball-shaped that is used for the treatment of colitis (pellet) pellet preparations on 1999 publications such as grade, this microball preparation mainly by carry a pill core (budesonide, ondansetron and fiber butyrate are formed, abbreviation: the CAB micropill) and form with EUDRAGIT S material coating, to the micropill of PH sensitivity.The preparation technology of this medicine carrying micropill is dissolved in organic solvent with budesonide, ondansetron, adds macromolecular material fiber butyrate, evaporates organic solvent then and gets.
Summary of the invention
Because the water solublity extreme difference of budesonide (budesonide), thereby be the pellet preparations of active constituents of medicine with the budesonide, generally all adopting organic solvent in producing preparation is decentralized photo, and the present invention adopts with beta-schardinger dextrin-(β-cyclodextrins), solubilizing agent, antiplastering aid etc., water-insoluble active constituents of medicine budesonide is prepared into hydrophilic prodrugs, thereby has realized adopting the production technology of aqueous coatings to prepare the budesonide micropill.When preparing the budesonide micropill with the inventive method, decentralized photo is water, does not use any organic solvent, production equipment and need not in process of production to adopt explosion-protection equipment or explosion precaution, and production security improves greatly; Simplify production technology simultaneously, reduced production cost.
The round shaped grain colon-targeted pellets of budesonide of the present invention is to be made of the blank nuclear core that does not contain active component, the coating layer and the enteric coat layer that contain the active component budesonide.Described coating layer is made up of budesonide, beta-schardinger dextrin-, solubilizing agent, antiplastering aid and methyl acrylate copolymer, the shared percentage by weight of each material can be in the coating layer: budesonide 0.1%～20%, beta-schardinger dextrin-1%～40%, solubilizing agent 5%～70%, antiplastering aid 1%～30%, methyl acrylate copolymer 10%～80%.Described enteric coat layer is made up of methyl acrylate copolymer, antiplastering aid and plasticizer, and the shared percentage by weight of each material can be a methyl acrylate copolymer 60%～99% in coatings, antiplastering aid 0.5%～30%, plasticizer 0.1%～25%.
Preferred following material of the present invention and proportioning preparation:
Coating layer (weight ratio): budesonide 5%～15%, beta-schardinger dextrin-10%～30%, solubilizing agent 15%～40%, antiplastering aid 3%～10%, methyl acrylate copolymer 20%～45%.
Enteric coat layer (weight ratio): methyl acrylate copolymer 75%～95%, antiplastering aid 3%～15%, plasticizer 5%～12%.Most preferably be:
Coating layer (weight ratio): budesonide 10.9%, beta-schardinger dextrin-23.9%, solubilizing agent 23.9%, antiplastering aid 6.5%, methyl acrylate copolymer 34.8%.
Colon coatings (weight ratio): methyl acrylate copolymer 83.3%, antiplastering aid 8.3%, plasticizer 8.4%.
Solubilizing agent in the described coating layer can be selected polyethylene glycol 6000, Macrogol 4000 or their mixture for use, preferred polyethylene glycol 6000; Antiplastering aid in described coating layer or the enteric coat layer is preferably used Pulvis Talci; Plasticizer in the described enteric coat layer can be selected triethyl citrate, ethyl sebacate or 1,2-propylene glycol, optimization citric acid triethyl for use.
In order to reach end product quality preferably, to keep certain weight ratio between coating layer, enteric coat layer and the blank nuclear core.
The coating layer should be 1%～130% (weight ratio) of blank nuclear core, is more preferably 5%～20% (weight ratio) of blank nuclear core, most preferably is 9.2% (weight ratio) of blank nuclear core.
Enteric coat layer should be 2%～90% (weight ratio) of blank nuclear core, is more preferably 5%～20% (weight ratio) of blank nuclear core, most preferably is 14.4% (weight ratio) of blank nuclear core.
