CN101108170A - Aceclofenac in extended-released tablets and method of manufacturing the same - Google Patents
Aceclofenac in extended-released tablets and method of manufacturing the same Download PDFInfo
- Publication number
- CN101108170A CN101108170A CNA2007100700193A CN200710070019A CN101108170A CN 101108170 A CN101108170 A CN 101108170A CN A2007100700193 A CNA2007100700193 A CN A2007100700193A CN 200710070019 A CN200710070019 A CN 200710070019A CN 101108170 A CN101108170 A CN 101108170A
- Authority
- CN
- China
- Prior art keywords
- aceclofenac
- extended
- preparation
- released tablets
- binding agent
- 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
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 title claims abstract description 72
- 229960004420 aceclofenac Drugs 0.000 title claims abstract description 72
- 238000004519 manufacturing process Methods 0.000 title description 3
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 29
- 239000000314 lubricant Substances 0.000 claims abstract description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- -1 hydroxypropyl Chemical group 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 16
- 239000011230 binding agent Substances 0.000 claims description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- 230000001476 alcoholic effect Effects 0.000 claims description 12
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 12
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 12
- 239000008187 granular material Substances 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- 239000007779 soft material Substances 0.000 claims description 8
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 3
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 238000005469 granulation Methods 0.000 claims description 2
- 230000003179 granulation Effects 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 238000007873 sieving Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 27
- 229940079593 drug Drugs 0.000 abstract description 20
- 210000004369 blood Anatomy 0.000 abstract description 13
- 239000008280 blood Substances 0.000 abstract description 13
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 abstract description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 abstract description 13
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 3
- 239000007939 sustained release tablet Substances 0.000 abstract 3
- 239000000853 adhesive Substances 0.000 abstract 1
- 230000001070 adhesive effect Effects 0.000 abstract 1
- 239000003405 delayed action preparation Substances 0.000 abstract 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 abstract 1
- 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 abstract 1
- 239000004615 ingredient Substances 0.000 abstract 1
- 238000012423 maintenance Methods 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 30
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 18
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 18
- 230000000694 effects Effects 0.000 description 14
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 10
- 206010067484 Adverse reaction Diseases 0.000 description 8
- 230000006838 adverse reaction Effects 0.000 description 8
- 229920002683 Glycosaminoglycan Polymers 0.000 description 7
- 206010061218 Inflammation Diseases 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 210000002784 stomach Anatomy 0.000 description 7
- 206010013786 Dry skin Diseases 0.000 description 6
- 230000001186 cumulative effect Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 208000025865 Ulcer Diseases 0.000 description 5
- 229960001259 diclofenac Drugs 0.000 description 5
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 231100000397 ulcer Toxicity 0.000 description 5
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229920003081 Povidone K 30 Polymers 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 4
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 229960000905 indomethacin Drugs 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229960002009 naproxen Drugs 0.000 description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- 206010000087 Abdominal pain upper Diseases 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 206010013082 Discomfort Diseases 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- 206010060860 Neurological symptom Diseases 0.000 description 2
- 101710098398 Probable alanine aminotransferase, mitochondrial Proteins 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 206010041349 Somnolence Diseases 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 2
- 208000019790 abdominal distention Diseases 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940109239 creatinine Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000002173 dizziness Diseases 0.000 description 2
- 210000003754 fetus Anatomy 0.000 description 2
- 231100000025 genetic toxicology Toxicity 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- 238000002562 urinalysis Methods 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- 206010049778 Neonatal anuria Diseases 0.000 description 1
- 208000001184 Oligohydramnios Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 231100000026 common toxicity Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000003017 ductus arteriosus Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 231100001048 fetal toxicity Toxicity 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 230000007674 genetic toxicity Effects 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 231100000734 genotoxic potential Toxicity 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229960005249 misoprostol Drugs 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 229960000965 nimesulide Drugs 0.000 description 1
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a drug sustained-release preparation and its preparation method, in particular to an aceclofenac sustained-release tablet and its preparation method, which comprises the following ingredients according to the weight percentage: aceclofenac of 60 to 95 per cent, skelecton retarder of 3 to 30 per cent, adhesive of 1 to 10 per cent and lubricant of 0.5 to 15 per cent. The hydroxypropylmethyl cellulose and carboxyvinyl polymer are adopted as optimized skelecton retarder. With such a technical proposal in the invention, the one aceclofenac sustained-release tablet can be taken a day to effectively reduce the fluctuation of blood drug level, prolong the maintenance duration of effective blood drug level and lower down the incitement to gastrointestinal tract. Besides, the invention also provides the preparation method of the aceclofenac sustained-release tablet.
