JP2018090573A - Solid preparations - Google Patents
Solid preparations Download PDFInfo
- Publication number
- JP2018090573A JP2018090573A JP2017225341A JP2017225341A JP2018090573A JP 2018090573 A JP2018090573 A JP 2018090573A JP 2017225341 A JP2017225341 A JP 2017225341A JP 2017225341 A JP2017225341 A JP 2017225341A JP 2018090573 A JP2018090573 A JP 2018090573A
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- JP
- Japan
- Prior art keywords
- salt
- fexofenadine
- tablet
- solid preparation
- ephedrines
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000007787 solid Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 28
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims abstract description 25
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims abstract description 22
- 229960003592 fexofenadine Drugs 0.000 claims abstract description 17
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052751 metal Inorganic materials 0.000 claims abstract description 13
- 239000002184 metal Substances 0.000 claims abstract description 13
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 13
- 229960002179 ephedrine Drugs 0.000 claims abstract description 10
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 15
- 229960003908 pseudoephedrine Drugs 0.000 claims description 11
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 claims description 11
- RRJFVPUCXDGFJB-UHFFFAOYSA-N Fexofenadine hydrochloride Chemical compound Cl.C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RRJFVPUCXDGFJB-UHFFFAOYSA-N 0.000 claims description 8
- 229960000354 fexofenadine hydrochloride Drugs 0.000 claims description 6
- FMCGSUUBYTWNDP-ONGXEEELSA-N (1R,2S)-2-(dimethylamino)-1-phenyl-1-propanol Chemical compound CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-ONGXEEELSA-N 0.000 claims description 4
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 229960002221 methylephedrine Drugs 0.000 claims description 4
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims description 4
- 229960000395 phenylpropanolamine Drugs 0.000 claims description 4
- FMCGSUUBYTWNDP-UHFFFAOYSA-N N-Methylephedrine Natural products CN(C)C(C)C(O)C1=CC=CC=C1 FMCGSUUBYTWNDP-UHFFFAOYSA-N 0.000 claims description 3
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- 239000007909 solid dosage form Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 11
- 238000010828 elution Methods 0.000 abstract description 7
- 238000009472 formulation Methods 0.000 abstract description 6
- 238000013329 compounding Methods 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 47
- 238000000034 method Methods 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 10
- 238000007922 dissolution test Methods 0.000 description 9
- 238000005469 granulation Methods 0.000 description 8
- 230000003179 granulation Effects 0.000 description 8
- 235000019700 dicalcium phosphate Nutrition 0.000 description 7
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 7
- 239000008187 granular material Substances 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229940024546 aluminum hydroxide gel Drugs 0.000 description 5
- SMYKVLBUSSNXMV-UHFFFAOYSA-K aluminum;trihydroxide;hydrate Chemical compound O.[OH-].[OH-].[OH-].[Al+3] SMYKVLBUSSNXMV-UHFFFAOYSA-K 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000465 moulding Methods 0.000 description 5
- 239000012085 test solution Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000011812 mixed powder Substances 0.000 description 4
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 description 4
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 206010039085 Rhinitis allergic Diseases 0.000 description 3
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 3
- 201000010105 allergic rhinitis Diseases 0.000 description 3
- 230000000954 anitussive effect Effects 0.000 description 3
- 230000001387 anti-histamine Effects 0.000 description 3
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- CAVQBDOACNULDN-NRCOEFLKSA-N (1s,2s)-2-(methylamino)-1-phenylpropan-1-ol;sulfuric acid Chemical compound OS(O)(=O)=O.CN[C@@H](C)[C@@H](O)C1=CC=CC=C1.CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 CAVQBDOACNULDN-NRCOEFLKSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 206010028741 Nasal inflammation Diseases 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 2
- 229940124584 antitussives Drugs 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000000378 calcium silicate Substances 0.000 description 2
- 229910052918 calcium silicate Inorganic materials 0.000 description 2
- 235000012241 calcium silicate Nutrition 0.000 description 2
