KR100336090B1 - Solid dispersed preparation of poorly water-soluble drug containing oil, fatty acid or mixture thereof - Google Patents
Solid dispersed preparation of poorly water-soluble drug containing oil, fatty acid or mixture thereof Download PDFInfo
- Publication number
- KR100336090B1 KR100336090B1 KR1019990024437A KR19990024437A KR100336090B1 KR 100336090 B1 KR100336090 B1 KR 100336090B1 KR 1019990024437 A KR1019990024437 A KR 1019990024437A KR 19990024437 A KR19990024437 A KR 19990024437A KR 100336090 B1 KR100336090 B1 KR 100336090B1
- Authority
- KR
- South Korea
- Prior art keywords
- solid dispersion
- peg
- oil
- poorly soluble
- oleic acid
- Prior art date
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- 229940079593 drug Drugs 0.000 title claims abstract description 89
- 239000003814 drug Substances 0.000 title claims abstract description 89
- 239000000203 mixture Substances 0.000 title claims abstract description 68
- 235000014113 dietary fatty acids Nutrition 0.000 title claims abstract description 19
- 239000000194 fatty acid Substances 0.000 title claims abstract description 19
- 229930195729 fatty acid Natural products 0.000 title claims abstract description 19
- 150000004665 fatty acids Chemical class 0.000 title claims abstract description 19
- 239000007787 solid Substances 0.000 title claims description 29
- 239000003921 oil Substances 0.000 title claims description 26
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 239000007962 solid dispersion Substances 0.000 claims abstract description 115
- 239000000843 powder Substances 0.000 claims abstract description 69
- 238000009472 formulation Methods 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000008187 granular material Substances 0.000 claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 239000003826 tablet Substances 0.000 claims abstract description 13
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 11
- 239000002775 capsule Substances 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 6
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 claims description 57
- 229960004420 aceclofenac Drugs 0.000 claims description 50
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 49
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 48
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 48
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 48
- 239000005642 Oleic acid Substances 0.000 claims description 48
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 48
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 48
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims description 28
- 229960004125 ketoconazole Drugs 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
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- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 claims description 21
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 20
- 229920000053 polysorbate 80 Polymers 0.000 claims description 20
- 108010036949 Cyclosporine Proteins 0.000 claims description 17
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 claims description 17
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 16
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- 239000002270 dispersing agent Substances 0.000 claims description 15
- 239000004094 surface-active agent Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 12
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
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- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 claims description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical group CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 claims description 3
- CMPDPBDUZTUXAD-UHFFFAOYSA-N [3-hydroxy-2-(16-methylheptadecanoyloxy)propyl] 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCC(C)C CMPDPBDUZTUXAD-UHFFFAOYSA-N 0.000 claims description 3
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 claims description 3
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- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 claims description 3
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- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 claims description 2
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- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 2
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- JWZSXZWCWMCYPE-RSAXXLAASA-M sodium;(4s)-4-amino-5-dodecoxy-5-oxopentanoate Chemical compound [Na+].CCCCCCCCCCCCOC(=O)[C@@H](N)CCC([O-])=O JWZSXZWCWMCYPE-RSAXXLAASA-M 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- WNIFXKPDILJURQ-UHFFFAOYSA-N stearyl glycyrrhizinate Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=O)OCCCCCCCCCCCCCCCCCC)(C)CC5C4=CC(=O)C3C21C WNIFXKPDILJURQ-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- 229960003288 sulfaethidole Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- HDOZVRUNCMBHFH-UHFFFAOYSA-N zotepine Chemical compound CN(C)CCOC1=CC2=CC=CC=C2SC2=CC=C(Cl)C=C12 HDOZVRUNCMBHFH-UHFFFAOYSA-N 0.000 description 1
- 229960004496 zotepine Drugs 0.000 description 1
Classifications
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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Abstract
본 발명은 난용성 약물의 고형분산제제에 관한 것으로서, 구체적으로 난용성 약물을 오일, 지방산 또는 이들의 혼합물에 용해 또는 분산시키고 수용성 고분자 기제에 혼합한 다음, 건조하여 분쇄함으로써 제조되는 고형분산분말제제와, 약학적으로 허용가능한 핵에 분사하여 과립화함으로써 얻어지는 고형분산과립제제를 제공한다.The present invention relates to a solid dispersion agent of poorly soluble drugs, specifically, a solid dispersion powder preparation prepared by dissolving or dispersing a poorly soluble drug in an oil, a fatty acid or a mixture thereof, mixing the water-soluble polymer base, and then drying and pulverizing it. And it provides a solid dispersion granules obtained by granulation by spraying to the pharmaceutically acceptable nucleus.
본 발명의 난용성 약물의 고형분산분말제제 또는 고형분산과립제제는 약물의 위장관에서의 용해도, 즉 용출을 향상시켜 생체이용율을 증가시킬 뿐만 아니라, 성형 및 가공이 곤란한 기존의 반고형 또는 액상제제의 제제학적인 문제점을 개선하여, 유기용매를 사용하지 않고도 간편하고 신속하게 최종제품을 성형, 제조 및 가공할 수 있으며, 각종 산제, 과립제, 정제 또는 캡슐제의 형태로 성형될 수 있는 장점이 있다.The solid dispersion powder or solid dispersion granule formulation of the poorly soluble drug of the present invention improves the solubility in the gastrointestinal tract, that is, dissolution, increases bioavailability, and is difficult to form and process. By improving the pharmaceutical problems, it is possible to mold, manufacture and process the final product easily and quickly without using an organic solvent, there is an advantage that can be molded in the form of various powders, granules, tablets or capsules.
Description
본 발명은 난용성 약물의 고형분산제제에 관한 것으로서, 구체적으로 난용성 약물을 오일, 지방산 또는 이들의 혼합물에 용해 또는 분산시킨 후, 수용성 고분자 기제에 혼합하여 건조한 후 분쇄하여 제조되는 고형분산분말제제와 상기 혼합액을 약학적으로 허용가능한 핵에 분사하여 제조되는 고형분산과립제제에 관한 것이다.The present invention relates to a solid dispersion of a poorly soluble drug, specifically a solid dispersion powder prepared by dissolving or dispersing a poorly soluble drug in an oil, a fatty acid or a mixture thereof, mixed with a water-soluble polymer base, dried and then ground And it relates to a solid dispersion granulated preparation prepared by injecting the mixture into a pharmaceutically acceptable nucleus.
의약품으로 사용되는 약물의 상당수는 난용성이어서 생체에 투여되었을 때체내로 흡수되는 과정에서 소화액에서의 용해도와 용출 속도가 낮아 약물 흡수가 지연되므로 생체이용율이 낮아 진다는 단점이 있다. 이러한 문제점을 해결하고자 난용성 약물의 가용화 또는 용출 속도의 증가를 목적으로 하는 다양한 제제화 수단이 개발되고 있다. 예를 들면, 생체이용율을 향상시키는 방법으로서 미세화 (micronization)법, 계면활성제에 의한 미셀 (micelle)화법, 용매침착(solvent deposit)법, 건조 엘릭서 (dry elixir)법, 분산 건조 (spray drying)법, 수용성 고분자물질 (inert water soluble carrier)에 의한 공침법, 고체 분산 (solid dispersion)법 및 사이클로덱스트린 (cyclodextrin)류를 이용하는 포접 복합체 (inclusion complex)법 등이 폭넓게 보고되었으나, 사용방법에 따라 약물의 용해도가 증가하는 정도가 불규칙하며, 이러한 방법들을 이용하기에는 제조방법, 상업성 및 효율성 측면에서 문제점이 많았다.Many of the drugs used as medicines are poorly soluble, so when they are administered to a living body, they have a disadvantage in that bioavailability is lowered because the absorption of the drug is delayed due to low solubility and dissolution rate in the digestive fluid. In order to solve this problem, various formulation means have been developed for the purpose of solubilizing or increasing the dissolution rate of poorly soluble drugs. For example, as a method for improving bioavailability, micronization method, micelle formation with surfactant, solvent deposit method, dry elixir method, and spray drying method , Coprecipitation by inert water soluble carrier, solid dispersion method and inclusion complex method using cyclodextrins have been widely reported. The degree of solubility increases is irregular, and there are many problems in manufacturing method, commerciality and efficiency in using these methods.
한편, 약물이 난용성이어서 체내 흡수가 나쁜 경우, 약물을 오일 또는 지방산류 등에 분산시킴으로써 체내에 투여하였을 때에 생체이용율을 높이려는 시도가 있었으나, 그 제형이 반고형 또는 액상이어서 성형, 제조 및 가공 등에 있어서 제제학적으로 많은 문제점이 있었다.On the other hand, when the drug is poorly soluble and poorly absorbed by the body, there have been attempts to increase the bioavailability when the drug is administered to the body by dispersing the drug in oils or fatty acids, etc., but since the formulation is semi-solid or liquid, There were many problems in formulation.
본 발명자들은 전술한 난용성 약물의 생체내로의 흡수 및 제형화에서의 문제점을 개선하고자 연구한 결과, 약물의 위장관에서의 용해도, 즉 용출을 향상시켜 생체이용율을 증가시킬 뿐만 아니라, 기존의 반고형 또는 액상제제의 제제학적 문제점을 개선하여, 유기용매를 사용하지 않고도 간편하고 신속하게 최종제품을 성형, 제조 및 가공할 수 있는 경제적인 고형분산제제를 개발하여 본 발명을 완성하였다.The present inventors have studied to improve the above-mentioned problems in the absorption and formulation of the poorly soluble drugs in vivo, as a result of improving the solubility of the drug in the gastrointestinal tract, that is, dissolution to increase the bioavailability, as well as the existing semi-solid In addition, the present invention has been completed by improving the pharmaceutical problems of liquid formulations, and developing economical solid dispersion formulations that can easily, quickly and easily form, manufacture, and process the final product without using an organic solvent.
본 발명의 목적은 위장관에서의 약물의 용출을 향상시켜 생체이용율을 증가시키며, 간편하고 신속하게 최종제품을 성형, 제조 및 가공할 수 있는 난용성 약물의 고형분산제제를 제공하는 것이다.It is an object of the present invention to improve the dissolution of drugs in the gastrointestinal tract, to increase the bioavailability, and to provide a solid dispersion of poorly soluble drugs that can be molded, manufactured and processed the final product simply and quickly.
도 1은 실험용 쥐에 사이클로스포린을 함유하는 고형분산제제와 시판제제를 각각 투여한 후, 시간에 따라 사이클로스포린의 혈중농도를 측정한 결과를 나타낸 그래프이고, 1 is a graph showing the results of measuring the blood concentration of cyclosporin with time after administration of a solid dispersion and a commercial formulation containing cyclosporin to the experimental rat, respectively,
--◆-- 시판제제 (Neoral)-◆-Commercial formulations (Neoral)
--■-- 실시예 15의 제제-■-Formulation of Example 15
--▲-- 실시예 16의 제제-▲-Formulation of Example 16
도 2는 실험용 쥐에 아세클로페낙 함유 고형분산제제와 약물분말을 경구투여한 후 아세클로페낙의 혈중농도를 측정한 결과를 나타낸 그래프이고, Figure 2 is a graph showing the results of measuring the blood concentration of aceclofenac after oral administration of aceclofenac-containing solid dispersion and drug powder in a rat,
--●-- 아세클로페낙 분말-●-Aceclofenac Powder
--○-- 고형분산제제(올레인산 5%)-○-Solid Dispersant (5% Oleic Acid)
도 3은 비글견(beagle dog)에서 아세클로페낙 함유 고형분산제제와 시판 에어탈 정을 경구투여한 후 아세클로페낙의 혈중농도를 측정한 결과를 나타낸 그래프이고, 3 is a graph showing the results of measuring the blood concentration of aceclofenac after oral administration of aceclofenac-containing solid dispersion and a commercial airtal tablet in a beagle dog,
--●-- 고형분산제제를 100mg 함유한 캅셀-●-Capsule containing 100mg of solid dispersion
--○-- 시판 에어탈 정 100mg-○-Commercial Airtal Tablet 100mg
도 4는 사람에게 아세클로페낙 고형분산제제와 시판 에어탈 정을 경구투여한 후 아세클로페낙의 혈중농도를 측정한 결과를 나타낸 그래프이고, 4 is a graph showing the results of measuring the blood concentration of aceclofenac after oral administration of aceclofenac solid dispersion and a commercially available airtal tablet to a human,
--●-- 고형분산제제를 100mg 함유한 캅셀-●-Capsule containing 100mg of solid dispersion
--○-- 시판 에어탈 정 100mg-○-Commercial Airtal Tablet 100mg
도 5는 사람에게 시사프라이드 함유 고형분산과립제제와 시판 프레팔시드 정제의 경구투여 후 혈중농도를 측정한 결과를 나타낸 그래프이다. FIG. 5 is a graph showing the results of blood concentration measurement after oral administration of cisapride-containing solid dispersion granules and commercial prepalside tablets.
--●-- 프레팔시드(prepulsid) 10mg-●-Prepulsid 10mg
--○-- 고형분산과립제제 10mg-○-Solid Dispersion Granule 10mg
상기 목적을 달성하기 위하여 본 발명자들은 난용성 약물을 오일, 지방산 또는 이들의 혼합물에 용해시키거나 분산시키고 수용성 고분자 기제에 혼합한 다음, 건조하여 분쇄함으로써 분말화하거나, 약학적으로 허용가능한 핵에 분사하여 과립화함으로써 얻어지는 난용성 약물의 고형분산제제를 제공한다.In order to achieve the above object, the present inventors dissolve or disperse poorly soluble drugs in oils, fatty acids or mixtures thereof, mix them with water-soluble polymer bases, and then dry and pulverize them to powder or spray them into pharmaceutically acceptable nuclei. It provides a solid dispersion of poorly soluble drug obtained by granulation.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명에서 제공되는 난용성 약물의 고형분산제제는 고형분산분말제제 또는 고형분산과립제제를 포함한다.The solid dispersion preparation of the poorly soluble drug provided in the present invention includes a solid dispersion powder preparation or a solid dispersion granulation preparation.