Description
Technical field
The present invention relates to a kind of medical slow releasing preparation and preparation method thereof, relate in particular to a kind of aceclofenac in extended-released tablets and preparation method thereof.
Background technology
Aceclofenac (Aceclofenac) is the potent nonsteroidal anti-inflammatory drug of a kind of new oral that Spain Prodesfarma company at first introduced to the market in 1992.Aceclofenac can be brought into play multiple pharmacological effect at lesions position as NSAID (non-steroidal anti-inflammatory drug), provides advantage for realizing its potent antiinflammatory, analgesic, analgesic activity.Under the normal condition, the glycosaminoglycan of cartilaginous tissue extracellular matrix and collagen protein are in a kind of dynamic equilibrium.When glycosaminoglycan is synthetic when being suppressed, this balance is just destroyed, and the synthetic of collagen protein promptly is affected, so " inflammation " that promptly occur it has often been said at joint part.Aceclofenac can suppress to stop the synthetic interleukin 1 β of glycosaminoglycan (Interleukin, IL-1 β) and the activity of tumor necrosis factor (TumorNecrosisFactor-α), improve the activity of endogenous somatomedin, thereby promote the synthetic of glycosaminoglycan, recover the glycosaminoglycan of inflammation part and the equilibrium relation of collagen protein.Simultaneously, aceclofenac can also suppress arachidonic metabolism, reduces the inflammation part Prostaglandin PGE
2Generation.By these two kinds of mechanism, aceclofenac has not only played the effect of the position symptom that reduces inflammation, and can also effectively repair the damage of inflammation part.And other NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) influence the synthetic nothing of glycosaminoglycan as piroxicam, aspirin, nabumetone; Indomethacin, ibuprofen, naproxen and nimesulide suppress the synthetic of glycosaminoglycan on the contrary.Therefore, these medicines only can alleviate the inflammation of focus, and can not really reach the purpose that diminishes inflammation.
Find that in contrast experiment's research of carrying out with ability of most NSAIDs another noticeable pharmacological characteristic of aceclofenac is that its lighter stomach causes the ulcer influence.No matter be acute or repeat administration, its side effect incidence rate only is 2～24.5%, is lower than diclofenac and indomethacin 2 times and 6 times respectively, and this illustrates that it is very slight to the injury of stomach.Safety coefficient (the LD that compares this product and other NSAIDs
50/ ED
50) or cause ulcer coefficient (UD
50/ ED
50) zoopery find that this product is one of safest medicine among the conventional NSAID s.Its ulcer function that causes is lower than diclofenac or indomethacin 4～7 times, has shown good tolerability.
The market prospect of aceclofenac, also very good.The anti-inflammatory analgesic kind that China produces at present is more, as aspirin, ibuprofen, naproxen, indometacin, diclofenac etc.These kinds are bigger to GI irritation, serious caused upper digestive tract hemopoietic, ulcer or perforation, thereby have to discontinue medication.In decades, many in the world pharmacy workers are seeking to solve the method that NSAID (non-steroidal anti-inflammatory drug) causes gastroenteritic ulcer, now obtained certain achievement, be used to prevent NSAID (non-steroidal anti-inflammatory drug) to cause the medicine misoprostol of gastric ulcer as external approved, compound preparation is made with itself and naproxen by U.S. Sesrle company, and has released the compound preparation with diclofenac.And aceclofenac is accepted by the patient easily because of characteristics such as it is little to GI irritation, determined curative effect, better tolerance, use are comparatively safe.
The production of domestic at present existing aceclofenac sheet, aceclofenac capsule, aceclofenac enteric coatel tablets and enteric coated capsule.(CN1543359) discloses a kind of compositions and preparation methods for bioavailable oral aceclofenac dosage forms as Chinese invention patent; Chinese invention patent (CN1989957) discloses a kind of aceclofenac granule.But the half-life of aceclofenac is shorter, for keeping effective blood drug concentration, needed take medicine in one 2～3 times, and blood concentration fluctuation is bigger, and sick patients such as rheumatism, rheumatoid, generally need take medicine for a long time, thereby has increased the toxic and side effects of medicine.Have not yet to see the report of aceclofenac in extended-released tablets research, exploitation.
Summary of the invention
In order to solve above-mentioned technical problem, the purpose of this invention is to provide a kind of aceclofenac in extended-released tablets, the slow releasing tablet that it can take once on the 1st has reached the reduction blood concentration fluctuation, and effective blood drug concentration is held time longer, reduces the purpose of GI irritation.
Another object of the present invention provides the preparation method of above-mentioned aceclofenac in extended-released tablets.