Wherein, the granularity of described blank nuclear core is 0.01mm～2mm, and more preferably 0.1mm～1mm most preferably is 0.5mm～0.7mm.
The release of targeted micropill of the present invention satisfies the targeting preparation release requirement of CNS regulation fully.
The assay method of release is as follows: get this product by drug release determination method (two appendix XC first methods of Chinese Pharmacopoeia version in 2000), preceding two hours is solvent with the 0.1mol/1 hydrochloric acid solution, phosphate buffer with PH7.0 is a release medium later on, Revolution Per Minute 100 changes, operation in accordance with the law, got solution filtered in 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours and 24 hours, measure trap at 236nm wavelength place according to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2000), press C
25H
24O
6Trap be contrast, calculate the release of targeted micropill.Preceding two hours burst sizes less than 10%, 4 hour be 40～60%, 6 hours be 55～80%, 8 hours be 70～85%, 12 hours greater than 75%, 24 hour more than 90%.
Description of drawings
Fig. 1: with the content collection of illustrative plates of high effective liquid chromatography for measuring crude drug (1) and targeted micropill preparation (2).
The release collection of illustrative plates of Fig. 2: embodiment 1～6.
Fig. 3: embodiment 7～11 identical coating layers, the release collection of illustrative plates of different coating thicknesses.
The specific embodiment
Budesonide colon-targeted pellets of the present invention can adopt general preparation method preparation, preferably by following method preparation:
At room temperature, take by weighing budesonide by foregoing weight ratio, beta-schardinger dextrin-, solubilizing agent, each material of coating such as antiplastering aid and methyl acrylate copolymer layer and be equivalent to the water of 0.5 times to 10 times of each material gross weight of coating layer, with budesonide, beta-schardinger dextrin-, solubilizing agent and antiplastering aid are added to the water respectively and make the aqueous dispersion suspension, this suspension is under agitation slowly joined in the aforementioned methyl acrylate copolymer that takes by weighing, mix, this mixed liquor is crossed 120 mesh sieves, be prepared into coating water dispersive suspension, adopt the fluidized bed coating method that this suspension is sprayed on to form the coating layer on the blank micropill nuclear of the sucrose core of weight ratio noted earlier to prepare the pastille micropill.
Take by weighing methyl acrylate copolymer, antiplastering aid and each material of plasticizer enteric coat layer and be equivalent to the water of 0.1 times to 2 times of each material gross weight of coatings by foregoing weight ratio, antiplastering aid and plasticizer be scattered in make the aqueous dispersion suspension in the water, then this suspension is under agitation slowly joined in the aforementioned methyl acrylate copolymer that takes by weighing, after the mixing this mixed liquor is crossed 120 mesh sieves, make enteric coating water dispersive suspension.Adopt and the identical process conditions of sprinkling coating layer, this enteric coating suspension is sprayed on the pastille micropill of aforementioned preparation, be prepared into colon-targeted pellets in its outside colon coatings that forms.
The condition of fluid bed can be determined routinely according to the final needs of product, for example can be with the condition enactment of fluid bed: intake 85m
3/ h, air press 3.0 handkerchiefs, 36～40 ℃ of inlet temperature, 30～33 ℃ of temperature of outgoing airs, 28～31 ℃ of product temperature (sample temperature), nozzle diameter 1mm, spray velocity 5～10ml/min, 5 minutes drying times.
The rounding micropill for preparing is put under 40～50 ℃ of drying conditions and to be got final product in dry 2～4 hours.
In order to understand the present invention better, the present invention is further described by the following embodiment, but do not limit the present invention.
In following examples of the present invention, methyl acrylate copolymer is all selected the EUDRAGIT that is produced by Degussa Rohm company for use
FS30D, this product are the suspensions with the copolymer of methacrylic acid, acrylic acid methyl ester. and methyl methacrylate preparation, described in an embodiment EUDRAGIT
The amount of FS30D all refers to its solid content.
