CN101057837A - Dextro-ketoprofen enteric coated preparation and its preparation method - Google Patents
Dextro-ketoprofen enteric coated preparation and its preparation method Download PDFInfo
- Publication number
- CN101057837A CN101057837A CN 200610031522 CN200610031522A CN101057837A CN 101057837 A CN101057837 A CN 101057837A CN 200610031522 CN200610031522 CN 200610031522 CN 200610031522 A CN200610031522 A CN 200610031522A CN 101057837 A CN101057837 A CN 101057837A
- Authority
- CN
- China
- Prior art keywords
- micropill
- dexketoprofen
- ketoprofen
- dextro
- enteric
- 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.)
- Granted
Links
- 229960000991 ketoprofen Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims description 32
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 36
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 36
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 36
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229960002783 dexketoprofen Drugs 0.000 claims description 49
- DKYWVDODHFEZIM-NSHDSACASA-N dexketoprofen Chemical compound OC(=O)[C@@H](C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-NSHDSACASA-N 0.000 claims description 49
- 235000010603 pastilles Nutrition 0.000 claims description 46
- 238000007789 sealing Methods 0.000 claims description 37
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 34
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 34
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 34
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 24
- 239000012055 enteric layer Substances 0.000 claims description 19
- 229920002472 Starch Polymers 0.000 claims description 17
- 229930006000 Sucrose Natural products 0.000 claims description 17
- 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 17
- 239000008107 starch Substances 0.000 claims description 17
- 239000005720 sucrose Substances 0.000 claims description 17
- 235000019698 starch Nutrition 0.000 claims description 16
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 15
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 15
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 15
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound 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 12
- 239000006185 dispersion Substances 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 9
- 229960003943 hypromellose Drugs 0.000 claims description 9
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 9
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 9
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000001069 triethyl citrate Substances 0.000 claims description 8
- 235000013769 triethyl citrate Nutrition 0.000 claims description 8
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 8
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 6
- 229920000053 polysorbate 80 Polymers 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 5
- -1 phthalic acid ester Chemical class 0.000 claims description 5
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000011347 resin Substances 0.000 claims description 4
- 229920005989 resin Polymers 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 2
- 229930064664 L-arginine Natural products 0.000 claims description 2
- 235000014852 L-arginine Nutrition 0.000 claims description 2
- RZAPELUKMZWLLG-UHFFFAOYSA-N acetic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O RZAPELUKMZWLLG-UHFFFAOYSA-N 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 2
- 229920001610 polycaprolactone Polymers 0.000 claims description 2
- 239000004632 polycaprolactone Substances 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 239000001828 Gelatine Substances 0.000 claims 1
- 229920000159 gelatin Polymers 0.000 claims 1
- 235000019322 gelatine Nutrition 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 21
- 238000000034 method Methods 0.000 abstract description 9
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 abstract description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 4
- 238000007493 shaping process Methods 0.000 abstract 3
- 239000006187 pill Substances 0.000 abstract 2
- 230000000638 stimulation Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 238000012216 screening Methods 0.000 description 17
- 238000003756 stirring Methods 0.000 description 12
- 239000000463 material Substances 0.000 description 11
- 238000000576 coating method Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 239000011230 binding agent Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000002702 enteric coating Substances 0.000 description 7
- 238000009505 enteric coating Methods 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 239000008188 pellet Substances 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- 229960004756 ethanol Drugs 0.000 description 4
- 239000010408 film Substances 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 208000006820 Arthralgia Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 206010061297 Mucosal erosion Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 206010053692 Wound complication Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000011229 interlayer Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 208000024765 knee pain Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides an enteric soluble micro-pill agent of clockwise ketoprofen and the preparing method, comprising medicine-containing micro-pill composed of clockwise ketoprofen and one or more than one kind of medical shaping agent, insulating layer composed of hydroxypropylmethylcellulose and other medical shaping agent, and enteric soluble layer made by one or more than one kind of medical shaping agent. The product is characterized by even medicine release, high biological utilization rate and small stimulation to gastrointestinal tract.
Description
Technical field
The invention belongs to the Western medicine invention field, relate to good enteric coated preparation of a kind of 2-aryl propionic non-steroid antiphlogistic chipal compounds dexketoprofen and preparation method thereof.