In order to reach first purpose, the present invention has adopted following technical scheme:
Aceclofenac in extended-released tablets comprises following composition by weight percentage: aceclofenac 60～95%, skeleton blocker 3～30%, binding agent 1～10%, lubricant 0.5～15%.The packing material that certainly, can also contain other in the prescription of the present invention.
As preferably, above-mentioned skeleton blocker is selected hydroxypropyl emthylcellulose and carbopol for use.As preferred again, described hydroxypropyl emthylcellulose content is 2～20%, and carbopol content is 1～10%.
Comprise following composition by weight percentage as preferred again, above-mentioned aceclofenac in extended-released tablets:
Aceclofenac 80～92%,
Hydroxypropyl emthylcellulose 2～10%,
Carbopol 1～8%,
Binding agent 1～10%,
Lubricant 0.5～10%.
As most preferably, above-mentioned aceclofenac in extended-released tablets is made up of following composition by weight percentage:
Aceclofenac 88.2%,
Hydroxypropyl emthylcellulose 4.9%,
Carbopol 2.7%,
Binding agent 3.1%,
Lubricant 0.1%.
As preferably, above-mentioned binding agent is selected one or more in methylcellulose, carboxycellulose sodium, hydroxypropyl emthylcellulose, ethyl cellulose and the polyvinylpyrrolidone for use.
As preferably, above-mentioned binding agent lubricant is selected one or more in stearic acid, magnesium stearate and the calcium stearate for use.
In order to realize second above-mentioned purpose, the preparation method of aceclofenac in extended-released tablets of the present invention comprises the steps:
(1) aceclofenac and skeleton blocker are sieved mix homogeneously respectively;
(2) binding agent is mixed with solution and above-mentioned material mixing system soft material after, the granulation of sieving;
Dry under (3) 60～80 ℃ of temperature, granulate sieves;
(4) it is even to add mix lubricant, tabletting.
As preferably, above-mentioned binding agent is selected the polyvinylpyrrolidone aqueous solution of 8～40% (W/V) for use.Perhaps, binding agent is selected the polyvinylpyrrolidone alcoholic solution of 8～40% (W/V) for use.
The selection of slow-released system is because aceclofenac is almost insoluble in water, 0.1mol/L hydrochloric acid solution and 0.1mol/L sodium hydroxide solution.Therefore, the present invention selects the slow-released system of matrix type.
The preferred skeleton blocker of selecting is hydroxypropyl emthylcellulose and carbopol.Hydroxypropyl emthylcellulose has good hydrophilicity.Contain a large amount of carboxyls in the carbopol structure, meet water and can form gel, the free carboxy of carbopol can provide proton, can form hydrogen bond with gastrointestinal mucosa behind the formation gel, stick on the gastrointestinal wall, thus the holdup time of prolong drug in gastrointestinal tract.Can provide a small amount of proton for aceclofenac for acidic drug, improve the adhesiveness of carbopol gel.
The present invention is owing to adopted above technical scheme, and the aceclofenac in extended-released tablets that can take once in 1st has reached the reduction blood concentration fluctuation, and effective blood drug concentration is held time longer, reduces the purpose of GI irritation.
The specific embodiment
Embodiment 1
Every prescription is as follows:
Aceclofenac 200mg
Hydroxypropyl emthylcellulose (HPMC K4M) 86mg
14% (W/V) PVP K-30 alcoholic solution 50ml
Magnesium stearate 3mg;
Preparation method is as follows:
With aceclofenac, HPMC K4M, mistake 100 mesh sieves, and mix homogeneously respectively.With the moistening preparation soft material of 14% (w/v) PVPK30 alcoholic solution, 16 mesh sieves are granulated, and in 60～80 ℃ of dryings, 20 mesh sieve granulate add the magnesium stearate mixing, tabletting.
24 hours cumulative release rates of present embodiment product are 71%.
Embodiment 2
Every prescription is as follows:
Aceclofenac 200mg
Hydroxypropyl emthylcellulose (HPMC E4M) 86mg
14% (W/V) PVP K-30 alcoholic solution 50ml
Magnesium stearate 3mg;
Preparation method is as follows:
With aceclofenac, HPMC E4M, mistake 100 mesh sieves, and mix homogeneously respectively.With the moistening preparation soft material of 14% (w/v) PVPK30 alcoholic solution, 16 mesh sieves are granulated, and in 60～80 ℃ of dryings, 20 mesh sieve granulate add the magnesium stearate mixing, tabletting.
24 hours cumulative release rates of present embodiment product are 72%.