The blank micropill nuclear core that does not contain active component used among the embodiment 1～11 is the cane sugar type medicinal fine pellet core that granularity is 0.5-0.7mm, ball core weight 500 grams.
Take by weighing 1 gram budesonide, 8 gram beta-schardinger dextrin-s, 5 gram polyethylene glycol 6000s, 1 gram Pulvis Talci, under agitation above-mentioned material is scattered in the 40 gram water; This suspension under agitation slowly is scattered in 10 gram EUDRAGIT
In FS30D (in solid content) the polymer suspension, cross 120 mesh sieves and be prepared into coating water dispersive suspension (being called for short＜1〉liquid); Other takes by weighing Pulvis Talci 3 grams, triethyl citrate 5 grams, adds entry 20 gram mixings and makes the aqueous dispersion suspension, this suspension is under agitation slowly joined the 25 gram EUDRAGIT that take by weighing
Form the aqueous dispersion suspension among the FS30D, and this mixed liquor is crossed 120 mesh sieves, be prepared into colon coating solution (being called for short＜2〉liquid).Adopt the fluidized bed coating method, will＜1 〉,＜2〉liquid be sprayed on the sugared core micropill and prepare colon-targeted pellets.Prepared micropill is carried out assay, and the result is: crude drug (reference substance) bimodal is 18.298 minutes and 20.132 minutes when reaching the peak; The peak time of micropill fine powder is 18.282 minutes and 20.148 minutes, and is basic identical with reference substance.Measurement result is seen Fig. 1.
Take by weighing 40g budesonide, 110g beta-schardinger dextrin-, 100g polyethylene glycol 6000,100g Macrogol 4000,18g Pulvis Talci, under agitation above-mentioned material is scattered in the 600g water; This suspension under agitation slowly is scattered in the EUDRAGIT of 150g
In FS30D (in solid content) the polymer suspension, cross 120 mesh sieves and be prepared into coating water dispersive suspension (being called for short＜1〉liquid); Other takes by weighing Pulvis Talci 18g, triethyl citrate 3g, adds entry 30g mixing and makes the aqueous dispersion suspension, this suspension is under agitation slowly joined the coating material EUDRAGIT that takes by weighing
Form the aqueous dispersion suspension among FS30D (in the solid content) 215g, and this mixed liquor is crossed 120 mesh sieves, be prepared into colon coating solution (being called for short＜2〉liquid).Adopt the fluidized bed coating method, will＜1 〉,＜2〉liquid be sprayed on the sugared core micropill and prepare colon-targeted pellets.The release of surveying is seen Fig. 2.
Embodiment 3
Take by weighing 30g budesonide, 60g beta-schardinger dextrin-, 15g polyethylene glycol 6000,45g Macrogol 4000,18g Pulvis Talci, under agitation above-mentioned material is scattered in the 300g water; This suspension under agitation slowly is scattered in the EUDRAGIT of 40g
In FS30D (in solid content) the polymer suspension, cross 120 mesh sieves and be prepared into coating water dispersive suspension (being called for short＜1〉liquid); Other takes by weighing Pulvis Talci 5g, triethyl citrate 10g, adds entry 60g mixing and makes the aqueous dispersion suspension, this suspension is under agitation slowly joined the coating material EUDRAGIT that takes by weighing
Form the aqueous dispersion suspension among the FS30D150g, and this mixed liquor is crossed 120 mesh sieves, be prepared into colon coating solution (being called for short＜2〉liquid).Adopt the fluidized bed coating method, will＜1 〉,＜2〉liquid be sprayed on the sugared core micropill and prepare colon-targeted pellets.Measure release and the results are shown in Figure 2.