Background technology
Dexketoprofen is the active dextroisomer of ketoprofen, by the exploitation of Italian Menarini company, went on the market in Spain first in 1996, has good antiinflammatory, analgesic and analgesic effect, and effect is better than aspirin, Phenylbutazone or acetaminophen etc., be widely used in the treatment of chronic rheumatoid arthritis, osteoarthrisis deformans knee, wound and postoperative pain at present, enjoy various countries clinician and patient's favor because of its good curative effect.
Yet the shortcoming of NSAID (non-steroidal anti-inflammatory drug) maximum is gastrointestinal tract toxic and side effects such as damage stomach and duodenum.Compare with the racemization ketoprofen, though dexketoprofen dosage on identical drug effect level is littler, less adverse effect, clinical practice is wider, but still does not break away from some shortcomings similar to ketoprofen, as is insoluble in water, absorbs relatively poorly, and gastrointestinal toxicity is bigger etc.Especially damage stomach and duodenum, high 5 times (its reason mainly is suppressed the gastrointestinal wall prostaglandin synthetic to the hemorrhage rate of user's upper gastro-intestinal tract than user not, the physicochemical characteristics of medicine can cause aggravating toxicity etc. in the drug accumulation of coat of the stomach), so influence its potential applicability in clinical practice.The preparation of using clinically mostly is common enteric coated tablet or capsule at present, has limited dexketoprofen and has brought into play quick refrigeration function, also can not fundamentally address the above problem.The dextro-ketoprofen enteric coated above-mentioned deficiency that overcome involved in the present invention both can reduce GI irritation, had controlled release and targeted therapy effect again, was a kind of novel good enteric coated preparation of dexketoprofen.
Summary of the invention
It is even that purpose of the present invention aims to provide a kind of release, and the bioavailability height is to little dextro-ketoprofen enteric coated of GI irritation, to solve the problems such as gastrointestinal tract toxic and side effects of dexketoprofen.
Another object of the present invention aims to provide a kind of preparation method of good enteric coated preparation of dexketoprofen.
The objective of the invention is to realize by following manner:
Enteric coated micropill of the present invention comprises the pastille micropill be made up of dexketoprofen and one or more pharmaceutically useful excipient, the sealing coat of being made up of hydroxypropyl methylcellulose and other pharmaceutically useful excipient and the enteric layer of being made up of one or more pharmaceutically useful excipient.
Described pastille micropill also can be made by celphere and dexketoprofen and one or more pharmaceutically acceptable excipient of being deposited on this celphere.
The excipient that the pastille micropill is adopted is one or more in hydroxypropyl methylcellulose, sodium lauryl sulphate, carboxymethyl starch sodium, polyvidone, microcrystalline Cellulose, starch, L-arginine, polycaprolactone, carboxymethyl cellulose phthalic acid ester, plant gum, wax, nonreducing sugar such as the sucrose; Described sealing coat contains one or more in Pulvis Talci, magnesium stearate, crosslinked ketopyrrolidine, hydroxypropyl methylcellulose, sodium lauryl sulphate, non-reducing sugar such as the sucrose; Enteric layer contain in the pharmaceutically acceptable excipient of promising crylic acid resin such as methacrylic acid copolymer aqueous dispersion, Pulvis Talci, citric acid triacetic acid, tween 80, the sodium lauryl sulphate one or more.
Contain the 2.5-30mg dexketoprofen in the enteric coated pellets formulation of the present invention.
It is preferable to contain the 5-20mg dexketoprofen in the enteric coated pellets formulation of the present invention.
The present invention is dextro-ketoprofen enteric coated, and it is good containing following composition:
The pastille micropill
Celphere 70-90mg
Dexketoprofen 12.5mg
Microcrystalline Cellulose 15-30mg
Hydroxypropyl methylcellulose 5-12mg
The sodium lauryl sulphate trace
Sealing coat
Pastille micropill 102.5-152.5mg
The sodium lauryl sulphate trace
Hypromellose 8-20mg
Sucrose 5-15mg
Enteric layer
Sealing coat micropill 115.5-187.5mg
Methacrylic acid copolymer aqueous dispersion 180-250mg
Pulvis Talci 8-18mg
Triethyl citrate 4-9mg
Crosslinked ketopyrrolidine 15-30mg
Sodium lauryl sulphate 4-10mg.