Embodiment 3
Every prescription is as follows:
Aceclofenac 200mg
Hydroxypropyl emthylcellulose (HPMC K4M) 86mg
Carbopol (Carbopol) 934 P 3mg
14% (W/V) PVP K-30 alcoholic solution 50ml
Magnesium stearate 3mg;
Preparation method is as follows:
Aceclofenac, HPMC K4M, carbopol (Carbopol) 934 P are crossed 100 mesh sieves respectively, and mix homogeneously.With the moistening preparation soft material of 14% (w/v) PVP K30 alcoholic solution, 16 mesh sieves are granulated, and in 60～80 ℃ of dryings, 20 mesh sieve granulate add the magnesium stearate mixing, tabletting.
24 hours cumulative release rates of present embodiment product are 65%.
Embodiment 4
Every prescription is as follows:
Aceclofenac 200mg
Hydroxypropyl emthylcellulose (HPMC E4M) 86mg
Carbopol (Carbopol) 934 P 3mg
14% (W/V) PVP K-30 alcoholic solution 50ml
Magnesium stearate 3mg;
Preparation method is as follows:
Aceclofenac, HPMC E4M, carbopol (Carbopol) 934 P are crossed 100 mesh sieves respectively, and mix homogeneously.With the moistening preparation soft material of 14% (w/v) PVP K30 alcoholic solution, 16 mesh sieves are granulated, and in 60～80 ℃ of dryings, 20 mesh sieve granulate add the magnesium stearate mixing, tabletting.
24 hours cumulative release rates of present embodiment product are 57%.
Embodiment 5
Every prescription is as follows:
Aceclofenac 200mg
Hydroxypropyl emthylcellulose (HPMC K4M) 12mg
Carbopol (Carbopol) 934 P 5mg
14% (W/V) PVP K-30 alcoholic solution 50ml
Magnesium stearate 2.2mg;
Preparation method is as follows:
Aceclofenac, HPMC K4M, carbopol (Carbopol) 934 P are crossed 100 mesh sieves respectively, and mix homogeneously.With the moistening preparation soft material of 14% (w/v) PVP K30 alcoholic solution, 16 mesh sieves are granulated, and in 60～80 ℃ of dryings, 20 mesh sieve granulate add the magnesium stearate mixing, tabletting.
The release test result of getting above-mentioned 3 batch samples is shown in table-1.
The cumulative release percentage rate (n=6) of 3 batch samples of table-1 embodiment 5
| Lot number | ?2h | ?4h | ?6h | ?8h | ?12h | ?16h | ?24h |
| ?1 | ?9.7 | ?22.0 | ?42.8 | ?58.6 | ?70.2 | ?83.5 | ?94.6 |
| ?2 | ?9.2 | ?19.8 | ?40.2 | ?58.2 | ?72.8 | ?82.9 | ?95.1 |
| ?3 | ?10.1 | ?23.3 | ?47.1 | ?60.2 | ?76.0 | ?86.6 | ?94.1 |
Embodiment 6
Every prescription is as follows:
Aceclofenac 200mg
Hydroxypropyl emthylcellulose (HPMC K4M) 11mg
Carbopol (Carbopol) 934 P 6mg
14% (W/V) PVP K-30 aqueous solution 50ml
Magnesium stearate 2.2mg;
Preparation method is as follows:
Aceclofenac, HPMC K4M, carbopol (Carbopol) 934 P are crossed 100 mesh sieves respectively, and mix homogeneously.With the moistening preparation soft material of 14% (w/v) PVP K30 aqueous solution, 16 mesh sieves are granulated, and in 60～80 ℃ of dryings, 20 mesh sieve granulate add the magnesium stearate mixing, tabletting.
The release test result of getting above-mentioned 3 batch samples is shown in table-2, and hardness is 10～12kg.
The cumulative release percentage rate (n=6) of table-2 embodiment 6 samples
| Lot number | 2h | ?4h | ?6h | ?8h | ?12h | ?16h | ?24h |
| ?1 | 12.05 | ?27.74 | ?43.86 | ?58.12 | ?75.17 | ?87.38 | ?99.40 |
1 quality test of test example
From above-mentioned test result as can be seen embodiment 6 be preferred forms of the present invention.The assay that to embodiment 6 is the product that makes adopts ultraviolet spectrophotometry, and this law principal agent concentration is in 4.4～31 μ g/ml scopes, and trap and concentration are the good linear relation, and stable and repeatability is good.
The release test has selected for use the phosphate buffered solution of pH6.8 as release medium, adopt ultraviolet spectrophotometry to measure trap in the 274nm place, change the basket method, 75 rev/mins, be respectively more than 10～30%, 30～70% and 70% of labelled amount in the burst size of 2,6,12 hours three time points.