Take by weighing 5g budesonide, 3g beta-schardinger dextrin-, 8g Macrogol 4000,10g Pulvis Talci, under agitation above-mentioned material is scattered in the 100g water; This suspension under agitation slowly is scattered in the EUDRAGIT of 10g
In the FS30D polymer suspension, cross 120 mesh sieves and be prepared into coating water dispersive suspension (being called for short＜1〉liquid); Other takes by weighing Pulvis Talci 5g, triethyl citrate 2g, adds entry 60g mixing and makes the aqueous dispersion suspension, this suspension is under agitation slowly joined the coating material EUDRAGIT that takes by weighing
Form the aqueous dispersion suspension among FS30D (in the solid content) 90g, and this mixed liquor is crossed 120 mesh sieves, be prepared into colon coating solution (being called for short＜2〉liquid).Adopt the fluidized bed coating method, will＜1 〉,＜2〉liquid be sprayed on the sugared core micropill and prepare colon-targeted pellets.Measure release and the results are shown in Figure 2.
Take by weighing 5g budesonide, 11g beta-schardinger dextrin-, 11g polyethylene glycol 6000,3g Pulvis Talci, under agitation above-mentioned material is scattered in the 80g water; This suspension under agitation slowly is scattered in the EUDRAGIT of 16g
In FS30D (in solid content) the polymer suspension, cross 120 mesh sieves and be prepared into coating water dispersive suspension (being called for short＜1〉liquid); Other takes by weighing Pulvis Talci 3g, triethyl citrate 10g, adds entry 60g mixing and makes the aqueous dispersion suspension, this suspension is under agitation slowly joined the EUDRAGIT of 50g
Form the aqueous dispersion suspension among the FS30D, and this mixed liquor is crossed 120 mesh sieves, be prepared into colon coating solution (being called for short＜2〉liquid).Adopt the fluidized bed coating method, will＜1 〉,＜2〉liquid be sprayed on the sugared core micropill and prepare colon-targeted pellets.Measure release and the results are shown in Figure 2.
Take by weighing 3g budesonide, 9g beta-schardinger dextrin-, 23g polyethylene glycol 6000,3g Pulvis Talci, under agitation above-mentioned material is scattered in the 100g water; This suspension under agitation slowly is scattered in the EUDRAGIT of 42g
In FS30D (in solid content) the polymer suspension, cross 120 mesh sieves and be prepared into coating water dispersive suspension (being called for short＜1〉liquid); Other takes by weighing Pulvis Talci 5g, triethyl citrate 5g, adds entry 60g mixing and makes the aqueous dispersion suspension, this suspension is under agitation slowly joined the EUDRAGIT of 50g
Form the aqueous dispersion suspension among the FS30D (in solid content), and this mixed liquor is crossed 120 mesh sieves, be prepared into colon coating solution (being called for short＜2〉liquid).Adopt the fluidized bed coating method, will＜1 〉,＜2〉liquid be sprayed on the sugared core micropill and prepare colon-targeted pellets.Measure release and the results are shown in Figure 2.
Targeted micropill among six embodiment of following examples 7-11, coating layer and example 5 are identical, but colon coatings thickness difference, each example is measured release respectively, sees Fig. 3.
Embodiment 7
Take by weighing Pulvis Talci 6g, triethyl citrate 6g adds entry 30g mixing and makes the aqueous dispersion suspension, this suspension is under agitation slowly joined the EUDRAGIT of 60g
Form the aqueous dispersion suspension among the FS30D, and this mixed liquor is crossed 120 mesh sieves, be prepared into colon coating solution preparation＜2〉liquid, and by preparing micropill with embodiment 5 identical operations.
Take by weighing EUDRAGIT
FS30D 30g, water 40g, Pulvis Talci 2g, triethyl citrate 8g, with the operation preparation＜2〉liquid of embodiment 7, and by preparing micropill with embodiment 5 identical operations.
Embodiment 9
Take by weighing EUDRAGIT
FS30D30g, water 40g, Pulvis Talci 2g, ethyl sebacate 8g is with the operation preparation＜2〉liquid of embodiment 7.Be prepared into micropill by embodiment 5 identical operations
Take by weighing EUDRAGIT
FS30D40g, water 60g, Pulvis Talci 5g, 1,2-propylene glycol 5g, with the operation preparation＜2〉liquid of embodiment 7, and by preparing micropill with embodiment 5 identical operations.