Described celphere contains following composition:
Starch 30-45mg
Microcrystalline Cellulose 30-45mg
Sucrose 10-25mg
Micropill of the present invention contains following composition for best:
The pastille micropill
Celphere 75-80mg
Dexketoprofen 12.5mg
Microcrystalline Cellulose 15-25mg
Hydroxypropyl methylcellulose 5-10mg
The sodium lauryl sulphate trace
Sealing coat
Pastille micropill 112-134mg
The sodium lauryl sulphate trace
Hypromellose 10-15mg
Sucrose 8-12mg
Enteric layer
Sealing coat micropill 130-160mg
Methacrylic acid copolymer aqueous dispersion 200-225mg
Pulvis Talci 10-15mg
Triethyl citrate 5-8mg
Crosslinked ketopyrrolidine 20-25mg
Sodium lauryl sulphate 4-8mg.
The preparation method of micropill of the present invention is: A, provide the pastille micropill of being made up of dexketoprofen and one or more pharmaceutically useful excipient; B, on the pastille micropill, apply the sealing coat that one deck contains one or more pharmaceutically acceptable excipient; D, on sealing coat, apply the enteric layer that one deck contains hydroxypropyl methylcellulose and one or more pharmaceutically acceptable excipient.
The untoward reaction of dexketoprofen is an injury of gastrointestinal tract, and hemorrhage as dyspepsia, mucosal erosion, gastric and duodenal ulcers, severe patient can cause perforation etc.This is the modal untoward reaction of non-steroidal antibiotic.The present invention is after carrying out scrutiny by the preparation process to dexketoprofen, adopt advanced preparation process that dexketoprofen is prepared into enteric coated micropill, then above-mentioned enteric coated micropill is filled in the common enteric coated capsule and is prepared from, can avoid like this occurring causing the phenomenon that local drug concentration is too high when common enteric dosage form discharges in intestinal, will have significant clinical superiority.But said preparation is to the manufacturing technique requirent height, and this medicine is not changed when the stomach by the patient, and can dissolve rapidly and release of active ingredients when it leaves stomach and enters small intestinal.Active component wherein is in the inside of micropill and wraps in thin film or tunicle promptly in " enteric coating ".Described enteric coating is insoluble in sour environment such as stomach, and is soluble in nearly neutral environment such as small intestinal.
Enteric coated pellets formulation involved in the present invention has been concentrated the advantage of pellet preparations, two kinds of dosage forms of enteric coated preparation, thereby makes the medicine release even, and the bioavailability height is little to GI irritation.
The specific embodiment
The various compositions and the layer of micropill below will be discussed respectively, and the concrete simultaneously various compositions of interpolation of introducing progressively make up dextro-ketoprofen enteric coated method.
Pastille micropill among the present invention can directly be prepared from by dexketoprofen and one or more pharmaceutically useful excipient.Also another kind of mode be can adopt, dexketoprofen and excipient on celphere, applied.
Preferred pastille micropill is coated on the celphere by the interlayer that will contain dexketoprofen and is prepared.Described celphere is that pharmaceutical field can be bought or make by oneself.The most preferred celphere of the present invention be the starch that is used for drug manufacture, microcrystalline Cellulose and hydroxypropyl methylcellulose preparation and the ball core.Yet, the hollow ball core that also can use any pharmaceutically acceptable excipient to make, described excipient comprises for example sucrose, wax, plant gum etc.Be primarily characterized in that be inert for the patient of other excipient in dexketoprofen and the micropill and this micropill that will take.
The size of pastille micropill depends on the required size of micropill to be produced.Usually, micropill can be as small as 0.1mm or greatly to 2mm.Preferred nuclear core is 0.2mm to 1.0mm, so as finally to obtain required preferred size, diameter is the micropill of about 0.5-1.5mm.
The amount of used pastille micropill depends on the weight and the thickness of the interpolation layer beyond the pastille micropill, and usually, the pastille micropill accounts for the 10-70% of product.More preferably the pastille micropill accounts for about 15-45% of product.