Test example 2 stability tests
Carried out influence factors' such as illumination, high temperature, high humility, air at room temperature test, the result is:
4000Lx illumination 10 days, outward appearance, related substance, content and release have no significant change.Place under 40 ℃, the 60 ℃ conditions, release increase in time has the trend of slowing down, and 60 ℃ just had part slice, thin piece release to be lower than standard 10 days the time.Place under 80 ℃ of conditions, release is slowed down more obvious, just has the slice, thin piece release to be lower than standard in the time of 5 days.Other indexs do not have significant change.
Place under 25 ℃ of RH75% conditions, release has the trend of quickening; Place under 25 ℃ of RH92.5% conditions, release is obviously accelerated, and part slice, thin piece release is above standard in the time of 10 days, and outward appearance is also omited variation.Other index does not have significant change.
Placed 10 days in the air at room temperature, every index does not have significant change.
The research of test example 3 pharmacological toxicologies
1. pharmacological action
This product is a NSAID (non-steroidal anti-inflammatory drug), has antiinflammatory, analgesic activity.Its mechanism of action mainly is by suppressing cyclooxygenase activity, reducing thereby prostaglandin is synthesized.
2. toxicological study
Repeat administration toxicity: the continuous oral administration of rat 1 month, dosage is respectively 15,50 and 100mg/kg/ day, the result only organizes and animal dead occurs 100mg/kg/ day, and with fecal occult blood, stomach or intestinal mucosa irritant reaction appear in visible this treated animal of histopathological examination.Similar with other NSAID (non-steroidal anti-inflammatory drug), experimental animal is relatively poor to the toleration of this product.In addition, the pharmacokinetic difference of animals and human beings causes its genotoxic potential to be difficult to judge, but the toxicological test result of administration under maximum tolerated dose shows rat (can be diclofenac with the aceclofenac metabolism) and monkey (some last metabolic prototype medicine), and this product end is seen the common toxicity of nonsteroidal antiinflammatory drug other toxic action in addition.
Genetoxic: this product genetic toxicity test is feminine gender as a result.
Genotoxicity: it is reported that anti-inflammatory agent suppresses the synthetic effect of prostaglandin may cause serious fetal toxicity.Can suppress uterine contraction, thereby cause childbirth to postpone.Can cause that the uterus fetus ductus arteriosus is narrow or close, cause neonate pulmonary hypertension and respiratory insufficiency.Anti-inflammatory agent can also suppress the fetus platelet function and influence its renal function, causes oligohydramnios and neonatal anuria disease.Therefore, banned use of anti-inflammatory agent in last three months in gestation.But bibliographical information is arranged, in gestation, early stage this product can influence fetus equally and send out the region between the heart and the diaphragm.It is not immediately clear whether this product drains through people's milk, therefore, unless the doctor thinks that in case of necessity women breast-feeding their children should not use this product.
Carcinogenecity: the end sees that this product has carcinogenesis in the carcinogenecity research that mice and rat carry out.
The test of test example 4 pharmacokineticss
1, animal pharmacokinetics test
After Beagle dog single dose is irritated stomach 200mg aceclofenac in extended-released tablets and ordinary tablet (production of Spain Prodesfarma company), the Tmax of this slow releasing tablet, T1/2, MRT, Cmax is respectively: 5.0 ± 2.7h, 6.03 ± 1.95h, 9.79 ± 1.71h, 61.36 ± 20.75 μ g/ml.And the analog value of aceclofenac ordinary tablet is: 2.3 ± 0.6h, 4.97 ± 1.95h, 7.41 ± 1.90h, 81.35 ± 15.63 μ g/ml.Show that through variance analysis the T1/2 of slow releasing tablet, Tmax, MRT are significantly greater than ordinary tablet, Cmax significantly is lower than ordinary tablet, illustrates to have slow release effect.The two single T of survey tests show the AUC24 and the AUC bioequivalence of two preparations.Relative bioavailability is 91.42 ± 11.17%.
Stable state peak concentration, plateau concentration, paddy concentration, the coefficient of variation of multiple dose Beagle dog filling stomach aceclofenac in extended-released tablets compared with peak concentration, plateau concentration, paddy concentration, the coefficient of variation of ordinary preparation does not all have obviously work difference.With the ordinary tablet is contrast, and the bioavailability under the stable state is 93.4%.