Take by weighing EUDRAGIT
FS30D60g, water 80g, Pulvis Talci 10g, triethyl citrate 10g, with the operation preparation＜2〉liquid of embodiment 7, and by preparing micropill with embodiment 5 identical operations.
Claims (9)
1, a kind of colon-targeted pellets that contains budesonide, constitute with the coating layer and the enteric coat layer that contain the active component budesonide by the blank nuclear core that does not contain active component, it is characterized in that described coating layer percentage by weight consists of: budesonide 0.1%～20%, beta-schardinger dextrin-1%～40%, solubilizing agent 5%～70%, antiplastering aid 1%～30%, methyl acrylate copolymer 10%～80%; Described enteric coat layer percentage by weight consists of: methyl acrylate copolymer 60%～99%, antiplastering aid 0.5%～30%, plasticizer 0.1%～25%;
Described methyl acrylate copolymer is the copolymer with methacrylic acid, acrylic acid methyl ester. and methyl methacrylate preparation.
2, according to the described targeted micropill of claim 1, the weight that it is characterized in that described coating layer is 1%～130% of blank nuclear core; The weight of described enteric coat layer is 2%～90% of blank nuclear core; The granularity of described blank nuclear core is 0.01mm～2mm.
3, according to the described targeted micropill of claim 1, the percentage by weight that it is characterized in that described coating layer consists of: budesonide 5%～15%, beta-schardinger dextrin-10%～30%, solubilizing agent 15%～40%, antiplastering aid 3%～10%, methyl acrylate copolymer 20%～45%; The percentage by weight of described enteric coat layer consists of: methyl acrylate copolymer 75%～95%, antiplastering aid 3%～15%, plasticizer 5%～12%.
4, according to the described targeted micropill of claim 3, the weight that it is characterized in that described coating layer is 5%～20% of blank nuclear core; The weight of described enteric coat layer is 5%～20% of blank nuclear core, and the granularity of described blank nuclear core is 0.1mm～1mm.
5, according to the described targeted micropill of claim 1, it is characterized in that the percentage by weight of described coating layer consists of: budesonide 10.9%, beta-schardinger dextrin-23.9%, solubilizing agent 23.9%, antiplastering aid 6.5%, coating material methyl acrylate copolymer 34.8%; The percentage by weight of described enteric coat layer consists of: methyl acrylate copolymer 83.3%, antiplastering aid 8.3%, plasticizer 8.4%.
6, according to the described targeted micropill of claim 5, the weight that it is characterized in that described coating layer is 9.2% of blank nuclear core; The weight of described enteric coat layer is 14.4% of blank nuclear core; The granularity of described blank nuclear core is 0.5mm～0.7mm.
7,, it is characterized in that the solubilizing agent in the described coating layer is polyethylene glycol 6000, Macrogol 4000 or their mixture according to claim 1,3 or 5 described targeted micropills; Antiplastering aid in described coating layer or the enteric coat layer is a Pulvis Talci; Plasticizer in the described enteric coat layer is triethyl citrate, ethyl sebacate or 1, the 2-propylene glycol.
8, according to claim 1,3 or 5 described targeted micropills, the solubilizing agent in the described coating layer is that the antiplastering aid in polyethylene glycol 6000, described coating layer or the enteric coat layer is a Pulvis Talci, and the plasticizer in the described enteric coat layer is a triethyl citrate; Described blank nuclear core is the cane sugar type medicinal micro.
