WO2012156023A1 - Process for producing inorganic particulate material - Google Patents
Process for producing inorganic particulate material Download PDFInfo
- Publication number
- WO2012156023A1 WO2012156023A1 PCT/EP2012/001769 EP2012001769W WO2012156023A1 WO 2012156023 A1 WO2012156023 A1 WO 2012156023A1 EP 2012001769 W EP2012001769 W EP 2012001769W WO 2012156023 A1 WO2012156023 A1 WO 2012156023A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- particulate material
- modified release
- gel
- agent
- inorganic
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 55
- 230000008569 process Effects 0.000 title claims abstract description 42
- 239000011236 particulate material Substances 0.000 title claims abstract description 29
- 239000012867 bioactive agent Substances 0.000 claims abstract description 38
- 239000000463 material Substances 0.000 claims abstract description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 80
- 239000011148 porous material Substances 0.000 claims description 42
- 239000002245 particle Substances 0.000 claims description 40
- 239000003795 chemical substances by application Substances 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 29
- 239000011159 matrix material Substances 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 21
- 239000002243 precursor Substances 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 19
- 150000002902 organometallic compounds Chemical class 0.000 claims description 16
- 239000000843 powder Substances 0.000 claims description 16
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 13
- 239000004202 carbamide Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims description 11
- 238000001704 evaporation Methods 0.000 claims description 10
- 239000003826 tablet Substances 0.000 claims description 10
- 239000002736 nonionic surfactant Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000007943 implant Substances 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 7
- 239000006071 cream Substances 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 229920003169 water-soluble polymer Polymers 0.000 claims description 7
- 238000001354 calcination Methods 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 238000007911 parenteral administration Methods 0.000 claims description 6
- 239000011859 microparticle Substances 0.000 claims description 5
- 239000002674 ointment Substances 0.000 claims description 5
- 229910052814 silicon oxide Inorganic materials 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 230000000699 topical effect Effects 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 238000011200 topical administration Methods 0.000 claims description 4
- 230000007704 transition Effects 0.000 claims description 4
- 239000008298 dragée Substances 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 230000001788 irregular Effects 0.000 claims description 2
- 239000000499 gel Substances 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- -1 silicon alkoxide Chemical class 0.000 description 25
- 239000000243 solution Substances 0.000 description 23
- 238000005191 phase separation Methods 0.000 description 22
- 239000000377 silicon dioxide Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 238000009826 distribution Methods 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 239000003814 drug Substances 0.000 description 16
- 229910010272 inorganic material Inorganic materials 0.000 description 12
- 239000011147 inorganic material Substances 0.000 description 12
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 239000011521 glass Substances 0.000 description 11
- 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 description 10
- 238000004090 dissolution Methods 0.000 description 10
- 238000012377 drug delivery Methods 0.000 description 10
- 229960004130 itraconazole Drugs 0.000 description 10
- 239000008213 purified water Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000007792 addition Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 7
- 150000004703 alkoxides Chemical class 0.000 description 7
- LFQCEHFDDXELDD-UHFFFAOYSA-N tetramethyl orthosilicate Chemical compound CO[Si](OC)(OC)OC LFQCEHFDDXELDD-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 6
- 229940074355 nitric acid Drugs 0.000 description 6
- 229910017604 nitric acid Inorganic materials 0.000 description 6
- 238000002336 sorption--desorption measurement Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 239000013335 mesoporous material Substances 0.000 description 5
- 150000002736 metal compounds Chemical class 0.000 description 5
- XQMTUIZTZJXUFM-UHFFFAOYSA-N tetraethoxy silicate Chemical compound CCOO[Si](OOCC)(OOCC)OOCC XQMTUIZTZJXUFM-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000007884 disintegrant Substances 0.000 description 4
- 238000004945 emulsification Methods 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000003825 pressing Methods 0.000 description 4
- 229910052710 silicon Inorganic materials 0.000 description 4
- 239000010703 silicon Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 239000001828 Gelatine Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 3
- 239000005662 Paraffin oil Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 229960001680 ibuprofen Drugs 0.000 description 3
- 238000005470 impregnation Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000001149 thermolysis Methods 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MWRWFPQBGSZWNV-UHFFFAOYSA-N Dinitrosopentamethylenetetramine Chemical compound C1N2CN(N=O)CN1CN(N=O)C2 MWRWFPQBGSZWNV-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 235000012216 bentonite Nutrition 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- 239000003462 bioceramic Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 229920000831 ionic polymer Polymers 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- 238000002459 porosimetry Methods 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 125000005372 silanol group Chemical group 0.000 description 2
- 238000003980 solgel method Methods 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000009210 therapy by ultrasound Methods 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- AGBXYHCHUYARJY-UHFFFAOYSA-N 2-phenylethenesulfonic acid Chemical compound OS(=O)(=O)C=CC1=CC=CC=C1 AGBXYHCHUYARJY-UHFFFAOYSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 238000004438 BET method Methods 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 244000287680 Garcinia dulcis Species 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229920000469 amphiphilic block copolymer Polymers 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- NKSJNEHGWDZZQF-UHFFFAOYSA-N ethenyl(trimethoxy)silane Chemical compound CO[Si](OC)(OC)C=C NKSJNEHGWDZZQF-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- SBRXLTRZCJVAPH-UHFFFAOYSA-N ethyl(trimethoxy)silane Chemical compound CC[Si](OC)(OC)OC SBRXLTRZCJVAPH-UHFFFAOYSA-N 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000008309 hydrophilic cream Substances 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910001510 metal chloride Inorganic materials 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- BFXIKLCIZHOAAZ-UHFFFAOYSA-N methyltrimethoxysilane Chemical compound CO[Si](C)(OC)OC BFXIKLCIZHOAAZ-UHFFFAOYSA-N 0.000 description 1
- 239000012229 microporous material Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229920002114 octoxynol-9 Polymers 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920000083 poly(allylamine) Polymers 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 125000005373 siloxane group Chemical group [SiH2](O*)* 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229920000428 triblock copolymer Polymers 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B33/00—Silicon; Compounds thereof
- C01B33/113—Silicon oxides; Hydrates thereof
- C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
- C01B33/14—Colloidal silica, e.g. dispersions, gels, sols
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B33/00—Silicon; Compounds thereof
- C01B33/113—Silicon oxides; Hydrates thereof
- C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
- C01B33/14—Colloidal silica, e.g. dispersions, gels, sols
- C01B33/141—Preparation of hydrosols or aqueous dispersions
- C01B33/142—Preparation of hydrosols or aqueous dispersions by acidic treatment of silicates
- C01B33/143—Preparation of hydrosols or aqueous dispersions by acidic treatment of silicates of aqueous solutions of silicates
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B33/00—Silicon; Compounds thereof
- C01B33/113—Silicon oxides; Hydrates thereof
- C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
- C01B33/18—Preparation of finely divided silica neither in sol nor in gel form; After-treatment thereof
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B33/00—Silicon; Compounds thereof
- C01B33/113—Silicon oxides; Hydrates thereof
- C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
- C01B33/18—Preparation of finely divided silica neither in sol nor in gel form; After-treatment thereof
- C01B33/187—Preparation of finely divided silica neither in sol nor in gel form; After-treatment thereof by acidic treatment of silicates
- C01B33/193—Preparation of finely divided silica neither in sol nor in gel form; After-treatment thereof by acidic treatment of silicates of aqueous solutions of silicates
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
Definitions
- the present invention is directed to a process for producing inorganic particulate material, the material obtainable by such process, a modified release delivery system comprising the material and the use of the materi al for the admin istration of a bioactive agent.