2, human pharmacokinetics
The single oral dose aceclofenac in extended-released tablets, through the time blood drug level change procedure, meet the compartment model that one-level absorbs.Main pharmacokinetic parameters is: T1/2Ka (h)=1.30 ± 0.39, T1/2Ke (h)=4.66 ± 0.29, Tmax (h)=4.00 ± 0.46, C
Max(μ gmL
-1)=10.87 ± 1.04, MRT (h)=7.52 ± 0.40, AUC
0～24(μ gh-1mL
-1)=73.23 ± 10.35, AUC
0～∞(μ gh
-1ML
-1)=81.81 ± 11.00.The multi-dose oral aceclofenac in extended-released tablets reached steady plasma-drug concentration in continuous 9 days, through the time blood drug level change procedure, meet the compartment model that one-level absorbs.The 9th God wants pharmacokinetic parameters to be: T
1/2Ka(h)=0.87 ± 0.31, T
1/2Ke(h)=3.29 ± 0.30, T
Max(h)=2.05 ± 0.22, C
Max(μ gmL
-1)=17.43 ± 1.72, MRT (h)=4.83 ± 0.25, AUC
0～16(μ gh
-1ML
-1)=69.85 ± 10.80, AUC
0～∞(μ gh
-1ML
-1)=75.99 ± 11.76.
5 clinical trials of test example
This clinical trial adopt multicenter, at random, the double blinding dual analog, estimate curative effect and the safety of aceclofenac in extended-released tablets that China Medicine University's development, Zhejiang Prov JianFeng Pharmaceutical Co., Ltd bid to host to China RA and OA patient with the method for aceclofenac sheet contrast.The result of study that amounts to the effective case of 262 examples (RA:135 example, OA:127 example) by three tame hospitals shows:
In RA patient's effectiveness study, finish effective case 135 examples altogether, test group 67 examples wherein, matched group 68 examples.Test group finish 2 the week courses of treatment 67 example, effective percentage is 49.25%; Matched group finish 2 the week courses of treatment 68 example, effective percentage is 52.94%.Test group finish 4 the week courses of treatment 67 example, effective percentage is 71.64%; Matched group finish 4 the courses of treatment 68 in week example, effective percentage is a relatively no difference of science of statistics (P＞0.05) of 66.18%, two group of curative effect.Two medicines all can significantly improve RA patient's deadlock in morning, rest pain, tenderness index, swelling index, function of joint, reduce the scoring of patient to present disease condition, but right-hand man's grip and erythrocyte sedimentation rate are not had obvious influence.
In RA patient's safety research, treated for 2 weeks, the test group adverse reaction rate is 7.35%, matched group is 7.25%; Treated for 4 weeks, the test group adverse reaction rate is 2.94%, and matched group is 5.80%; The total adverse reaction rate of test group is 9.59%, and the total adverse reaction rate of matched group is 9.72%.Two groups of patients all have some cases gastrointestinal symptom to occur in therapeutic process, show as nauseating, vomiting, stomach burn feeling, stomachache, abdominal distention etc.; Dizziness, insomnia, neurological symptom such as drowsiness appear in some cases; Pruritus, menoxenia and infection etc. appear in some cases.These uncomfortable performance major parts are slight discomforts, and symptom is slight, disappears or recovery from illness after course of treatment end or the drug withdrawal.Two medicines relatively do not have statistically-significant difference to the variation tendency unanimity of each index such as hemoglobin, leukocyte, platelet, routine urinalysis, serum creatinine, blood urea nitrogen, glutamate pyruvate transaminase influence, and show that relatively two medicines all do not have influence to These parameters before the treatment.
Performance is good in RA patient's compliance, tolerance studies, test group and matched group comparing difference not statistically significant.
In OA patient's effectiveness study, finish effective case 127 examples altogether, wherein test group 63 examples; Matched group 64 examples.Test group finish 2 the week courses of treatment 63 example, effective percentage is 52.38%; Matched group finish 2 the week courses of treatment 61 example, effective percentage is 50.82%.Test group finish 4 the week courses of treatment 63 example, effective percentage is 84.13%; Matched group finish 4 the courses of treatment 64 in week example, effective percentage is a relatively no difference of science of statistics (P＞0.05) of 76.56%, two group of curative effect.Two medicines all can significantly improve OA patient's activeness pain, tenderness index, swelling index, function of joint, reduce the scoring of patient to present disease condition; All can improve patient's activity of daily living, to the improvement degree of each index with to improve percentage rate close.
In OA patient's safety research, treated for 2 weeks, the test group adverse reaction rate is 8.70%, matched group is 8.57%; Treated for 4 weeks, the test group adverse reaction rate is 7.25%, and matched group is 8.57%; The total adverse reaction rate of test group is 13.04%; The total adverse reaction rate of matched group is 12.86%.Two groups of patients have some cases gastrointestinal symptom to occur in therapeutic process, show as nauseating, vomiting, stomach burn feeling, stomachache, abdominal distention etc., neurological symptoms such as dizzy, drowsiness appear in some cases, pruritus, frequent micturition etc. appear in some cases, these uncomfortable performance major parts are slight discomforts, symptom is slight, transference cure or recovery from illness after course of treatment end or the drug withdrawal.Two medicines relatively do not have statistically-significant difference to the variation tendency unanimity of each index such as hemoglobin, leukocyte, platelet, routine urinalysis, serum creatinine, blood urea nitrogen, glutamate pyruvate transaminase influence, and show that relatively two medicines all do not have influence to These parameters before the treatment.
