KR20130010531A - Composition of release-controlled loxoprofen - Google Patents
Composition of release-controlled loxoprofen Download PDFInfo
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- KR20130010531A KR20130010531A KR1020110071218A KR20110071218A KR20130010531A KR 20130010531 A KR20130010531 A KR 20130010531A KR 1020110071218 A KR1020110071218 A KR 1020110071218A KR 20110071218 A KR20110071218 A KR 20110071218A KR 20130010531 A KR20130010531 A KR 20130010531A
- Authority
- KR
- South Korea
- Prior art keywords
- release
- preparing
- cetyl alcohol
- weight
- roxofene
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 19
- 229960002373 loxoprofen Drugs 0.000 title abstract description 4
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 title abstract 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000003814 drug Substances 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 22
- 229960000541 cetyl alcohol Drugs 0.000 claims abstract description 18
- 239000007884 disintegrant Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 10
- 229920000642 polymer Polymers 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 238000013265 extended release Methods 0.000 claims abstract description 8
- 239000007787 solid Substances 0.000 claims abstract description 7
- 239000011230 binding agent Substances 0.000 claims abstract description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 6
- 239000008187 granular material Substances 0.000 claims abstract description 5
- 239000007791 liquid phase Substances 0.000 claims abstract description 5
- 239000000314 lubricant Substances 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000001035 drying Methods 0.000 claims abstract description 3
- 239000007790 solid phase Substances 0.000 claims abstract description 3
- 238000005550 wet granulation Methods 0.000 claims abstract description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 19
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 19
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 19
- 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 description 19
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000003405 delayed action preparation Substances 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 230000002035 prolonged effect Effects 0.000 claims description 2
- 238000009472 formulation Methods 0.000 abstract description 10
- 238000013268 sustained release Methods 0.000 abstract description 8
- 239000012730 sustained-release form Substances 0.000 abstract description 8
- 238000010828 elution Methods 0.000 abstract description 2
- 238000002156 mixing Methods 0.000 abstract description 2
- 230000008961 swelling Effects 0.000 abstract description 2
- 238000004090 dissolution Methods 0.000 description 17
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 12
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 12
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 12
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 8
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 8
- 239000008108 microcrystalline cellulose Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 238000007922 dissolution test Methods 0.000 description 5
- -1 light Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 206010028391 Musculoskeletal Pain Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000003628 erosive effect Effects 0.000 description 2
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 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
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- TURGQPDWYFJEDY-UHFFFAOYSA-N 1-hydroperoxypropane Chemical compound CCCOO TURGQPDWYFJEDY-UHFFFAOYSA-N 0.000 description 1
- NEQWCRAMEZANLS-UHFFFAOYSA-N 2-[4-(2-oxocyclopentyl)phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1C(=O)CCC1 NEQWCRAMEZANLS-UHFFFAOYSA-N 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 244000141359 Malus pumila Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 235000021016 apples Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KULDXINYXFTXMO-UHFFFAOYSA-N bis(2-chloroethyl) (3-chloro-4-methyl-2-oxochromen-7-yl) phosphate Chemical compound C1=C(OP(=O)(OCCCl)OCCCl)C=CC2=C1OC(=O)C(Cl)=C2C KULDXINYXFTXMO-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 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 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pain & Pain Management (AREA)
Abstract
Description
본 발명은 록소프로펜을 서방화 하기 위하여 위체류제제로 만드는 방법에 관한 것이다.The present invention relates to a method for making a gastroretentive agent for sustained release of roxofene.
본 발명은 록소프로펜을 제어 방출 제제화함으로써 유효 약물 농도를 적절하게 유지하게 하여 치료효과를 상승시키며 근골격계 통증 환자의 투약 요법을 1 일 3 회 요법에서 1 일 2 회로 단순화하여 환자의 복약 편의성 및 복용 순응도를 향상시키는 제제의 개발에 관한 것이다.The present invention provides a controlled release formulation of roxofene to maintain the effective drug concentration, thereby increasing the therapeutic effect, and simplifying the dosing regimen of patients with musculoskeletal pain, from three times a day to two times a day, for patients' convenience of medication and It relates to the development of a formulation to improve dose compliance.