우선, 고형분산분말제제는 난용성 약물을 오일, 지방산 또는 이들의 혼합물에 용해시키거나 분산시킨 후, 수용성 고분자 기제에 혼합하여 건조하고 이를 분쇄하여 분말화함으로써 얻어지는 난용성 약물의 고형분산제제이다.First, the solid dispersion powder preparation is a solid dispersion preparation of a poorly soluble drug obtained by dissolving or dispersing a poorly soluble drug in an oil, a fatty acid or a mixture thereof, mixing the mixture with a water-soluble polymer base, drying it, and pulverizing it.
또한 본 발명의 고형분산과립제제는 난용성 약물을 오일, 지방산 또는 이들의 혼합물에 용해시키거나 분산시키고 수용성 고분자 기제에 혼합한 다음, 이를 약학적으로 허용가능한 핵에 분사하여 과립화함으로써 얻어지는 난용성 약물의 고형분산제제이다. 상기 약학적으로 허용가능한 핵물질로는 슈가 미립구가 바람직하다.In addition, the solid dispersion granules of the present invention are poorly soluble obtained by dissolving or dispersing a poorly soluble drug in an oil, a fatty acid or a mixture thereof, and mixing it in a water-soluble polymer base, and then granulating it by spraying it into a pharmaceutically acceptable nucleus. It is a solid dispersion of the drug. As the pharmaceutically acceptable nucleus material, sugar microspheres are preferable.
본 발명의 고형분산분말제제 또는 고형분산과립제제는 실제 환자에게 적용하는데 있어 산제, 과립제, 정제 또는 캡슐제 등 약학적으로 가능한 모든 내복제의 형태로 성형될 수 있다.The solid dispersion powder formulation or the solid dispersion granule formulation of the present invention may be molded in the form of all pharmaceutically possible oral preparations such as powders, granules, tablets or capsules in the application to the actual patient.
이하, 본 명세서에서 특별한 언급이 없는 한 '고형분산제제'는 '고형분산분말제제'와 '고형분산과립제제'를 포함하는 의미로 사용된다.Hereinafter, unless otherwise stated, 'solid dispersion formulation' is used to mean 'solid dispersion powder formulation' and 'solid dispersion granulation formulation'.
이 때, 오일, 지방산 또는 이들의 혼합물은 단독으로 사용될 수도 있고, 이들을 포함하는 에멀젼 (emulsion) 또는 마이크로에멀젼 (microemulsion)의 형태로 사용될 수 있다.In this case, oils, fatty acids or mixtures thereof may be used alone or in the form of emulsions or microemulsions containing them.
또한, 난용성 약물을 오일, 지방산 또는 이들의 혼합물에 용해시키거나 분산시키는 것에 더하여, 계면활성제를 첨가할 수도 있다.In addition to dissolving or dispersing poorly soluble drugs in oils, fatty acids or mixtures thereof, surfactants may be added.
그리고, 상기 수용성 고분자 기제는 단독으로 사용할 수도 있고, 다른 수용성 기제와 혼합하여 사용할 수도 있다.The water-soluble polymer base may be used alone or in combination with other water-soluble bases.
상기 오일로는 알파-비사볼롤 (α-bisabolol), 스테아릴 글리세레티네이트(stearyl glycyrrhetinate), 살리실산 (salicylic acid), 토코페릴 아세테이트 (tocopheryl acetate), 물과 알콜과 페릴라 추출물 (water and alcohol and Perilla extract), 히알루론산 나트륨 (sodium hyaluronate), 판테놀 (panthenol), 프로필렌 글리콜과 애플 (propylene glycol and apple(Pirus Malus)), 프로필렌 글리콜과 파인애플 (propylene glycol and pineapple), 아이비 추출물과 1,3-비지 (ivy(Hedera halix) extract and 1,3-B.G), 복숭아잎 추출물(PEACH(Prums persica) leaf extract), 가수분해된 콩분말 (hydrolyzed soy flour), 밀 단백질 (wheat(Triticum Vulgare) protein), 자작나무 추출물과 1,3-비지 (birch(Betula alba) extract and 1,3-B.G), 우엉 추출물과 1,3-비지 (burdock(Arctium majus) extract and 1,3-B,G) 등의 지질성 첨가물; 리포솜 (liposome)류; 포스파티딜콜린 (phosphatidylcholine)류; 글리세릴 스테아레이트 (glyceryl stearate), 카프틸릭/카프릭 트리글리세라이드 (captylic/capric triglyceride), 세틸 옥탄올레이트 (cetyl octanolate), 이소프로필 미리스테이트 (isopropyl myristate), 2-에틸렌 이소펠라고네이트 (2-ethylene isopelagonate), 디-c12-13 알킬 말레이트 (di-c12-13 alkyl malate), 세테아틸 옥타노에이트 (ceteatyl octanoate), 부틸렌 글리콜 디카프틸레이트/디카프레이트 (butylene glycol dicaptylate/dicaprate), 이소노닐 이소스테아레이트 (isononyl isostearate), 이소스테아릴 이소스테아레이트 (isostearyl isostearate), 코코-카프틸레이트/ 카프레이트 (coco-captylate/ caprate), 세틸 옥타노에이트 (cetyl octanoate), 옥틸도데실 미리스테이트 (octyldodecyl myristate), 세틸 에스테르류 (cetyl esters), c10-30 콜레스테롤/라노스테롤 에스테르 (c10-30 cholesterol/lanosterol ester), 수소화 카스터 오일 (hydrogenated castor oil), 모노글리세라이드 (mono-glycerides), 디글리세라이드 (diglycerides), 트리글리세라이드 (triglycerides) 등의 에스테르류: 비스왁스 (beeswax), 카나우바 왁스 (canauba wax), 숙토스 디스테아레이트 (suctose distearate), PEG-8 비스왁스 (PEG-8 beeswax), 칸델리아 왁스 (candelilla(euphorbia cerifera) wax) 등의 히드로카본류; 세레신 (ceresin), 오조케리트 (ozokerite) 등의 광물류; 마카다미아유 (macadamia ternifolia nut oil), 수소화 고-에루식산 평지씨유 (hydrogenated hi-erucic acid rape seed oil), 올리브유 (olive oil), 호호바유 (jojoba oil), 혼성 해바라기유 (hybrid sunflower(Helian thus annuus) oil), 닌씨유( neen(melia azadirachta) seed oil) 또는 들장미유 (dog rose(rosa canina) lips oil) 등의 식물류 등이 사용될 수 있으며, 바람직하게는 미네랄 오일, 스쿠알렌 (squalene), 스쿠알란 (squalane), 모노글리세라이드, 디글리세라이드, 트리글리세라이드, 중간 사슬 글리세라이드, 미글리올(myglyol), 크레모포(cremophor), 수소화 캐스터 오일, 옥수수유, 깨유, 면실유 또는 지용성 비타민 등이 사용될 수 있다.The oils include alpha-bisabolol (α-bisabolol), stearyl glycyrrhetinate, salicylic acid, tocopheryl acetate, water and alcohol and perilla extract (water and alcohol and Perilla extract, sodium hyaluronate, panthenol, propylene glycol and apple (Pirus Malus), propylene glycol and pineapple, ivy extract and 1,3- Ivy (ivy (Hedera halix) extract and 1,3-BG), peach leaf extract (PEACH (Prums persica) leaf extract), hydrolyzed soy flour, wheat protein (wheat (Triticum Vulgare) protein) Birch (Betula alba) extract and 1,3-BG, Burdock (Arctium majus) extract and 1,3-B, G, etc. Lipidic additives; Liposomes; Phosphatidylcholine; Glyceryl stearate, captylic / capric triglyceride, cetyl octanolate, isopropyl myristate, 2-ethylene isofellagonate (2 -ethylene isopelagonate, di-c12-13 alkyl malate, ceteatyl octanoate, butylene glycol dicaptylate / dicaprate , Isononyl isostearate, isostearyl isostearate, coco-captylate / caprate, cetyl octanoate, octyldodecyl Octyldodecyl myristate, cetyl esters, c10-30 cholesterol / lanosterol esters, hydrogenated castor oils, mono-glycerides, diglycerides, triglycerides and other esters: beeswax, canauba wax, stoolose distearate hydrocarbons such as distearate), PEG-8 biswax (PEG-8 beeswax) and candelilla (euphorbia cerifera) wax; Minerals such as ceresin and ozokerite; Macadamia oil (macadamia ternifolia nut oil), hydrogenated high-erucic acid rape seed oil, olive oil, jojoba oil, hybrid sunflower (Helian thus plant oils such as annuus oil), neen (melia azadirachta) seed oil, or dog rose (rosa canina) lips oil may be used. Preferably, mineral oil, squalene (squalene) and squalane are used. (squalane), monoglycerides, diglycerides, triglycerides, medium chain glycerides, myglyol, cremophor, hydrogenated castor oil, corn oil, sesame oil, cottonseed oil or fat soluble vitamins, etc. may be used. have.
상기 지방산으로는 올레인산 (oleic acid), 세틸 알콜 (cetyl alcohol), 스테아릴 알콜 (stearyl alcohol), 스테아린산 (stearic acid), 미리스틱산 (myristic acid), 리놀레산 (linoleic acid) 또는 라우릭산 (lauric acid) 등이 사용될 수 있으며, 바람직하게는 올레인산, 리놀레산 또는 이소프로필미리스틱산 등이 사용될 수 있다.The fatty acid may be oleic acid, cetyl alcohol, stearyl alcohol, stearic acid, myristic acid, linoleic acid or lauric acid. ) May be used, and preferably oleic acid, linoleic acid or isopropyl mystic acid may be used.
상기 수용성 고분자 기제로는 폴리에틸렌 글리콜 (이하 'PEG'라 약칭함), 카보왁스 (carbowax) 또는 폴리비닐 피롤리돈(이하 'PVP'라 약칭함) 등이 사용될 수 있다.Polyethylene glycol (hereinafter, abbreviated as 'PEG'), carbowax, or polyvinyl pyrrolidone (hereinafter, referred to as 'PVP') may be used as the water-soluble polymer base.
상기 수용성 고분자 기제와 혼합하여 사용할 수 있는 다른 수용성 기제로는 젤라틴 (gelatin), 검류 (gum), 탄수화물류 (carbohydrate), 셀룰로오스류 (cellulose), 폴리비닐알코올 (polyvinyl alcohol), 폴리아크릴산 (polyacrylic acid), 무기물질 (inorganic) 또는 이들의 혼합물 등의 수용성 기제; 히드록시프로필메틸셀룰로오스 아세틸 숙신산 (HPMCAS), 셀룰로오스 아세테이트 프탈레이트, 쉘락 (shellac), 제인 (zein), 폴리비닐 아세테이트 프탈레이트, 유드라짓 L100, 유드라짓 S100, 알긴산 나트륨 또는 폴리-L-라이신 등의 장용성 기제 등을 사용할 수 있다.Other water soluble bases that can be mixed with the water soluble polymer base include gelatin, gum, carbohydrates, cellulose, polyvinyl alcohol, polyacrylic acid ), An aqueous base such as an inorganic substance or a mixture thereof; Hydroxypropylmethylcellulose acetyl succinic acid (HPMCAS), cellulose acetate phthalate, shellac, zein, polyvinyl acetate phthalate, Eudragit L100, Eudragit S100, sodium alginate or poly-L-lysine Enteric bases and the like can be used.
상기 계면활성제로는 글리세릴 스테아레이트 (glyceryl stearate), 폴리솔베이트 60 (polysorbate 60), 폴리솔베이트 80 (polysorbate 80), 솔비탄 트리올레인산염 (sorbitan trioleate), 솔비탄 세스퀴올레인산염 (sorbitan sesquioleate), 솔비탄 스테아레이트 (sorbitan stearate), PEG-20 글리세릴 이소스테아레이트 (PEG-20 glyceryl isostearate), 세테트-25 (ceteth-25), PEG-60 수소화 카스터 오일 (PEG-60 hydrogenated castor oil), 노녹시놀-15 (nonoxynol-15), PEG-6-데실테트라데세트-20 (PEG-6-decyltetradeceth-20), 디메티콘 코폴리올 (dimethiconecopolyol), 글리세릴 디이소스테아레이트 (glyceryl diisostearate), 세테트-24 (ceteth-24), 세테아릴 알콜 (cetearyl alcohol), 폴리옥실에틸렌 노니페닐 에테르 (polyoxylethylene nonyphenyl ether), PEG-40 수소화 카스터 오일 (PEG-40 hydrogenated castor oil), 세틸 디메티콘 코폴리올 (cetyl dimethicone copolyol), 폴리글리세릴-3 메틸글루코오스 디스테아레이트 (polyglyceryl-3 methylglucose distearate), PEG-100 스테아레이트 (PEG-100 stearate), 솔비탄 이소스테아레이트 (sorbitan isostearate), 라우릴 글루타메이트 나트륨 (sodium lauryl glutamate), 코코암포디아세테이트 디나트륨 (disodium cocoamphodiacetate), 디에탄올아미드 라우릭산 (lauric acid diethanolamide), 코코넛 지방산 디에탄올아미드 (coconut fatty acid diethanolamide), N,N-비스-(2-히드록시 에틸)-코코미드 (N,N-Bis-(2-hydroxy ethyl)-cocomide) 또는 코코아미도프로필 베타인 (cocoamidopropyl betain) 등이 사용될 수 있다.The surfactant is glyceryl stearate, polysorbate 60, polysorbate 80, sorbitan trioleate, sorbitan sesquioleate (sorbitan) sesquioleate, sorbitan stearate, PEG-20 glyceryl isostearate, ceteth-25, PEG-60 hydrogenated castor oil (PEG-60 hydrogenated castor oil, nonoxynol-15, PEG-6-decyltetradeceth-20, dimethiconecopolyol, glyceryl diisostearate ( glyceryl diisostearate, ceteth-24, cetearyl alcohol, polyoxylethylene nonyphenyl ether, PEG-40 hydrogenated castor oil Cetyl dimethicone copolyol, polyglycol Polyglyceryl-3 methylglucose distearate, PEG-100 stearate, sorbitan isostearate, sodium lauryl glutamate, cocoam Disodium cocoamphodiacetate, diethanolamide lauric acid diethanolamide, coconut fatty acid diethanolamide, N, N-bis- (2-hydroxyethyl) -coamide (N , N-Bis- (2-hydroxy ethyl) -cocomide) or cocoamidopropyl betain may be used.