- Inorganic materials are receiving a great interest in the field of biomedical science in the last few years.
- Two main routes have been traditionally used for drug intake: oral administration and injection.
- Inorganic materials especially bioceramics, have some porosity that can be used for drug delivery including chemically synthesized substances such as, for example, ibuprofen or nimodipine, but also biologically derived substances such as, for example, releasing growth factors or proteins.
- chemically synthesized substances such as, for example, ibuprofen or nimodipine
- biologically derived substances such as, for example, releasing growth factors or proteins.
- silica-based ordered mesoporous materials are possible candidates as reservoir bioceramics where drugs can be confined.
- these materials are characterized by large specific surface areas, ordered pore systems, and narrow pore size distributions.
- these mesoporous materials have been reported to be excellent candidates to be used in tissue engineering nanotechnology, because they show the capability to perform as controlled delivery systems of a wide range of drugs and to promote bone tissue regeneration.
- inorganic materials can be classified as microporous, mesoporous or macroporous.
- microporous materials are understood to have a pore size ⁇ 2 nm
- mesoporous materials are understood to have a pore size from 2 to 100 nm
- macroporous materials are understood to have a pore size > 100 nm.
- porous materials have been increasingly studied for the use as drug delivery systems. From such materials mesoporous silica has been of specific interest.
- mesoporous silica for the formulation of drug delivery systems is to increase the dissolution rate of poorly water- soluble or water-insoluble active pharmaceutical ingredients. Poorly water- soluble or insoluble active pharmaceutical ingredients usually have a very low bioavailability due to their poor solubility in digestive fluids causing incomplete absorption.
- the rationale of using mesoporous silica for use in drug delivery systems is to increase the dissolution rate of poorly water- soluble or water-insoluble active pharmaceutical ingredients and thereby to improve their bioavailability.
- MCM-41 Mobil Composition of Matter number forty one
- SBA- 15 Spanta Barbara Amorphous number fifteen
- SBA-15 was first described by Zhao et al. and is the result of a templating procedure based on a hexagonal arrangement of amphiphilic block copolymers (D.Y. Zhao et al.: Triblock copolymer syntheses of mesoporous silica with periodic 50 to 300 angstrom pores, Science 279 (1998) 548-552).
- MCM-41 is obtained by the template action of long chain alkylammonium surfactant molecules (J.S.
- Vallet-Regi et al. were one of the first to explore the drug release properties of these materials in an attempt to prolong the release of ibuprofen using MCM-41 as a carrier (M. Vallet-Regi et al.: A new property of MCM-41 : drug delivery system, Chem. Mater. 13 (2001) 308-311).
- the release kinetics of drugs from mesoporous silica carriers is dependent on several material characteristics including pore size (P. Horcajada et al.: Influence of pore size of MCM-41 matrices on drug delivery rate,
- WO 2006/026840 A2 discloses a controlled release delivery system wherein amorphous mesoporous non-fibrous silica is used as matrix carrier for the release of bioactive compounds and wherein such matrix carrier further comprises micropores having a mean size in the range of 0.4 to 2.0 nm.
- WO 2005/000740 A2 discloses a crystalline mesoporous silica material comprising a framework of zeolite type micropores (designated as nanometer size building units), which does not give rise in Bragg type diffraction in x-ray diffraction, and its use for drug delivery.
- Z.G. Shi et al. describe mesoporous silica particles for drug delivery, which beside the mesopores further contain macropores (Z.G. Shi et al.: Drug delivery devices based on macroporous silica spheres, Micropor. Mesopor. Mater. 126 (2011) 826-831). Due to its penetrable macropores the mesopores of such material can be sufficiently and efficiently loaded with drug.
- the silica particles described by said publication from Z.G. Shi et al. are produced by using sol-gel technique in combination with an emulsion method and phase separation as described by Z.G. Shi et al. in 2008 (Z.G. Shi et al.: Synthesis and characterization of hierarchically porous silica microspheres with penetrable macropores and tunable mesopores,
- the obtained calcined silica was size classified by using liquid elutriation involving the steps dispersion of the silica particles into water by ultrasonic treatment for 5 min., subsiding the particles in the dispersion by keeping it static for 2 hours, and discarding the upper water solution containing the small particles. Such size- classification was repeated for five times and the particles were collected.
- an inorganic particulate material mainly composed of silicon oxide, wherein the particulate material comprises mesopores and macropores can be easily provided by a process comprising the following steps:
- step b (a) dissolving a water-soluble polymer or another pore forming agent and a precursor for a matrix dissolving agent in a medium that promotes the hydrolysis of the metalorganic compound (see step b);
- the invention is directed to a process for producing inorganic particulate material mainly composed of silicon oxide, wherein the particulate material comprises mesopores and macropores and the process includes the steps of:
- step b (a) dissolving a water-soluble polymer or another pore forming agent and a precursor for a matrix dissolving agent in a medium that promotes the hydrolysis of the metalorganic compound (see step b);
- the process of the invention leads to particulate material having a mean diameter from about 1 pm to about 2000 pm, preferably from about 1 pm to
- the process described in the prior art involves an emulsification step, which requires distribution of the solution containing the water-soluble polymer (polyethylene oxide) and the metal organic compound (TEOS) in a different vessel containing paraffin oil.
- the vessel used for the process is a closable one, which allows the formation saturated vapor pressure, so that the liberation of the matrix dissolving agent from its precursor can be performed in an easy and time efficient manner as described later on.
- the process of the invention leads to particulate material having a uniform particle size distribution, which can be adjusted to the requirements by controlling the process conditions.
- the process of the invention is based on the classical sol-gel method as known in the art, which in principle is a gel formation of metalorganic compound by polymerization under suitable conditions.
- metalorganic compound having hydrolyzable ligands is hydrolyzed by mixing with an acidic aqueous solution of water-soluble polymer or some other pore-forming phase, the subsequent sol-gel reaction results in the formation of solidified gel in which the phase separated domains one rich in solvent the other rich in silica (gel skeleton, matrix) exist.
- the gel is aged by setting free the matrix dissolving agent from the precursor.
- the matrix dissolving agent leads to dissolution and re-precipitation of the inner wall, resulting in the loss of smaller pores and an increase of larger pores thereby creating sharply distributed mesopores.
- the gel skeleton Prior further solidification the gel skeleton is disintegrated into particles.
- Such disintegrating step can be performed by stirring as, for example, with an agitator, a high shear mixer (e.g. Ultraturrax ® ) or by ultrasonics.
- the particle sizes and distribution can be controlled over a broad range by adjusting the starting time of the disintegration and/or the agitation speed.
- the process of the invention further offers a simple method to produce particles having a uniform size distribution so that successive classification steps as described in the prior art can be avoided.
- the gel skeleton is transferred and homogenized to a particulate material by using an agitator.
- Particle size and distribution can be controlled by selecting the conditions of the process, especially the time period from phase separation until stirring as well as by the speed and size of the agitator.
- particle formation having a small size and a narrow particle size distribution is promoted by short time periods from phase separation until stirring and by using an agitator having larger blades whereas increased particle sizes is promoted by increasing the time period from phase separation until stirring and using an agitator having a smaller blade.
- Typical time periods from phase separation until stirring are in the range from 15 to 120 minutes. For example, if the time period from phase separation until stirring is 15 minutes, and an agitator with a large blade is used a material having a mean particle size of about 11 ⁇ and a narrow particle size distribution (d 10 : 5 ⁇ , d 5 o: 11 ⁇ , d 90 : 21 ⁇ ) is obtained, if the time period is about 120 minutes a mean particle size of about 200 ⁇ and a broader particle size distribution (d 10 : 5 ⁇ , d 50 : 216 ⁇ , d 90 : 956 ⁇ ) is obtained.
- a water-soluble polymer suitable to induce pore formation by a phase separation process or other pore forming agents are being used to control porosity of the material.
- the pore forming agents have considerable solubility in water and water-alcohol mixed solvents and have to be uniformly dissolved in the solvent mixture generated during the hydrolysis reaction of metalorganic compound containing hydrolyzable ligands.
- Pore forming agents which can be used as part of the pore forming phase in producing the porous material according to the invention are desired to have considerable solubility in water and water-alcohol mixed solvents. They have to be uniformly dissolved in the solvent mixture generated during the hydrolysis reaction of the
- metalorganic compound containing hydrolyzable ligands such as, for example, silicon alkoxide.
- Water-soluble polymers suitable to induce pore formation are, for example, polymeric salts such as poly(sodium styrenesulfonate) or poly(potassiurr) styrenesulfonate), polymeric acids which may dissociate to become polyanion such as poly(acrylic acid), polymeric bases which may dissociate to become polycation such as poly(allylamine) or
- poly(ethyleneimine), non-ionic polymers having ether oxygen in the main chain such as poly(ethylene oxide ), non-ionic polymers having lactone units in the side chain such as poly(vinylpyrrolidone) are suitable examples.
- Preferred polymers are non-ionic surfactants such as ether derivatives of polyoxyethylene, especially those containing an alkyl-, aryl-, alkylaryl- (e.g. an alkylphenyl), or arylalkyl (e.g. phenylalkyl) residue.
- Non-ionic surfactants possessing polyoxypropylene residues as hydrophilic moiety, such as polyoxypropylene alkyl ethers can also be used.
- Preferred polyethylene oxide containing surfactants are those which are derivatized with a lipophilic alkyl group with 8 to 20 C atoms, or with a lipophilic aryl group which can be substituted with one or several alkyl groups, and which have 6 to 25 C- atoms in total.
- Examples of the latter group of polyethylene oxide containing surfactants are polyoxyethylene nonylphenyl ether, polyoxyethylene octylphenyl ether, or polyoxyethylene (1 ,1,3,3-tetramethylbutyl)-phenyl ether. However, these examples are not limitative.
- the hydrophilic lipophilic balance (HLB) system can be used to facilitate to estimate the behavior of nonionic surfactants, and can be used as guideline for exchanging different non-ionic surfactants.
- the amount of non- ionic surfactant to be added varies, depending on the type of said non-ionic surfactant and also on the type and the amount of the metal alkoxide added, but may be from 1.0 to 10.0 g, preferably from .5 to 6.0 g, per 10 g of the metal alkoxide.
- the non-ionic surfactant has the function of inducing both sol-gel conversion and phase separation at the same time. While being gelled, the reaction system is separated into a solvent-rich phase and a silica rich phase. According to a preferred embodiment of the invention is directed to the process as described, wherein the pore forming agent is the non-ionic surfactant.
- Metalorganic compound can be applied by hydrolyzing metal alkoxides, metal chlorides, metal salts or coordinated compounds.
- an organic polymer is used, which is compatible with the solution of the metal alkoxide or its polymer, and which undergoes phase separation during the hydrolysis-polymerization step.
- This method comprises preparing a gel which has a solvent-rich phase capable of giving macropores of not smaller than about 100 nanometers in size, through sol-gel conversion in the presence of a pore forming agent, and finally drying and calcining the material.
- the porous inorganic materials produced by this process display connected open macropores. Examples of pore forming agents disclosed in these documents are: Adding lower alkyl alcohols like methanol or ethanol to the gelling mixture can also be used to modify the size of the
- the sol-gel method is used to control the pore size of the porous inorganic material.
- Metalorganic compounds having a hydrolysable ligand like metal alkoxides are used as starting materials with additions of appropriate chemical substances to result in the formation of characteristic phase- separated structure of which solvent-rich pore forming phase converts to the macropore of the dried gel material: Such starting materials and the conditions necessary to hydrolyse these starting materials are known in the art.
- Preferred metal alkoxides are silicon alkoxides, which may include, for example, tetramethoxysilane (TMOS), tetraethoxysilane (TEOS), methyltrimethoxysilane, ethyltrimethoxysilane and vinyl trimethoxysilane.
- TMOS tetramethoxysilane
- TEOS tetraethoxysilane
- methyltrimethoxysilane ethyltrimethoxysilane
- vinyl trimethoxysilane vinyl trimethoxysilane
- the conditions are chosen so as to hydrolyze the metal compound having a hydrolyzable functional group and to cause polymerization of the metal compound.
- the sol-gel transition of the reacting solution and the phase separation into solvent rich phase and a phase rich in metal compound (skeleton phase) are induced.
- the hydrolysis is done in an acidic medium. Diluted organic or inorganic acids are preferred in this case. Especially preferred is the use of acetic acid, hydrochloric acid or nitric acid using concentrations between 1 mmol/l and 2 mol/l.
- Other acidic media suitable to carry out the hydrolysis of silicon alkoxides are known in the art. Suitable reagents for the hydrolysis of other metalorganic compounds are known in the art as well.
- the process of the present invention further includes a precursor, i.e. a precursor for a matrix dissolving agent, which is used to control
- Matrix dissolving agents to be liberated from the precursor are basic substances such as ammonia.
- Precursors which can used in the present invention to liberate ammonia are, for example, urea and organic amides such as formamide, N- methylformamide, ⁇ , ⁇ ,-dimethylformamide, acetamide, N- methylacetamide, and ⁇ , ⁇ -dimethylacetamide.
- Preferred precursors are compounds having an amido group or an alkyl amido group, especially preferred is urea. Accordingly, one embodiment of the invention is directed to the process for producing the inorganic particulate material, wherein said precursor of the matrix dissolving agent is a compound having an amido group or an alkylamido group, preferably urea.
- thermolyzable compound in the reaction system of the present invention may vary, depending on the type of said compound.
- the heating temperature for the thermolysis of urea may fall between 60°C and 200°C. It is preferred that the thermolyzing step is executed in a closed container in order to make the vapor pressure of the thermolyzed product saturated and to rapidly make the solvent have a steady pH-value.
- the pH of the solvent is preferably from 8.0 to 11.0.
- the time after which the pore structure of the gel stays substantially unchanged under the processing conditions depends on the type of the precursor for the matrix dissolving agent and on the conditions applied (e.g.
- the gel is treated with urea at 110°C for about 4 hours which leads to a mesoporous material with ca. 10-13 nm pore size.
- the partly solidified gel skeleton is disintegrated into particles by appropriate means, preferably by stirring with an agitator.
- a further preferred embodiment of the invention is directed to the process for producing the inorganic particulate material, wherein step (e) is executed by stirring with an agitator, a high shear mixer or by ultrasonics. Early after the phase separation the gel is still soft which would possibly allow the use of an ultra sonic treatment for the particle formation.
- the final preparation steps for the manufacture of the porous inorganic particulate materials according to the present invention include an optional rinsing step, e.g. with water, a drying step, and a calcining step.
- drying is achieved at temperatures between 20 and 80°C; this step can be facilitated using an oven with air circulation or by applying reduced pressure.
- Calcining is typically done at final temperatures between 400 and 900°C for one to several hours.
- the final temperature is reached using a temperature program, typically rising the temperature between 50 and 200°C per hour.
- the pore size of macropores is determined using mercury porosimetry. It is also possible to estimate the pore dimensions from scanning electron micrographs (SEM). The pore size of mesopores and their specific surface area are determined using nitrogen adsorption/ desorption measurements (BET-method) which are performed by following standard protocols.
- the silica particles having mesopores as well as macropores as described in the prior art are prepared by using an emulsion technique (Z.G. Shi et al. (2008), see above), whereas the particles obtained by the process of the present invention are formed by the disintegration of a gel after phase separation.
- Emulsification leads to spherical droplets of the gel, which are isolated and dried, which results in a particular material having a spherical shape.
- the process of the present invention does not use emulsification for particle formation but disintegration, and, therefore, leads to a new particulate product, which differs from the prior art product at least in that it has a different particle shape.
- the invention is also directed to a new inorganic particulate material mainly composed of silicon oxide, wherein the particulate material comprises macropores and mesopores, wherein the macropores have a mean diameter > 0.1 pm and the mesopores have a mean diameter between 2 and 100 nm, obtainable by the process of the present invention as described herein.
- the particulate material obtainable by the process has a mean diameter from about 1 pm to about 2000 pm, preferably from about 1 pm to 1000 pm and more preferably from about 1 pm to 500 pm.
- one preferred embodiment of the invention is directed to such mesoporous particulate material, wherein said material has an irregular non-spherical shape.
- the material provided by the present invention can be used as matrix forming agent in a modified release delivery system for a bioactive agent. Therefore, the present invention is also directed to a modified release delivery system comprising a bioactive agent and inorganic mesoporous and macroporous particulate material as it is obtainable according to the process of the present invention.
- a bioactive agent, which can be present in the modified release system can be any chemical substance or protein, which are capable of providing a local or systemic biological, physiological, or therapeutic effect in the subject to which it is applied.
- a bioactive agent are pharmaceutical drugs, vitamins or minerals.
- the bioactive agent, which can be present in the modified release system can be, for example an agent that act to control or prevent infection or inflammation, enhance cell growth and tissue regeneration, control tumor growth, act as an analgesic, promote anti-cell attachment or enhance bone growth, among other functions.
- Other suitable bioactive agents can include anti-viral agents, hormones, antibodies, or therapeutic proteins.
- Still other bioactive agents include prodrugs, which are agents that are not biologically active when administered but upon administration to a subject are converted to bioactive agents through metabolism or some other
- the modified release delivery system contain a pharmaceutical drug. Therefore, one embodiment of the invention is directed to a modified release delivery system, wherein the bioactive agent is a pharmaceutical drug.
- modified release means that the release of the bioactive agent from the delivery system or a portion thereof upon contact of the dosage form or portion thereof with a liquid medium is different to the release of the same bioactive agent from a conventional immediate release formulation, wherein the release is mainly controlled by the solubility of the bioactive agent in the liquid medium. Accordingly, modified release includes, but is not limited to accelerated release (i.e. an increased dissolution rate), sustained-release, extended release, slow release, delayed release and the like.
- the inorganic particulate material comprising macropores and
- mesopores as it is obtainable by the process of the present invention is especially usable to increase the dissolution of bioactive agents especially suitable to increase the dissolution rate of poorly water-soluble or water- insoluble bioactive agents.
- Poorly water-soluble substances are understood to have a solubility in water of ⁇ 10 mg/ml, in particular ⁇ 5 mg/ml and more particularly ⁇ 1 mg/ml, practically water-insoluble or insoluble substances are those having a solubility in water of ⁇ 0.1 mg/ml.
- water- solubility or "solubility in water” in the present application refers to the respective solubility measured at 25°Celsius.
- one further object of the present invention is directed to a modified release system comprising a bioactive agent and inorganic mesoporous and macroporous particulate material as it is obtainable by the process according to the present invention, wherein the bioactive agent has a water-solubility of ⁇ about 10 mg/ml, preferably from about 0.1 mg/ml to about 5 mg/ml and more preferably from about ⁇ 1 mg/ml.
- the modified release system according to the present invention contains the bioactive agent in an amount of from about 0.1 to about 90% by weight, preferably from about 0.2 to about 75% by weight, more preferably from about 5 to about 40% by weight most preferably from about 10 to about 30% by weight.
- the invention is also directed to a modified release system as described herein, wherein the bioactive agent is present in an amount of from about 0.1 to about 90% by weight, preferably from about 0.2 to about 75% by weight, more preferably from about 5 to about 40% by weight most preferably from about 10 to about 30% by weight.
- the bioactive agent can be applied to the inorganic particulate material by using the loading techniques known in the art, as, for example, by adsorption from a solution of the bioactive agent in a suitable solvent to the inorganic material and subsequent separation, by wetness impregnation of the inorganic material with a concentrated solution of the bioactive agent in a suitable solvent such as, for example, ethanol, CH2CI2 or acetone and subsequent solvent evaporation, by spray-drying of a mixture of bioactive agent in a suitable solvent, by heating of a mixture of the bioactive agent and the particulate material or by drug loading with supercritical fluids.