Performance is good in OA patient's compliance, tolerance studies, test group and matched group comparing difference not statistically significant.
In sum, aceclofenac in extended-released tablets can significantly improve symptom, the sign that RA, OA are tried the patient, has obvious therapeutic action, its curative effect, toleration, safety are close with the aceclofenac sheet, but only need take medicine once in one day, overcome inferior more than a day in the past inconvenience of taking medicine, be worth using to clinical recommendation.
Claims (10)
1. aceclofenac in extended-released tablets is characterized in that comprising by weight percentage following composition:
Aceclofenac 60～95%,
Skeleton blocker 3～30%,
Binding agent 1～10%,
Lubricant 0.5～15%.
2. aceclofenac in extended-released tablets according to claim 1 is characterized in that the skeleton blocker selects hydroxypropyl emthylcellulose and carbopol for use.
3. aceclofenac in extended-released tablets according to claim 2 is characterized in that hydroxypropyl emthylcellulose content is 2～20%, and carbopol content is 1～10%.
4. aceclofenac in extended-released tablets according to claim 3 is characterized in that comprising by weight percentage following composition:
Aceclofenac 80～92%,
Hydroxypropyl emthylcellulose 2～10%,
Carbopol 1～8%,
Binding agent 1～10%,
Lubricant 0.5～10%.
5. aceclofenac in extended-released tablets according to claim 4 is characterized in that being made up of following composition by weight percentage:
Aceclofenac 88.2%,
Hydroxypropyl emthylcellulose 4.9%,
Carbopol 2.7%,
Binding agent 3.1%,
Lubricant 0.1%.
6. according to any described aceclofenac in extended-released tablets of claim of claim 1～5, it is characterized in that binding agent selects one or more in methylcellulose, carboxycellulose sodium, hydroxypropyl emthylcellulose, ethyl cellulose and the polyvinylpyrrolidone for use.
7. according to any described aceclofenac in extended-released tablets of claim of claim 1～5, it is characterized in that lubricant selects one or more in stearic acid, magnesium stearate and the calcium stearate for use.
8. the preparation method of aceclofenac in extended-released tablets according to claim 1 is characterized in that comprising the steps:
(1) aceclofenac and skeleton blocker are sieved mix homogeneously respectively;
(2) binding agent is mixed with solution and above-mentioned material mixing system soft material after, the granulation of sieving;
Dry under (3) 60～80 ℃ of temperature, granulate sieves;
(4) it is even to add mix lubricant, tabletting.
9. the preparation method of aceclofenac in extended-released tablets according to claim 8 is characterized in that binding agent selects the polyvinylpyrrolidone aqueous solution of 8～40% (W/V) for use.
10. the preparation method of aceclofenac in extended-released tablets according to claim 8 is characterized in that binding agent selects the polyvinylpyrrolidone alcoholic solution of 8～40% (W/V) for use.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100700193A CN100528144C (en) | 2007-07-13 | 2007-07-13 | Aceclofenac in extended-released tablets and method of manufacturing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100700193A CN100528144C (en) | 2007-07-13 | 2007-07-13 | Aceclofenac in extended-released tablets and method of manufacturing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101108170A true CN101108170A (en) | 2008-01-23 |
| CN100528144C CN100528144C (en) | 2009-08-19 |
Family
ID=39040560
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2007100700193A Active CN100528144C (en) | 2007-07-13 | 2007-07-13 | Aceclofenac in extended-released tablets and method of manufacturing the same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100528144C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102917696A (en) * | 2010-06-01 | 2013-02-06 | 韩国联合制药株式会社 | Aceclofenac slow-release preparation providing an optimum pharmacological clinical effect when administered once a day |
| CN102307575B (en) * | 2009-02-04 | 2013-02-13 | 韩国联合制药株式会社 | Aceclofenac-containing controlled-release oral drug preparations and their manufacturing process |
| CN103239419A (en) * | 2013-05-15 | 2013-08-14 | 瑞阳制药有限公司 | Method for preparing theophylline sustained release |
-
2007
- 2007-07-13 CN CNB2007100700193A patent/CN100528144C/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102307575B (en) * | 2009-02-04 | 2013-02-13 | 韩国联合制药株式会社 | Aceclofenac-containing controlled-release oral drug preparations and their manufacturing process |