본 발명의 고형분산제제는 용해도가 낮은 모든 난용성 약물군에 이용될 수 있으나, 바람직하게는 케토코나졸 (ketoconazole); 이트라코나졸 (itraconazole)류 및 그 유도체; 사이클로스포린 (cyclosporine); 시사프라이드 (cisapride); 아세트아미노펜 (acetaminophen); 아스피린 (aspirin); 아세틸살리실산 (acetylsalicylic acid); 인도메타신 (indomethacin); 나프록센 (naproxen); 와파린 (warfarin); 파파베린 (papaverine); 티오아벤다졸 (thiabendazole); 미코나졸 (miconazole); 시나리진 (cinnarizine); 독소루비신 (doxorubicin); 오메프라졸 (omeprazole); 콜레칼시페롤 (cholecalciferol); 멜팔란 (melphalan); 니페디핀 (nifedipine); 디곡신 (digoxin); 벤조산 (benzoic acid); 트립토판 (tryptophan); 타이로신 (tyrosine); 페닐알라닌 (phenylalanine); 아즈트레오남 (aztreonam); 이부프로펜 (ibuprofen); 펜옥시메틸페니실린 (phenoxymethylpenicillin); 탈리도마이드 (thalidomide); 메틸테스토스테론 (methyltestosterone); 프로클로르페라진 (prochlorperazine); 히드로코티손 (hydrocortisone); 디데옥시퓨린 뉴클레오사이드 (dideoxypurine nucleoside); 비타민 디 투 (vitamin D2); 술폰아미드 (sulfonamide); 술포닐우레아 (sulfonylurea); 파라아미노벤조산 (p-aminobenzoic acid); 멜라토닌 (melatonin); 벤질페니실린 (benzylpenicillin); 클로람뷰실 (chlorambucil); 디아제핀 (diazepin); 디기톡신 (digitoxin); 히드로코티손 뷰레이트 (hydrocortisone butyrate); 메트로니다졸 벤조산염 (metronidazole benzoate); 톨부타마이드 (tolbutamide); 프로스타글란딘 (prostaglandin E1(PGE1)) ; 플루드로코티손 (fludrocortisone); 그리세오풀빈 (griseofulvin); 미코나졸 질산염 (miconazole nitrate); 류코트라이엔 비포 억제제 (leukotriene B4antagonist); 프로프라놀롤 (propranolol) ; 테오필린 (theophylline); 플러비프로펜 (flubiprofen); 벤조산 나트륨 (sodium benzoate); 벤조산 (benzoic acid); 리보플라빈 (riboflavin); 벤조디아제핀 (benzodiazepine); 페노바비탈 (phenobarbital) ; 글리뷰라이드 (glyburide); 설파디아진 (sulfadiazine); 설파에틸티아디아졸 (sulfaethylthiadiazole); 디클로페낙 나트륨 (sodium diclofenac); 피니로인(phyniroin); 히오리다진히드로클로라이드 (hioridazinehydrochloride); 브로피리민 (bropirimine); 히드로클로로티아지드 (hydrochlorothiazide); 또는 플루코나졸 (fluconazole); 아사이클로비르(acyclovir); 부실라민(bucillamine); 시프로플루옥사신(ciprofluoxacin); 아세틸-L-카르니틴(acetyl-L-carnitine); 이트라코나졸(itraconazole); 바클로펜(baclofen); 소듐 알렌드로네이트(sodium alendronate); 로보카르니틴(lovocarnitine); 니모디핀(nimodipine or nimodifine); 아테놀롤(atenolol); 프라바스타틴 소듐(pravastatin sodium); 로바스타틴(lovastatin); 아세클로페낙(aceclofenac); 이소트레티노인(isotretinoin); 에티드로네이트 디소듐(etidronate disodium); 독시플루리딘(doxifluridine); 포스포미신 칼슘(fosfomycin calcium); 조테핀(zotepine); 에피나스틴 하이드로클로라이드(epinastine hydrochloride); 카베딜롤(carvedilol); 포시노프릴(fosinopril); 트란돌라프릴(trandolapril); 에트레티네이트 캅(etretinate cap); 메테르골린(metergoline); 머캅토퓨린(mercaptopurine); 반코마이신 하이드로클로라이드(vancomycin hydrochlroide); 세픽심(cefixime); 세푸록심 악세틸(cefuroxim axetil); 디리트라마이신(dirithramycin); 디다노신(didanosine) 등에 이용될 수 있으며, 바람직하게는 케토코나졸, 이트라코나졸 및 그의 유도체, 시사프라이드, 아세클로페낙,사이클로스포린 및 니페디핀 등에 이용될 수 있다.The solid dispersion agent of the present invention may be used in all poorly soluble drug groups having low solubility, preferably ketoconazole; Itraconazoles and derivatives thereof; Cyclosporine; Cisapride; Acetaminophen; Aspirin; Acetylsalicylic acid; Indomethacin; Naproxen; Warfarin; Papaverine; Thiobendazole; Miconazole; Cinnarizine; Doxorubicin; Omeprazole; Cholecalciferol; Melphalan; Nifedipine; Digoxin; Benzoic acid; Tryptophan; Tyrosine; Phenylalanine; Aztreonam; Ibuprofen; Phenoxymethylpenicillin; Thalidomide; Methyltestosterone; Prochlorperazine; Hydrocortisone; Dideoxypurine nucleoside; Vitamin D 2 (vitamin D 2 ); Sulfonamides; Sulfonylureas; Para-aminobenzoic acid; Melatonin; Benzylpenicillin; Chlorambucil; Diazepin; Digitoxin (digitoxin); Hydrocortisone butyrate; Metronidazole benzoate; Tolbutamide; Prostaglandin (prostaglandin E1 (PGE 1 )); Fludrocortisone; Griseofulvin; Miconazole nitrate; Leukotriene B 4 antagonist; Propranolol; Theophylline; Flubiprofen; Sodium benzoate; Benzoic acid; Riboflavin; Benzodiazepine; Phenobarbital; Glyburide; Sulfadiazine; Sulfaethylthiadiazole; Sodium diclofenac; Phyniroin; Hioridazinehydrochloride; Bropirimine; Hydrochlorothiazide; Or fluconazole; Acyclovir; Bucillamine; Ciprofluoxacin; Acetyl-L-carnitine; Itraconazole; Baclofen; Sodium alendronate; Lobocarnitine; Nimodipine or nimodifine; Atenolol; Pravastatin sodium; Lovastatin; Aceclofenac; Isotretinoin; Etidronate disodium; Doxifluridine; Fosfomycin calcium; Zotepine; Epinastine hydrochloride; Carvedilol; Fosinopril; Trandolapril; Etretinate cap; Metergoline; Mercaptopurine; Vancomycin hydrochlroide; Cefixime; Cefuroxim axetil; Dirithramycin; Didanosine and the like, and preferably ketoconazole, itraconazole and its derivatives, cisapride, aceclofenac, cyclosporine, nifedipine and the like.
본 발명의 고형분산분말제제를 제조하기 위해 우선, 난용성 약물을 오일, 지방산 또는 이들의 혼합물에 균등히 혼화·분산시킨 후, 상온 혹은 약 60∼80 ℃의온도에서 녹인 수용성 고분자 기제에 가하여 신속히 상온으로 냉각한 다음 오븐에서 12시간 이상 건조한다. 건조된 고형분산제제를 유발에서 분말화한 후, 체를 사용하여 일정 크기의 분말을 얻는다. 전술한 바와 같이 약물을 오일, 지방산 또는 이들의 혼합물에 용해 또는 분산시키는 과정에서 오일 및 지방산을 에멀젼화하여, 또는 마이크로에멀젼화하여 사용할 수 있으며 또한, 이 과정에서 계면활성제를 더 첨가할 수 있다.In order to prepare the solid dispersion powder preparation of the present invention, first, the poorly soluble drug is mixed and dispersed evenly in an oil, a fatty acid or a mixture thereof, and then rapidly added to a water-soluble polymer base dissolved at room temperature or about 60 to 80 ° C. After cooling down, it is dried in an oven for at least 12 hours. After the dried solid dispersion is powdered in the mortar, a sieve is used to obtain a powder of a certain size. As described above, the oil and the fatty acid may be emulsified or microemulsified in the process of dissolving or dispersing the drug in the oil, the fatty acid or a mixture thereof, and further, a surfactant may be further added in the process.
한편, 난용성 약물을 오일, 지방산 또는 이들의 혼합물에 균등하게 혼화, 분산시킨 후, 상온 혹은 약 60∼80℃의 온도에서 녹인 수용성 고분자 기제에 가하여 혼합한 다음 상기 혼합액을 약학적으로 허용되는 핵에 분사하여 고형분산과립제제의 형태로 제조할 수도 있다.On the other hand, the poorly soluble drug is mixed and dispersed evenly in oil, fatty acids or mixtures thereof, and then added to a water-soluble polymer base dissolved at room temperature or about 60 ~ 80 ℃ and mixed, and then the mixed solution is a pharmaceutically acceptable nucleus It can also be prepared in the form of a solid dispersion granules by spraying on.
본 발명의 고형분산제제에 대하여 증류수 및 인공장액에서의 용해도를 알아본 결과, 난용성 약물 자체의 분말에 비해 본 발명의 고형분산제제의 용해도가 증가하였으며, 특히, 올레인산을 함유한 고형분산제제 및 올레인산을 함유하는 마이크로에멀젼을 사용한 고형분산제제에서 난용성 약물의 용해도가 현저히 증가함을 알 수 있었다.As a result of checking the solubility in distilled water and artificial intestine solution for the solid dispersion agent of the present invention, the solubility of the solid dispersion agent of the present invention was increased compared to the powder of the poorly soluble drug itself, in particular, the solid dispersion agent containing oleic acid and It was found that the solubility of the poorly soluble drug was significantly increased in the solid dispersion using the microemulsion containing oleic acid.
한편, 본 발명의 고형분산제제에 대하여 인공위액 및 인공장액에서의 용출실험을 수행한 결과, 난용성 약물 자체의 분말에 비해 본 발명의 고형분산제제의 용출속도가 증가하였으며, 특히, 올레인산을 함유한 고형분산제제 및 올레인산을 함유하는 마이크로에멀젼을 사용한 고형분산제제에서 난용성 약물의 용출속도가 현저히 증가함을 알 수 있었고, 이러한 고형분산제제에 의해 용출속도가 증가되는 현상은 약물의 난용성 조건인 인공장액에서 더욱 현저히 나타남을 알 수 있었다.On the other hand, as a result of the dissolution test in artificial gastric juice and intestinal fluid with respect to the solid dispersion of the present invention, the dissolution rate of the solid dispersion of the present invention increased compared to the powder of the poorly soluble drug itself, in particular, containing oleic acid It was found that the dissolution rate of the poorly soluble drug was significantly increased in the solid dispersion using a solid dispersion and a microemulsion containing oleic acid. It was found to be more prominent in phosphorus artificial intestinal fluid.
한편, 본 발명의 고형분산제제에 대하여 위장관에서의 흡수성을 알아 본 실험 결과, 단순히 가용성 기제만을 사용한 경우에도 약물의 흡수율이 약간 증가하였으나, 올레인산을 함유하는 고형분산제제에서 난용성 약물의 흡수율이 더욱 증가하였으며, 특히 올레인산을 함유하는 마이크로에멀젼을 사용한 고형분산제제에서 난용성 약물의 흡수율이 현저히 증가함을 알 수 있었다.On the other hand, as a result of experiments to determine the absorbency in the gastrointestinal tract of the solid dispersion of the present invention, the absorption rate of the drug slightly increased even if only soluble base was used, but the absorption rate of the poorly soluble drug in the solid dispersion containing oleic acid is further increased. In particular, it was found that the absorption rate of poorly soluble drugs was significantly increased in the solid dispersion using microemulsion containing oleic acid.
또한, 본 발명에서 제조된 고형분산제제와 시판제제를 경구 투여한 후에 혈중농도 양상을 알아보는 비교 실험 결과, 본 발명에서 제조된 고형분산제제가 시판제제와 유사한 혈중농도 양상을 보여, 제제학적 관점에서 시판 제제를 대체할 수 있다는 것을 알 수 있었다.In addition, as a result of a comparative experiment to determine the blood concentration pattern after oral administration of the solid dispersion and commercial formulation prepared in the present invention, the solid dispersion prepared in the present invention showed a similar blood concentration pattern as the commercial formulation, from a pharmaceutical standpoint It was found that commercial formulations could be substituted.
이하 본 발명을 실시예에 의하여 더욱 상세하게 설명한다.Hereinafter, the present invention will be described in more detail with reference to Examples.
단, 하기 실시예들은 본 발명을 예시하는 것으로 본 발명의 내용이 실시예에 의해 한정이 되는 것은 아니다.However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the examples.
실시예에 앞서, 하기 제조예는 실시예에 사용되는 에멀젼 및 마이크로에멀젼의 조성을 나타낸다.Prior to the examples, the following preparations show the composition of the emulsions and microemulsions used in the examples.