록소프로펜(화학명: 2-[4-(2-옥소사이클렌펜틸)페닐]프로피온산)은 프로피온계 비스테로이드성 소염진통제(NSAID)로서, 주로 록소프로펜의 소디움염 형태인 록소프로펜 소디움(Loxoprofen Sodium)으로 사용되고 있다.Roxopropene (chemical name: 2- [4- (2-oxocyclopentyl) phenyl] propionic acid) is a propion-based nonsteroidal anti-inflammatory analgesic (NSAID), mainly in the form of sodium salt of roxofene, It is used as Loxoprofen Sodium.
록소프로펜은 만성 관절류마티즘, 변형성 관절증, 요통증, 견관절 주위염 등에 효과적이고, 이외에도 수술후 또는 외상후 및 발치후 통증 개선에도 효과적인 것으로 알려져 있으며, 현재 경구용 정제로 폭넓게 사용되고 있다. 이 약물은 또다른 프로피온산계 비스테로이드성 소염진통제인 케토프로펜(Ketoprofen) 또는 이부프로펜(Ibuprofen) 등과는 상이한 작용기전을 가지며, 염증과 통증의 원인 물질인 프로스타글란딘(Prostaglandin)의 생합성을 억제함으로써 뛰어난 소염진통 효과를 나타낸다.Roxoprofen is known to be effective for chronic arthritis, deformed arthrosis, back pain, periarthritis, and also effective for pain relief after surgery, post-traumatic and post-extraction, and is widely used as an oral tablet. The drug has a different mechanism of action than ketoprofen or ibuprofen, another propionic acid-based nonsteroidal anti-inflammatory drug, and has excellent anti-inflammatory effect by inhibiting the biosynthesis of prostaglandin, a cause of inflammation and pain. It has an analgesic effect.
본 발명은 관절염 등 소염진통에 효과적 약물인 록소프로펜의 서방성제제 제조 방법에 관한 것이다. 록소프로펜은 물에 매우 난용성인 약물로 위장계 전체 범위에서도 낮은 용출율을 나타낸다. 유효약물의 용출율은 흡수과정과 생체이용율에 중요한 작용을 함으로 난용성약물의 용출율 향상을 위한 방법들과 이러한 약물의 복약순응을 높이기 위한 서방성제제의 여러 제조방법들이 제시되어왔다.
The present invention relates to a method for preparing a sustained-release preparation of loxoprofen, which is an effective drug for anti-inflammatory pain, such as arthritis. Roxopropene is a very poorly soluble in water and has a low dissolution rate over the entire gastrointestinal tract. As the effective drug dissolution rate plays an important role in the absorption process and bioavailability, methods for improving the dissolution rate of poorly soluble drugs and various preparation methods for sustained-release preparations for enhancing drug compliance have been proposed.
본 발명의 목적은 록소프로펜을 1 일 2 회 용법의 제어 방출성 제제화하는 것이다. 상기와 같은 방법으로 제조된 본 발명에 따른 제제는 유효 약물의 방출에 있어, 1 일 2 회 90 mg 복용법으로, 초기에는 진통에 유효한 농도를 방출하고, 이후 장시간 약물이 지속적으로 방출되게 함으로써 12 시간 약효가 지속될 수 있고, 유효 약물 농도를 일정하게 유지하게 하여 치료효과를 상승시키며 근골격계 통증 환자의 제약 제제 요법을 단순화하여 환자의 복약 편의성 및 복용 순응도를 향상시키는 이점을 가진다.It is an object of the present invention to formulate a controlled release of lysopropene twice daily. The preparation according to the present invention prepared by the above method is twice a day 90 mg dosage for the release of the effective drug, initially to release the effective concentration for analgesic, and then to continue to release the drug for a long time 12 hours Drug efficacy can be sustained, and the effective drug concentration can be kept constant, thereby increasing the therapeutic effect and simplifying the pharmaceutical formulation therapy of patients with musculoskeletal pain, thereby improving patient convenience and dose compliance.
아래에서 제시된 목적을 이루기 위한 본 발명의 구성을 상세하게 설명한다.The configuration of the present invention for achieving the object set forth below will be described in detail.