| CN102917696A (en) * | 2010-06-01 | 2013-02-06 | 韩国联合制药株式会社 | Aceclofenac slow-release preparation providing an optimum pharmacological clinical effect when administered once a day |
| EP2583674A2 (en) * | 2010-06-01 | 2013-04-24 | Korea United Pharm, Inc. | Aceclofenac slow-release preparation providing an optimum pharmacological clinical effect when administered once a day |
| EP2583674A4 (en) * | 2010-06-01 | 2014-06-25 | Korea United Pharm Inc | Aceclofenac slow-release preparation providing an optimum pharmacological clinical effect when administered once a day |
| CN102917696B (en) * | 2010-06-01 | 2015-04-01 | 韩国联合制药株式会社 | Aceclofenac slow-release preparation providing an optimum pharmacological clinical effect when administered once a day |
| CN103239419A (en) * | 2013-05-15 | 2013-08-14 | 瑞阳制药有限公司 | Method for preparing theophylline sustained release |
| CN103239419B (en) * | 2013-05-15 | 2016-01-20 | 瑞阳制药有限公司 | The preparation method of Theo-Dur |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100528144C (en) | 2009-08-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI93608B (en) | Process for the preparation of solid drug preparations containing xanthan gum | |
| JPS6388122A (en) | Blend of quick absorption and action sulindac or sodium sulindac together with base | |
| US20240165034A1 (en) | Mazindol ir/sr multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (adhd) | |
| CN102125531A (en) | Nifedipine sustained-release tablet | |
| JP5828609B2 (en) | Persistent antipyretic analgesic anti-inflammatory agent | |
| CN100528144C (en) | Aceclofenac in extended-released tablets and method of manufacturing the same | |
| JP2006001920A (en) | Medicinal preparation | |
| CN101264080A (en) | Pharmaceutical composition containing dexchlorpheniramine and preparation thereof | |
| JP5879358B2 (en) | Pharmaceutical compositions comprising bicarbonate and their use as medicaments in the treatment and / or prevention of urolithiasis and related diseases | |
| CN101342177B (en) | Lornoxicam double-layer sustained release tablets | |
| CN101084912A (en) | Compound ambroxol hydrochloride sustained-release tablet and preparation method thereof | |
| CN102755310A (en) | Composition drug preparation containing levodopa | |
| CN112007006B (en) | A pharmaceutical composition for treating oral ulcer, and its preparation method | |
| CN101810572A (en) | Nimesulide suspension and preparation method thereof | |
| RU2166937C1 (en) | Paracetamol-base drug | |
| CN103432596B (en) | Method for researching abirritation mechanism of Chinese herbal medicinal ingredients of Xinhuang tablets | |
| KR102669683B1 (en) | Oral solid formulation for colon cleansing | |
| WO2022036506A1 (en) | Composition and use of sglt-2 inhibitor and angiotensin receptor blockers | |
| CN101766608B (en) | Compound pseudoephedrine hydrochloride slow release preparation and preparing method thereof | |
| BRPI0617184A2 (en) | delayed-release pralnacasan formulation | |
| CN101757001B (en) | Compound slow-release preparation of benorilate, pseudoephedrine and chlorphenamine | |
| CN101647771B (en) | Silybin dihemisuccinate disodium oral preparation and preparation method thereof | |
| Radhakrishnan | Formulation Development and In-Vitro Evaluation of Potassium Chloride Extended Release Tablets | |
| CN116098883A (en) | Carbododopa stomach retention sustained-release tablet and preparation method and application thereof | |
| CN101129358A (en) | Moguisteine sustained-release tablet and method of preparing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Aceclofenac in extended-released tablets and method of manufacturing the same Effective date of registration: 20150128 Granted publication date: 20090819 Pledgee: Bank of Communications Ltd Jinhua branch Pledgor: Zhejiang Jiafeng Pharmaceutical Co., Ltd. Registration number: 2015990000078 |
|
| PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20150626 Granted publication date: 20090819 Pledgee: Bank of Communications Ltd Jinhua branch Pledgor: Zhejiang Jiafeng Pharmaceutical Co., Ltd. Registration number: 2015990000078 |
|
| PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Aceclofenac in extended-released tablets and method of manufacturing the same Effective date of registration: 20171207 Granted publication date: 20090819 Pledgee: Bank of Communications Ltd Jinhua branch Pledgor: Zhejiang Jiafeng Pharmaceutical Co., Ltd. Registration number: 2017330000262 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20190118 Granted publication date: 20090819 Pledgee: Bank of Communications Ltd Jinhua branch Pledgor: Zhejiang Jiafeng Pharmaceutical Co., Ltd. Registration number: 2017330000262 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |