CN103127108B - Telmisartan amlodipine tablet, and preparation method and use thereof - Google Patents
Telmisartan amlodipine tablet, and preparation method and use thereof Download PDFInfo
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- CN103127108B CN103127108B CN201310076765.9A CN201310076765A CN103127108B CN 103127108 B CN103127108 B CN 103127108B CN 201310076765 A CN201310076765 A CN 201310076765A CN 103127108 B CN103127108 B CN 103127108B
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- telmisartan
- amlodipine
- micropill
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- besylate tablet
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- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 title claims abstract description 221
- 239000005537 C09CA07 - Telmisartan Substances 0.000 title claims abstract description 111
- 229960005187 telmisartan Drugs 0.000 title claims abstract description 111
- 229960000528 amlodipine Drugs 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title 1
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 claims abstract description 115
- 229960004005 amlodipine besylate Drugs 0.000 claims abstract description 48
- 239000003814 drug Substances 0.000 claims abstract description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 51
- 239000008187 granular material Substances 0.000 claims description 50
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 38
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 29
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 22
- 238000000576 coating method Methods 0.000 claims description 22
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 22
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 22
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 22
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 21
- 229920002472 Starch Polymers 0.000 claims description 21
- 239000000600 sorbitol Substances 0.000 claims description 21
- 239000008107 starch Substances 0.000 claims description 21
- 235000019698 starch Nutrition 0.000 claims description 21
- 239000011248 coating agent Substances 0.000 claims description 20
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 17
- 229960003194 meglumine Drugs 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000004925 Acrylic resin Substances 0.000 claims description 14
- 229920000178 Acrylic resin Polymers 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 14
- 239000003085 diluting agent Substances 0.000 claims description 13
- 239000012670 alkaline solution Substances 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 10
- 206010020772 Hypertension Diseases 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- 239000003381 stabilizer Substances 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 4
- 238000011017 operating method Methods 0.000 claims description 4
- 230000001631 hypertensive effect Effects 0.000 claims description 3
- 238000005352 clarification Methods 0.000 claims description 2
- 229940043097 telmisartan and amlodipine Drugs 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 239000002245 particle Substances 0.000 abstract 1
- 239000008188 pellet Substances 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 28
- 235000010356 sorbitol Nutrition 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 238000012216 screening Methods 0.000 description 15
- 235000019359 magnesium stearate Nutrition 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 13
- 239000002671 adjuvant Substances 0.000 description 10
- 238000005286 illumination Methods 0.000 description 8
- 239000007779 soft material Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- 229930195725 Mannitol Natural products 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 239000000594 mannitol Substances 0.000 description 6
- 235000010355 mannitol Nutrition 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 229920003081 Povidone K 30 Polymers 0.000 description 4
- 229910000831 Steel Inorganic materials 0.000 description 4
- 238000005056 compaction Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000006193 liquid solution Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 238000000465 moulding Methods 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- RSGAIWOEJXRYRV-UHFFFAOYSA-M sodium;2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]methyl]phenyl]benzoate Chemical compound [Na+].CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C([O-])=O RSGAIWOEJXRYRV-UHFFFAOYSA-M 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 239000010959 steel Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000004584 weight gain Effects 0.000 description 4
- 235000019786 weight gain Nutrition 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- -1 telmisartan amlodipine compound Chemical class 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 241000406668 Loxodonta cyclotis Species 0.000 description 1
- 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 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical group 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000007788 roughening Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a telmisartan amlodipine tablet, which is the preparation prepared from telmisartan particles and amlodipine besylate tablet pellets, which are firstly prepared independently, and then mixed and tabletted. According to the telmisartan amlodipine tablet, telmisartan and amlodipine are processed by a specific preparation technology; the stability of the telmisartan amlodipine tablet is obviously improved; and the security of the drug is ensured; meanwhile, the preparation disclosed by the invention is simpler in technology, and lower in cost, and benefits the popularization of the product.
Description
Technical field
The present invention relates to a kind of stable telmisartan amlodipine tablets, and its production and use.