에멀젼emulsion
<제조예 1><Manufacture example 1>
왁스류 : KALCHOL 6870 ................... 1.800(%)Waxes: KALCHOL 6870 ......... 1.800 (%)
EMERSOL 132 .................... 1.000(%)EMERSOL 132 ..... 1.000 (%)
멀티 왁스 W-445 ................. 1.700Multi Wax W-445 ......... 1.700
유화제 : ATLAS G-114 .................... 1.800Emulsifier: ATLAS G-114 ..................... 1.800
ATLAS G-610 .................... 1.900ATLAS G-610 ..................... 1.900
ATMOS 370 ...................... 0.800ATMOS 370 ...... 0.800
KM-105 ......................... 2.000KM-105 ............... 2.000
오일류 : CRODALAN SWL ..................... 1.500OIL: CRODALAN SWL ..................... 1.500
LEXOL GT 865 ..................... 4.000LEXOL GT 865 ........... 4.000
NIKKOL CIO ....................... 4.000NIKKOL CIO ....................... 4.000
SUPERIOR JOJOBA OIL ............... 1.000SUPERIOR JOJOBA OIL ............... 1.000
SF 1202 .......................... 0.200SF 1202 ..................... 0.200
KF-96(100CS) ...................... 0.300KF-96 (100CS) ... 0.300
DRAKEOL 7 ........................ 5.000DRAKEOL 7 ........................ 5.000
스쿠알란 .......................... 2.000Squalane ..................... 2.000
dl-a-토코페릴 아세테이트 ........... 0.100dl-a-tocopheryl acetate ........... 0.100
POLYOLPERPOLYMER-2 ................. 0.200POLYOLPERPOLYMER-2 ................. 0.200
수상 : DI-WATER .......................... 60.852Award: DI-WATER ........... 60.852
글리세린 ........................... 2.000Glycerin ................. 2.000
P.G .............................. 7.000P.G .............................. 7.000
NATURAL EXT. AP ..................... 0.500NATURAL EXT. AP ........... 0.500
LUBRAGEL CG ........................ 0.200LUBRAGEL CG ........................ 0.200
카보폴 940 ........................ 0.100Carbopol 940 ........................ 0.100
KELTROL F .......................... 0.020KELTROL F ..................... 0.020
수산화나트륨 ........................ 0.028Sodium Hydroxide ..................... 0.028
<제조예 2><Manufacture example 2>
왁스류 : KALCHOL 6870 ........................ 1.800Waxes: KALCHOL 6870 ........................ 1.800
EMERSOL 132 .......................... 1.000EMERSOL 132 ..................... 1.000
멀티 왁스 W-445 ....................... 1.700Multi Wax W-445 ......... 1.700
유화제 : RHEODOL AO-15 ......................... 0.800Emulsifier: RHEODOL AO-15 ............... 0.800
RHEODOL MS-162 ......................... 2.000RHEODOL MS-162 .................... 2.000
RHEODOL TW-S120 ........................ 1.900RHEODOL TW-S120 ........................ 1.900
KM-105 ................................. 2.000KM-105 ................................. 2.000
오일류 : CRODALAN SWL ............................ 1.500OIL: CRODALAN SWL ...... 1.500
LEXOL GT 865 ............................. 5.000LEXOL GT 865 ...... 5.000
NIKKOL CIO .............................. 2.500NIKKOL CIO ............... 2.500
마카다미아 열매유 ........................ 1.000Macadamia Fruit Oil .....................
SF 1202 ................................. 0.300SF 1202 ....................... 0.300
KF-96(100CS) ............................. 0.300KF-96 (100CS) ............. 0.300
DRAKEOL 7 ............................... 7.000DRAKEOL 7 ..................... 7.000
스쿠알란 ................................ 0.500Squalane ............ 0.500
dl-a-토코페릴 아세테이트 .................. 0.100dl-a-tocopheryl acetate .................. 0.100
POLYOLPERPOLYMER-2 ......................... 0.100POLYOLPERPOLYMER-2 ..................... 0.100
수상 : DI-WATER ................................. 61.780Award: DI-WATER ........................ 61.780
글리세린 .................................. 2.000Glycerin ..................... 2.000
1,3-B.G ................................... 6.0001,3-B.G ......... 6.000
NATURAL EXT. AP ............................ 0.300NATURAL EXT. AP ............ 0.300
LUBRAGEL CG ............................... 0.200LUBRAGEL CG ............... 0.200
카보폴 940 ................................ 0.100Carbopol 940 ...
KELTROL F ................................. 0.020KELTROL F ..................... 0.020
T E A ..................................... 0.100T E A ..................................... 0.100
<제조예 3><Manufacture example 3>
왁스류 : KALCHOL 6870 ............................. 0.500Waxes: KALCHOL 6870 ............. 0.500
EMERSOL 132 .............................. 0.500EMERSOL 132 ..................... 0000
비스 왁스 ................................ 0.400Bis wax ...... 0.400
유화제 : ATLAS G-114 .............................. 2.200Emulsifier: ATLAS G-114 .............. 2.200
ATLAS G-610 ............................... 0.800ATLAS G-610 ............... 0.800
ATMOS 370 .................................. 0.800ATMOS 370 .........
KM-105 .................................... 0.700KM-105 ..................... 0.700
오일류 : CRODALAN SWL ............................... 0.500OIL: CRODALAN SWL ..................... 0.500
LEXOL GT 865 ............................... 3.000LEXOL GT 865 ............... 3.000
NIKKOL CIO ................................. 3.000NIKKOL CIO ......................... 3.000
SUPERIOR JOJOBA OIL ........................ 0.500SUPERIOR JOJOBA OIL ........................ 0.500
SF 1202 .................................... 0.200SF 1202 ..................... 0.200
KF-96(100CS) ................................ 0.100KF-96 (100CS) .................. 0.100
DRAKEOL 7 ................................... 3.000DRAKEOL 7 ................................... 3.000
스쿠알란 .................................... 0.500Squalane ......................................... 0.500
dl-a-토코페릴 아세테이트 .................... 0.100dl-a-tocopheryl acetate ..................... 0.100
POLYOLPERPOLYMER-2 .......................... 0.200POLYOLPERPOLYMER-2 ..................... 0.200
수상 : DI-WATER ................................... 74.146Award: DI-WATER ..................... 74.146
글리세린 .................................... 2.000Glycerin ..................... 2.000
P. G ...................................... 6.000P. G .........
NATURAL EXT. AP ............................ 0.500NATURAL EXT. AP ............... 0.500
LUBRAGEL CG ................................ 0.200LUBRAGEL CG ......... 0.200
카보폴 940 ................................ 0.100Carbopol 940 ...
KELTROL F .................................. 0.020KELTROL F ..................... 0.020
수산화나트륨 ............................... 0.0336Sodium Hydroxide ......................................... 0.0336
<제조예 4><Manufacture example 4>
왁스류 : KALCHOL 6870 ................................. 0.400Waxes: KALCHOL 6870 ................................. 0.400
EMERSOL 132 ................................... 0.500EMERSOL 132 .................... 0.500
멀티 왁스 W-445 ............................... 0.400Multi Wax W-445 ............... 0.400
유화제 : RHEODOL AO-15 ................................. 0.800Emulsifier: RHEODOL AO-15 ................................. 0.800
RHEODOL MS-165 ................................. 2.200RHEODOL MS-165 ................................. 2.200
RHEODOL TW-S120 ................................ 0.800RHEODOL TW-S120 .................. 0.800
KM-105 ......................................... 0.600KM-105 ......................................... 0.600
오일류 : CRODALAN SWL ................................... 0.500OIL: CRODALAN SWL ................................. 0.500
LEXOL GT 865 .................................... 3.000LEXOL GT 865 ..................... 3.000
NIKKOL CIO ...................................... 2.000NIKKOL CIO ..................... 2.000
마카다미아 열매유 ............................... 1.000Macadamia Fruit Oil .....................
SF 1202 ......................................... 0.400SF 1202 ............... 0.400
DRAKEOL 7 ....................................... 4.500DRAKEOL 7 ....................... 4.500
스쿠알란 ........................................ 0.500Squalane ....................................... 0.500
dl-a-토코페릴 아세테이트 ........................ 0.100dl-a-tocopheryl acetate ........................ 0.100
POLYOLPERPOLYMER-2 .............................. 0.100POLYOLPERPOLYMER-2 .............. 0.100
수상 : DI-WATER ....................................... 73.480Award: DI-WATER ........................ 73.480
글리세린 ....................................... 2.000Glycerin ..................... 2.000
1,3-B.G ........................................ 6.0001,3-B.G ........................ 6.000
NATURAL EXT. AP ................................ 0.300NATURAL EXT. AP ....................... 0.300
LUBRAGEL CG .................................... 0.200LUBRAGEL CG ..................... 0.200
카보폴 941 ..................................... 0.100Cabopol 941 ..................... 0.100
KELTROL F ...................................... 0.020KELTROL F ..................... 0.020
T E A .......................................... 0.100T E A ..................... 0.100
마이크로에멀젼Microemulsion
<제조예 5>Production Example 5
왁스류 : 세틸 알콜 ...................................... 3.000Waxes: Cetyl Alcohol ...
유화제 : NIKKOL HCO-60 .................................. 5.000Emulsifier: NIKKOL HCO-60 ........................ 50
RHEODOL TW-O120 ................................ 5.000RHEODOL TW-O120 ...... 5.000
크레모포 EL .................................... 20.000Cremofo EL .................................... 20.000
오일류 : I.P.M .......................................... 5.000Oils: I.P.M ..................... 5.000
CAPTEX .......................................... 5.000CAPTEX ..................... 5.000
수상 : DI-WATER ......................................... 52.000Award: DI-WATER ......................... 52.000
에탄올 ........................................... 5.000Ethanol ..................................... 5.000
<제조예 6><Manufacture example 6>
유화제 : NIKKOL HCO-60 ................................... 5.000Emulsifier: NIKKOL HCO-60 ......................... 50
RHEODOL TW-O120 ................................... 5.000RHEODOL TW-O120 ......................... 50
크레모포 EL ....................................... 25.000Cremophor EL ......................... 25.000
오일류 : I.P.M ............................................ 5.000Oils: I.P.M ....................................... 5.000
라놀린유 ........................................... 5.000Lanolin oil ........................... 5.000
CAPTEX ............................................ 5.000CAPTEX ....................................... 5.000
수상 : DI-WATER .......................................... 50.000Award: DI-WATER ..................... 50.000
<제조예 7><Manufacture example 7>
계면활성제 : LABRASOL ....................................... 15.000Surfactant: LABRASOL ....................................... 15.000
보조계면활성제 : 폴리글리세릴 올레인산염 ...................... 5.000Cosurfactant: Polyglyceryl Oleate .........
PLURL OLEIQUE .................................. 5.000PLURL OLEIQUE ........................ 5.000
유상 : LABRAFIL M1994CS ..................................... 4.500Paid: LABRAFIL M1994CS ..................... 4.500
보조용매 : 트랜스쿠톨 .......................................... 5.000Cosolvent: Transcutol ......................................... 50
수상 : 인산완충액(pH 6) .................................... 64.500Award: Phosphate Buffer (pH 6) ......................... 64.500
<제조예 8><Manufacture example 8>
유상 : GELUCIRE 44/14 ...................................... 11.429Paid: GELUCIRE 44/14 ... 11.429
GELUCIRE 48/09 ....................................... 11.429GELUCIRE 48/09 ..................... 11.429
계면활성제 : LABRAFAC CM 10 .................................... 10.714Surfactant: LABRAFAC CM 10 ......................................... 10.714
보조계면활성제 : LAUROGLYCOL ................................... 7.143Cosurfactant: LAUROGLYCOL ...
트랜스쿠톨 ..................................... 59.285Transcutol ............... 59.285
<제조예 9><Manufacture example 9>
수상 : 물(완충액) .......................................... 57.050Water phase: water (buffer) ......................... 57.050
생리식염수 ........................................... 4.000Physiological saline ......................................... 4.000
포도당 ............................................. 1.000Glucose ......................................... 1.000
프로필렌 글리콜PEG 300,400 ........................... 5.000Propylene GlycolPEG 300,400 ........................... 5.000
글리세롤 ............................................. 5.000Glycerol ......................................................... 50
유상 : 지방산의 에스테르류 .................................. 5.000Oil phase: esters of fatty acids ........................ 50
변성 식물유 ......................................... 0.500Denatured vegetable oil ...............
실리콘 오일 .......................................... 0.500Silicone Oil ......................................... 0.500
보조계면활성제 : 긴사슬 알콜 ...................................... 3.750Auxiliary Surfactant: Long Chain Alcohol ............... 750
글리콜의 유도체 ................................... 2.500Derivatives of Glycol ............... 2500
프로필렌 글리콜의 유도체 .......................... 1.200Derivatives of Propylene Glycol ............................... 200
폴리글리세롤의 유도체 ............................. 4.500Derivatives of Polyglycerol ............... 500
계면활성제 : 비이온성 계면활성제 ................................ 10.000Surfactant: Nonionic Surfactant ....................... 10.000
<제조예 10>Production Example 10
유상 : 올레인산 ............................................. 6.250Oily price: Oleic acid ......................................................... 6.250
계면활성제 : 트윈 80 ........................................... 12.500Surfactant: Tween 80 ..................................... 12.500
보조계면활성제 : 트랜스쿠톨 .................................... 8.750Cosurfactant: Transcutol ............... 750
수상 : 물 .................................................. 72.500Water: Water ......................................... ... 72.500
<제조예 11>Production Example 11
유상 : 카프텍스 ............................................ 5.000Paid: Captex ............................ 50
계면활성제 : 크레모포 ......................................... 12.500Surfactant: Cremofo ......................................... 12.500
보조계면활성제 : 트랜스쿠톨 .................................... 6.250Cosurfactant: Transcutol ......................................................... 6.250
수상 : 물 ................................................. 76.250Water: Water ......................................... .. 76.250
<비교예 1>Comparative Example 1
PEG 6000 90 g을 약 70 ℃의 온도에서 녹인 후, 녹인 PEG 용액에 케토코나졸 10 g을 가하여 신속히 상온으로 냉각한 다음 오븐에서 12시간 이상 건조하였다. 건조된 고형분산제제를 유발에서 곱게 갈아 분말로 만든 후, 체를 사용하여 일정 크기의 분말을 얻었다.After dissolving 90 g of PEG 6000 at a temperature of about 70 ° C., 10 g of ketoconazole was added to the dissolved PEG solution, and then rapidly cooled to room temperature, and then dried in an oven for at least 12 hours. The dried solid dispersion was ground finely in a mortar into a powder, and then a size of powder was obtained using a sieve.
<실시예 1><Example 1>
PEG 6000 85 g을 약 70 ℃의 온도에서 녹인 후, 케토코나졸 10 g을 올레인산 5 g에 녹여 균등하게 혼화·분산시킨 다음 PEG 용액에 가하여 신속히 상온으로 냉각한 다음 오븐에서 12시간 이상 건조하였다. 건조된 고형분산제제를 유발에서 곱게 갈아 분말로 만든 후, 체를 사용하여 일정 크기의 분말을 얻었다..After dissolving 85 g of PEG 6000 at a temperature of about 70 ° C., 10 g of ketoconazole was dissolved in 5 g of oleic acid, mixed and dispersed evenly, and then added to a PEG solution, cooled to room temperature rapidly, and dried in an oven for 12 hours or more. The dried solid dispersion was ground finely in a mortar to make powder, and then powder was obtained using a sieve.