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- PGZIKUPSQINGKT-UHFFFAOYSA-N dialuminum;dioxido(oxo)silane Chemical compound [Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O PGZIKUPSQINGKT-UHFFFAOYSA-N 0.000 description 2
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 description 2
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 2
- -1 dl-methylephedrine saccharin salt Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229960001545 hydrotalcite Drugs 0.000 description 2
- 229910001701 hydrotalcite Inorganic materials 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229960004159 pseudoephedrine sulfate Drugs 0.000 description 2
- 206010039083 rhinitis Diseases 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 239000005526 vasoconstrictor agent Substances 0.000 description 2
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010028735 Nasal congestion Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004115 Sodium Silicate Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- NTCYWJCEOILKNG-ROLPUNSJSA-N [(1r,2s)-1-hydroxy-1-phenylpropan-2-yl]-dimethylazanium;chloride Chemical compound Cl.CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 NTCYWJCEOILKNG-ROLPUNSJSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- DCOLOVHTJKNUOI-UHFFFAOYSA-J [OH-].[OH-].[OH-].[OH-].[Mg++].[Mg++] Chemical compound [OH-].[OH-].[OH-].[OH-].[Mg++].[Mg++] DCOLOVHTJKNUOI-UHFFFAOYSA-J 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 201000010435 allergic urticaria Diseases 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 229940124579 cold medicine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-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
- 239000007884 disintegrant Substances 0.000 description 1
- 229940005636 dl- methylephedrine Drugs 0.000 description 1
- 229940073563 dl- methylephedrine hydrochloride Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000007542 hardness measurement Methods 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- NEMFQSKAPLGFIP-UHFFFAOYSA-N magnesiosodium Chemical compound [Na].[Mg] NEMFQSKAPLGFIP-UHFFFAOYSA-N 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940051020 methylephedrine hydrochloride Drugs 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical class C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910052911 sodium silicate Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229940127230 sympathomimetic drug Drugs 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、固形製剤に関し、非鎮静性抗ヒスタミン薬とエフェドリン類を含有する製剤に関する。 The present invention relates to a solid preparation, and relates to a preparation containing a non-sedating antihistamine and ephedrines.
近年、花粉症やハウスダストによるアレルギー性鼻炎に悩む患者は増加の一途にある。また、ウイルス等によるインフルエンザや感冒等、いわゆる「かぜ」の諸症状の一つとしての鼻炎症状を示す患者は絶えることがない。
多くの鼻炎患者は複数、繰り返して、又は慢性的に発現している。そのような状態が長期間にわたって持続すると、患者の生活の質（ＱＯＬ）が低下し、日常生活に支障をきたすことになる。
従来、鼻炎症状に対する薬物治療は、主として抗ヒスタミン薬、交感神経興奮薬（血管収縮薬）、副交感神経遮断薬、抗炎症剤、消炎酵素等の薬物を経口内服剤、もしくは点鼻剤として投与することによって行われている。特に近年は、副作用が少なく、効果に持続性のある非鎮静性抗ヒスタミン薬の需要が高まっている。
In recent years, an increasing number of patients suffer from allergic rhinitis caused by hay fever and house dust. In addition, patients who show nasal inflammation as one of the symptoms of so-called “cold” such as influenza due to viruses and colds, etc. are invariable.
Many rhinitis patients develop multiple, repetitive, or chronically. If such a state persists for a long period of time, the quality of life (QOL) of the patient will be reduced, which will interfere with daily life.
Conventionally, pharmacological treatment for nasal inflammation is mainly administered as an antihistamine, sympathomimetic drug (vasoconstrictor), parasympatholytic agent, anti-inflammatory agent, anti-inflammatory enzyme, etc. Is done by that. Particularly in recent years, there has been an increasing demand for non-sedating antihistamines with few side effects and long-lasting effects.
非鎮静性抗ヒスタミン薬のフェキソフェナジンは、一般に、アレルギー性鼻炎、蕁麻疹、皮膚疾患（湿疹・皮膚炎、皮膚掻痒症、アトピー性皮膚炎）に伴う掻痒に対して、フェキソフェナジン塩酸塩を１回６０ｍｇ、１日２回経口投与されている（非特許文献１）。我が国においては、２０１２年末にフェキソフェナジン塩酸塩単味成分の「アレルギー専用鼻炎薬」が、スイッチＯＴＣ医薬品として上市されている。
エフェドリン類は、交感神経興奮作用に基づく気管支拡張作用により、鎮咳効果をもたらすことが知られている。このため、鎮咳成分として、総合感冒薬、鎮咳去痰薬に配合され、また、血管収縮作用による鼻づまりの緩和を目的として鼻炎用内服薬等に配合される薬物である（非特許文献２及び３）。また、エフェドリン類は溶解度が高く速やかに溶出するため、即効性を期待される成分である。
Fexofenadine, a non-sedating antihistamine, is generally used for allergic rhinitis, urticaria, and pruritus associated with skin diseases (eczema / dermatitis, cutaneous pruritus, atopic dermatitis). Is orally administered 60 mg once a day (Non-patent Document 1). In Japan, fexofenadine hydrochloride simple ingredient "allergic rhinitis drug" was put on the market as a switch OTC drug at the end of 2012.
Ephedrines are known to have an antitussive effect by bronchodilating action based on sympathomimetic action. For this reason, it is a drug compounded in general cold medicine and antitussive expectorant as an antitussive component, and in oral medicine for rhinitis etc. for the purpose of alleviating nasal congestion due to vasoconstrictive action (Non-patent Documents 2 and 3). In addition, ephedrines are components that are expected to have immediate effect because of their high solubility and rapid dissolution.
本発明者らは、フェキソフェナジン又はその塩とエフェドリン類を含有する固形製剤の製造を試みたところ、エフェドリン類の溶出性がフェキソフェナジンの配合により悪化することを見出した。したがって、本発明の目的は、フェキソフェナジンまたはその塩及びエフェドリン類を配合した固形製剤に関し、エフェドリン類の溶出性に優れた固形製剤を提供することである。 The inventors of the present invention tried to produce a solid preparation containing fexofenadine or a salt thereof and ephedrine, and found that the dissolution of ephedrine deteriorated due to the incorporation of fexofenadine. Accordingly, an object of the present invention is to provide a solid preparation excellent in the dissolution of ephedrines, which relates to a solid preparation containing fexofenadine or a salt thereof and ephedrines.
本発明者らは、上記課題を解決すべく、種々の検討を行った結果、驚くべきことに、無機金属塩ならびに二酸化ケイ素を配合すると、エフェドリン類が速やかな溶出性を示すことを見出し、本発明を完成するに至った。 As a result of various studies to solve the above problems, the present inventors have surprisingly found that when an inorganic metal salt and silicon dioxide are blended, ephedrines exhibit rapid elution. The invention has been completed.
すなわち、本発明は、
（１）（ａ）フェキソフェナジン及び／又はその塩 （ｂ）エフェドリン類、（ｃ）無機金属塩、及び（ｄ）二酸化ケイ素を含有することを特徴とする固形製剤、
（２）フェキソフェナジン又はその塩が、フェキソフェナジン塩酸塩である、（１）に記載の固形製剤、
（３）エフェドリン類が、プソイドエフェドリン、ノルエフェドリン、及びメチルエフェドリンからなる群から選ばれる少なくとも１種である、（１）に記載の固形製剤、
（４）無機金属塩に含まれる金属が、アルミニウム塩、マグネシウム塩、及びカルシウム塩からなる群から選択される少なくとも１種である、（１）に記載の固形製剤、
（５）二酸化ケイ素が、軽質無水ケイ酸及び／又は含水二酸化ケイ素である、（１）に記載の固形製剤、
（６）剤形が錠剤である（１）〜（５）のいずれかに記載の固形製剤、
である。
That is, the present invention
(1) (a) fexofenadine and / or a salt thereof (b) an ephedrine, (c) an inorganic metal salt, and (d) a solid preparation comprising silicon dioxide,
(2) The solid preparation according to (1), wherein the fexofenadine or a salt thereof is fexofenadine hydrochloride,
(3) The solid preparation according to (1), wherein the ephedrine is at least one selected from the group consisting of pseudoephedrine, norephedrine, and methylephedrine,
(4) The solid preparation according to (1), wherein the metal contained in the inorganic metal salt is at least one selected from the group consisting of an aluminum salt, a magnesium salt, and a calcium salt,
(5) The solid preparation according to (1), wherein the silicon dioxide is light anhydrous silicic acid and / or hydrous silicon dioxide,
(6) The solid preparation according to any one of (1) to (5), wherein the dosage form is a tablet,
It is.
本発明により、フェキソフェナジン又はその塩とエフェドリン類を配合し、エフェドリン類の溶出性に優れ、即効性の高い固形製剤を提供することが可能となった。 According to the present invention, fexofenadine or a salt thereof and ephedrines can be blended to provide a solid preparation having excellent ephedrine dissolution and high immediate effect.
本発明におけるフェキソフェナジンは医薬上許容される塩を形成してもよい 。フェキソフェナジンの塩としては、無機酸や有機酸、無機塩基や有機塩基等との塩が挙げられ、例えば、塩酸塩、酒石酸塩、マレイン酸塩、フマル酸塩、ジフェニルジスルホン酸塩、テオクル酸塩、サリチル酸塩、タンニン酸塩、ベシル酸塩、ナパジシル酸塩、リン酸塩等が挙げられる。好ましくは塩酸塩である。上述のフェキソフェナジンは、公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。本発明におけるフェキソフェナジン塩酸塩の含有量は、本発明の固形製剤全質量に対して１〜７０質量％含有するのが好ましく、１〜５０質量％含有するのがより好ましく、１〜２０質量％含有するのが特に好ましい。 The fexofenadine in the present invention may form a pharmaceutically acceptable salt. Examples of the salt of fexofenadine include salts with inorganic acids, organic acids, inorganic bases, organic bases, etc., for example, hydrochloride, tartrate, maleate, fumarate, diphenyldisulfonate, teocric acid Examples thereof include salts, salicylates, tannates, besylate, napadisylate, and phosphate. Hydrochloride is preferable. The above-mentioned fexofenadine is a known compound and can be produced by a known method, or a commercially available product can be used. The content of fexofenadine hydrochloride in the present invention is preferably 1 to 70% by mass, more preferably 1 to 50% by mass, and more preferably 1 to 20% by mass with respect to the total mass of the solid preparation of the present invention. % Content is particularly preferable.
本発明におけるエフェドリン類とは、エフェドリン及びエフェドリンの誘導体並びにそれらの塩が挙げられる。エフェドリンの誘導体としては、ノルエフェドリン（フェニルプロパノールアミン）、メチルエフェドリン、プソイドエフェドリン等が挙げられる。また、塩としては、薬学上許容される無機酸や有機酸の塩ならば限定されるものではないが、例えば、塩酸塩、硫酸塩、サッカリン塩が挙げられ、好ましくは塩酸塩である。また、エフェドリンには２つの不斉炭素が存するため、種々の光学異性体が存するが、本発明においては、いずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。本発明においては、ｌ−体、ｄｌ−体が好ましい。本発明におけるエフェドリン類としては、例えば、ｌ−メチルエフェドリン塩酸塩、ｄｌ−メチルエフェドリン塩酸塩、ｌ−メチルエフェドリンサッカリン塩、ｄｌ−メチルエフェドリンサッカリン塩、プソイドエフェドリン塩酸塩、プソイドエフェドリン硫酸塩等が挙げられ、これらを単独で、又は２種以上を組合わせて用いることができる。なお、エフェドリンとプソイドエフェドリンは互いにエナンチオマーの関係にあるものである。本発明においては、プソイドエフェドリン塩酸塩、プソイドエフェドリン硫酸塩が好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。本発明のおけるエフェドリン類の含有量は、本発明の固形製剤全質量に対して０．１〜３０質量％含有するのが好ましく、０．５〜２０質量％含有するのがより好ましく、１〜１０質量％含有するのが特に好ましい。 The ephedrines in the present invention include ephedrine and ephedrine derivatives and salts thereof. Examples of ephedrine derivatives include norephedrine (phenylpropanolamine), methylephedrine, pseudoephedrine and the like. The salt is not limited as long as it is a pharmaceutically acceptable salt of an inorganic acid or organic acid. Examples of the salt include hydrochloride, sulfate, and saccharin salt, and hydrochloride is preferable. In addition, since ephedrine has two asymmetric carbons, there are various optical isomers. In the present invention, any optical isomer may be included, and a single optical isomer may be used. A mixture of In the present invention, l-form and dl-form are preferable. Examples of the ephedrines in the present invention include 1-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, 1-methylephedrine saccharin salt, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, pseudoephedrine sulfate, and the like. These can be used alone or in combination of two or more. Ephedrine and pseudoephedrine are in an enantiomeric relationship with each other. In the present invention, pseudoephedrine hydrochloride and pseudoephedrine sulfate are preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used. The content of ephedrines in the present invention is preferably 0.1 to 30% by mass, more preferably 0.5 to 20% by mass based on the total mass of the solid preparation of the present invention. It is particularly preferable to contain 10% by mass.
本発明における無機金属塩は、アルミニウム塩、マグネシウム塩及びカルシウム塩から選ばれる少なくとも１種以上であり、無機金属塩は医薬上許容されるものであれば使用できる。例えば、炭酸マグネシウム、塩化マグネシウム、ケイ酸マグネシウムアルミニウム、硫酸マグネシウム、硫酸マグネシウム、ケイ酸マグネシウムナトリウム、水酸化アルミニウムゲル、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミン酸マグネシウム、リン酸水素カルシウム、無水リン酸水素カルシウム、無水リン酸水素カルシウム造粒物、リン酸カルシウム、ヒドロキシアパタイト、ハイドロタルサイト、ケイ酸アルミニウム、ゼオライト、無水ケイ酸、含水ケイ酸、炭酸カルシウム、ケイ酸カルシウム、ケイ酸マグネシウム、酸化マグネシウム、水酸化マグネシウム、水酸化アルミナマグネシウム、乾燥水酸化アルミニウムゲル、炭酸マグネシウムなどが挙げられる。このうち好ましいのは、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミン酸マグネシウム、リン酸水素カルシウム、無水リン酸水素カルシウム、無水リン酸水素カルシウム造粒物、ハイドロタルサイト、炭酸カルシウム、ケイ酸カルシウム及び乾燥水酸化アルミニウムゲルであり、さらに好ましくは、リン酸水素カルシウムである。本発明における無機金属塩の含有量は、本発明の固形製剤全質量に対し、好ましくは３０質量％〜９０質量％、より好ましくは５０質量％〜８０質量％である。 The inorganic metal salt in the present invention is at least one selected from aluminum salt, magnesium salt and calcium salt, and the inorganic metal salt can be used as long as it is pharmaceutically acceptable. For example, magnesium carbonate, magnesium chloride, magnesium aluminum silicate, magnesium sulfate, magnesium sulfate, magnesium sodium silicate, aluminum hydroxide gel, magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous hydrogen phosphate Calcium, anhydrous calcium hydrogen phosphate granules, calcium phosphate, hydroxyapatite, hydrotalcite, aluminum silicate, zeolite, anhydrous silicic acid, hydrous silicic acid, calcium carbonate, calcium silicate, magnesium silicate, magnesium oxide, hydroxylation Examples thereof include magnesium, magnesium hydroxide magnesium, dry aluminum hydroxide gel, and magnesium carbonate. Of these, preferred are magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, hydrotalcite, calcium carbonate, calcium silicate and dried An aluminum hydroxide gel, more preferably calcium hydrogen phosphate. The content of the inorganic metal salt in the present invention is preferably 30% by mass to 90% by mass and more preferably 50% by mass to 80% by mass with respect to the total mass of the solid preparation of the present invention.
本発明における二酸化ケイ素は、医薬品業界で一般に用いられているものであれば特に限定されるものではない。例えば軽質無水ケイ酸、重質無水ケイ酸、含水二酸化ケイ素などが挙げられるが、好ましくは軽質無水ケイ酸、含水二酸化ケイ素である。また二酸化ケイ素の平均粒子径は０．０００１〜５０μｍが好ましい。本発明における二酸化ケイ素の含有量は、本発明の固形製剤全質量に対し、好ましくは０．１質量％〜１０質量％、より好ましくは０．５質量％〜５質量％である。 The silicon dioxide in the present invention is not particularly limited as long as it is generally used in the pharmaceutical industry. For example, light anhydrous silicic acid, heavy anhydrous silicic acid, hydrous silicon dioxide and the like can be mentioned, and preferred are light anhydrous silicic acid and hydrous silicon dioxide. The average particle diameter of silicon dioxide is preferably 0.0001 to 50 μm. The content of silicon dioxide in the present invention is preferably 0.1% by mass to 10% by mass, more preferably 0.5% by mass to 5% by mass with respect to the total mass of the solid preparation of the present invention.
本発明の固形製剤には、本発明の効果に支障のない限り、一般に用いられる種々の有効成分、添加剤を含んでいてもよい。このような添加剤として、例えば、賦形剤、崩壊剤、結合剤、酸味剤、発泡剤、甘味剤、嬌味剤、香料、滑沢剤、着色剤、流動化剤、界面活性剤、可塑剤等が挙げられる。添加剤の含有量は、本発明の固形製剤全量に対し、１０〜９０重量％、好ましくは１０〜８０重量％である。 The solid preparation of the present invention may contain various commonly used active ingredients and additives as long as the effects of the present invention are not hindered. Examples of such additives include excipients, disintegrants, binders, sour agents, foaming agents, sweeteners, flavoring agents, fragrances, lubricants, colorants, fluidizing agents, surfactants, plasticizers. Agents and the like. The content of the additive is 10 to 90% by weight, preferably 10 to 80% by weight, based on the total amount of the solid preparation of the present invention.
本発明の固形製剤には、従来行われている製造方法により、製造することができる。すなわち、本製剤は、医薬有効成分と上述のような添加剤を混合機などの適当な混合機で混合して錠剤用混合末を製造した後、当該混合末を直接圧縮打錠する方法、または、顆粒を圧縮打錠する方法等により製造することができる。顆粒の製造方法は、乾式造粒法、湿式造粒法であれば、撹拌造粒法、流動層造粒法、乾式造粒法、押し出し造粒法、転動造粒法、噴霧造粒等で製造すればよいが、好ましくは撹拌造粒法、流動層造粒法である。 The solid preparation of the present invention can be produced by a conventional production method. That is, the present preparation is a method of directly compressing and compressing the mixed powder after producing a mixed powder for tablets by mixing the pharmaceutically active ingredient and the above-mentioned additive with an appropriate mixer such as a mixer. It can be produced by a method of compressing and compressing granules. The granule production method is dry granulation method, wet granulation method, stirring granulation method, fluidized bed granulation method, dry granulation method, extrusion granulation method, rolling granulation method, spray granulation, etc. However, the stirring granulation method and the fluidized bed granulation method are preferable.
錠剤用混合末または当該混合末の顆粒を圧縮打錠する機械としては、単発打錠機、ロー
タリー式打錠機等を用いることができる。
A single tableting machine, a rotary tableting machine, or the like can be used as a machine for compressing and compressing mixed powder for tablets or granules of the mixed powder.
本固形製剤の剤形は、特に限定されず、日本薬局方の製剤通則に規定されている剤形であればよいが、好ましくは錠剤、顆粒剤、散剤である。また、錠剤は口腔内崩壊錠、チュアブル錠、発泡錠であってもよい。錠剤に割線や識別性向上のためのマーク、刻印を設けることができる。さらに、本製剤の錠剤は、丸錠であってもよいし、異型錠であってもよい。 The dosage form of the solid preparation is not particularly limited as long as it is a dosage form prescribed in the Japanese Pharmacopoeia, but is preferably a tablet, granule, or powder. The tablets may be orally disintegrating tablets, chewable tablets, and effervescent tablets. The tablet can be provided with a score line and a mark for improving discrimination. Furthermore, the tablet of this preparation may be a round tablet or an atypical tablet.
以下に実施例及び比較例を挙げ、本発明をより詳しく説明するが、本発明はこれら実施例等に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples and the like.
（比較例１）
以下表１に示すようにフェキソフェナジン塩酸塩、プソイドエフェドリン塩酸塩、低置換度ヒドロキシプロピルセルロース、乳糖、軽質無水ケイ酸を秤量し混合した。混合物をヒドロキシプロピルセルロース水溶液で流動層造粒した後、十分に乾燥した。その後、得られた乾燥品を目開き７１０μｍの篩に全量通過させ、造粒物を得た。造粒物にステアリン酸マグネシウムを秤量し、混合した後、卓上簡易錠剤成型機（商品名：ＨＡＮＤＴＡＢ；市橋精機）を用いて打錠し、錠剤硬度が約１２ｋｇｆとなる錠剤径９ｍｍの錠剤を得た。
(Comparative Example 1)
As shown in Table 1, fexofenadine hydrochloride, pseudoephedrine hydrochloride, low-substituted hydroxypropylcellulose, lactose, and light anhydrous silicic acid were weighed and mixed. The mixture was subjected to fluidized bed granulation with an aqueous hydroxypropylcellulose solution and then sufficiently dried. Thereafter, the entire amount of the obtained dried product was passed through a sieve having an opening of 710 μm to obtain a granulated product. The granulated product is weighed and mixed with magnesium stearate, and then tableted using a tabletop simple tablet molding machine (trade name: HANDTAB; Ichihashi Seiki) to obtain a tablet with a tablet diameter of 9 mm and a tablet hardness of about 12 kgf. It was.