The preparation process of enteric coated micropill involved in the present invention comprises the preparation of dexketoprofen pastille micropill, sealing coat coated micropill and enteric coated micropill.Step is as follows: the preparation of A, dexketoprofen pastille micropill: with the celphere is carrier, and proper auxiliary materials such as sodium lauryl sulphate are dissolved in the suitable quantity of water, and the adding dexketoprofen stirs to make and is uniformly dispersed, and adds an amount of dehydrated alcohol, stirs; Hydroxypropyl methylcellulose is disperseed with an amount of ethanol, be prepared into solution or suspension with certain bonding force, even spraying is coated in hollow ball core outside, makes that micropill increases under the state of rotation that rolls, drying, forms the pastille micropill.B, the preparation of dexketoprofen sealing coat micropill: hydroxypropyl methylcellulose, sodium lauryl sulphate etc. is mixed with coating solution, pastille nuclear core is carried out isolation coat.C, dextro-ketoprofen enteric coated preparation: Pulvis Talci, triethyl citrate, tween 80 etc. are mixed with enteric coating liquid, will wrap the sealing coat micropill and carry out enteric coating.
Is " powder coating method " with dexketoprofen to the method that makes things convenient for that celphere carries out coating, in the method, celphere with thick liquid or binding agent moistening, is made the medicine slurry with the dexketoprofen powder of crushing screening and sparged on the celphere, then with the mixture drying.This method is used in the industrialization drug manufacture usually, and suitable device is a usual means.All used this device in many steps of the inventive method, also available fluidized bed plant or rotating plate device prepare product of the present invention.
The preparation of dexketoprofen pastille micropill also can be as follows: proper auxiliary materials such as sodium lauryl sulphate, microcrystalline Cellulose, starch etc. are dissolved in the suitable quantity of water, add dexketoprofen and stir to make and be uniformly dispersed, add an amount of dehydrated alcohol, stir; Hydroxypropyl methylcellulose is disperseed with an amount of ethanol, be prepared into solution or suspension with certain bonding force, granulate, sieve, the granule of getting between the 50-60 order is a parent nucleus, rest materials is suspended in the binding agent, even spraying is coated in parent nucleus outside, makes that micropill increases under the state of rotation that rolls, drying, forms the pastille micropill.
Among the present invention various excipient determine it all is that the inventor passes through repeatedly to test, update and the principal agent dexketoprofen suitable of the present invention that obtains, can better prepare the proper auxiliary materials of micropill of the present invention.The inventor also further obtains being fit to best proportioning of the present invention by following experiment.Below done experiment, so that determine corresponding auxiliary material of the present invention better by the inventor.
Because roundness, the friability of celphere directly influence drug of topical application effect, thereby influence the content and the quality of pastille micropill, so select suitable blank core ball material extremely important.The inventor considers the microcrystalline Cellulose stable in properties, and good moldability and chance water have expansion, do not influence the release of medicine; Starch has certain mouldability, has certain disintegrate effect concurrently; Sucrose has hygroscopicity to be easy to into granule.Therefore, the inventor drafts from these three kinds of adjuvants the material of screening preparation celphere by experiment, as binding agent, and screens preferable solvent and concentration thereof simultaneously with the fine little element of hydroxypropyl methyl.
The celphere prescription screening
Draft the screening prescription, see Table 1.
The screening prescription of table 1 celphere
Through the above result of analysis-by-synthesis, prescription three is more excellent.
After making the celphere preparation, be that other composition of pastille micropill is determined with that.The inventor considers that with the fine little element of hydroxypropyl methyl be binding agent, and screens its concentration by experiment; The disintegrate of medicine and release for the benefit of, we add the microcrystalline Cellulose with disintegration in medicated layer, add an amount of sodium lauryl sulphate to increase the lubricity of medicine slurry, produce static when preventing to produce, and help the release of medicine.Screen medicine by experiment and starch the consumption of each component,, purpose ball yield whether bright and clean with balling-up, hardness, the surface of pastille micropill, result of extraction are index, determine the best composition and the ratio of medicine slurry.
The prescription screening of pastille micropill medicinal liquid
Draft the screening prescription, see Table 2:
The screening prescription of table 2 pastille micropill medicinal liquid
Behind the analysis-by-synthesis, found that prescription four is more excellent, and by experiment it is verified.
The inventor determines to have carried out further exploratory development to the prescription of sealing coat.
Because the dexketoprofen raw material is stable under alkali condition among the present invention, extremely unstable under acid condition, so consider bag sealing coat earlier, wrap enteric layer again.The sealing coat of this product adopts film property hydroxypropyl emthylcellulose preferably, sealing coat weightening finish 5%, and the inventor also further screens its suitable concentration by experiment.Phenomenon, film property, yield, dissolution with the coating process of micropill are index, determine the preferred plan of sealing coat.