- the loading techniques known in the art, as, for example, by adsorption from a solution of the bioactive agent in a suitable solvent to the inorganic material and subsequent separation, by wetness impregnation of the inorganic material with a concentrated solution of the bioactive agent in a suitable solvent such as, for example, ethanol, CH2CI2 or acetone and subsequent
- the modified release system can be formulated as an oral, a topical or a parenteral administration form, preferably as an oral administration form. Consequently, the invention is further directed to the use of the modified release system as described herein, wherein said system is an oral or a topical or a parenteral administration form.
- Suitable for oral administration forms include tablets, capsules, powders, dragees, suspensions; suitable topical administration forms include ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. If an oral administration form is used, tablets, capsules and powders are preferred, if a topical administration form is used, ointments, creams, suspensions and powders are preferred.
- the invention is also directed to a modified release system as described herein, wherein said release system is an oral application form, which is a tablet, a capsule, a powder, or a dragee, or a topical administration form, which is an ointment, a cream, a suspension or a powder and a parenteral administration form, which comprises microparticles or is an implant.
- oral application form which is a tablet, a capsule, a powder, or a dragee
- a topical administration form which is an ointment, a cream, a suspension or a powder and a parenteral administration form, which comprises microparticles or is an implant.
- the modified release system is suitable to be used for the administration of at least one bioactive agent to mammal, preferably to a human.
- the invention is also directed to the use of the modified release system as described herein for the administration of at least one bioactive agent to a mammal, preferably to a human.
- the bioactive agent loaded inorganic material can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like.
- an oral, non-toxic and pharmaceutically acceptable inert excipient such as, for example, ethanol, glycerol, water and the like.
- Powders can be composed of the bioactive agent loaded inorganic material itself, which may be further comminuted, or can be prepared, for example, by mixing the bioactive agent loaded inorganic, which may have been comminuted, with a comminuted pharmaceutical excipient, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol.
- a flavour, preservative, dispersant and dye may likewise be present.
- Capsules can be produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith.
- Glidants and lubricants such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation.
- a disintegrant or solubiliser such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medicament after the capsule has been taken.
- suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
- the lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- the disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like.
- the tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a
- a powder mixture is prepared by mixing the active agent loaded in a inorganic, which may have been comminuted in a suitable manner, with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbent, such as, for example, bentonite, kaolin or dicalcium phosphate.
- a binder such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone
- a dissolution retardant such as, for example, paraffin
- an absorption accelerator such as, for example, a quaternary salt
- an absorbent such as, for example, bentonite, kaolin or dicalcium phosphate.
- the powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve.
- a binder such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials
- the powder mixture can be run through a tabletting machine, giving lumps of non-uniform shape which are broken up to form granules.
- the granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets.
- the bioactive agent loaded inorganic material can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps.
- a transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.
- the formulations are preferably applied as topical ointment or cream.
- the bioactive agent loaded inorganic material can be employed either with a paraffinic or a water- miscible cream base.
- the bioactive agent loaded inorganic material can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.
- implant denotes a solid modified release delivery system, which is deposited in any suitable body tissues or cavities to form a reservoir or pool which slowly migrates to surrounding tissues and organs and eventually becomes systemically distributed.
- solid modified release delivery system which is deposited in any suitable body tissues or cavities to form a reservoir or pool which slowly migrates to surrounding tissues and organs and eventually becomes systemically distributed.
- implants which are placed beneath the epidermal layer of the skin, i. e. between the epidermis and the dermis of the skin of the patient being treated.
- Such an implant will be formulated in accordance with well known principles and materials commonly used in this delivery technology, and may be prepared in such a way as to provide controlled-, sustained-, and/or delayed-release of the active ingredient into the systemic circulation of the patient.
- Such type of implant can be easily administered and removed by minimal incision or can be applied by using an implant syringe, which are well known in the art for such purpose.
- the solid modified release delivery system can be also parenterally applied in the form of microparticles via a syringe using a carrier liquid.
- the microparticles are mixed with the carrier liquid to be injected into a patient.
- the microparticles mixed with an organic solvent to produce a liquid or gel which may be injected into a patient.
- compositions adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes.
- the silica gel is poured into a pressure resistant glass bottle and aged in a steam autoclave for 4 h at 110°C.
- the solvent is exchanged over a glass suction filter in four steps: purified water, nitric-acid, purified water and water/ethanol (2:1).
- the silica is washed four times with about 200 mL of each solvent and filtered to dryness.
- the semi-dried silica gel is replaced into an evaporating dish which is covered by a paper filter followed by a drying step in an oven for 5 days at 40°C.
- the dried gel is calcined for 4 h at 600°C with a heating rate of 50 K/h.
- the calcined gel is analysed by Hg-lntrusion and N 2 -Adsorption/ Desorption
- Hg-lntrusion PoreMaster 60 from Quantachrome Instruments, 1900
- the silica gel is poured into a pressure resistant glass bottle and aged in a steam autoclave for 4 h at 110°C.
- the solvent is exchanged over a glass suction filter in four steps: purified water, nitric- acid, purified water and water/ethanol (2:1).
- the silica is washed four times with about 200 ml_ of each solvent and filtered to dryness.
- the semi-dried silica gel is replaced into an evaporating dish which is covered by a paper filter followed by a drying step in an oven for 5 days at 40°C.
- the dried gel is calcined for 4 h at 600°C with a heating rate of 50 K/h.
- the calcined gel is analysed by Hg-lntrusion and N 2 -Adsorption/ Desorption (BET-measurements). Further, the particle size distribution is measured by the Malvern Laserbeugung method.
- the silica gel is poured into a pressure resistant glass bottle and aged in a steam autoclave for 4 h at 110°C.
- the solvent is exchanged over a glass suction filter in four steps: purified water, nitric- acid, purified water and water/ethanol (2:1).
- the silica is washed four times with about 200 mL of each solvent and filtered to dryness.
- the semi-dried silica gel is replaced into an evaporating dish which is covered by a paper filter followed by a drying step in an oven for 5 days at 40°C.
- the dried gel is calcined for 4 h at 600°C with a heating rate of 50 K/h.
- the calcined gel is analysed by Hg-lntrusion and N 2 -Adsorption/ Desorption (BET-measurements). Further, the particle size distribution is measured by the Malvern Laserbeugung method.
- the semi solid silica gel gel is roughly cracked with a spatula and afterwards stirred with a speed of 450 rpm for 3.5 h and with 300 rpm over night. Afterwards the silica gel is poured into a pressure resistant glass bottle and aged in a steam autoclave for 4 h at 110°C. The solvent is exchanged over a glass suction filter in four steps: purified water, nitric-acid, purified water and water/ethanol (2:1). The silica is washed four times with about 200 mL of each solvent and filtered to dryness.