상기한 종래 기술들을 이용한 서방형 제제들은 제제의 용출율이 낮거나, 방출의 제어가 잘 안되는 단점이 있었다. 특히, 종래기술을 이용하면 제제의 제조에 별도의 설비가 필요하여 제조 과정이 복합하고 고가의 장비를 사용해야만 했다.Sustained release formulations using the prior arts described above have disadvantages of low dissolution rate or poor control of release. In particular, the use of the prior art requires a separate facility for the preparation of the formulation, requiring a complex manufacturing process and the use of expensive equipment.
본 발명에서는 산, 알카리, 빛, 공기 등에도 안정하며 각종 유화제로 널리 쓰이고 있는 고급 알코올류와 친수성 팽윤기질인 셀룰로오스 중합체류를 함께 사용하여, 상기한 문제를 해결하여 제조과정을 단순화하고 저렴한 제조장비를 사용하여 서방성 제제를 제조하고자 한다.In the present invention, it is stable to acid, alkali, light, air, etc., using high alcohols widely used as various emulsifiers and cellulose polymers of hydrophilic swelling substrate, solving the above problems, simplifying the manufacturing process and inexpensive manufacturing equipment To prepare a sustained release formulation.
따라서 본 발명의 목적은 록소프로펜을 유효성분으로 하는 서방성제제의 제조에 있어 약물의 수난용성문제 해결과 동시에 연장방출을 적절히 수행할 수 있는 연장방출형 고형제제을 제공하는 데 있다.
Accordingly, an object of the present invention is to provide an extended-release solid preparation that can properly perform extended release at the same time to solve the poor water solubility problem of the drug in the preparation of a sustained-release preparation using a lysopropene as an active ingredient.
본 발명에서는 서방형 제제에 있어서, 고급알코올류인 세틸알콜을 가열시켜 반고상인에서 액상으로 상변화 시키는 단계; 상기 액상의 세틸알콜에 난용성 약물을 용해시켜 용액으로 제조하는 단계; 상기 용액에 팽윤성 폴리머, 붕해제 및 부형제를 첨가하여 혼합물을 제조하는 단계; 상기 혼합물에 결합제를 첨가하여 습식과립법으로 과립을 제조하는 단계; 상기 과립을 건조 후 활택제를 혼합시킨 다음 정제 또는 코팅정으로 제조하는 단계; 를 거쳐 제조되는 것을 특징으로 하는 난용성 약물의 연장방출형 고형제제의 제조방법을 제공하고자 한다.In the present invention, in the sustained-release formulation, the step of heating the higher alcohols such as cetyl alcohol from the semi-solid phase to the liquid phase; Preparing a solution by dissolving a poorly soluble drug in the liquid cetyl alcohol; Preparing a mixture by adding a swellable polymer, a disintegrant, and an excipient to the solution; Adding a binder to the mixture to prepare granules by wet granulation; Drying the granules, mixing the lubricant, and then preparing the tablets or coated tablets; An object of the present invention is to provide a method for preparing an extended release solid preparation of a poorly soluble drug, characterized in that it is prepared through.
이에 따른 본 발명의 주요 기술사상은 고급 알코올류인 세틸알콜(cetyl alcohol)을 60 ～ 70oC로 가온하여 고상인 세틸알콜을 투명한 액체상태로 상변화 시킨 후, 이 액에 유효 성분인 록소프로펜을 첨가 용해시켜 메트릭스층을 제조한 다음 셀룰로오스 중합체를 포함한 부형제 혼합물과 연합시켜 서방성제제를 간편하고 용이하게 제조하는 것이다. 세틸알콜(cetyl alcohol)은 록소프로펜의 수난용성 문제해결과 동시에 서방화기재로 활용하기위한 구성 성분으로 C 16 H 34 O로 구성되어 있으며, 연고, 크림 등의 유화제 및 습윤제로 사용되고 있다. 유중수(Water in Oil)에멀젼 제조시 유화제로의 기능은 미비하나 수분흡수의 기능을 발휘한다. 그 성분함량은 록소프로펜 1 중량부에 대하여 0.5～20 중량부 이며, 바람직하게는 1～10 중량부를 사용한다.Accordingly, the main technical idea of the present invention is to warm the higher alcohols such as cetyl alcohol (60 ~ 70 o C) to change the solid cetyl alcohol to a transparent liquid phase, the active ingredient in this solution is roxopro The pen is added to dissolve to prepare a matrix layer, and then associated with an excipient mixture including a cellulose polymer to prepare a sustained release preparation simply and easily. Cetyl alcohol is composed of C 16 H 34 O as a component for solving the poor water solubility problem of roxofene and used as a sustained release material, and is used as an emulsifier and a humectant such as an ointment or a cream. Water-in-oil emulsions are insufficient in their function as emulsifiers, but they do absorb water. The content of the component is 0.5 to 20 parts by weight, preferably 1 to 10 parts by weight, based on 1 part by weight of roxofene.
또한, 본 발명에서 지속적인 유효성분의 연장방출은 겔 시스템을 이용한다. 이러한 형태의 시스템은 시간이 경과함에 따라 표면침식이 서서히 진행되고 팽창되 면서 분산에 의한 방출이 진행되는 것으로 방출속도는 겔 시스템에 이용되는 수팽윤성 폴리머의 점도에 기인한다고 볼 수 있다.In addition, the extended release of the active ingredient in the present invention uses a gel system. In this type of system, surface erosion gradually progresses and expands over time, and the dispersal release proceeds. The release rate is due to the viscosity of the water-swellable polymer used in the gel system.
수팽윤성 폴리머는 히드록시프로필메틸셀룰로오스(HPMC)가 적합하며 본 발명에서는 시간별 유효성분의 지속적이고 적절한 방출을 유도하기 위해서 점도차가 큰 두 종류의 히드록시프로필메틸셀룰로오스를 동시에 사용한다.Hydroxypropylmethylcellulose (HPMC) is suitable for the water swellable polymer, and in the present invention, two kinds of hydroxypropylmethylcellulose having a large difference in viscosity are simultaneously used to induce continuous and proper release of the active ingredient over time.
통상적으로 히드록시프로필메틸셀룰로오스는 메톡시(methoxy)기와 히드록시프로폭시(hydroxypropoxy)기의 비율이 다른 다양한 종류의 것들이 생산되며 이에 따라 다양한 점도의 것들이 사용된다.In general, hydroxypropyl methyl cellulose is produced in a variety of different kinds of methoxy (hydroxypropoxy) group having a ratio of hydroxypropoxy (hydroxypropoxy) group is used according to the various viscosity.
본 발명에서 사용한 히드록시프로필메틸셀룰로오스는 흔히 HPMC2910이라 불리는 것으로 점도가 50cps인 것과 4000cps인 것의 두 종류를 사용한다. 이때, 히드록시프로필메틸렐룰로오스의 점도는 한 종류는 30 ～ 70 cps, 다른 한 종류는 3500 ～ 4500cps 정도의 것을 사용하는 것이 바람직하다. 또한, 사용 비율은 록소프로펜 1 중량부에 대해 점도 50cps 히드록시프로필메틸셀룰로오스는 2～30 중량부이며 바람직하게는 5～20 중량부이다. 점도 4000cps 히드록시메틸셀룰로오스는 0.5～25중량부, 바람직하게는 1～15 중량부 이다.The hydroxypropylmethylcellulose used in the present invention is commonly referred to as HPMC2910 and uses two kinds of ones having a viscosity of 50 cps and 4000 cps. At this time, as for the viscosity of hydroxypropyl methyl cellulose, it is preferable to use about 30-70 cps for one type and about 3500 to 4500 cps for the other type. In addition, the use ratio is 2-30 weight part of viscosity 50cps hydroxypropylmethylcellulose with respect to 1 weight part of roxofene pens, Preferably it is 5-20 weight part. The viscosity 4000 cps hydroxymethyl cellulose is 0.5 to 25 parts by weight, preferably 1 to 15 parts by weight.
결합제로는 셀룰로오스의 폴리하이드록시에테르(poly hydroxypropyl ether)가 부분적으로 치환되어 습윤기질이 있는 히드록시프로필셀룰로오스(HPC)를 알코올에 용해시킨 후 사용하며 이는 흡습으로 인해 약물의 붕해 효과를 가지게 한다. 히드록시프로필셀룰로오스의 분자량은 대개 50,000～1,250,000정도이며 점도에 따라 다양한 제품이 생산되고 있으나, 본 발명에서는 정제의 붕해제로 사용하기 위하여 저치환도의 제품을 사용한다.As a binder, poly hydroxypropyl ether of cellulose is partially substituted to dissolve hydroxypropyl cellulose (HPC) having a wet substrate in alcohol, which has a disintegrating effect of the drug due to moisture absorption. The molecular weight of hydroxypropyl cellulose is generally 50,000 ~ 1,250,000, and various products are produced according to the viscosity, but in the present invention, a low-substituted product is used for use as a disintegrant in tablets.