The screening of sealing coat coating fluid prescription
Draft the screening prescription and see Table 3:
Table 3 sealing coat coating fluid prescription screening table
| Sucrose | 40 | 60 | 25 |
Comprehensive analysis results is found the prescription three micropill sealing coat best results of wrapping, and yield reaches 98%.
Be that the inventor explores enteric layer prescription screening and research at last.
Concrete condition according to the coating process is improved, with the material state of micropill coating process, film property, 2 hours releases, yields are that index is screened in the phosphate buffer of 1 hour and pH value 6.8 in hydrochloric acid solution (9 → 1000) 900ml, to determine best prescription and technology.
The prescription screening of enteric coating liquid sees Table 4.
The prescription screening table of table 4 enteric coating liquid
5.4 enteric liquid prescription screening the results are shown in Table 5:
Table 5 enteric liquid prescription screening result
| The cumulative release degree | 95.2 | 98.7 | 93.1 |
| Yield (%) | 94.0 | 95.1 | 92.2 |
The above result of analysis-by-synthesis, gained enteric coated-pellet film property, material whitewashing state is all fine.Take the release of three prescription gained micropills in sour neutralization buffer into consideration, for guaranteeing the quality of the pharmaceutical preparations, the inventor selects to adopt prescription two to be the prescription of this preparation enteric coating coating solution, enteric layer weightening finish 35%.And by experiment it is verified that yield reaches 95.1%, and gained micropill release in acid is 0.73%, and release is 97.4% in buffer, and the accumulation dissolution is 98.7%, and is effective, reached Expected Results.
Embodiment 1:
12.5mg dextro-ketoprofen enteric coated capsule
Stock chart
The pastille micropill
Celphere 90mg (30-40 order)
Dexketoprofen 12.5mg
The sodium lauryl sulphate trace
Hydroxypropyl methylcellulose 7.5mg
Microcrystalline Cellulose 20mg
Sealing coat
Pastille micropill 130mg
The sodium lauryl sulphate trace
Hypromellose 12mg
Sucrose 10mg
Enteric layer
Sealing coat micropill 152mg
Methacrylic acid copolymer aqueous dispersion 245mg
Pulvis Talci 12mg
Triethyl citrate 6mg
Sodium lauryl sulphate 6mg
Take by weighing hydroxypropyl methylcellulose and add absolute ethyl alcohol and stirring and make and be uniformly dispersed, add purified water and make it abundant swelling, sieve, as binding agent.The microcrystalline Cellulose pulverizing is sieved, take by weighing starch and its mix homogeneously, granulate, sieve, the granule of getting between the 50-60 order is a parent nucleus, and rest materials is suspended in the binding agent, crosses 80 mesh sieves, is sprayed on the parent nucleus, and oven dry is sieved, and is the purpose ball with 30-40 order ball core.
Sodium lauryl sulphate is dissolved in the suitable quantity of water, and the dexketoprofen that adds crushing screening stirs to make and is uniformly dispersed, and adds an amount of dehydrated alcohol, stirs; In addition hypromellose is disperseed with an amount of ethanol, add microcrystalline Cellulose and be uniformly dispersed; Above-mentioned two solution stirring are made into the homogeneous system, sieve and make the medicine slurry.Medicine slurry with the suspension sample that obtains is coated on the hollow micropill of microcrystalline Cellulose-starch then.After having applied the dexketoprofen suspension of aequum, with pastille micropill drying.
Sodium lauryl sulphate is dissolved in the suitable quantity of water, its aqueous solution is joined in the alcohol dispersion liquid of hydroxypropyl methylcellulose, stirring makes the hydroxypropyl methylcellulose complete swelling to even,
Pulvis Talci, triethyl citrate, sodium lauryl sulphate are added homogenate in the pure water successively, suspension after the homogenate is added in the methacrylic acid copolymer aqueous dispersion, stirring makes into uniform suspension, sieve, form with aqueous suspension is coated to enteric layer on the micropill of sealing coat then, behind the suspension that has applied aequum, with the micropill finish-drying.Promptly get enteric coated micropill.
Analyze the content of dexketoprofen in the gained micropill, and fill it in the capsulae vacuus to obtain containing the enteric-coated pellet capsule of 12.5mg dexketoprofen.