9, according to the preparation method of the described targeted micropill of arbitrary claim in the claim 1 to 8, it comprises the following steps:
1), under the room temperature, takes by weighing each material of coating layer by described percentage by weight: budesonide, beta-schardinger dextrin-, solubilizing agent, antiplastering aid and methyl acrylate copolymer;
2), get the water of 0.5 times to 10 times of each material gross weight of coating layer, budesonide, beta-schardinger dextrin-, solubilizing agent, antiplastering aid are added to the water is prepared into the aqueous dispersion suspension:
3), with step 2) suspension that makes under agitation slowly joins in the methyl acrylate copolymer that takes by weighing in the step 1), mixes, and this mixed liquor is crossed 120 mesh sieves, is prepared into coating water dispersive suspension;
4), take by weighing each material of enteric coat layer: methyl acrylate copolymer, antiplastering aid and plasticizer by described percentage by weight;
5), get the water of 0.1 times to 2 times of each material gross weight of enteric coat layer, antiplastering aid and the plasticizer that takes by weighing in the step 4) be scattered in become mixed liquor in the water;
6) mixed liquor that step 5) is made under agitation slowly joins in the methyl acrylate copolymer that takes by weighing in step 4), mixes, and this mixed liquor is crossed 120 mesh sieves, is prepared into coating water dispersive suspension;
7), use spray mode at the bottom of the fluid bed, the aqueous dispersion suspension of step 3) preparation is sprayed on the blank made from sugar examines on the core, be prepared into the pastille micropill; Fluid bed condition: intake 85m
3/ h, air press 3.0 handkerchiefs, 36～40 ℃ of inlet temperature, 30～33 ℃ of temperature of outgoing airs, 28～31 ℃ of sample temperatures, nozzle diameter 1mm, spray velocity 5～10ml/min, 5 minutes drying times;
8), the employing condition identical with step 7), will be sprayed on the pastille micropill of step 7) preparation in the coating water dispersive suspension of step 6) preparation, be prepared into the round shaped grain colon-targeted pellets;
9) micropill that, prepares was put under 40～50 ℃ of drying conditions dry 2～4 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100728710A CN100333727C (en) | 2004-11-25 | 2004-11-25 | Budesonide target-direction microball and preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100728710A CN100333727C (en) | 2004-11-25 | 2004-11-25 | Budesonide target-direction microball and preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1778301A CN1778301A (en) | 2006-05-31 |
| CN100333727C true CN100333727C (en) | 2007-08-29 |
Family
ID=36768839
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100728710A Expired - Fee Related CN100333727C (en) | 2004-11-25 | 2004-11-25 | Budesonide target-direction microball and preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100333727C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101744725B (en) * | 2008-12-09 | 2013-04-17 | 北京华素制药股份有限公司 | Optimization method for coating process parameter of sustained-release pellets |
| CN101926805A (en) * | 2009-06-24 | 2010-12-29 | 天津金耀集团有限公司 | Pharmaceutical composition containing 16, 17 isoxazolidine steroidal compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5932249A (en) * | 1993-09-23 | 1999-08-03 | Dr. Falk Pharma Gmbh | Budesonide pellets with a controlled released pattern and process for producing the same |
| CN1243434A (en) * | 1997-01-20 | 2000-02-02 | 阿斯特拉公司 | New formulation for inhalation having a poured bulk density of from 0.28 to 0.38 g/ml, comprising budesonide |
| CN1284869A (en) * | 1998-02-09 | 2001-02-21 | 乔尔·博朗尼克 | Treatment of Chronic Gastrointestinal Inflammation |
-
2004
- 2004-11-25 CN CNB2004100728710A patent/CN100333727C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5932249A (en) * | 1993-09-23 | 1999-08-03 | Dr. Falk Pharma Gmbh | Budesonide pellets with a controlled released pattern and process for producing the same |
| CN1243434A (en) * | 1997-01-20 | 2000-02-02 | 阿斯特拉公司 | New formulation for inhalation having a poured bulk density of from 0.28 to 0.38 g/ml, comprising budesonide |