이는 저치환도의 히드록시프로필셀룰로오스가 적정수준의 습윤을 통하여 정제의 침식을 용이하게 해 지속적인 연장방출을 유도할 수 있기 때문이다. 그 성분비율은 록소프로펜 1중량부에 대해 0.5 내지 10 중량부이며 바람직하게는 펠로디핀 1 중량부에 대하여 1～5 중량부가 가장 바람직하다.This is because low-substituted hydroxypropyl cellulose can facilitate the erosion of tablets through proper level of wetting and induce continuous prolonged release. The component ratio is 0.5 to 10 parts by weight based on 1 part by weight of loxopropene, and preferably 1 to 5 parts by weight based on 1 part by weight of felodipine.
또한, 본 발명에서 사용 가능한 붕해제와 활택제등은 경구용 제제에서 통상적으로 사용하는 부형제를 사용하였다. 예로서 무수유당이나 백당, 중조, 알긴산, 락토오스, 자당, 소르비톨, 만니톨, 전분, 아밀로펙틴, 미결정셀룰로오스, 카제인, 합성규산알루미늄 등이 가능하며, 바람직하게는 붕해제로 백당, 중조, 미결정셀룰로오스, 전분글리콘산나트륨이며, 활택제로는 합성규산알루미늄, 스테아린산마그네슘이 바람직하다. 이들의 사용 비율은 록소프로펜 1 중량부에 대하여 1 ～ 25 중량부를 사용하였다.In addition, disintegrants and lubricants usable in the present invention used an excipient commonly used in oral formulations. For example, anhydrous lactose, white sugar, sodium bicarbonate, alginic acid, lactose, sucrose, sorbitol, mannitol, starch, amylopectin, microcrystalline cellulose, casein, synthetic aluminum silicate, and the like, and preferably as a disintegrant, white sugar, sodium bicarbonate, microcrystalline cellulose, starch. Sodium glyconate, and preferred lubricants are synthetic aluminum silicate and magnesium stearate. These used ratios used 1-25 weight part with respect to 1 weight part of roxofene pens.
본 발명에서는 붕해제로서 습윤성 붕해제인 히드록시프로필셀룰로오스와 함께 수용성물질을 사용함으로써 보다 효율적인 방출제어의 역할을 수행하였으며, 백당을 곱게 분쇄한 분당을 첨가하여 사용한다. 붕해제로 사용한 분당은 경구용 약품의 붕해제로 흔히 사용되고 있으며, 본 발명에서는 붕해 속도를 조절하는 용도로 사용한다.In the present invention, by using a water-soluble substance together with hydroxypropyl cellulose, a wet disintegrating agent as a disintegrating agent, the role of more efficient emission control was performed, and fine sugar ground finely divided into sugars was used. Bundang used as a disintegrant is commonly used as a disintegrant of the oral drug, it is used in the present invention to control the disintegration rate.
본 발명은 불용성약물의 가용화제 및 서방화기제의 사용목적으로 고급알코올류인 세틸알코올에 수팽윤성 폴리머, 습윤성 붕해제 및 방출조절용 부형제가 일정중량비로 구성되어있는 난용성 록소프로펜의 서방화제제를 통상의 제조방법으로 간단히 제조하는데 있으며 기존 록소프로펜을 유효성분으로 한 제제 및 기타 서방성제제의 제조방법과 차별화된 제조비용 및 물질의 안전성 등에 장점을 가지는 효과가 있다.The present invention provides a slow-release agent for poorly soluble roxofene, in which a water swellable polymer, a wet disintegrating agent, and an excipient for controlling release are constituted in a certain weight ratio in cetyl alcohol, which is a high-alcohol, for the use of a solubilizer and a sustained-release agent of an insoluble drug. It is to prepare simply by a conventional manufacturing method and has the advantage of advantages, such as manufacturing cost and safety of the material and the manufacturing method and other sustained-release preparations using the existing roxofene as an active ingredient.