Embodiment 2:
12.5mg dextro-ketoprofen enteric coated capsule
Stock chart
The pastille micropill
Sucrose 90mg
Hydroxypropyl methylcellulose 25mg
Dexketoprofen 12.5mg
The sodium lauryl sulphate trace
Carboxymethyl starch sodium 25mg
Sealing coat
Pastille micropill 152.5mg
Hypromellose 20mg
Magnesium stearate 24mg
The sodium lauryl sulphate trace
Enteric layer
Sealing coat micropill 196.5mg
No. 2 resin 30mg
Pulvis Talci 20mg
Tween 80 0.08ml
Sucrose, carboxymethyl starch sodium etc. is dissolved in the suitable quantity of water, and the adding dexketoprofen stirs to make and is uniformly dispersed, and adds an amount of dehydrated alcohol, stirs; Hydroxypropyl methylcellulose is disperseed with an amount of ethanol, be prepared into solution or suspension with certain bonding force, granulate, sieve, the granule of getting between the 50-60 order is a parent nucleus, rest materials is suspended in the binding agent, even spraying is coated in parent nucleus outside, makes that micropill increases under the state of rotation that rolls, drying, forms the pastille micropill.
It is described then to press the foregoing description 1, respectively sealing coat and enteric layer is applied up, is prepared into micropill.
Embodiment 3:
12.5mg dextro-ketoprofen enteric coated capsule
Stock chart
The pastille micropill
Celphere (sucrose 75mg, hydroxypropyl methylcellulose 10mg) 30-40 order
Dexketoprofen 12.5mg
The sodium lauryl sulphate trace
Hydroxypropyl methylcellulose 25mg
Sealing coat
Pastille micropill 122.5mg
Titanium dioxide 12mg
Hypromellose 20mg
Polyvidone 18mg
Enteric layer
Sealing coat micropill 172.5mg
Enteric resin 15mg
Triethyl citrate 6mg
Magnesium stearate 15mg
Embodiment 4
Celphere
Microcrystalline Cellulose 25mg
Starch 60mg
Hydroxypropyl methylcellulose 5mg
The pastille micropill
Celphere 85mg
Dexketoprofen 12.5mg
The sodium lauryl sulphate trace
Hydroxypropyl methylcellulose 10mg
Carboxymethyl starch sodium 30mg
Sealing coat
Pastille micropill 137.5mg
The sodium lauryl sulphate trace
Hypromellose 20mg
Enteric layer
Sealing coat micropill 157.5mg
Methacrylic acid copolymer aqueous dispersion 180mg
Pulvis Talci 15mg
Tween 80 0.05ml
Sodium lauryl sulphate 9g.
Other step is substantially with embodiment 1.
Embodiment 5
The pastille micropill
Sucrose 30mg
Starch 60mg
L-arginase 12 0mg
Dexketoprofen 12.5mg
The sodium lauryl sulphate trace
Hydroxypropyl methylcellulose 10mg
Sealing coat
Pastille micropill 132.5mg
The sodium lauryl sulphate trace
Hypromellose 25mg
Enteric layer
Sealing coat micropill 157.5mg
Methacrylic acid copolymer aqueous dispersion 250mg
Triethyl citrate 9mg
Tween 80 0.05ml
Sodium lauryl sulphate 9g.
Substantially can prepare this product by the foregoing description 1 method therefor.Gained micropill and capsule administration field method commonly used detects, and the equal quality of sample is stable.
Clinical and experimental study shows, micropill of the present invention and capsule not only have the characteristics of conventional enteric coated preparation, when also having the generic condition that micropill touches small intestinal, can discharge contained dexketoprofen rapidly equably, thereby solve the too high problem of local drug concentration that general enteric dosage form is run into.
Claims (10)
1, a kind of dextro-ketoprofen enteric coated, it is characterized in that it comprises the pastille micropill of being made up of dexketoprofen and one or more pharmaceutically useful excipient, sealing coat of forming by hydroxypropyl methylcellulose and other pharmaceutically acceptable excipient and the enteric layer of forming by one or more pharmaceutically useful excipient.
2, according to claim 1 dextro-ketoprofen enteric coated, it is characterized in that described pastille micropill can and be deposited on dexketoprofen on this celphere and one or more pharmaceutically acceptable excipient be made by celphere.