<실시예 2><Example 2>
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 케토코나졸 10 g을 올레인산 5 g 및 트윈 80 (Tween 80)에 녹여 균등히 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PEG 6000 at a temperature of about 70 ° C., 10 g of ketoconazole was dissolved in 5 g of oleic acid and Tween 80, mixed and dispersed evenly, and then added to the PEG solution in the same manner as in Example 1 A powder of size was obtained.
<실시예 3><Example 3>
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 케토코나졸 10 g을 이소프로필미리스테이트 5 g에 녹여 균등히 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PEG 6000 at a temperature of about 70 ° C., 10 g of ketoconazole was dissolved in 5 g of isopropyl myristate, mixed and dispersed evenly, and then added to the PEG solution to prepare a powder of a predetermined size in the same manner as in Example 1. Got it.
<실시예 4><Example 4>
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 케토코나졸 10 g을 리퀴드 파라핀 (liquid paraffin) 5 g에 녹여 균등히 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PEG 6000 at a temperature of about 70 ° C., 10 g of ketoconazole was dissolved in 5 g of liquid paraffin, mixed and dispersed evenly, and then added to the PEG solution in the same manner as in Example 1 A powder was obtained.
<실시예 5>Example 5
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 케토코나졸 10 g을 크레모포 5 g에 녹여 균등하게 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PEG 6000 at a temperature of about 70 ° C., 10 g of ketoconazole was dissolved in 5 g of cremophor, mixed and dispersed evenly, and then added to the PEG solution to obtain a powder having a predetermined size in the same manner as in Example 1. .
<실시예 6><Example 6>
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 케토코나졸 10 g을 크레모포 5 g 및 트윈 80 5 g에 녹여 균등하게 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PEG 6000 at a temperature of about 70 ° C., 10 g of ketoconazole was dissolved in 5 g of cremofo and 5 g of tween 80, mixed and dispersed evenly, and then added to the PEG solution in the same manner as in Example 1 A powder of size was obtained.
<실시예 7><Example 7>
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 케토코나졸 10 g을 이소프로필미리스테이트 5 g 및 트윈 80 5 g에 녹여 균등하게 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PEG 6000 at a temperature of about 70 ° C., 10 g of ketoconazole was dissolved in 5 g of isopropyl myristate and 5 g of Tween 80, mixed and dispersed evenly, and then added to the PEG solution as in Example 1 Powder of a certain size was obtained.
<실시예 8><Example 8>
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 케토코나졸 10 g을 리퀴드 파라핀 5 g 및 트윈 80 5 g에 녹여 균등하게 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PEG 6000 at a temperature of about 70 ° C., 10 g of ketoconazole was dissolved in 5 g of liquid paraffin and 5 g of tween 80, mixed and dispersed evenly, and then added to the PEG solution in the same manner as in Example 1 A powder of size was obtained.
<실시예 9>Example 9
우선, 크레모포 5 g, 올레인산 5 g, 알콜 35 g 및 트랜스쿠톨 (Transcutol) 1g을 함유하는 마이크로에멀젼에 케토코나졸 10 g을 녹여 균등하게 혼화·분산시킨 후, 오븐에서 알콜을 증발시켰다. 건조된 고형 성분을 미리 70 ℃의 온도에서 녹인 43 g의 PEG 6000 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.First, 10 g of ketoconazole was dissolved in a microemulsion containing 5 g of cremofo, 5 g of oleic acid, 35 g of alcohol, and 1 g of transcutol, and then mixed and dispersed evenly, and the alcohol was evaporated in an oven. The dried solid component was added to 43 g of a PEG 6000 solution, which was previously dissolved at a temperature of 70 ° C., to obtain a powder having a predetermined size in the same manner as in Example 1.
<실시예 10><Example 10>
우선, 크레모포 5 g, 올레인산 5 g 및 트랜스쿠톨 1 g을 함유하는 마이크로에멀젼에 케토코나졸 10 g을 녹여 균등하게 혼화한 후 증류수 35 g을 가하여 분산시킨 다음 오븐에서 증류수를 증발시켰다. 건조된 고형 성분을 미리 70 ℃의 온도에서 녹인 43 g의 PEG 6000 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.First, 10 g of ketoconazole was dissolved and mixed in a microemulsion containing 5 g of cremofo, 5 g of oleic acid, and 1 g of transcutol, and then mixed with 35 g of distilled water. The dried solid component was added to 43 g of PEG 6000 solution, which was previously dissolved at a temperature of 70 ° C., to obtain a powder having a predetermined size in the same manner as in Example 1.
<실시예 11><Example 11>
우선, 올레인산 5 g에 케토코나졸 10 g을 녹여 균등하게 혼화·분산시킨 후, 장용성 기제인 히드록시프로필메틸셀룰로오스 (hydroxypropylmethylcelullose) 40 g을 미리 70 ℃의 온도에서 녹인 40 g의 PEG 6000 용액에 가하고, 여기에 상기 혼합물을 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.First, 10 g of ketoconazole is dissolved in 5 g of oleic acid, mixed and dispersed evenly, and then 40 g of hydroxypropylmethyl cellulose (enteric enteric substance) is added to 40 g of PEG 6000 solution previously dissolved at a temperature of 70 ° C. To the mixture was added to obtain a powder of a certain size in the same manner as in Example 1.
<실시예 12><Example 12>
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 이트라코나졸 10 g을 올레인산 5 g에 녹여 균등하게 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.80 g of PEG 6000 was dissolved at a temperature of about 70 ° C., 10 g of itraconazole was dissolved in 5 g of oleic acid, mixed and dispersed evenly, and then added to the PEG solution to obtain a powder having a predetermined size in the same manner as in Example 1.
<실시예 13>Example 13
우선, 올레인산 5 g에 이트라코나졸 10 g을 녹여 균등하게 혼화·분산시킨 후, 장용성 기제인 히드록시프로필메틸셀룰로오스 40 g을 미리 70 ℃의 온도에서 녹인 40 g의 PEG 6000 용액에 가하여 가하고, 여기에 상기 혼합물을 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.First, 10 g of itraconazole was dissolved in 5 g of oleic acid, mixed and dispersed evenly, and then 40 g of hydroxypropylmethylcellulose, an enteric base, was added to a 40 g PEG 6000 solution previously dissolved at a temperature of 70 ° C., and the above was added thereto. The mixture was added to obtain a powder of a certain size in the same manner as in Example 1.
<실시예 14><Example 14>
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 이트라코나졸 유도체 (동아제약 합성) 10 g을 올레인산 5 g에 녹여 균등하게 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PEG 6000 at a temperature of about 70 ° C., 10 g of itraconazole derivative (synthesis of Dong-A Pharmaceutical) was dissolved in 5 g of oleic acid, mixed and dispersed evenly, and then added to the PEG solution in the same manner as in Example 1 A powder of size was obtained.
<실시예 15><Example 15>
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 사이클로스포린 10 g을 올레인산 5 g에 녹여 균등하게 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PEG 6000 at a temperature of about 70 ° C., 10 g of cyclosporin was dissolved in 5 g of oleic acid, mixed and dispersed evenly, and then added to the PEG solution to obtain a powder having a predetermined size in the same manner as in Example 1.
<실시예 16><Example 16>
우선, 사이클로스포린 10 g을 올레인산 5 g에 녹여 균등하게 혼화·분산시킨 후, 장용성 기제인 히드록시프로필메틸셀룰로오스 40 g을 미리 70 ℃의 온도에서 녹인 40 g의 PEG 6000 용액에 가하고, 여기에 상기 혼합물을 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.First, 10 g of cyclosporine is dissolved in 5 g of oleic acid, mixed and dispersed evenly, and then 40 g of an enteric base hydroxypropylmethylcellulose is added to a 40 g PEG 6000 solution previously dissolved at a temperature of 70 ° C., and the mixture is added thereto. Was added to obtain a powder of a certain size in the same manner as in Example 1.
<실시예 17><Example 17>
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 시사프라이드 10 g을 올레인산 5 g에 녹여 균등하게 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PEG 6000 at a temperature of about 70 ° C., 10 g of cisapride was dissolved in 5 g of oleic acid, mixed and dispersed evenly, and then added to the PEG solution to obtain a powder having a predetermined size in the same manner as in Example 1.
<실시예 18>Example 18
PEG 6000 80 g을 약 70 ℃의 온도에서 녹인 후, 시사프라이드 10 g을 올레인산 5 g 및 트윈 80 5 g에 녹여 균등하게 혼화·분산시킨 다음, 상기 PEG 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PEG 6000 at a temperature of about 70 ° C., 10 g of cisapride was dissolved in 5 g of oleic acid and 5 g of tween 80, mixed and dispersed evenly, and then added to the PEG solution in the same manner as in Example 1 A powder of size was obtained.
<실시예 19>Example 19
우선, 크레모포 10 g, 올레인산 5 g 및 트랜스쿠톨 7 g을 함유하는 마이크로에멀젼에 이트라코나졸 10 g을 녹여 균등하게 혼화·분산시킨 후, 오븐에서 알콜을 증발시켰다. 건조된 고형 성분을 미리 70 ℃의 온도에서 녹인 43 g의 PEG 6000 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.First, 10 g of itraconazole was dissolved in a microemulsion containing 10 g of cremofo, 5 g of oleic acid, and 7 g of transcutol, and then mixed and dispersed evenly, and the alcohol was evaporated in an oven. The dried solid component was added to 43 g of a PEG 6000 solution, which was previously dissolved at a temperature of 70 ° C., to obtain a powder having a predetermined size in the same manner as in Example 1.
<실시예 20>Example 20
우선, 크레모포 10 g, 카프텍스 (captex) 4 g 및 트랜스쿠톨 5 g을 함유하는마이크로에멀젼에 사이클로스포린 10 g을 녹여 균등하게 혼화·분산시킨 후, 오븐에서 알콜을 증발시켰다. 건조된 고형 성분을 미리 70 ℃의 온도에서 녹인 43 g의 PEG 6000 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.First, 10 g of cyclosporin was dissolved in a microemulsion containing 10 g of cremofo, 4 g of captex, and 5 g of transcutol, and then mixed and dispersed evenly, and the alcohol was evaporated in an oven. The dried solid component was added to 43 g of a PEG 6000 solution, which was previously dissolved at a temperature of 70 ° C., to obtain a powder having a predetermined size in the same manner as in Example 1.
<실시예 21>Example 21
우선, 크레모포 10 g, 올레인산 5 g 및 트랜스쿠톨 7 g을 함유하는 마이크로에멀젼에 시사프라이드 10 g을 녹여 균등하게 혼화·분산시킨 후, 오븐에서 알콜을 증발시켰다. 건조된 고형 성분을 미리 70 ℃의 온도에서 녹인 43 g의 PEG 6000 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.First, 10 g of cisapride was dissolved in a microemulsion containing 10 g of cremofo, 5 g of oleic acid, and 7 g of transcutol, mixed and dispersed evenly, and the alcohol was evaporated in an oven. The dried solid component was added to 43 g of a PEG 6000 solution, which was previously dissolved at a temperature of 70 ° C., to obtain a powder having a predetermined size in the same manner as in Example 1.
<실시예 22><Example 22>
PVP 80 g을 녹인 후, 케토코나졸 10 g을 올레인산 5 g에 녹여 균등하게 혼화·분산시킨 다음, 상기 PVP 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PVP, 10 g of ketoconazole was dissolved in 5 g of oleic acid, mixed and dispersed evenly, and then added to the PVP solution to obtain a powder having a predetermined size in the same manner as in Example 1.
<실시예 23><Example 23>
PVP 80 g을 녹인 후, 올레인산 5 g을 함유하는 마이크로에멀젼에 케토코나졸 10 g을 가하여 균등하게 혼화·분산시킨 것을 녹인 PVP 용액에 가하여 실시예 1과 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 80 g of PVP, 10 g of ketoconazole was added to a microemulsion containing 5 g of oleic acid, and then mixed and dispersed evenly to the dissolved PVP solution to obtain a powder having a predetermined size in the same manner as in Example 1.
<비교예 2>Comparative Example 2
PEG 6000 2.5g을 약 75℃의 온도에서 녹인 후, 녹인 PEG 용액에 아세클로페낙 1.75g을 가하여 신속히 냉각한 다음, 동결 건조기에서 24시간 이상 동결 건조하였다. 건조된 고형분산제제를 그라인더에서 곱게 갈아 분말로 만든 후, 체를 사용하여 일정크기의 분말을 얻었다.After 2.5 g of PEG 6000 was dissolved at a temperature of about 75 ° C., 1.75 g of aceclofenac was added to the dissolved PEG solution, which was then rapidly cooled, and lyophilized in a freeze dryer for at least 24 hours. The dried solid dispersion was ground finely in a grinder to form a powder, and then a sieve was used to obtain a powder of a certain size.
<실시예 24><Example 24>
PEG 6000 2.5g을 약 75℃의 온도에서 녹인 후, 아세클로페낙 1.75g을 올레인산 0.25g과 트윈 80 (Tween 80) 0.50g에 녹여 균등하게 혼화 및 분산시킨 것을 녹인 PEG 용액에 가하여 신속히 냉각한 다음, 동결건조기에서 24시간 이상 동결 건조하였다. 건조된 고형분산제제를 그라인더에서 곱게 갈아 분말로 만든 후, 체를 사용하여 일정크기의 분말을 얻었다..After dissolving 2.5 g of PEG 6000 at a temperature of about 75 ° C., 1.75 g of aceclofenac was dissolved in 0.25 g of oleic acid and 0.50 g of Tween 80, and then mixed and dispersed evenly to the dissolved PEG solution, and then rapidly cooled. Lyophilized in a drier for at least 24 hours. The dried solid dispersion was ground finely in a grinder to form a powder, and then a sieve was used to obtain a powder of a predetermined size.