- the semi-dried silica gel is replaced into an evaporating dish which is covered by a paper filter followed by a drying step in an oven for 5 days at 40°C.
- the dried gel is calcined for 4 h at 600°C with a heating rate of 50 K/h.
- the calcined gel is analysed by Hg-lntrusion and N 2 -Adsorption/ Desorption (BET-measurements). Further, the particle size distribution is measured by the Malvern Laserbeugung method.
- the silica gel is poured into a pressure resistant glass bottle and aged in a steam autoclave for 4 h at 1 10°C.
- the solvent is exchanged over a glass suction filter in four steps: purified water, nitric- acid, purified water and water/ethanol (2: 1).
- the silica is washed four times with about 200 mL of each solvent and filtered to dryness.
- the semi-dried silica gel is replaced into an evaporating dish which is covered by a paper filter followed by a drying step in an oven for 5 days at 40°C.
- the dried gel is calcined for 4 h at 600°C with a heating rate of 50 K/h.
- the calcined gel is analysed by Hg-lntrusion and N 2 -Adsorption/ Desorption (BET-measurements). Further, the particle size distribution is measured by the Malvern Laserbeugung method.
- the calcined silica gel is suspended in a beaker with water which is placed in an autoclave for 3 h at 130°C. Afterwards the rehydroxylated gel is washed with methanol over a glass suction filter until all solvent is removed. The silica gel is then placed in an evaporating dish covered with a paper filter and dried in an oven for 5 days at 40°C.
- the resulting material posess hydrophilic properties due to a
- Itraconazole a synthetic triazole antifungal agent, which is poorly soluble in aqueous solutions (1 ng/mL at pH 7 and 4 pg/mL at pH 1 ; see Six, K. et al., Eur J Pharm Sci 24 (2005) 179-186), was used as model drug.
- the silica material of the present invention was drug loaded with itraconazole by using wetness impregnation.
- 1 .0 g of itraconazole was dissolved in 130 mL of acetone at 53°C.
- a 250 mL three necked flask (heated by a water bath at 60°C; equipped with an overhead stirrer and paddle) was filled with 2.3 g of silica material synthesized in accordance to Example 5.
- the itraconazole solution was added pro rata (10 ml_ per impregnation step) to the flask while acetone was evaporated by a nitrogen stream under stirring. The procedure of impregnating and subsequently evaporating was repeated until the entire itraconazole solution was evaporated. Additionally, the obtained powder was dried under vacuum at 40°C over night. The resulting drug load aimed to 30% by weight.
- the itraconazole loaded samples tested contained 50 mg of itraconazole which was confirmed by high performance liquid chromatography (HPLC) with UV detector, pure crystalline itraconazole was tested in the same amount (50 mg).
- FIG 1 summarizes the dissolution rates of the samples tested.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Inorganic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Silicates, Zeolites, And Molecular Sieves (AREA)
- Silicon Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/117,041 US9517268B2 (en) | 2011-05-13 | 2012-04-25 | Process for producing inorganic particulate material |
ES12717608.9T ES2657822T3 (en) | 2011-05-13 | 2012-04-25 | Process to produce a particulate inorganic material |
BR112013029149A BR112013029149A2 (en) | 2011-05-13 | 2012-04-25 | inorganic particulate material production process |
SG2013082342A SG194820A1 (en) | 2011-05-13 | 2012-04-25 | Process for producing inorganic particulate material |
EA201301264A EA201301264A1 (en) | 2011-05-13 | 2012-04-25 | METHOD OF OBTAINING INORGANIC MATERIAL IN THE FORM OF PARTICLES |
JP2014509629A JP6040497B2 (en) | 2011-05-13 | 2012-04-25 | Method for producing inorganic particulate matter |
AU2012258092A AU2012258092B2 (en) | 2011-05-13 | 2012-04-25 | Process for producing inorganic particulate material |
MX2013013135A MX352176B (en) | 2011-05-13 | 2012-04-25 | Process for producing inorganic particulate material. |
CN201280023311.9A CN103534208B (en) | 2011-05-13 | 2012-04-25 | The manufacture method of inorganic particulate material |
CA2836782A CA2836782A1 (en) | 2011-05-13 | 2012-04-25 | Process for producing inorganic particulate material |
DK12717608.9T DK2707329T3 (en) | 2011-05-13 | 2012-04-25 | PROCEDURE FOR MANUFACTURING INORGANIC PARTICULATE MATERIAL |
KR1020137033128A KR101906792B1 (en) | 2011-05-13 | 2012-04-25 | Process for producing inorganic particulate material |
EP12717608.9A EP2707329B1 (en) | 2011-05-13 | 2012-04-25 | Process for producing inorganic particulate material |
IL229209A IL229209A (en) | 2011-05-13 | 2013-11-03 | Process for producing inorganic particulate material |
ZA2013/09469A ZA201309469B (en) | 2011-05-13 | 2013-12-12 | Process for producing inorganic particulate material |
US15/346,377 US10577250B2 (en) | 2011-05-13 | 2016-11-08 | Process for producing of inorganic particulate material |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11003961.7 | 2011-05-13 | ||
EP11003961 | 2011-05-13 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/117,041 A-371-Of-International US9517268B2 (en) | 2011-05-13 | 2012-04-25 | Process for producing inorganic particulate material |
US15/346,377 Division US10577250B2 (en) | 2011-05-13 | 2016-11-08 | Process for producing of inorganic particulate material |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2012156023A1 true WO2012156023A1 (en) | 2012-11-22 |
WO2012156023A8 WO2012156023A8 (en) | 2014-01-30 |
Family
ID=46022158
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2012/001769 WO2012156023A1 (en) | 2011-05-13 | 2012-04-25 | Process for producing inorganic particulate material |
Country Status (18)
Country | Link |
---|---|
US (1) | US9517268B2 (en) |
EP (1) | EP2707329B1 (en) |
JP (1) | JP6040497B2 (en) |
KR (1) | KR101906792B1 (en) |
CN (1) | CN103534208B (en) |
AR (1) | AR086346A1 (en) |
AU (1) | AU2012258092B2 (en) |
BR (1) | BR112013029149A2 (en) |
CA (1) | CA2836782A1 (en) |
DK (1) | DK2707329T3 (en) |
EA (1) | EA201301264A1 (en) |
ES (1) | ES2657822T3 (en) |
IL (1) | IL229209A (en) |
MX (1) | MX352176B (en) |
PT (1) | PT2707329T (en) |
SG (1) | SG194820A1 (en) |
WO (1) | WO2012156023A1 (en) |
ZA (1) | ZA201309469B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015078552A1 (en) | 2013-11-26 | 2015-06-04 | Merck Patent Gmbh | Process for producing inorganic particulate material |
US20150283090A1 (en) * | 2012-11-12 | 2015-10-08 | Merck Patent Gmbh | Use of silicon oxide-based material for the modified release of biologically active agents |
WO2020127281A1 (en) | 2018-12-20 | 2020-06-25 | Merck Patent Gmbh | A release system comprising a bioactive agent and a particulate material |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10577250B2 (en) | 2011-05-13 | 2020-03-03 | Merck Patent Gmbh | Process for producing of inorganic particulate material |
CN110678206B (en) | 2017-05-19 | 2023-03-21 | 株式会社德山 | Medicine raw material medicine carrier and its manufacturing method |
CN110133765A (en) * | 2018-02-08 | 2019-08-16 | 法国圣戈班玻璃厂 | Optical module and its preparation method and application with resistance to pollution layer |
JP7352936B2 (en) * | 2018-08-17 | 2023-09-29 | 地方独立行政法人東京都立産業技術研究センター | Porous silica, functional material and method for producing porous silica |
WO2021220507A1 (en) * | 2020-05-01 | 2021-11-04 | 昭和電工マテリアルズ株式会社 | Coating solution for forming porous body, porous body, and method for manufacturing porous body |
JP6924338B1 (en) * | 2021-01-29 | 2021-08-25 | 三井金属鉱業株式会社 | Equipment and methods for producing sol, gel and silica porous bodies |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1070216A (en) * | 1964-03-09 | 1967-06-01 | Grace W R & Co | Improvements in or relating to silica and silica-alumina gels |
US6107351A (en) * | 1997-02-24 | 2000-08-22 | Dow Corning Corporation | Neutral-aged hydrophobic silica gels with reduced surface area |
EP1298097A1 (en) * | 1996-12-26 | 2003-04-02 | MERCK PATENT GmbH | Method for producing porous inorganic materials |
WO2005000740A2 (en) | 2003-06-27 | 2005-01-06 | K.U. Leuven Research & Development | Crystalline mesoporous oxide based materials useful for the fixation and controlled release of drugs |
WO2006026840A2 (en) | 2004-09-09 | 2006-03-16 | K.U.Leuven Research & Development | Controlled release delivery system for bio-active agents |
US20070224133A1 (en) * | 2006-03-23 | 2007-09-27 | Mcgill Patrick D | High-cleaning silica materials made via product morphology control under high shear conditions |
US20090291144A1 (en) * | 1999-08-16 | 2009-11-26 | Henceforth Hibernia, Inc. | Therapeutic and Prophylactic Compositions Including Catalytic Biomimetic Solids and Methods to Prepare and Use Them |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3985170B2 (en) | 1996-12-26 | 2007-10-03 | 直弘 曽我 | Method for producing inorganic porous body |
JP3985171B2 (en) | 1996-12-26 | 2007-10-03 | 直弘 曽我 | Method for producing inorganic porous body |
DE69841079D1 (en) | 1998-01-23 | 2009-10-01 | Merck Patent Gmbh | METHOD FOR PRODUCING INORGANIC MATERIAL IN A CAPILLARY |
JPH11292528A (en) | 1998-01-23 | 1999-10-26 | Naohiro Soga | Production of inorganic porous material |
RU2270167C2 (en) | 2001-08-13 | 2006-02-20 | Родиа Шими | Method for production of silicium dioxides, silicium dioxides with specific sizing and/or pore distribution and uses thereof, in particular in polymer reinforcement |
RU2342953C2 (en) * | 2003-02-24 | 2009-01-10 | Фармасьютикал Продакшенз, Инк. | Transmucosal system of delivery of medical products |
JP4519433B2 (en) * | 2003-09-17 | 2010-08-04 | 株式会社トクヤマ | Particulate mesoporous silica |
US20070003492A1 (en) | 2003-09-11 | 2007-01-04 | Kabushiki Kaisha Toyota Chuo Kenkyusho | Porous silica having substance carried thereon |
JP2009013142A (en) * | 2007-07-09 | 2009-01-22 | Kyoto Univ | Mesoporous silica for sustained release |
CN101348713A (en) | 2007-07-20 | 2009-01-21 | 同济大学 | Magnetic composite nano microsphere capable of emitting fluorescence and preparation thereof |
CN101113247A (en) * | 2007-09-05 | 2008-01-30 | 广州市飞雪化工有限公司 | Method for preparing transparent friction particle |
CN101250313B (en) | 2008-03-19 | 2010-12-08 | 中国科学院化学研究所 | Nano-particle compound and preparation method thereof |
CN101343065A (en) * | 2008-09-04 | 2009-01-14 | 复旦大学 | Nano-silicon dioxide hollow sphere material and method of preparing the same |
CN101412517A (en) * | 2008-11-14 | 2009-04-22 | 华东理工大学 | Preparation and use of pore diameter controllable mesoporous silicon dioxide microsphere |
JP5426869B2 (en) * | 2008-11-19 | 2014-02-26 | パナソニック株式会社 | Method for producing mesoporous silica fine particles, mesoporous silica fine particle-containing composition, and mesoporous silica fine particle-containing molded product |
JP4521477B1 (en) * | 2009-01-15 | 2010-08-11 | 水澤化学工業株式会社 | Amorphous silica |
CN101559952A (en) * | 2009-05-13 | 2009-10-21 | 南京工业大学 | Method for preparing nanoscale mesoporous silica spheres |
CN101829331A (en) * | 2010-05-28 | 2010-09-15 | 沈阳药科大学 | Three-dimensionally ordered macroporous silicon dioxide medicament administration system suitable for slightly soluble medicament |
-
2012
- 2012-04-25 JP JP2014509629A patent/JP6040497B2/en not_active Expired - Fee Related
- 2012-04-25 EA EA201301264A patent/EA201301264A1/en unknown
- 2012-04-25 EP EP12717608.9A patent/EP2707329B1/en not_active Not-in-force
- 2012-04-25 ES ES12717608.9T patent/ES2657822T3/en active Active
- 2012-04-25 CA CA2836782A patent/CA2836782A1/en not_active Abandoned
- 2012-04-25 MX MX2013013135A patent/MX352176B/en active IP Right Grant
- 2012-04-25 BR BR112013029149A patent/BR112013029149A2/en not_active Application Discontinuation
- 2012-04-25 WO PCT/EP2012/001769 patent/WO2012156023A1/en active Application Filing
- 2012-04-25 US US14/117,041 patent/US9517268B2/en not_active Expired - Fee Related
- 2012-04-25 KR KR1020137033128A patent/KR101906792B1/en active IP Right Grant
- 2012-04-25 SG SG2013082342A patent/SG194820A1/en unknown
- 2012-04-25 CN CN201280023311.9A patent/CN103534208B/en not_active Expired - Fee Related
- 2012-04-25 PT PT127176089T patent/PT2707329T/en unknown
- 2012-04-25 DK DK12717608.9T patent/DK2707329T3/en active
- 2012-04-25 AU AU2012258092A patent/AU2012258092B2/en not_active Ceased
- 2012-05-11 AR ARP120101657A patent/AR086346A1/en active IP Right Grant
-
2013
- 2013-11-03 IL IL229209A patent/IL229209A/en active IP Right Grant
- 2013-12-12 ZA ZA2013/09469A patent/ZA201309469B/en unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1070216A (en) * | 1964-03-09 | 1967-06-01 | Grace W R & Co | Improvements in or relating to silica and silica-alumina gels |