3, according to claim 1 dextro-ketoprofen enteric coated, it is characterized in that: the excipient that the pastille micropill is adopted is one or more in hydroxypropyl methylcellulose, sodium lauryl sulphate, carboxymethyl starch sodium, polyvidone, microcrystalline Cellulose, starch, L-arginine, polycaprolactone, carboxymethyl cellulose phthalic acid ester, plant gum, wax, nonreducing sugar such as the sucrose; Described sealing coat contains one or more in Pulvis Talci, magnesium stearate, crosslinked ketopyrrolidine, hydroxypropyl methylcellulose, sodium lauryl sulphate, non-reducing sugar such as the sucrose; Enteric layer contain in the pharmaceutically acceptable excipient of promising crylic acid resin such as methacrylic acid copolymer aqueous dispersion, Pulvis Talci, citric acid triacetic acid, tween 80, the sodium lauryl sulphate one or more.
4, a kind of preparation that contains any described enteric dexketoprofen micropill among a large amount of claim 1-3.
5, dextro-ketoprofen enteric coated preparation according to claim 4 is characterized in that containing the 2.5-30mg dexketoprofen.
6, dextro-ketoprofen enteric coated preparation according to claim 4 is characterized in that containing the 5-20mg dexketoprofen.
7, dextro-ketoprofen enteric coated preparation according to claim 4 is characterized in that containing following composition:
The pastille micropill
Celphere, 30-35 order 70-90mg
Dexketoprofen 12.5mg
Microcrystalline Cellulose 12-30mg
Hydroxypropyl methylcellulose 5-12mg
The sodium lauryl sulphate trace
Sealing coat
Pastille micropill 102.5-152.5mg
The sodium lauryl sulphate trace
Hypromellose 8-20mg
Sucrose 5-15mg
Enteric layer
Sealing coat micropill 115.5-187.5mg
Methacrylic acid copolymer aqueous dispersion 180-250mg
Pulvis Talci 8-18mg
Triethyl citrate 4-9mg
Crosslinked ketopyrrolidine 15-30mg
Sodium lauryl sulphate 4-10mg.
8, according to claim 7 dextro-ketoprofen enteric coated, it is characterized in that: described celphere contains following composition:
Starch 30-45mg
Microcrystalline Cellulose 30-45mg
Sucrose 10-25mg
9, a kind of gelatine capsule that contains the described preparation of claim 4.
10, the described dextro-ketoprofen enteric coated preparation method of claim 1 is characterized in that step is: A, provide the pastille micropill of being made up of dexketoprofen and one or more pharmaceutically useful excipient; B, on the pastille micropill, apply the sealing coat that one deck contains one or more pharmaceutically acceptable excipient; D, on sealing coat, apply the enteric layer that one deck contains hydroxypropyl methylcellulose and one or more other pharmaceutically acceptable excipient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100315223A CN101057837B (en) | 2006-04-20 | 2006-04-20 | Dextro-ketoprofen enteric coated preparation and its preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100315223A CN101057837B (en) | 2006-04-20 | 2006-04-20 | Dextro-ketoprofen enteric coated preparation and its preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101057837A true CN101057837A (en) | 2007-10-24 |
| CN101057837B CN101057837B (en) | 2010-12-22 |
Family
ID=38864242
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006100315223A Expired - Fee Related CN101057837B (en) | 2006-04-20 | 2006-04-20 | Dextro-ketoprofen enteric coated preparation and its preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101057837B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110917165A (en) * | 2019-12-26 | 2020-03-27 | 北京鑫开元医药科技有限公司海南分公司 | Ibuprofen orally disintegrating tablet and preparation method thereof |
| CN112641756A (en) * | 2020-12-29 | 2021-04-13 | 卓和药业集团有限公司 | Posaconazole enteric-coated pellet and preparation method thereof |
| CN116236463A (en) * | 2023-02-16 | 2023-06-09 | 山东省药学科学院 | Dexketoprofen sustained-release pellet capsule and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5910319A (en) * | 1997-05-29 | 1999-06-08 | Eli Lilly And Company | Fluoxetine enteric pellets and methods for their preparation and use |
| CN1260172A (en) * | 1998-12-18 | 2000-07-19 | 国家医药管理局上海医药工业研究院 | Dextro-betoprofen preparation |
| CN1321642C (en) * | 2003-12-12 | 2007-06-20 | 南京长澳医药科技有限公司 | Enteric-coated pantoprazole sodium minipill |