실시예 1 . Example 1 .
세틸알콜 1.2그람을 60～70 o C 로 가온하여 액화시키고, 여기에 록소프로펜0.5그람을 넣고 교반하여 용해시킨다. 따로 분당 3.0그람, HPMC2910 4000cps 3.0그람, HPMC2910 50cps 8.0그람, 합성규산알루미늄 2.0그람, 미결정셀룰로오스 0.4그람을 잘 혼합하고 록소프로펜이 첨가된 메트릭스층과 연합시킨다. 결합제인 HPC 1.0그람은 적당량의 에탄올에 완전히 용해 시켜 상기 연합 완료된 혼합물에 첨가해 다시 연합시키고 25호 채에 사과한 후 70～80o C 의 온도를 유지하면서 2시간 건조시킨다. 이후 스테아린산 마그네슘 0.4그람을 넣어 혼합시킨 후 직경7mm 펀치를 사용하여 타정하여 록소프로펜 정제를 완료하였다.1.2 grams of cetyl alcohol is liquefied by heating to 60-70 ° C., and 0.5 grams of roxofene penetrate to dissolve it. Separately, 3.0 grams per minute, HPMC2910 4000 cps 3.0 grams, HPMC2910 50 cps 8.0 grams, 2.0 grams of synthetic aluminum silicate, 0.4 grams of microcrystalline cellulose were mixed well and associated with the matrix layer added with roxofene. 1.0 g of HPC, a binder, is completely dissolved in an appropriate amount of ethanol, added to the combined mixture again, re-associated, apples in No. 25, and dried for 2 hours while maintaining a temperature of 70 ~ 80 ° C. Thereafter, 0.4 grams of magnesium stearate was added thereto, mixed, and then compressed into tablets using a 7 mm diameter punch to complete roxofene tablets.
록소프로펜 0.5g0.5 g of roxofene
세틸알코올 1.2gCetyl Alcohol 1.2g
분당 3.0g3.0g per minute
히드록시프로필메틸셀룰로오스 50cps 8.0gHydroxypropylmethylcellulose 50cps 8.0g
히드록시프로필메틸셀룰로오스 4000cps 3.0gHydroxypropylmethylcellulose 4000cps 3.0g
합성규산알루미늄 2.0gSynthetic Aluminum Silicate 2.0g
미결정셀룰로오스 0.4g0.4g of microcrystalline cellulose
히드록시프로필셀룰로오스 1.0g1.0 g of hydroxypropyl cellulose
스테아린산마그네슘 0.4g0.4 g magnesium stearate
에탄올 적량Ethanol
제조완료 된 서방형 정제를 록소프로펜 원료와 비교용출 시험을 실시해 용출패턴 결과를 비교하였다. 용출시험법은 First supplement, USP26-NF 'Extended-Release Tablet' 에 등재되어있는 용출시험법으로 시험을 실시했으며 용출액은 1.0M 인산이수소나트륨용액, 0.5M인산일수소나트륨용액, 라우릴황산나트륨을 사용하여 만든 pH6.5완충액을 900ml를 사용하였고 2, 6, 10시간 후에 용출액10ml 씩 취하여 이를 0.45㎚멤버레인 필터로 여과하여 고The prepared sustained-release tablets were subjected to a comparative dissolution test with a lysopropene raw material to compare the dissolution pattern results. The dissolution test was carried out using the dissolution test method listed in First supplement, USP26-NF 'Extended-Release Tablet'. The elution solution was 1.0M sodium dihydrogen phosphate solution, 0.5M sodium dihydrogen phosphate solution, and sodium lauryl sulfate. 900 ml of pH 6.5 buffer solution was used and 10 ml of eluate was taken after 2, 6, and 10 hours, and the resultant was filtered with a 0.45 nm membrane filter.
속액체크로마토그래피법(HPLC)로 분석하였다.Analysis was performed by Sox Liquid Chromatography.
실시예2Example 2
붕해제로 백당을 대신해 물의 흡수 능력이 빠르고 우수해 캅셀이나 정제 등의 경구용 의약품의 강력한 붕해제로 사용되고 있는 소디움스타치글리콜레이트(sodium starch glycolate)을 해당비율로 첨가해 실시예1과 동일한 방법으로 제조하였다.