EP1298097A1 (en) * | 1996-12-26 | 2003-04-02 | MERCK PATENT GmbH | Method for producing porous inorganic materials |
US6107351A (en) * | 1997-02-24 | 2000-08-22 | Dow Corning Corporation | Neutral-aged hydrophobic silica gels with reduced surface area |
US20090291144A1 (en) * | 1999-08-16 | 2009-11-26 | Henceforth Hibernia, Inc. | Therapeutic and Prophylactic Compositions Including Catalytic Biomimetic Solids and Methods to Prepare and Use Them |
WO2005000740A2 (en) | 2003-06-27 | 2005-01-06 | K.U. Leuven Research & Development | Crystalline mesoporous oxide based materials useful for the fixation and controlled release of drugs |
WO2006026840A2 (en) | 2004-09-09 | 2006-03-16 | K.U.Leuven Research & Development | Controlled release delivery system for bio-active agents |
US20070224133A1 (en) * | 2006-03-23 | 2007-09-27 | Mcgill Patrick D | High-cleaning silica materials made via product morphology control under high shear conditions |
Non-Patent Citations (10)
Title |
---|
B. MUNOZ ET AL.: "MCM-41 organic modification as drug delivery rate regulator", CHEM. MATER., vol. 15, 2003, pages 500 - 503 |
D.Y. ZHAO ET AL.: "Triblock copolymer syntheses of mesoporous silica with periodic 50 to 300 angstrom pores", SCIENCE, vol. 279, 1998, pages 548 - 552 |
J. ANDERSSON ET AL.: "Influences of material characteristics on ibuprofen drug loading and release profiles from ordered micro- and mesoporous silica matrices", CHEM. MATER., vol. 16, 2004, pages 4160 - 4167 |
J.S. BECK ET AL.: "A new family of mesoporous molecular sieves prepared with liquid-crystal templates", J. AM. CHEM. SOC., vol. 114, 1992, pages 10834 - 10843 |
J.S. BECK ET AL.: "A new family of mesoporousmolecular sieves prepared with liquid-crystal templates", J. AM. CHEM. SOC., vol. 114, 1992, pages 10834 - 10843 |
M. VALLET-REGI ET AL.: "A new property of MCM-41: drug delivery system", CHEM. MATER., vol. 13, 2001, pages 308 - 311 |
P. HORCAJADA ET AL.: "Influence of pore size of MCM-41 matrices on drug delivery rate", MICROPOROUS MESOPOROUS MATER., vol. 68, 2004, pages 105 - 109 |
SIX, K. ET AL., EURJ PHARM SCI, vol. 24, 2005, pages 179 - 186 |
Z.G. SHI ET AL.: "Drug delivery devices based on macroporous silica spheres", MICROPOR. MESOPOR. MATER., vol. 126, 2011, pages 826 - 831 |
Z.G. SHI ET AL.: "Synthesis and characterization of hierarchically porous silica microspheres with penetrable macropores and tunable mesopores", MICROPOR. MESOPOR. MATER., vol. 116, 2008, pages 701 |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150283090A1 (en) * | 2012-11-12 | 2015-10-08 | Merck Patent Gmbh | Use of silicon oxide-based material for the modified release of biologically active agents |
WO2015078552A1 (en) | 2013-11-26 | 2015-06-04 | Merck Patent Gmbh | Process for producing inorganic particulate material |
CN105764852A (en) * | 2013-11-26 | 2016-07-13 | 默克专利股份有限公司 | Process for producing inorganic particulate material |
JP2016539903A (en) * | 2013-11-26 | 2016-12-22 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | Process for producing inorganic particulate material |
AU2014356854B2 (en) * | 2013-11-26 | 2017-11-16 | Merck Patent Gmbh | Process for producing inorganic particulate material |
WO2020127281A1 (en) | 2018-12-20 | 2020-06-25 | Merck Patent Gmbh | A release system comprising a bioactive agent and a particulate material |
Also Published As
Publication number | Publication date |
---|---|
EA201301264A1 (en) | 2014-04-30 |
ZA201309469B (en) | 2014-08-27 |
KR20140033122A (en) | 2014-03-17 |
US9517268B2 (en) | 2016-12-13 |
AU2012258092A1 (en) | 2014-01-09 |
ES2657822T3 (en) | 2018-03-07 |
EP2707329B1 (en) | 2017-11-01 |
CN103534208B (en) | 2017-07-18 |
CN103534208A (en) | 2014-01-22 |
CA2836782A1 (en) | 2012-11-22 |
AR086346A1 (en) | 2013-12-04 |
AU2012258092B2 (en) | 2015-08-20 |
KR101906792B1 (en) | 2018-10-11 |
MX352176B (en) | 2017-11-13 |
IL229209A0 (en) | 2014-01-30 |
BR112013029149A2 (en) | 2017-02-07 |
US20140336274A1 (en) | 2014-11-13 |
WO2012156023A8 (en) | 2014-01-30 |
IL229209A (en) | 2016-12-29 |
JP6040497B2 (en) | 2016-12-07 |
DK2707329T3 (en) | 2018-01-15 |
SG194820A1 (en) | 2013-12-30 |
EP2707329A1 (en) | 2014-03-19 |
PT2707329T (en) | 2018-02-07 |
MX2013013135A (en) | 2014-02-11 |
JP2014522363A (en) | 2014-09-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2707329B1 (en) | Process for producing inorganic particulate material | |
JP6557745B2 (en) | Use of silicon oxide-based materials for modified release of bioactive substances | |
US7579014B2 (en) | Mesoporous compositions for use in drug delivery | |
JP2008546614A (en) | Particles containing a hydrophobic substance therein | |
EP3074344B1 (en) | Process for producing inorganic particulate material | |
CN113562737B (en) | Mesoporous silica nanoparticle with adjustable chiral structure and preparation method and application thereof | |
US10577250B2 (en) | Process for producing of inorganic particulate material | |
Liang et al. | Construction and properties of venlafaxine hydrochloride sustained release system based on hollow mesoporous silica microspheres | |
Bilo et al. | Millimeter-sized micellar-templated silica beads and phenylene-bridged mesoporous organosilica beads |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12717608 Country of ref document: EP Kind code of ref document: A1 |
|
REEP | Request for entry into the european phase |
Ref document number: 2012717608 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012717608 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2836782 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2013/013135 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2014509629 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20137033128 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14117041 Country of ref document: US Ref document number: 201301264 Country of ref document: EA |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112013029149 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2012258092 Country of ref document: AU Date of ref document: 20120425 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112013029149 Country of ref document: BR Kind code of ref document: A2 Effective date: 20131112 |