| CN100362996C (en) * | 2004-10-14 | 2008-01-23 | 上海医药工业研究院 | A kind of duloxetine enteric-coated pellet capsule and preparation method thereof |
-
2006
- 2006-04-20 CN CN2006100315223A patent/CN101057837B/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110917165A (en) * | 2019-12-26 | 2020-03-27 | 北京鑫开元医药科技有限公司海南分公司 | Ibuprofen orally disintegrating tablet and preparation method thereof |
| CN112641756A (en) * | 2020-12-29 | 2021-04-13 | 卓和药业集团有限公司 | Posaconazole enteric-coated pellet and preparation method thereof |
| CN116236463A (en) * | 2023-02-16 | 2023-06-09 | 山东省药学科学院 | Dexketoprofen sustained-release pellet capsule and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101057837B (en) | 2010-12-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1036763C (en) | Pharmaceutical composition pharmaceutical granulate and process for their preparation | |
| CN1223341C (en) | Spheroids, preparation method and pharmaceutical compositions | |
| CN1155370C (en) | Process for preparing medicinal granule | |
| CN1399543A (en) | Controlled release composition comprising nimesulide | |
| CN1089471A (en) | Stable prolongation release oral dosage composition | |
| CN1143317A (en) | oral excipient composition | |
| CN1228700A (en) | Tablet with controlled release of alfuzosine chlorydrate | |
| CN1250371A (en) | Pharmaceutical compositions for controlled release of active substances | |
| CN1134666A (en) | Multiple Unit Tablet I | |
| CN1277535C (en) | Ibuprofen containing active agent preparation | |
| CN1195986A (en) | Paroxetine controlled release compositions | |
| CN1883458A (en) | Enteric coated preparation of lansoprazole sodium and preparation method thereof | |
| CN1094756C (en) | Combined antipyretic analgesic drug | |
| CN1863518A (en) | Pharmaceutical composition containing fenofibrate and method for the preparation thereof | |
| CN1527700A (en) | Compaction process for manufacture of sodium phenytoin dosage form | |
| CN101045044A (en) | Thipronin enteric-coated delayed-release agent | |
| CN1235544A (en) | Controlled release dosage form of R-(Z)-alpha-methoxyimino-alpha-(1-azabicyclo 2,2 oct-c-yl) acetonitrile monohydrochloride | |
| CN101057837A (en) | Dextro-ketoprofen enteric coated preparation and its preparation method | |
| CN1420763A (en) | Oral administration controlled release system for once daily administration of ciprofloxacin | |
| CN1762357A (en) | Oral medicinal formulation of moxifloxacin and its preparation method | |
| CN1682719A (en) | Enteric-coated sustained-release tablet containing huperzine A and preparation method thereof | |
| CN1823805A (en) | Ground erythromycin enteric micropill and its preparation method | |
| CN1813728A (en) | Enteric controlled release film coated omeprazol zinc oral solid formulation, oral semi-solid formulation and its preparing method | |
| CN1265793C (en) | Oral compound levocetirizine pseudoephedrine formulation and its preparation | |
| CN1264520C (en) | Enteric-coated azithromycin preparation and its preparing process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: HUNAN JIUDIAN PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: ZHU ZHIHONG Effective date: 20100908 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 410011 ROOM 1105, XINTIAN BUILDING, SHAOSHAN NORTH ROAD, CHANGSHA CITY, HUNAN PROVINCE TO: 410005 24/F, CTA WEALTH CENTER, BOBO TIANXIACHENG, NO.368, SECTION 1 OF FURONG SOUTH ROAD, CHANGSHA CITY, HUNAN PROVINCE |
|
| TA01 | Transfer of patent application right |
Effective date of registration: 20100908 Address after: 410005, Hunan, Changsha province Furong South Road section 368 BOBO world city CTA wealth center, 24 floor Applicant after: Hunan Jiudian Pharmaceutical Co., Ltd. Address before: 410011, room 1105, Xin Tian mansion, Shaoshan North Road, Changsha, Hunan Applicant before: Zhu Zhihong |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 410005, Hunan, Changsha province Furong South Road section 368 BOBO world city CTA wealth center, 24 floor Patentee after: HUNAN JIUDIAN PHARMACEUTICAL CO., LTD. Address before: 410005, Hunan, Changsha province Furong South Road section 368 BOBO world city CTA wealth center, 24 floor Patentee before: Hunan Jiudian Pharmaceutical 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: 20101222 Termination date: 20170420 |