Sodium starch glycolate, which is used as a powerful disintegrant for oral medicines such as capsules and tablets, is added in the same ratio as in Example 1, because it has a fast and excellent water absorption ability as a disintegrating agent. It was prepared by.
록소프로펜 0.5g0.5 g of roxofene
세틸알코올 1.2gCetyl Alcohol 1.2g
소디움스타치글리콜레이트 3.0gSodium starch glycolate 3.0 g
히드록시프로필메틸셀룰로오스50cps 8.0gHydroxypropylmethylcellulose 50cps 8.0g
히드록시프로필메틸셀룰로오스4000cps 3.0gHydroxypropylmethylcellulose 4000cps 3.0g
합성규산알루미늄 2.0gSynthetic Aluminum Silicate 2.0g
미결정셀룰로오스 0.4g0.4g of microcrystalline cellulose
히드록시프로필셀룰로오스 1.0g1.0 g of hydroxypropyl cellulose
스테아린산마그네슘 0.4g0.4 g magnesium stearate
에탄올 적량
Ethanol
실시예Example 3 3
실시예1과 동일한 방법으로 제조하였으나 록소프로펜을 세틸알코올에 용해시킨 후 계면활성제로 폴리소르베이트를 소량 첨가하고 분당과 히드록시프로필셀룰로오스50cps, 4000cps의 첨가비를 조정하여 시중에 유통되고 있는 동아제약 록소닌정과 함께 용출율의 변화를 비교, 확인하고자 하였다.
It was prepared in the same manner as in Example 1, but after dissolving roxofene in cetyl alcohol, a small amount of polysorbate was added as a surfactant, and the distribution ratio of 50 cps and 4,000 cps of hydroxypropyl cellulose was adjusted in the market. We tried to compare and confirm the change of dissolution rate with Dong-A Pharm.
록소프로펜 0.5g0.5 g of roxofene
세틸알코올 1.2gCetyl Alcohol 1.2g
폴리소르베이트80 1.0gPolysorbate 80 1.0 g
분당 5.0g5.0g per minute
히드록시프로필메틸셀룰로오스50cps 7.0gHydroxypropylmethylcellulose 50cps 7.0g
히드록시프로필메틸셀룰로오스4000cps 1.0gHydroxypropylmethylcellulose 4000cps 1.0g
합성규산알루미늄 2.0gSynthetic Aluminum Silicate 2.0g
미결정셀룰로오스 0.4g0.4g of microcrystalline cellulose
히드록시프로필셀룰로오스 1.0g1.0 g of hydroxypropyl cellulose
스테아린산마그네슘 0.4g0.4 g magnesium stearate
에탄올 적량Ethanol
실시예Example 4 4
실시예1과 동일한 방법으로 제조하고 붕해제인 분당과 결합제인 히드록시프로필셀룰로오스의 첨가비를 조정해 용출율의 변동을 확인하고자 했다.
It was prepared in the same manner as in Example 1 and adjusted the addition ratio of Bundang, which is a disintegrant, and hydroxypropyl cellulose, which is a binder, to check the change in dissolution rate.
록소프로펜 0.5g0.5 g of roxofene
세틸알코올 1.2gCetyl Alcohol 1.2g
폴리소르베이트80 1.0gPolysorbate 80 1.0 g
분당 2.5g2.5 g per minute
히드록시프로필메틸셀룰로오스50cps 7.0gHydroxypropylmethylcellulose 50cps 7.0g
히드록시프로필메틸셀룰로오스4000cps 1.0gHydroxypropylmethylcellulose 4000cps 1.0g
합성규산알루미늄 2.0gSynthetic Aluminum Silicate 2.0g
미결정셀룰로오스 0.4g0.4g of microcrystalline cellulose
히드록시프로필셀룰로오스 3.5gHydroxypropyl Cellulose 3.5g
스테아린산마그네슘 0.4g0.4 g magnesium stearate
에탄올 적량
Ethanol
실시예5Example 5
계면활성제로 사용된 폴리소르베이트80 대신, 폴리옥시에틸렌 피마자유 중 현재 시판되고 있는 크레모포르 RH40(Cremophor RH40)를 사용하여 제조하였다. 크레모포르는 친수성부분이 17%정도를 차지하고 75%정도가 소수성부분으로 구성된 비이온성 계면활성제로서 휘발성오일의 가용화제로도 사용되는 성분이다.