<실시예 25><Example 25>
PEG 6000 2.5g을 약 75℃의 온도에서 녹인 후, 아세클로페낙 1.75g을 크레모포 0.25g과 트윈 80 0.50g에 녹여 균등하게 혼화 및 분산시킨 것을 녹인 PEG 용액에 가하여 실시예 24와 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 2.5 g of PEG 6000 at a temperature of about 75 ° C., 1.75 g of aceclofenac was dissolved in 0.25 g of Cremofo and 0.50 g of Tween 80, and then mixed and dispersed in an equal amount to PEG solution. Powder was obtained.
<실시예 26>Example 26
PEG 6000 2.5g을 약 75℃의 온도에서 녹인 후, 아세클로페낙 1.75g을 라브라솔 0.25g과 트윈 80 0.50g에 녹여 균등하게 혼화 및 분산시킨 것을 녹인 PEG 용액에 가하여 실시예 24와 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 2.5 g of PEG 6000 at a temperature of about 75 ° C., 1.75 g of aceclofenac was dissolved in 0.25 g of Labrasol and 0.50 g of Tween 80, and then mixed and dispersed evenly to the dissolved PEG solution in the same manner as in Example 24. A powder of size was obtained.
<실시예 27>Example 27
PEG 6000 2.5g을 약 75℃의 온도에서 녹인 후, 아세클로페낙 1.75g을 트랜스쿠톨0.25g과 트윈 80 0.50g에 녹여 균등하게 혼화 분산시킨 것을 녹인 PEG 용액에 가하여 실시예 24와 같은 방법으로 일정 크기의 분말을 얻었다.After dissolving 2.5 g of PEG 6000 at a temperature of about 75 ° C., 1.75 g of aceclofenac was dissolved in 0.25 g of Transcutol and 0.50 g of Tween 80, and then mixed with the PEG solution. A powder was obtained.
<실시예 28><Example 28>
아세클로페낙 10g, 올레인산 2.5g, 트윈 80 2.5g, 탈크(talc) 5g과 PEG 6000 10g을 섞어 약 80℃의 온도로 가온한 다음 다시 알콜 150ml에 섞고 균등하게 혼화하였다. 상기 혼합액을 유동층 코팅장치 (노즐 0.8mm)를 사용하여 4ml/min의 속도로 35g의 슈가 미립구(sugar spheres)에 분사하여 고형분산과립를 제조하였다. 상기와 같이 제조된 과립을 빈 캡슐에 충전하여 캡슐로 제조하였다.10 g of aceclofenac, 2.5 g of oleic acid, 2.5 g of Tween 80, 5 g of talc and 10 g of PEG 6000 were mixed and warmed to a temperature of about 80 ° C., and then mixed again with 150 ml of alcohol and mixed evenly. The mixed solution was sprayed onto 35 g of sugar spheres at a rate of 4 ml / min using a fluidized bed coating apparatus (nozzle 0.8 mm) to prepare solid dispersed granules. The granules prepared as above were filled into empty capsules to prepare capsules.
<실시예 29><Example 29>
아세클로페낙 10g, 올레인산 2.5g, 트윈 80 2.5g, 탈크 3g, 유드래짓(Eudragit, 독일 Rhmpharm사 제품) RS30D 25g과 유드래짓 L30D 25g을 균등하게 혼화하였다. 상기 혼합액을 유동층 코팅장치 (노즐 0.8mm)를 사용하여 4ml/min의 속도로 분사하여, 실시예 28에서 제조된 약물이 함유된 35g의 슈가 미립구(sugar spheres)에 코팅하였다.Aceclofenac 10g, Oleic Acid 2.5g, Tween 80 2.5g, Talc 3g, Eudragit, Germany Rh mpharm) 25g of RS30D and 25g of Eudragit L30D were equally mixed. The mixed solution was sprayed at a rate of 4 ml / min using a fluidized bed coating apparatus (nozzle 0.8 mm) and coated on 35 g of sugar spheres containing the drug prepared in Example 28.
<실시예 30><Example 30>
아세클로페낙 10g, 올레인산 2.5g, 트윈 80 2.5g, 탈크 3g, 유드래짓 RS30D 50g를 균등히 혼화한 후 유동층 코팅장치 (노즐 0.8mm)를 사용하여 4ml/min의 속도로 분사하여, 실시예 28에서 제조된 약물이 함유된 35g의 슈가 미립구(sugar spheres)에 상기 혼합액을 코팅하였다.10 g of aceclofenac, 2.5 g of oleic acid, 2.5 g of Tween 80, 3 g of talc, 50 g of Eudragit RS30D were evenly mixed, and then sprayed at a rate of 4 ml / min using a fluidized bed coating apparatus (nozzle 0.8 mm) to prepare in Example 28. The mixture was coated on 35 g of sugar spheres containing the drug.
<실시예 31><Example 31>
시사프라이드 2.5g, 올레인산 2.5g, 트윈 80 2.5g, 탈크 5g과 PEG 6000 23g을 약 80℃의 온도로 가온한 후 다시 아세톤/물의 1:1 혼합액 150ml와 섞었다. 상기 혼합액을 유동층 코팅장치 (노즐 0.8mm)를 사용하여 4ml/min의 속도로 100g의 슈가 미립구에 분사하여 고형분산과립을 제조하였다.2.5 g of cisapride, 2.5 g of oleic acid, 2.5 g of Tween 80, 5 g of talc, and 23 g of PEG 6000 were warmed to a temperature of about 80 ° C. and again mixed with 150 ml of a 1: 1 mixture of acetone / water. The mixed solution was sprayed onto 100 g of sugar microspheres at a rate of 4 ml / min using a fluidized bed coating apparatus (nozzle 0.8 mm) to prepare solid dispersed granules.
<실시예 32><Example 32>
시사프라이드 2.5g, 올레인산 2.5g, 트윈 80 2.5g, 탈크 3g, 유드래짓 RS30D 25g과 유드래짓 L30D 25g를 아세톤 150ml와 균등히 혼화한 후 유동층 코팅장치 (노즐 0.8mm)를 사용하여 4ml/min의 속도로 실시예 31에서 제조된 약물이 함유된 70g의 슈가 미립구에 분사하여 코팅하였다.After mixing cisapride 2.5g, oleic acid 2.5g, Tween 80 2.5g, talc 3g, Eudragit RS30D 25g and Eudragit L30D 25g equally with 150ml of acetone, 4ml / min using a fluidized bed coating device (nozzle 0.8mm) 70 g of sugar microspheres containing the drug prepared in Example 31 was sprayed and coated at a rate of.
<실시예 33><Example 33>
아세클로페낙, 유당, 전분 및 탈크 등을 혼합하여 기존의 일반적인 방법으로 정제를 제조한 후 아세클로페낙 2.5g, 올레인산 2.5g, 트윈 80 2.5g, 탈크 3g, 유드래짓 RS30D 25g 과 유드래짓 L30D 25g을 균등하게 혼화한 액을 유동층 코팅장치(노즐 0.8mm)를 사용하여 4ml/min의 속도로 분사하여 고형분산 정제를 제조하였다.Aceclofenac, lactose, starch and talc are mixed to prepare tablets according to the conventional method, and then equalize aceclofenac 2.5g, oleic acid 2.5g, Tween 80 2.5g, talc 3g, Eudragit RS30D 25g and Eudragit L30D 25g. The mixed solution was sprayed at a rate of 4 ml / min using a fluidized bed coating apparatus (nozzle 0.8 mm) to prepare a solid dispersion tablet.
<실시예 34><Example 34>
시사프라이드, 유당, 전분 및 탈크 등을 혼합하여 기존의 일반적인 방법으로 정제를 제조한 후, 시사프라이드 2.5g, 올레인산 2.5g, 트윈 80 2.5g, 유드래짓 RS30D 25g 과 유드래짓 L30D 25g을 균등하게 혼화한 액을 유동층 코팅장치(노즐 0.8mm)를 사용하여 4ml/min의 속도로 분사하여 고형분산 정제를 제조하였다.After preparing the tablets by mixing cisapride, lactose, starch, and talc, the mixture of cisapride 2.5g, oleic acid 2.5g, Tween 80 2.5g, Eudragit RS30D 25g and Eudragit L30D 25g The mixed solution was sprayed at a rate of 4 ml / min using a fluidized bed coating apparatus (nozzle 0.8 mm) to prepare a solid dispersion tablet.
<실험예 1> 고형분산제제에 함유된 난용성 약물의 증류수 및 인공장액에서의<Experimental Example 1> Distilled water and artificial intestine of poorly soluble drugs contained in solid dispersion
용해도 측정Solubility Measurement
상기 <비교예> 및 <실시예>에서 제조된 난용성 약물을 함유하는 다양한 조성의 고형분산제제에 대해 증류수 및 인공장액에서의 용해도를 측정하기 위한 실험을 하였다. 먼저, 2 g의 고형분산제제를 증류수와 인공장액 각각에 녹여 얻어진 현탁액을 0.2 ㎛ 밀리포아 여과지(Millipore, Waters, Milford, MA, USA)로 여과한 후, 적절히 희석하여 약물 농도를 정량하였다. 그 결과 얻어진, 고형분산제제에 함유된 난용성 약물의 용해도는표 1에 나타나 있다.Experiments for measuring solubility in distilled water and artificial intestine were performed on solid dispersion agents of various compositions containing the poorly soluble drugs prepared in Comparative Examples and Examples. First, the suspension obtained by dissolving 2 g of the solid dispersion agent in each of distilled water and artificial intestine was filtered through 0.2 μm Millipore filter paper (Millipore, Waters, Milford, MA, USA), and then diluted appropriately to quantify drug concentration. As a result, the solubility of the poorly soluble drug contained in the solid dispersion is shown in Table 1 .
표 1에 나타난 바와 같이, 용액이 증류수인 경우 올레인산을 함유하는 고형분산제제에서의 약물의 용해도가 현저히 증가되었음을 알 수 있으며, 특히 올레인산을 함유하는 마이크로에멀젼을 사용하여 고형분산제제를 제조한 경우 증류수 및 인공장액에서의 약물의 용해도가 현저히 증가되었음을 알 수 있었다.As shown in Table 1 , it can be seen that the solubility of the drug in the solid dispersion containing oleic acid is significantly increased when the solution is distilled water, especially when the solid dispersion is prepared using a microemulsion containing oleic acid. And it was found that the solubility of the drug in the intestinal fluid significantly increased.
<실험예 2> 고형분산제제에 함유된 난용성 약물의 인공위액 및 인공장액에서의 용출속도 측정Experimental Example 2 Measurement of Dissolution Rate of Insoluble Soluble Drugs in Solid Dispersant
상기 <실시예>에서 제조된 케토코나졸 또는 시사프라이드 각각을 함유하는 고형분산제제에 대하여 인공위액 및 인공장액에서의 용출실험을 수행하였다.A solid dispersing agent containing each of ketoconazole or cisapride prepared in Example was carried out in an artificial gastric juice and intestinal fluid.
용출시험은 대한약전 제 6 개정 (KP VI)에 기재되어 있는 패들 (paddle)법에 의하여 인공위액 및 인공장액에서 수행하였다. 온도는 37±0.5 ℃로, 패들의 회전 속도는 50 rpm로 한 상태에서, 시간에 따라 인공위액 및 인공장액으로부터 시료를취한 후 0.2 ㎛ 밀리포아 여과지로 여과하여 여과액의 약물 농도를 정량하였다. 그 결과 얻어진 다양한 고형분산제제에 함유된 난용성 약물의 인공위액 및 인공장액에서의 용출농도 및 비율(%)이표 2와표 3에 각각 나타나 있다.The dissolution test was performed in gastric juice and intestinal fluid by the paddle method described in KP VI. With the temperature of 37 ± 0.5 ° C. and the rotational speed of the paddle at 50 rpm, samples were taken from the gastric juice and the intestinal fluid over time, and then filtered through 0.2 μm Millipore filter paper to quantify the drug concentration of the filtrate. The elution concentration and percentage (%) of the poorly soluble drugs in the various solid dispersions obtained as a result are shown in Table 2 and Table 3 , respectively.
표 2에 나타난 바와 같이, 케토코나졸은 약물 자체가 산성이므로 인공위액에서 어느정도 용출이 되었으나, 올레인산 함유 고형분산제제로부터의 약물의 용출이 상대적으로 더욱 증가되어 <실험예 1>의 결과와 같은 경향을 나타내었다. 한편 시사프라이드도 약물 자체의 용해도로 인해 어느 정도 용출이 되었으나, 고형분산제제로부터의 약물용출이 상대적으로 더욱 증가되어 케토코나졸과 같은 결과를 보였다.As shown in Table 2 , ketoconazole was eluted in artificial gastric fluid to some extent because the drug itself was acidic, but the dissolution of the drug from the oleic acid-containing solid dispersion was relatively increased, indicating the same trend as in <Experimental Example 1>. It was. On the other hand, cisapride was eluted to some extent due to the solubility of the drug itself, but the drug dissolution from the solid dispersant was relatively increased, showing the same result as ketoconazole.
고형분산제제에 의해 두 약물의 용출속도가 개선되는 효과는 두 약물의 난용성 조건인 인공장액에서 그 효과가 더욱 확실히 나타났다.표 3에 나타난 바와 같이, 지방산 및 오일을 함유하는 고형분산제제로부터의 약물 용출이 약물 분말에 비하여 우수하였고, 올레인산을 함유한 고형분산제제의 경우 그 개선효과가 더욱 향상되었으며, 특히 올레인산을 함유하는 마이크로에멀젼을 사용하여 고형분산제제를 제조한 경우에 약물 용출이 더욱 현저하게 개선된 것을 알 수 있었다.The effect of improving the dissolution rate of the two drugs by the solid dispersion was more apparent in the intestinal fluid, which is a poorly soluble condition of the two drugs. As shown in Table 3 , drug dissolution from solid dispersions containing fatty acids and oils was superior to drug powders, and solid dispersions containing oleic acid further improved the effect, in particular, containing oleic acid. It was found that drug dissolution was more markedly improved when a solid dispersion was prepared using a microemulsion.