Background technology
Hypertension is the most common cardiovascular diseases, is that weight in global range is to public health problem.Chinese residents nutrition and the Health Situation survey result of 2004 show, and China 18 years old and above prevalence of hypertension rate are 18.8%, estimate that national number of patients is more than 1.6 hundred million.Compared with 1991, prevalence rises 31%, number of patients increase about more than 7,000 ten thousand people.1998, China's cerebrovascular occupied the second of urbanite's cause of death, ranks first in rural area.The annual death in the whole nation is more than 1,000,000, and the patient about 5,000,000 ~ 6,000,000 of survival, wherein more than 75% leaves deformity in various degree, causes white elephant to individual, family and society.Explicitly point out in the hypertension practice guidelines that Europe cardiovascular and hypertension coordination board deliver for 2007, most primary hypertension patients, especially the patient that basic blood pressure is higher needs to use Drug therapy of more than two kinds, cannot realize controlling hypertensive object with single medicine.Be used alone a kind of antihypertensive drug and often can not receive good curative effect, the dissimilar medicine of low dose of conbined usage is at present by the hypertension therapeutic scheme of actively recommending.On October 16th, 2009 U.S. FDA have approved German Boehringer Ingelheim drugmaker telmisartan Amlodipine Besylate Tablet compound formulation listing (trade name:
be used for the treatment of hypertension.
Telmisartan is insoluble in water, and after being prepared into preparation, absorption difference, bioavailability are low, weak curative effect.In order to ensure the bioavailability of telmisartan, the Telmisartan formulations (as: Telmisartan Tablets etc.) of having gone on the market, is all after telmisartan is prepared into sodium salt, then is prepared into preparation, finally use clinically, to improve bioavailability and curative effect.Amlodipine Besylate Tablet is faintly acid, when it is in alkaline environment time, Amlodipine Besylate Tablet will be made to dissociate into amlodipine.As can be seen from the structural formula of amlodipine, there are fat key, in the basic conditions a facile hydrolysis.In the formulation, telmisartan sodium is sodium salt, band alkalescence, two kinds of raw materials mix, incompatibility can be produced, amlodipine will be caused to dissociate and hydrolysis, therefore two kinds of active component methods that are direct and mixed with excipients can not be applied to telmisartan and amlodipine compound tablet, otherwise will the instability of amlodipine be caused.
CNl01780078 discloses telmisartan and amlodipine compound preparation and preparation method thereof, and it is made up of the first micropill comprising telmisartan and the second micropill comprising amlodipine.But the method is comparatively time-consuming for strong dose thing pelletizing process, particularly telmisartan micropill, and technique is comparatively complicated, and loadings is excessive, brings great inconvenience to the compliance of patient.
CNl02008469 discloses telmisartan and amlodipine compound preparation and preparation method thereof, after active component is granulated respectively, mixes and the preparation method of tabletting.But special processing mode is not adopted to this characteristic unstable in slight alkali environment of amlodipine in its preparation process, be difficult to the long-time stability ensureing this compound preparation quality in shelf life.
Therefore, study a kind of without the need to special handling mode, have good stability and telmisartan amlodipine compound tablet easy to prepare, seem particularly necessary.
Summary of the invention
The object of the present invention is to provide a kind of telmisartan amlodipine tablets had good stability.
The invention provides a kind of telmisartan amlodipine tablets, it first independently prepares telmisartan granules and Amlodipine Besylate Tablet micropill, then by preparation that both mixed pressuring plates are prepared from.
Further, coatings is provided with outside described Amlodipine Besylate Tablet micropill.
Further, telmisartan granules is prepared from by telmisartan 20-100 part, alkaline reagent 2-8 part, stabilizing agent 10-30 part, solubilizing agent 10-30 part and diluent 150-350 part; Amlodipine Besylate Tablet micropill is prepared from by Amlodipine Besylate Tablet 5-20 part, diluent 0-200 part and coating materials 0-20 part; Described alkaline reagent is alkali metal hydroxide; Described stabilizing agent is meglumine; Described solubilizing agent is polyvidone; Described diluent is one or more the combination in starch, lactose, sucrose, sorbitol, mannitol, xylitol, microcrystalline Cellulose; Described coating materials is one or more the combination in hypromellose, acrylic resin, Opadry.
Closer, in telmisartan granules, described alkaline reagent is sodium hydroxide, described diluent is sorbitol; In amlodipine micropill, described diluent is that microcrystalline Cellulose is or/and starch; Described coating materials is that Opadry is or/and acrylic resin.
Closer, telmisartan granules is prepared from by telmisartan 40-80 part, sodium hydroxide 3-7 part, meglumine 12-24 part, polyvidone 12-24 part, sorbitol 160-340 part;
Amlodipine Besylate Tablet micropill is by Amlodipine Besylate Tablet 6-14 part, microcrystalline Cellulose 0-100 part, starch 0-100 part, Opadry 0-6 part, acrylic resin 0-6 part, being 0 when wherein microcrystalline Cellulose is different with starch, is 0 when Opadry is different from acrylic resin.