Instead of polysorbate 80 used as surfactant, it was prepared using Cremophor RH40, currently commercially available in polyoxyethylene castor oil. Cremophor is a nonionic surfactant composed of about 17% of the hydrophilic part and about 75% of the hydrophobic part, and is also used as a solubilizer for volatile oil.
록소프로펜 0.5g0.5 g of roxofene
세틸알코올 2.1gCetyl Alcohol 2.1g
크레모포르 1.0gCremophor 1.0g
분당 2.5g2.5 g per minute
히드록시프로필메틸셀룰로오스50cps 7.0gHydroxypropylmethylcellulose 50cps 7.0g
히드록시프로필메틸셀룰로오스4000cps 1.0gHydroxypropylmethylcellulose 4000cps 1.0g
합성규산알루미늄 2.0gSynthetic Aluminum Silicate 2.0g
미결정셀룰로오스 0.4g0.4g of microcrystalline cellulose
히드록시프로필셀룰로오스 3.5gHydroxypropyl Cellulose 3.5g
스테아린산마그네슘 0.4g0.4 g magnesium stearate
에탄올 적량
Ethanol
동일한 조건으로 용출시험을 실시하여 용출양상을 비교하였다.Dissolution test was performed under the same conditions to compare the dissolution patterns.
상기 실시예의 용출시험결과에 따라 난용성약물인 록소프로펜을 고급알코올류에 용해시키면 용출율의 향상을 기대할 수 있으나 그 정도가 미비하고 붕해제와 계면활성제를 첨가하여 이를 보완할 수 있었다. 붕해제는 습윤성기질을 포함하고 있는 물질과 수용성기질을 포함하는 두 종류의 붕해제를 첨가하는 것이 효과적이었다. 또한 계면활성제는 비이온성계면활성제를 사용하여 물성간의 가교역할을 수행하는 것이 바람직하였다. 서방화기재는 점도차가 큰 두 종류의 히드록시프로필메틸셀룰로오스를 사용해 일정한 방출제어를 유도할 수 있음을 확인할 수 있었다.According to the dissolution test results of the above example, dissolution of the poorly soluble drug loxopropene in the higher alcohols can be expected to improve the dissolution rate, but the degree is insufficient and can be supplemented by adding a disintegrant and a surfactant. Disintegrants were effective to add two types of disintegrants, including materials containing wettable substrates and water-soluble substrates. In addition, it is preferable that the surfactant performs a crosslinking role between physical properties by using a nonionic surfactant. Sustained release materials were found to be able to induce constant release control by using two types of hydroxypropylmethylcellulose having a large difference in viscosity.
Claims (3)
상기 액상의 세틸알콜에 록소프로펜을 용해시켜 용액으로 제조하는 단계;
상기 용액에 팽윤성 폴리머, 붕해제 및 부형제를 첨가하여 혼합물을 제조하는 단계;
상기 혼합물에 결합제를 첨가하여 습식과립법으로 과립을 제조하는 단계;
상기 과립을 건조 후 활택제를 혼합시킨 다음 정제 또는 코팅정으로 제조하는 것을 특징으로 하는 난용성 약물의 연장방출형 고형제제의 제조방법.In the sustained-release preparation, the step of heating the higher alcohols such as cetyl alcohol from the semi-solid phase to the liquid phase;
Preparing a solution by dissolving loxopropene in the liquid cetyl alcohol;
Preparing a mixture by adding a swellable polymer, a disintegrant, and an excipient to the solution;
Adding a binder to the mixture to prepare granules by wet granulation;
Method for producing a prolonged-release solid preparation of a poorly soluble drug, characterized in that after drying the granules, the lubricant is mixed and then prepared into tablets or coated tablets.
The water-swellable polymer according to claim 1, wherein the viscosity of 50 cps hydroxypropylmethyl cellulose is 2 to 30 parts by weight, and the viscosity of 4000 cps hydroxymethyl cellulose is 0.5 to 25 parts by weight alone or in combination with respect to 1 part by weight of roxofene. Method for producing extended-release solid preparation of poorly soluble drug, characterized in that
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