한편, 상기 <실시예>에서 제조된 이트라코나졸, 그의 유도체 및 사이클로스포린 각각을 함유하는 고형분산제제에 대하여 인공위액 및 인공장액에서의 용출실험을 수행한 결과가표 4에 나타나 있다. 이 경우에도 역시 올레인산을 함유한 고형분산제제로부터의 약물의 용출이 약물 분말에 비하여 우수함을 알 수 있었다.On the other hand, the solid dispersing agent containing each of the itraconazole, its derivatives and cyclosporin prepared in the <Example> is shown in Table 4 the results of the dissolution test in artificial gastric juice and artificial intestinal fluid. Also in this case, it was found that the dissolution of the drug from the solid dispersant containing oleic acid was superior to the drug powder.
<실험예 3> 고형분산제제에 함유된 난용성 약물의 토끼 위장관에서의 흡수성Experimental Example 3 Absorption of Rabbit Soluble Drugs Containing Solid Dispersion in the Rabbit Gastrointestinal Tract
조사Research
상기 <실시예>에서 제조된 고형분산제제에 함유된 케토코나졸의 토끼 위장관(jejunum)에서의 흡수성을 알아보기 위한 실험을 하여 그 결과를표 5에 나타내었다. 먼저, 토끼의 귀정맥에 공기를 주입하여 치사시킨 후, 위, 십이지장, 공장, 회장, 대장 및 직장을 적출하여 37 ℃의 생리식염수로 세척하였다. 적출된 조직을 프란츠 확산 셀 (Franz diffusion cell)의 리셉터와 도너 사이에 고정하고, 리셉터에는 생리식용수를 가하여 37 ℃를 유지하면서 마그네틱 교반자를 넣고 교반하였다. 도너에 <실시예>에서 제조한 고형분산제제를 가한 후, 약 6시간동안 일정 시간에 리셉터로부터 생리식염수를 취하여 투과된 약물 농도를 정량하였다. 리셉터로부터 약물을 취한 후에는 신선한 생리식염수를 보충하여 전체 생리식염수의 양이 변하지 않도록 하였다.The experiment was performed to determine the absorbency of the ketoconazole in the rabbit gastrointestinal tract (jejunum) contained in the solid dispersion preparation prepared in <Example>, and the results are shown in Table 5 . First, the air was injected into the rabbit's ear vein and lethal, and then the stomach, duodenum, jejunum, ileum, colon and rectum were extracted and washed with saline at 37 ° C. The extracted tissue was fixed between the receptor and the donor of the Franz diffusion cell, and the magnetic stirrer was added to the receptor while maintaining a 37 ° C., followed by stirring. After the solid dispersion prepared in Example was added to the donor, physiological saline was taken from the receptor at a predetermined time for about 6 hours to quantify the permeated drug concentration. After the drug was taken from the receptor, fresh physiological saline was supplemented to ensure that the total amount of physiological saline did not change.
표 5에 나타난 바와 같이, 올레인산을 함유한 고형분산제제를 사용한 경우, 단순히 가용성 기제를 가한 <비교예>의 경우에 비해 케토코나졸의 위장관 흡수율이 더욱 증가하였다. 특히 올레인산을 함유하는 마이크로에멀젼을 가하여 고형분산제제를 제조한 경우에 케토코나졸의 위장관 흡수율이 현저히 개선되어 <실험예 1> 내지 <실험예 3>과 같은 결과를 얻었다.As shown in Table 5, in the case of using a solid dispersion containing oleic acid, the gastrointestinal absorption rate of ketoconazole was further increased compared to the case of <Comparative Example> which was simply added a soluble base. In particular, when a microdispersion containing oleic acid was added to prepare a solid dispersion, the gastrointestinal absorption rate of ketoconazole was remarkably improved to obtain the same results as in <Experimental Example 1> to <Experimental Example 3>.
<실험예 4> 난용성 약물 함유 고형분산제제와 시판제제의 혈중농도 양상 비교Experimental Example 4 Comparison of Plasma Concentrations of Solid-Dispersion-Soluble Drug-Containing and Commercially Available Agents
실험Experiment
국립 보건원에서 구입한 250∼310 g의 실험용 수컷 흰쥐 (Sprague-Dawley계)를 약 1∼2 주일 동안 적응시킨 후 실험에 사용하였다. 실험전날부터 절식시킨 쥐를 에테르로 마취시키고 좌측 대퇴 동맥을 캐뉼레이션 (cannulation)하여, 80 IU/㎖의 헤파린 (heparin)이 채워진 주사기가 연결되어 있는 관을 삽입하였다. 약 2시간이 지나 쥐가 마취에서 깨어나면, 본 발명의 사이클로스포린 함유 고형분산제제 현탁액 또는 시판제제를 경구용 존데 (sonde)를 사용하여 투여한 후, 일정시간에 좌측 대퇴 동맥으로부터 혈액을 채혈하여 혈중 약물 농도를 정량하였다.250-310 g of experimental male rats (Sprague-Dawley) purchased from the National Institutes of Health were used for the experiment after adapting for about 1 to 2 weeks. Fasting mice were anesthetized with ether from the day before the experiment, and the left femoral artery was cannulated, and a tube to which a 80 IU / ml heparin-filled syringe was connected was inserted. After about 2 hours, when the rat awakes from anesthesia, the cyclosporin-containing solid dispersion suspension or commercially available formulation of the present invention is administered using oral sonde, and then blood is drawn from the left femoral artery at a predetermined time. Drug concentration was quantified.
도 1은 실험용 쥐에 사이클로스포린 함유 고형분산제제 현탁액 또는 시판제제를 투여한 후, 사이클로스포린의 혈중농도를 시간의 변화에 따라 측정한 결과를 나타낸 그래프이다.도 1에서 보는 바와 같이, 본 발명의 방법으로 사이클로스포린 함유 고형분산제제는 혈중농도의 변화 양상이 시판제제 (Neoral)와 비슷하였다. 전체적으로 혈중농도는 약간 낮은 경향을 나타내었으나, 제제학적 관점에서 볼 때, 본 발명의 사이클로스포린 함유 고형분산제제가 액체약물을 함유하는 시판 제제를 대체할 수 있음을 알 수 있다. 1 is a graph showing the results of measuring the blood concentration of cyclosporin according to time after administration of a cyclosporin-containing solid dispersion suspension or a commercially available formulation to a rat. As shown in Figure 1 , by the method of the present invention cyclosporin-containing solid dispersion was similar to the commercial formulation (Neoral) in terms of changes in blood concentration. Overall, blood concentrations tended to be slightly lower, but from a pharmaceutical point of view, it can be seen that the cyclosporin-containing solid dispersion of the present invention can replace a commercially available formulation containing a liquid drug.
한편, 비글견(beagle dog)을 사용하여 본 발명의 이트라코나졸 함유 고형분산제제 또는 시판제제를 경구로 투여한 후, 일정 시간에 정맥으로부터 채혈하여 혈중 약물 농도를 정량하여 그 결과를표 6에 나타내었다.On the other hand, after the oral administration of the itraconazole-containing solid dispersion or commercial formulation of the present invention using a beagle dog (beagle dog), the blood concentration was collected from the vein at a certain time to quantify the blood drug concentrations are shown in Table 6 .
표 6에서 보는 바와 같이, 이트라코나졸 함유 고형분산제제와 시판제제 (이타졸)는 절식 개에서 비슷한 혈중농도 양상을 나타내었으나, 실시예 12의 경우는 낮은 값을 보였다. 한편, 비절식 개에서는 시판제제를 투여한 경우에 약물의 최고 혈중농도가 높고 최고 혈중농도에 도달하는 시간이 빠른 반면, 실시예 13의 경우 혈중농도가 일정하게 유지되는 경향을 나타내었는데 이는 위장관에서의 가용화 특성 때문이다.As shown in Table 6 , the itraconazole-containing solid dispersion and commercially available formulation (itazol) showed similar blood concentrations in fasted dogs, but in the case of Example 12, the values were low. On the other hand, in a non-fasting dog, the highest blood concentration of the drug was high and the time to reach the highest blood concentration was high when the commercial preparation was administered, whereas in the case of Example 13, the blood concentration was maintained to be constant. This is because of the solubilization characteristics of
<실험예 5> 아세클로페낙의 여러 비이클 (Vehicles) 에서의 용해도 측정.Experimental Example 5 Determination of Solubility of Aceclofenac in Various Vehicles.
여러 종류의 비이클 5ml에 과량의 아세클로페낙을 넣은 시험관을 약물이 더 이상 녹지 않을때까지 충분히 볼텍싱 (Vortexing) 하여 37℃ 항온수조(Water bath)에서 3일간 방치후 0.2㎛ 밀리포아 여과지 (Millipore, Waters, Milford, MA,USA)로 여과하고 적절히 희석하여 약물 농도를 정량하였다. 그 결과, 얻어진 여러 비이클에서의 아세클로페낙의 용해도를표 7에 나타내었다.A test tube containing excess aceclofenac in 5 ml of various vehicles was vortexed sufficiently until the drug was no longer dissolved, and left in a 37 ° C. water bath for 3 days, followed by 0.2 μm Millipore filter paper (Millipore, Waters , Milford, MA, USA) was filtered and diluted appropriately to quantify drug concentration. As a result, the solubility of aceclofenac in the various vehicles obtained is shown in Table 7 .
표 7에 나타난 바와 같이, 아세클로페낙의 용해도는 지방산류, 트리아세틴, 피마자유 및 크레모포등에서 증가되었으며 특히 트랜스쿠톨, 라브라솔 및 트윈류에서 용해도가 현저히 증가함을 알 수 있다.As shown in Table 7 , the solubility of aceclofenac was increased in fatty acids, triacetin, castor oil, and cremofo, and it can be seen that the solubility in transcutol, labrasol, and twins increased significantly.
<실험예 6> 난용성 약물인 아세클로페낙을 함유하는 고형분산제제의 인공위액 및 인공장액에서의 용출Experimental Example 6 Elution of Solid Dispersant Containing Aceclofenac, a Soluble Drug, in Artificial Gastric Fluids and Intestinal Fluids
상기 실시예 24 내지 27에서 제조된 아세클로페낙 각각을 함유하는 고형분산제제에 대하여 인공위액 및 인공장액에서의 용출실험을 실험예 2와 같은 방법으로 수행하였다.The solid dispersing agent containing each of the aceclofenac prepared in Examples 24 to 27 was performed in the dissolution test in artificial gastric juice and artificial intestine in the same manner as in Experiment 2.
그 결과 얻어진 다양한 고형분산제제에 함유된 난용성 약물의 인공위액 및 인공장액에서의 용출속도 및 비율(%)을표 8과표 9에 각각 나타내었다.The dissolution rates and percentages (%) of the poorly soluble drugs in the various solid dispersions obtained as a result are shown in Tables 8 and 9 , respectively.
인공위액에서 아세클로페낙을 함유하는 고형분산제제로부터의 약물용출이 상대적으로 크게 증가하는 경향을 보였다.Drug dissolution from solid dispersions containing aceclofenac tended to increase significantly in artificial gastric juice.
아세클로페낙은 약물자체가 염기성이므로 인공장액에서 어느정도 용출이 되었으나, 고형분산제제로부터의 약물의 용출이 상대적으로 더욱 증가하였다.Aceclofenac was slightly eluted in artificial intestinal fluid because the drug itself was basic, but the dissolution of the drug from the solid dispersion was relatively increased.
<실험예 7> 난용성 약물인 아세클러페낙을 함유하는 고형분산제제와 순수분말 및 시판제제의 혈중농도 양상의 비교 실험Experimental Example 7 Comparative Experiment of Solid Concentration Formulation Containing Aceclofenac, a Soluble Drug, and Pure Powder and Commercial Formulations
국립 보건원에서 구입한 250∼310 g의 실험용 수컷 흰쥐 (Sprague-Dawley계)를 약 1∼2 주일 동안 적응시킨 후 실험에 사용하였다. 실험 전날부터 절식시킨 쥐를 에테르로 마취시키고 좌측 대퇴 동맥을 캐뉼레이션 (cannulation)하여, 50 IU/㎖의 헤파린 (heparin)이 채워진 주사기가 연결되어 있는 관을 삽입하였다. 약 2시간이 지나 쥐가 마취에서 깨어나면, 본 발명의 아세클로페낙 함유 고형분산제제 현탁액 또는 아세클로페낙 분말을 경구용 존데 (sonde)를 사용하여 투여한 후, 일정시간 후에 좌측 대퇴 동맥으로부터 혈액을 채취하여 혈중 약물 농도를 정량하였다. 한편 비글견(beagle dog)과 사람(human)을 사용하여 본 발명의 아세클로페낙 함유 고형분산제제 또는 시판제제를 경구로 투여한 후, 일정 시간후에 정맥으로부터 채혈하여 혈중 약물 농도를 정량하였다.250-310 g of experimental male rats (Sprague-Dawley) purchased from the National Institutes of Health were used for the experiment after adapting for about 1 to 2 weeks. Fasting mice were anesthetized with ether from the day before the experiment, and the left femoral artery was cannulated, and a tube to which a syringe filled with a heparin filled with 50 IU / ml was inserted. After about 2 hours, when the rat awakes from anesthesia, the aceclofenac-containing solid dispersion or aceclofenac powder of the present invention is administered using oral sonde, and after a certain time, blood is collected from the left femoral artery Drug concentration was quantified. Meanwhile, a beagle dog and a human were used to orally administer the aceclofenac-containing solid dispersion or commercial formulation of the present invention, and then, after a predetermined time, blood was collected from a vein to quantify blood drug concentrations.
쥐, 비글견 및 사람에서 아세클로페낙 함유 고형분산제제 또는 아세클로페낙 분말을 경구투여한 후 시간에 따른 혈중농도 양상을 각각 비교하여도 2에서도 4까지에 나타내었다.After oral administration of aceclofenac-containing solid dispersion or aceclofenac powder in rats, beagle dogs and humans, the concentrations of blood concentrations over time were compared with FIGS. 2 to 4 , respectively.
세종의 실험 동물 모두에서 고형분산 제제는 시판제제에 비하여 높은 혈중 농도를 나타내었으며 약물 동태학적 변수인 최고 혈중농도 및 곡선하 면적이 1.5-6배 이상 증가됨을 고찰하였다.In all three experimental animals, solid dispersions showed higher blood concentrations compared to commercially available formulations, and the highest pharmacokinetic parameters, peak blood concentration and area under the curve, increased by 1.5-6 fold.