Further preferably, polyvidone model is K30.
Present invention also offers the preparation method of above-mentioned telmisartan amlodipine tablets, it comprises following operating procedure:
(1) preparation of telmisartan granules
After alkaline reagent, stabilizing agent, telmisartan, solubilizing agent mixing, dry, then add diluent, granulate, granule is for subsequent use;
(2) preparation of Amlodipine Besylate Tablet micropill
Get Amlodipine Besylate Tablet, diluent prepares amlodipine ball core, add coating materials coating, gained coated micropill is for subsequent use;
(3) tabletting
Get telmisartan granules, Amlodipine Besylate Tablet micropill, then add moderate lubrication agent, after mixing, tabletting.
Further, it comprises following operating procedure:
(1) preparation of telmisartan granules
In 30 ~ 60 DEG C of water-baths, sodium hydroxide, telmisartan, polyvidone, meglumine are dissolved in order in water, mixing is until clarification, and obtained alkaline solution, by alkaline solution drying, obtains dry fine powder, then mix homogeneously with sorbitol, granulate, for subsequent use;
(2) preparation of Amlodipine Besylate Tablet micropill
Get Amlodipine Besylate Tablet, after mixing with diluent starch or microcrystalline Cellulose, prepare amlodipine ball core; Get coating materials, right
Ball core carries out coating, gained coated micropill, for subsequent use;
(3) tabletting
Get telmisartan granules, amlodipine micropill, add lubricant, mixing, tabletting.
Present invention also offers the purposes of above-mentioned telmisartan amlodipine tablets in the hypertensive medicine of preparation treatment.
Telmisartan amlodipine tablets of the present invention, passes through specific preparation process by telmisartan and amlodipine, the stability of telmisartan amlodipine tablets is significantly improved, has ensured Drug safety; Meanwhile, invention formulation technique is simpler, and cost is lower, is more conducive to the popularization of product.
Detailed description of the invention
The preparation (specification 40mg/5mg) of embodiment 1 telmisartan amlodipine tablets of the present invention
Prescription:
(1) telmisartan granules prescription
| Composition | Consumption (g/1000 sheet) |
| Telmisartan | 40 |
| Sodium hydroxide | 3.36 |
| Polyvidone | 12 |
| Meglumine | 12 |
| Sorbitol | 168.64 |
(2) amlodipine micropill prescription
| Composition | Consumption (g/1000 sheet) |
| Amlodipine Besylate Tablet | 6.935 |
| Starch | 100 |
| Polyvidone k30 aqueous solution | In right amount |
| Opadry | 5.347 |
(3) the total prescription of telmisartan amlodipine tablets
| Composition | Consumption (g/1000 sheet) |
| Telmisartan granules | 276 |
| Amlodipine micropill | 112.282 |
| Magnesium stearate | 2 |
(1) preparation of telmisartan granules
(1) at the temperature between 30-60 DEG C, the water of recipe quantity is inserted in suitable rustless steel container, under vigorous stirring sodium hydroxide 3.360g, telmisartan 40.0g, polyvidone 12.0g, meglumine 12.0g are dissolved in water in order, until clarify completely, have slightly faint yellow, obtained telmisartan alkaline solution.Sprayed into by gained alkaline solution in suitable spray dryer, the moisture content controlling dried material is≤6.0%, obtains dry telmisartan fine powder.
(2) by step (1) gained telmisartan fine powder and accessory sorbitol 168.64g, mix homogeneously, adopts compaction type dry granulating machine to granulate, and screening 20 ~ 80 object granules are for subsequent use.
(2) preparation of amlodipine micropill
(1) polyvidone is dissolved in suitable quantity of water and makes solution, is prepared into the polyvidone aqueous solution of 5%, for subsequent use.
(2) by Amlodipine Besylate Tablet 6.935g and starch 100g, mix homogeneously, with the polyvidone aqueous solution soft material of 5%, the soft material micropill made mechanism ball, the crushed 0.4mm sieve aperture of wet feed, strip wet grain cut off round as a ball, 60 DEG C of drying and mouldings, for subsequent use.
(3) be prepared into containing 8% aqueous dispersion liquid solution by 5.347g Opadry, in fluid bed, carry out sealing coat coating to the core ball containing amlodipine, coating weight gain is 3-5%.Finally make amlodipine micropill, screening 20 ~ 80 object micropills, for subsequent use.
(3) total mixed, tabletting
Telmisartan granules and amlodipine micropill and additional magnesium stearate 2.0g are always mixed, tabletting, makes 1000 telmisartan amlodipine tablets.
The preparation (specification 40mg/10mg) of embodiment 2 telmisartan amlodipine tablets
Prescription:
(1) telmisartan granules prescription
| Composition | Consumption (g/1000 sheet) |
| Telmisartan | 40 |
| Sodium hydroxide | 3.36 |
| Polyvidone | 12 |
| Meglumine | 12 |
| Sorbitol | 168.64 |
(2) amlodipine micropill prescription
| Composition | Consumption (g/1000 sheet) |
| Amlodipine Besylate Tablet | 13.87 |
| Microcrystalline Cellulose | 100 |
| Polyvidone k30 aqueous solution | In right amount |
| Acrylic resin | 5.347 |
(3) the total prescription of telmisartan amlodipine tablets
| Composition | Consumption (g/1000 sheet) |
| Telmisartan granules | 276 |
| Amlodipine micropill | 112.282 |
| Magnesium stearate | 2 |
(1) preparation of telmisartan granules
(1) at the temperature between 30-60 DEG C, the water of recipe quantity is inserted in suitable rustless steel container, under vigorous stirring sodium hydroxide 3.360g, telmisartan 40.0g, polyvidone 12.0g, meglumine 12.0g are dissolved in water in order, until clarify completely, have slightly faint yellow, obtained telmisartan alkaline solution.Sprayed into by gained alkaline solution in suitable spray dryer, the moisture content controlling dried material is≤6.0%, obtains dry telmisartan fine powder.
(2) by step (1) gained telmisartan fine powder and accessory sorbitol 168.64g, mix homogeneously, adopts compaction type dry granulating machine to granulate, and screening 20 ~ 80 object granules are for subsequent use.
(2) preparation of amlodipine micropill
(1) polyvidone is dissolved in suitable quantity of water and makes solution, is prepared into the polyvidone aqueous solution of 5%, for subsequent use.
(2) by Amlodipine Besylate Tablet 13.870g and microcrystalline Cellulose 100g, mix homogeneously, with the polyvidone aqueous solution soft material of 5%, make soft material micropill mechanism ball, the crushed 0.4mm sieve aperture of wet feed, strip wet grain cut off round as a ball, 60 DEG C of drying and mouldings, for subsequent use.
(3) be prepared into containing 8% aqueous dispersion liquid solution by 5.347g acrylic resin, in fluid bed, carry out sealing coat coating to the core ball containing amlodipine, coating weight gain is 3-5%.Finally make amlodipine micropill, screening 20 ~ 80 object micropills, for subsequent use.
(3) total mixed, tabletting
Telmisartan granules and amlodipine granule and additional magnesium stearate 2.0g are always mixed, tabletting, makes 1000 telmisartan amlodipine tablets.
The preparation (specification 80mg/5mg) of embodiment 3 telmisartan amlodipine tablets
Prescription:
(1) telmisartan granules prescription
| Composition | Consumption (g/1000 sheet) |
| Telmisartan | 80 |
| Sodium hydroxide | 6.720 |
| Polyvidone | 24 |
| Meglumine | 24 |
| Sorbitol | 337.28 |
(2) amlodipine micropill prescription
| Composition | Consumption (g/1000 sheet) |
| Amlodipine Besylate Tablet | 6.935 |
| Starch | 50 |
| Microcrystalline Cellulose | 50 |
| Polyvidone k30 aqueous solution | In right amount |
| Opadry | 5.347 |
(3) the total prescription of telmisartan amlodipine tablets
| Composition | Consumption (g/1000 sheet) |
| Telmisartan granules | 276 |
| Amlodipine micropill | 112.282 |
| Magnesium stearate | 2 |
(1) preparation of telmisartan granules
(1) at the temperature between 30-60 DEG C, the water of recipe quantity is inserted in suitable rustless steel container, under vigorous stirring sodium hydroxide 6.720g, telmisartan 80.0g, polyvidone 24.0g, meglumine 24.0g are dissolved in water in order, until clarify completely, have slightly faint yellow, obtained telmisartan alkaline solution.Sprayed into by gained alkaline solution in suitable spray dryer, the moisture content controlling dried material is≤6.0%, obtains dry telmisartan fine powder.
(2) by step (1) gained telmisartan fine powder and accessory sorbitol 337.28g, mix homogeneously, adopts compaction type dry granulating machine to granulate, and screening 20 ~ 80 object granules are for subsequent use.
(2) preparation of amlodipine micropill
(1) polyvidone is dissolved in suitable quantity of water and makes solution, is prepared into the polyvidone aqueous solution of 5%, for subsequent use.
(2) by Amlodipine Besylate Tablet 6.935g, starch 50g and microcrystalline Cellulose 50g, mix homogeneously, with the polyvidone aqueous solution soft material of 5%, make soft material micropill mechanism ball, the crushed 0.4mm sieve aperture of wet feed, strip wet grain cut off round as a ball, 60 DEG C of drying and mouldings, for subsequent use.
(3) be prepared into containing 8% aqueous dispersion liquid solution by 5.347g Opadry, in fluid bed, carry out sealing coat coating to the core ball containing Amlodipine Besylate Tablet, coating weight gain is 3-5%.Finally make amlodipine micropill, screening 20 ~ 80 object micropills, for subsequent use.
(3) total mixed, tabletting
Telmisartan granules and amlodipine granule and additional magnesium stearate 2.0g are always mixed, tabletting, makes 1000.
The preparation (specification 80mg/10mg) of embodiment 4 telmisartan amlodipine tablets
Prescription:
(1) telmisartan granules prescription:
| Composition | Consumption (g/1000 sheet) |
| Telmisartan | 80 |
| Sodium hydroxide | 6.720 |
| Polyvidone | 24.0 |
| Meglumine | 24.0 |
| Sorbitol | 337.28 |
(2) amlodipine micropill prescription
| Composition | Consumption (g/1000 sheet) |
| Amlodipine Besylate Tablet | 13.870 |
| Starch | 100.0 |
| Polyvidone k30 aqueous solution | In right amount |
| Acrylic resin | 5.347 |
(3) telmisartan amlodipine tablets prescription
| Composition | Consumption (g/1000 sheet) |
| Telmisartan granules | 276.0 |
| Amlodipine Besylate Tablet micropill | 112.282 |
| Magnesium stearate | 2.0 |
(1) preparation of telmisartan granules
(1) at the temperature between 30-60 DEG C, the water of recipe quantity is inserted in suitable rustless steel container, then under vigorous stirring sodium hydroxide 6.720g, telmisartan 80.0g, polyvidone 24.0g, meglumine 24.0g are dissolved in water in order, until clarify completely, have slightly faint yellow, obtained telmisartan alkaline solution.Sprayed into by gained alkaline solution in suitable spray dryer, the moisture content controlling dried material is≤6.0%, obtains dry telmisartan fine powder.
(2) by step (1) gained telmisartan fine powder and accessory sorbitol 337.28g, mix homogeneously, adopts compaction type dry granulating machine to granulate, and screening 20 ~ 80 object granules are for subsequent use.
(2) preparation of amlodipine micropill
(1) polyvidone is dissolved in suitable quantity of water and makes solution, is prepared into the polyvidone aqueous solution of 5%, for subsequent use.
(2) Amlodipine Besylate Tablet 13.870g, starch 100g, mix homogeneously, with the polyvidone aqueous solution soft material with 5%, make soft material micropill mechanism ball, the crushed 0.4mm sieve aperture of wet feed, strip wet grain cut off round as a ball, 60 DEG C of drying and mouldings, for subsequent use.
(3) be prepared into containing 8% aqueous dispersion liquid solution by 5.347g Opadry, in fluid bed, carry out sealing coat coating to the core ball containing amlodipine, coating weight gain is 3-5%.Finally make amlodipine micropill, screening 20 ~ 80 object micropills, for subsequent use.
(3) total mixed, tabletting
Telmisartan granules and amlodipine granule and additional magnesium stearate 2.0g are always mixed, tabletting, makes 1000 telmisartan amlodipine tablets.
The adjuvant of embodiment 5 telmisartan amlodipine tablets and prescription screening
1, the screening of telmisartan granules adjuvant
Telmisartan sodium is mixed according to following ratio with sodium hydroxide, microcrystalline Cellulose (MCC), polyvidone (PVP-K30), meglumine, sorbitol, lactose, starch and mannitol respectively:
Telmisartan: adjuvant=1:5;
Telmisartan is mixed according to following ratio with Opadry, magnesium stearate:
Telmisartan: adjuvant=20:1;
Take telmisartan as contrast, by the fine powder mixed above, respectively under the condition of light (5000Lx), heat 60 DEG C and wet RH92.5%, place 10 days.After 10 days, sampling.Measure content respectively, and the telmisartan sodium simultaneously placed with similarity condition compares.Concrete data see the following form one and two.
The stability of table one telmisartan raw material
| Condition | Illumination | High temperature | High humidity |
| Content (%) | 98.7 | 102.4 | 99.0 |
In table two telmisartan granules, different auxiliary material is to the study on the stability of telmisartan
Above data illustrate, the adjuvants such as telmisartan sodium and sodium hydroxide, microcrystalline Cellulose (MCC), polyvidone (PVP-K30), meglumine, sorbitol, lactose, starch, Opadry, mannitol and magnesium stearate all have the good compatibility.
2, Amlodipine Besylate Tablet micropill adjuvant screening test
Amlodipine Besylate Tablet is mixed according to following ratio with microcrystalline Cellulose (MCC), polyvidone (PVP-K30), sorbitol, lactose, starch and mannitol respectively:
Amlodipine Besylate Tablet: adjuvant=1:5;
Amlodipine Besylate Tablet is mixed according to following ratio with Opadry, acrylic resin, magnesium stearate respectively:
Amlodipine Besylate Tablet: adjuvant=20:1;
With crude drug Amlodipine Besylate Tablet for contrast, the fine powder mixed above is mixed homogeneously with Amlodipine Besylate Tablet, respectively under the condition of light (5000Lx), heat 60 DEG C and wet RH92.5%, place 10 days.Sample after 10 days, measure content respectively, and the Amlodipine Besylate Tablet simultaneously placed with similarity condition compares.Concrete data see the following form three and table four.
The stability of table three Amlodipine Besylate Tablet raw material
| Condition | Illumination | High temperature | High humidity |
| Content (%) | 99.4 | 102.0 | 101.1 |
Table four Amlodipine Besylate Tablet micropill different auxiliary material is to the stability influence of amlodipine
| Content (%) | MCC | PVP-K30 | Sorbitol | Lactose | Starch | Mannitol | Acrylic resin | Opadry | Magnesium stearate |
| Illumination | 98.4 | 102.8 | 100.8 | 99.5 | 98.8 | 101.0 | 100.7 | 100.1 | 101.7 |
| 60℃ | 101.4 | 100.6 | 101.2 | 102.3 | 100.0 | 98.2 | 99.9 | 98.9 | 99.8 |
| 92.50% | 100.5 | 99.3 | 99.0 | 100.8 | 101.2 | 99.7 | 101.4 | 99.4 | 100.2 |
Above data illustrate, the adjuvants such as Amlodipine Besylate Tablet and microcrystalline Cellulose, polyvidone, sorbitol, lactose, starch and mannitol, acrylic resin, Opadry and magnesium stearate have the good compatibility.
3, prescription screening test:
According to the compatibility experiments data of above principal agent and adjuvant, carried out following prescription screening test, concrete data see the following form five:
(1) telmisartan amlodipine besylate tablets prescription screening (unit: mg/ sheet)
Table five telmisartan amlodipine besylate tablets prescription screening
| Prescription | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| Telmisartan | 40 | 40 | 40 | 40 | 80 | 80 | 80 | 80 |
| Sodium hydroxide | 3.36 | 3.36 | 3.36 | 3.36 | 6.720 | 6.720 | 6.720 | 6.720 |
| Polyvidone | 12 | 12 | 12 | 12 | 24.0 | 24.0 | 24.0 | 24.0 |
| Meglumine | 12 | 12 | 12 | 12 | 24.0 | 24.0 | 24.0 | 24.0 |
| Sorbitol | 168.64 | 168.64 | 168.64 | 168.64 | 337.28 | 337.28 | 337.28 | 337.28 |
| Amlodipine Besylate Tablet | 6.935 | 6.935 | 6.935 | 6.935 | 13.870 | 13.870 | 13.870 | 13.870 |
| Microcrystalline Cellulose | 0 | 100 | 50 | 50 | 50 | 50 | 100 | 0 |
| Starch | 100 | 0 | 50 | 50 | 50 | 50 | 0 | 100 |
| Polyvidone k30 aqueous solution | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount |
| Opadry | 0 | 5.347 | 0 | 5.347 | 5.347 | 0 | 5.347 | 0 |
| Acrylic resin | 5.347 | 0 | 5.347 | 0 | 0 | 5.347 | 0 | 5.347 |
| Magnesium stearate | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount |
(2) study on the stability of the alternative prescription of telmisartan amlodipine tablets
Influence factor's test of illumination (4500 ± 500Lx), high temperature (60 DEG C) and high humidity (relative humidity 92.5%) is carried out according to " medicine stability test guideline " in Chinese Pharmacopoeia.The indexs such as its character, dissolution, related substance and content are measured respectively at the 0th, 10 day.
The sample of alternative prescription is placed 10 days character and all significant change is not occurred under illumination (4500 ± 500Lx) condition, be still white or off-white color, all surface is roughening to place 10 days under high humidity (92.5%) condition, moisture absorption weightening finish is up to 21.4%, placing 10 days character under high temperature (60 DEG C) condition and significant change does not occur, is still white.The sample of alternative prescription is placed 10 days dissolutions and is had no significant change under the condition of illumination (4500 ± 500Lx), high temperature (60 DEG C) and high humidity (relative humidity 92.5%).The sample of alternative prescription is placed 10 days related substances and is had no significant change under the condition of illumination (4500 ± 500Lx), high humidity (relative humidity 92.5%).And the related substance placing 10 days amlodipines under all alternative prescription high temperature (60 DEG C) conditions all slightly changes.The sample of alternative prescription is placed 10 days content and is had no significant change under the condition of illumination (4500 ± 500Lx), high temperature (60 DEG C) and high humidity (relative humidity 92.5%).
Shown by the study on the stability test of alternative prescription, the Formulation of this product is reasonable, well can ensure the quality of medicine.The easy moisture absorption of this product is reminded in the simultaneously study on the stability test of alternative prescription, and more responsive to temperature, therefore humidity resistance is packed well, resolves moistureproof problem, when preserving, controlling temperature well, just can control the quality of this product.
The study on the stability result of the test of the alternative prescription one of table six
The study on the stability result of the test of the alternative prescription two of table seven
The study on the stability result of the test of the alternative prescription three of table eight
The study on the stability result of the test of the alternative prescription four of table nine
The study on the stability result of the test of the alternative prescription five of table ten
The study on the stability result of the test of the alternative prescription six of table ten one
The study on the stability result of the test of the alternative prescription seven of table ten two
The study on the stability result of the test of the alternative prescription eight of table ten three
Below by way of concrete test example, beneficial effect of the present invention is described.
The contrast of test example 1 Tablets and existing tablet
According to the method obtained corresponding control sample respectively of embodiment 3 in patent CN101780078 embodiment 1 and CN102008469, carry out accelerated test (40 DEG C ± 2 DEG C, the RH75% ± 5%) contrast of 6 months with the sample of the alternative prescription 1 of this patent to investigate, concrete data are as following table.
The study on the stability result of the test of the prescription of the alternative prescription 1 of table ten four, patent (CN101780078) embodiment 1 and the prescription of patent (CN1020008469) embodiment 3
As can be seen from above-mentioned experimental result:
(1) accelerated test (40 DEG C ± 2 DEG C, RH75% ± 5%) the study on the stability result of 6 months of the alternative prescription 1 of the present invention is obviously better than patent (CN102008469) embodiment 3; Meanwhile, the present invention is without the need to doing special handling by alkaline reagent and telmisartan, more convenient to operate.
(2) accelerated test (40 DEG C ± 2 DEG C, RH75% ± 5%) the study on the stability result of 6 months of the alternative prescription 1 of the present invention is better than patent (CN101780078) embodiment 1; Meanwhile, the present invention only prepares a kind of micropill, and operation is more easy, and cost is lower, and actual application value is far above the tablet in CN101780078.
In sum, telmisartan amlodipine tablets of the present invention, passes through specific preparation process by telmisartan and amlodipine, the stability of telmisartan amlodipine tablets is significantly improved, has ensured Drug safety; Meanwhile, invention formulation technique is simpler, and cost is lower, is more conducive to the popularization of product.
Claims (5)
1. a telmisartan amlodipine tablets, is characterized in that: it first independently prepares telmisartan granules and Amlodipine Besylate Tablet micropill, then by preparation that both mixed pressuring plates are prepared from; Coatings is provided with outside described Amlodipine Besylate Tablet micropill;
Telmisartan granules is prepared from by telmisartan 40-80 part, sodium hydroxide 3-7 part, meglumine 12-24 part, polyvidone 12-24 part, sorbitol 160-340 part;
Amlodipine Besylate Tablet micropill is by Amlodipine Besylate Tablet 6-14 part, microcrystalline Cellulose 0-100 part, starch 0-100 part, Opadry 0-6 part, acrylic resin 0-6 part, being 0 when wherein microcrystalline Cellulose is different with starch, is 0 when Opadry is different from acrylic resin.
2. telmisartan amlodipine tablets according to claim 1, is characterized in that: polyvidone model is K30.
3. the preparation method of telmisartan amlodipine tablets according to claim 1, is characterized in that: it comprises following operating procedure:
(1) preparation of telmisartan granules
After alkaline reagent, stabilizing agent, telmisartan, solubilizing agent mixing, dry, then add diluent, granulate, granule is for subsequent use;
(2) preparation of Amlodipine Besylate Tablet micropill
Get Amlodipine Besylate Tablet, diluent prepares amlodipine ball core, add coating materials coating, gained coated micropill is for subsequent use;
(3) tabletting
Get telmisartan granules, Amlodipine Besylate Tablet micropill, then add moderate lubrication agent, after mixing, tabletting;
In telmisartan granules, described alkaline reagent is sodium hydroxide; Described stabilizing agent is meglumine; Described solubilizing agent is polyvidone; Described diluent is sorbitol; In amlodipine micropill, described diluent is that microcrystalline Cellulose is or/and starch; Described coating materials is that Opadry is or/and acrylic resin.
4. preparation method according to claim 3, is characterized in that: it comprises following operating procedure:
(1) preparation of telmisartan granules
In 30 ~ 60 DEG C of water-baths, sodium hydroxide, telmisartan, polyvidone, meglumine are dissolved in order in water, mixing is until clarification, and obtained alkaline solution, by alkaline solution drying, obtains dry fine powder, then mix homogeneously with sorbitol, granulate, for subsequent use;
(2) preparation of Amlodipine Besylate Tablet micropill
Get Amlodipine Besylate Tablet, after mixing with diluent starch or microcrystalline Cellulose, prepare amlodipine
Ball core; Get coating materials, coating is carried out to ball core, gained coated micropill, for subsequent use;
(3) tabletting
Get telmisartan granules, amlodipine micropill, add lubricant, mixing, tabletting.
5. the purposes of telmisartan amlodipine tablets according to claim 1 in the hypertensive medicine of preparation treatment.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310076765.9A CN103127108B (en) | 2012-03-12 | 2013-03-11 | Telmisartan amlodipine tablet, and preparation method and use thereof |
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| CN201210063595.6 | 2012-03-12 | ||
| CN201210063595 | 2012-03-12 | ||
| CN201310076765.9A CN103127108B (en) | 2012-03-12 | 2013-03-11 | Telmisartan amlodipine tablet, and preparation method and use thereof |
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| CN103127108B true CN103127108B (en) | 2015-01-21 |
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| CN 201320109098 Expired - Lifetime CN203123076U (en) | 2012-03-12 | 2013-03-11 | Telmisartan/amlodipine tablet |
| CN201310076765.9A Active CN103127108B (en) | 2012-03-12 | 2013-03-11 | Telmisartan amlodipine tablet, and preparation method and use thereof |
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| KR102406616B1 (en) * | 2019-12-19 | 2022-06-10 | 대원제약주식회사 | A pharmaceutical composition comprising angiotensin receptor blocker and preparation method thereof |
| CN115025057B (en) * | 2022-07-20 | 2023-05-30 | 江苏亚邦爱普森药业有限公司 | Amlodipine besylate folic acid tablet and preparation method thereof |
| CN115944600B (en) * | 2022-12-01 | 2024-05-28 | 山东齐都药业有限公司 | Oral tablet containing telmisartan and amlodipine besylate and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101780078A (en) * | 2010-02-10 | 2010-07-21 | 威特(湖南)药业有限公司 | Compound preparation of telmisartan and amlodipine and preparation method thereof |
| CN102008469A (en) * | 2010-11-16 | 2011-04-13 | 武汉武药科技有限公司 | Method for preparing telmisartan amlodipine tablets |
| CN102028670A (en) * | 2010-09-06 | 2011-04-27 | 邓俐丽 | Composite capsule containing telmisartan and calcium ion channel antagonist |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ES2452019T5 (en) * | 2004-11-05 | 2021-06-28 | Boehringer Ingelheim Int | Bilayer tablet comprising telmisartan and amlodipine |
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2013
- 2013-03-11 CN CN 201320109098 patent/CN203123076U/en not_active Expired - Lifetime
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101780078A (en) * | 2010-02-10 | 2010-07-21 | 威特(湖南)药业有限公司 | Compound preparation of telmisartan and amlodipine and preparation method thereof |
| CN102028670A (en) * | 2010-09-06 | 2011-04-27 | 邓俐丽 | Composite capsule containing telmisartan and calcium ion channel antagonist |
| CN102008469A (en) * | 2010-11-16 | 2011-04-13 | 武汉武药科技有限公司 | Method for preparing telmisartan amlodipine tablets |
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| CN203123076U (en) | 2013-08-14 |
| CN103127108A (en) | 2013-06-05 |
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