| CN1284869A (en) * | 1998-02-09 | 2001-02-21 | 乔尔·博朗尼克 | Treatment of Chronic Gastrointestinal Inflammation |
Non-Patent Citations (1)
| Title |
|---|
| 布地奈德结肠定位微丸的制备及释药特性研究 刘云、张钧寿、胡林森，中国药科大学学报，第34卷第5期 2003 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1778301A (en) | 2006-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Venkatesan et al. | Microencapsulation: a vital technique in novel drug delivery system | |
| CN101190179B (en) | Enteric medicinal composition for treating diabetes and preparation method thereof | |
| JPH0772129B2 (en) | Sustained release complex unit formulation | |
| JPH07173050A (en) | Spherical nucleus, spherical granule and their production | |
| CN101375869A (en) | Slow/controlled release pellet composition containing ginkgo leaf extracts and preparation method thereof | |
| AU2002223074B2 (en) | Microgranules based on active principle and method for making same | |
| EP1072257A1 (en) | Multiple-unit sustained release tablets | |
| CN102046155A (en) | Solid oral form with dual release profile, containing multiparticulates | |
| CN102727452B (en) | Eszopiclone-containing particle and its preparation method | |
| CN101190186A (en) | 22R-budesonide colon-targeted pellets and preparation method thereof | |
| CN100333727C (en) | Budesonide target-direction microball and preparation thereof | |
| EP0948321B1 (en) | Preparation in form of a matrix material-auxiliary agent compound containing optionally an active substance | |
| CN102552165B (en) | Sarpogrelate hydrochloride sustained release pellet and preparation method thereof | |
| JP2002284694A (en) | Multiparticle of lithium salt for oral administration suitable for once-daily administration | |
| CN101896166B (en) | Film coated tablets containing drospirenone as active agent and a method for the preparation thereof | |
| CN102188423B (en) | Metoprolol Tartaric Acid and Felodipine slow-release double-layer tablet and preparation method thereof | |
| CN101291652A (en) | Semi-permeable compositions providing reduced drying time for osmotic dosage forms | |
| EP1572160A2 (en) | Process for manufacturing sustained release microbeads containing venlafaxine hci | |
| CN106176669A (en) | A kind of pantoprazole sodium enteric-pellets capsules and preparation method | |
| CN102552164A (en) | Potassium citrate slow-release micro pill and preparation method thereof | |
| CN102106856A (en) | Entecavir medicinal composition and preparation method thereof | |
| EP3432865B1 (en) | Oral dosage form | |
| CN102397262B (en) | Amoxicillin sustained release solid medicinal composition and preparation method thereof | |
| CN105687158B (en) | A kind of mesalazine microparticle formulation of Time Dependent releasing mechanism and preparation method thereof | |
| CN101199836B (en) | Stage releasing CsA solid tiny milk agent and tiny milk curing method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: Cheng linzhuan Hedong District of Tianjin City Road 300161 No. 91 Patentee after: Tianjin Pharmaceutical Research Institute Co.,Ltd. Address before: Cheng linzhuan Hedong District of Tianjin City Road 300161 No. 91 Patentee before: TIANJIN PHARMACEUTICALS Group Corp. |
|
| CP01 | Change in the name or title of a patent holder | ||
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 300457 Tianjin Binhai New Area Tianjin Development Zone West District Xinye Jiujie north, Xinhuan West Road East Patentee after: Tianjin Pharmaceutical Research Institute Co.,Ltd. Address before: Cheng linzhuan Hedong District of Tianjin City Road 300161 No. 91 Patentee before: Tianjin Pharmaceutical Research Institute Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 300457 North Xinye 9th Street and East Xinhuan West Road, West District, Binhai New Area, Tianjin Patentee after: Tianjin Pharmaceutical Research Institute Co.,Ltd. Address before: 300457 Tianjin Binhai New Area Tianjin Development Zone West District Xinye Jiujie north, Xinhuan West Road East Patentee before: Tianjin Pharmaceutical Research Institute Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070829 Termination date: 20211125 |