한편 쥐, 비글견 및 사람에서 아세클로페낙 함유 고형분산제제 또는 아세클로페낙 분말을 경구투여한 후 시간에 따른 혈중농도를표 10내지표 12에 각각 나타내었다.On the other hand, after oral administration of aceclofenac-containing solid dispersion or aceclofenac powder in rats, beagle dogs and humans, blood concentrations with time are shown in Tables 10 to 12 , respectively.
표 10에 나타난 바와 같이, 아세클로페낙 함유 고형분산제제의 혈중농도 양상은 아세클로페낙 분말에 비해 상당히 증가함을 알 수 있다.As shown in Table 10 , it can be seen that the blood concentration of the aceclofenac-containing solid dispersion is significantly increased compared to the aceclofenac powder.
표 11에 나타난 바와 같이, 아세클로페낙 함유 고형분산제제의 혈중농도 양상은 시판제제에 비해 증가함을 알 수 있다.As shown in Table 11 , it can be seen that the blood concentration pattern of the aceclofenac-containing solid dispersion is increased compared to the commercially available formulation.
표 12에 나타난 바와 같이, 아세클로페낙 함유 고형분산제제의 혈중농도 양상은 시판제제에 비해 증가함을 알 수 있다.As shown in Table 12 , it can be seen that the blood concentration pattern of the aceclofenac-containing solid dispersion is increased compared to the commercially available formulation.
<실험예 8> 시사프라이드를 함유하는 고형분산제제의 인공위액 및 인공장액에서의 용출실험Experimental Example 8 Dissolution Test of Artificial Dispersion and Intestinal Fluid of Solid Dispersant Containing Cisapride
상기 실시예 31에서 제조된 시사프라이드를 함유하는 고형분산제제에 대하여 인공위액 및 인공장액에서의 실험예 2와 같은 방법으로 용출실험을 수행하였으며, 그 결과 얻어진 다양한 고형분산제제에 함유된 난용성 약물의 인공위액 및 인공장액에서의 용출속도 및 비율(%)을표 13에 각각 나타내었다.The dissolution test was performed in the same manner as Experimental Example 2 in artificial gastric juice and intestinal fluid with respect to the solid dispersion containing cisapride prepared in Example 31, and the poorly soluble drug contained in the various solid dispersions obtained as a result. The dissolution rate and percentage (%) in artificial gastric juice and intestinal fluid were shown in Table 13 , respectively.
실시예 31과 같은 방법으로 제조한 고형분산제제로부터 약물의 방출량은 인공위액 및 장액 모두에서 거의 직선적으로 크게 증가였으며 0차에 가까운 방출 양상을 보였다.The amount of drug released from the solid dispersion prepared in the same manner as in Example 31 was greatly increased almost linearly in both gastric juice and intestinal fluid, showing a near zero order of release.
<실험예 9> 시사프라이드를 함유하는 고형분산제제 및 시판제제의 혈중농도 양상의 비교 실험Experimental Example 9 Comparative Experiment of Blood Concentration of Solid Dispersion Formulation Containing Cisapride and Commercial Formulation
비글견(beagle dog)을 사용하여 본 발명의 실시예 32에서 제조한 시사프라이드 함유 고형분산제제 및 시판제제를 경구로 투여한 후, 일정 시간후에 정맥으로부터 채혈하여 혈중 약물 농도를 정량하였다.The beagle dog was orally administered with the cisapride-containing solid dispersion and the commercial preparation prepared in Example 32 of the present invention, and then, after a predetermined time, blood was collected from the vein to quantify blood drug concentrations.
도 5는 비글견에 시시프라이드 고형분산제제 또는 시판제제를 경구투여한 후 시간에 따른 혈중농도양상을 비교한 그래프로, 시판제제에 비하여 혈중 농도가 크게 증가함을 나타낸다. FIG. 5 is a graph comparing blood concentrations with time after oral administration of cispride solid dispersion or a commercial formulation to a beagle dog, indicating that blood concentration is significantly increased compared to a commercial preparation.
한편 개에 시시프라이드 고형분산제제 또는 시판제제를 경구투여한 후 시간에 따른 혈중농도양상을표 14에 나타내었다.On the other hand, after the oral administration of cispride solid dispersion or commercially available formulations in the dog, the blood concentration pattern with time is shown in Table 14 .
표 14에 나타난 바와 같이, 시사프라이드 함유 고형분산제제의 혈중농도 양상은 시판제제에 비해 크게 증가하였다.As shown in Table 14 , the plasma concentration of the cisapride-containing solid dispersion was significantly increased compared to the commercially available formulation.
이상에서 살펴본 바와 같이, 본 발명의 고형분산제제는 약물의 위장관에서의 용해도, 즉 용출을 향상시키고 생체이용율을 증가시킬 뿐만 아니라, 성형 및 가공이 곤란한 기존의 반고형 또는 액상제제의 제제학적인 문제점을 개선하여, 유기용매를 사용하지 않고도 간편하고 신속하게 최종제품을 성형, 제조 및 가공할 수 있는 경제적인 제제이다.As described above, the solid dispersion agent of the present invention not only improves the solubility of the drug in the gastrointestinal tract, that is, dissolution and increase bioavailability, but also is a pharmaceutical problem of the conventional semi-solid or liquid formulation that is difficult to form and process. It is an economical formulation that can form, manufacture and process the final product simply and quickly without using organic solvent.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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ATE329579T1 (en) | 1999-11-12 | 2006-07-15 | Abbott Lab | SOLID DISPERSION WITH RITONAVIR, FENOFIBRATE OR GRISEOFULVIN |
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PT1318791E (en) | 2000-09-22 | 2004-11-30 | Galephar M F | ISOTRETINOIN SEMI-SOLID PHARMACEUTICAL COMPOSITION |
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GB0118300D0 (en) * | 2001-07-26 | 2001-09-19 | Cortendo Ab | Formulations |
US7126015B2 (en) * | 2001-09-10 | 2006-10-24 | Tibotec Pharmaceuticals Ltd. | Method for the preparation of hexahydro-furo-[2,3-b]furan-3-ol |
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US20050232995A1 (en) | 2002-07-29 | 2005-10-20 | Yam Nyomi V | Methods and dosage forms for controlled delivery of paliperidone and risperidone |
KR100397349B1 (en) * | 2002-11-23 | 2003-09-13 | Korea United Pharm Inc | Solubilized aceclofenac, soft capsule using the same and manufacturing method thereof |
WO2004062692A1 (en) * | 2003-01-13 | 2004-07-29 | Solvay Pharmaceuticals B.V. | Formulation of poorly water-soluble active substances |
CA2532931A1 (en) | 2003-08-04 | 2005-02-10 | Pfizer Products Inc. | Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials |
US8377952B2 (en) | 2003-08-28 | 2013-02-19 | Abbott Laboratories | Solid pharmaceutical dosage formulation |
US8025899B2 (en) | 2003-08-28 | 2011-09-27 | Abbott Laboratories | Solid pharmaceutical dosage form |
KR100529766B1 (en) * | 2003-09-09 | 2005-11-17 | 한미약품 주식회사 | Oral itraconazole composition which is not affected by ingested food and preparation thereof |
US20050059583A1 (en) | 2003-09-15 | 2005-03-17 | Allergan, Inc. | Methods of providing therapeutic effects using cyclosporin components |
KR20050034299A (en) * | 2003-10-09 | 2005-04-14 | 한국유나이티드제약 주식회사 | Formulation and manufacturing process of self-microemulsified aceclofenac soft capsules |
KR100546047B1 (en) * | 2003-10-24 | 2006-01-24 | 지상철 | Sustained-release preparation of dihydropyridine-based compound and preparation method thereof |
US7659310B2 (en) | 2004-04-27 | 2010-02-09 | Formatech, Inc. | Methods of enhancing solubility of agents |
US7345093B2 (en) | 2004-04-27 | 2008-03-18 | Formatech, Inc. | Methods of enhancing solubility of compounds |
EP1748759B1 (en) * | 2004-04-27 | 2013-03-27 | Javeri, Indu | Methods of enhancing solubility in water of hydrophobic compounds by micellar dispersions |
US20070237823A1 (en) * | 2004-05-04 | 2007-10-11 | Thomas Bock | Solid Pharmaceutical Form Comprising and Ltb4 Antagonist |
KR100582604B1 (en) * | 2004-06-16 | 2006-05-23 | 보람제약주식회사 | IBUPROFEN and DEXIBUPROFEN MICRO EMULSION COMPOSITION AND LIQUID MEDICINE and SOFT CAPSULE DRUG THEREOF |
WO2006035417A2 (en) * | 2004-09-27 | 2006-04-06 | Sigmoid Biotechnologies Limited | Dihydropyrimidine microcapsule - formulations |
US7202209B2 (en) | 2005-07-13 | 2007-04-10 | Allergan, Inc. | Cyclosporin compositions |
US7297679B2 (en) | 2005-07-13 | 2007-11-20 | Allergan, Inc. | Cyclosporin compositions |
US7288520B2 (en) | 2005-07-13 | 2007-10-30 | Allergan, Inc. | Cyclosporin compositions |
US7276476B2 (en) | 2005-07-13 | 2007-10-02 | Allergan, Inc. | Cyclosporin compositions |
US20070015691A1 (en) | 2005-07-13 | 2007-01-18 | Allergan, Inc. | Cyclosporin compositions |
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US7745400B2 (en) | 2005-10-14 | 2010-06-29 | Gregg Feinerman | Prevention and treatment of ocular side effects with a cyclosporin |
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US9114071B2 (en) | 2007-04-04 | 2015-08-25 | Sigmoid Pharma Limited | Oral pharmaceutical composition |
EP2216015A4 (en) * | 2007-11-02 | 2012-12-19 | So Pharmaceutical Corp | Poorly soluble substance-surfactant complex product, and process for production thereof |
KR101631243B1 (en) * | 2009-05-13 | 2016-06-17 | 신일제약주식회사 | Method for preparing novel alendronate emulsion dried product and pharmaceutical composition containing the same |
WO2010133609A2 (en) | 2009-05-18 | 2010-11-25 | Sigmoid Pharma Limited | Composition comprising oil drops |
US8937150B2 (en) | 2009-06-11 | 2015-01-20 | Abbvie Inc. | Anti-viral compounds |
DK2455376T3 (en) | 2009-06-11 | 2015-03-02 | Abbvie Bahamas Ltd | Heterocyclic compounds as inhibitors of hepatitis C virus (HCV) |
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US10143652B2 (en) | 2009-09-23 | 2018-12-04 | Curirx Inc. | Methods for the preparation of liposomes |
EP2480208A1 (en) | 2009-09-23 | 2012-08-01 | Indu Javeri | Methods for the preparation of liposomes |
GB201007446D0 (en) * | 2010-05-05 | 2010-06-16 | Synergy Pharmaceuticals Pte Lt | Composition for treatment of H.pylori |
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KR101125453B1 (en) * | 2010-07-29 | 2012-03-27 | 주식회사 대웅제약 | Solubilizing Compositions of L-Tryptophan and Pharmaceutical preparation therefrom |
GB201020032D0 (en) | 2010-11-25 | 2011-01-12 | Sigmoid Pharma Ltd | Composition |
US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
US9034832B2 (en) | 2011-12-29 | 2015-05-19 | Abbvie Inc. | Solid compositions |
WO2013137694A1 (en) * | 2012-03-16 | 2013-09-19 | 한국콜마 주식회사 | Solid matter for water-insoluble material coated with amorphous surfactant containing fatty acid having straight alkyl chain 직쇄 알킬체인을 가진 지방산을 포함하는 무수무복계면물질 |
US9078925B2 (en) | 2012-06-18 | 2015-07-14 | Galephar Pharmaceutical Research, Inc. | Pharmaceutical semi-solid composition of isotretinoin |
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Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5756450A (en) * | 1987-09-15 | 1998-05-26 | Novartis Corporation | Water soluble monoesters as solubilisers for pharmacologically active compounds and pharmaceutical excipients and novel cyclosporin galenic forms |
EP0449960B1 (en) * | 1988-12-20 | 1993-09-08 | Medicontrol Corporation | Heat-dehydrated emulsion compositions |
JPH08157362A (en) * | 1994-12-06 | 1996-06-18 | Sankyo Co Ltd | Production of oily substance-containing solid preparation |
-
1999
- 1999-06-26 KR KR1019990024437A patent/KR100336090B1/en not_active IP Right Cessation
- 1999-06-28 AU AU46556/99A patent/AU4655699A/en not_active Withdrawn
- 1999-06-28 WO PCT/KR1999/000341 patent/WO2000000179A1/en not_active Application Discontinuation
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KR100449818B1 (en) * | 2001-03-02 | 2004-09-22 | 최영욱 | Soft capsule or injection formulation containg ibuprofen by smedds |
KR100425226B1 (en) * | 2001-07-03 | 2004-03-30 | 주식회사 팜트리 | Compositions and preparation methods for bioavailable oral aceclofenac dosage forms |
WO2017086545A1 (en) * | 2015-11-17 | 2017-05-26 | 연세대학교 산학협력단 | Sustained-release preparation of poorly soluble drug |
KR101749425B1 (en) * | 2015-11-17 | 2017-06-22 | 연세대학교 산학협력단 | Formulation comprising poorly soluble drug for sustained release |
US10668158B2 (en) | 2015-11-17 | 2020-06-02 | University-Industry Foundation, Yonsei University | Sustained-release preparation of poorly soluble drug |
KR20170078972A (en) * | 2015-12-29 | 2017-07-10 | 단국대학교 천안캠퍼스 산학협력단 | Pharmaceutical composition comprising cyclosporine |
KR101819310B1 (en) | 2015-12-29 | 2018-01-18 | 단국대학교 천안캠퍼스 산학협력단 | Pharmaceutical composition comprising cyclosporine |
Also Published As
Publication number | Publication date |
---|---|
AU4655699A (en) | 2000-01-17 |
KR20000006503A (en) | 2000-01-25 |
WO2000000179A1 (en) | 2000-01-06 |
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