（実施例１）
比較例１と同様にして、下記処方に従って、錠剤硬度が約１２ｋｇｆとなる錠剤径９ｍｍの錠剤を得た。
Example 1
In the same manner as in Comparative Example 1, a tablet with a tablet diameter of 9 mm having a tablet hardness of about 12 kgf was obtained according to the following formulation.
（試験例）
＜評価方法＞
比較例１及び実施例１の錠剤について、以下の各試験方法により、錠剤硬度の測定と溶出試験を行った。
（１）錠剤硬度
錠剤硬度計（シュロイニゲル社製）を用いて測定した。それぞれの錠剤の硬度を３回ずつ測定し、その平均値を求めた。
（２）溶出試験
得られた錠剤２錠につき、第十七改正日本薬局方の溶出試験法パドル法に従い、３７℃、パドル回転数５０ｒｐｍの条件で試験を行い、１５分後のプソイドエフェドリンの溶出率を算出した。試験液は溶出試験第１液及び溶出試験第２液で行った。なおプソイドエフェドリンの試験開始１５分後の溶出率が８５％以上を許容とした。
(Test example)
<Evaluation method>
The tablets of Comparative Example 1 and Example 1 were subjected to tablet hardness measurement and dissolution test by the following test methods.
(1) Tablet hardness It measured using the tablet hardness meter (made by Schleunigel). The hardness of each tablet was measured three times and the average value was determined.
(2) Dissolution test Two tablets obtained were tested under the conditions of 37 ° C and paddle rotation speed 50rpm according to the 17th revised Japanese Pharmacopoeia dissolution test paddle method, and the dissolution rate of pseudoephedrine 15 minutes later Was calculated. The test solution was a dissolution test first solution and a dissolution test second solution. The elution rate of pseudoephedrine 15 minutes after the start of the test was allowed to be 85% or more.
結果を表２に示す。 The results are shown in Table 2.
表２に示すように、同程度の錠剤硬度を持つ場合において、軽質無水ケイ酸を含有するが無機金属塩を配合していない比較例１ではどちらの試験液においても１５分８５％を上回らなかった。一方リン酸水素カルシウムと軽質無水ケイ酸の両者を配合した実施例１では両試験液においても１５分８５％以上の速い溶出を示した。 As shown in Table 2, in the case of having similar tablet hardness, Comparative Example 1 containing light anhydrous silicic acid but not containing inorganic metal salt did not exceed 85% for 15 minutes in either test solution. It was. On the other hand, in Example 1 in which both calcium hydrogen phosphate and light anhydrous silicic acid were blended, fast dissolution of 85% or more for 15 minutes was shown in both test solutions.
（比較例２）
以下表３に示すようにフェキソフェナジン塩酸塩、プソイドエフェドリン塩酸塩、低置換度ヒドロキシプロピルセルロース、結晶セルロース、乳糖を秤量し混合した。混合物とヒドロキシプロピルセルロース水溶液を用いて乳鉢にて練合した後、十分に乾燥した。その後、得られた乾燥品を目開き７１０μｍの篩に全量通過させ、造粒物を得た。造粒物にトウモロコシデンプン、軽質無水ケイ酸、低置換度ヒドロキシプロピルセルロース及びステアリン酸マグネシウムを加え、混合した後、卓上簡易錠剤成型機を用いて打錠し、錠剤硬度が約１０ｋｇｆとなる錠剤径９．５ｍｍの錠剤を得た。
(Comparative Example 2)
As shown in Table 3, fexofenadine hydrochloride, pseudoephedrine hydrochloride, low-substituted hydroxypropyl cellulose, crystalline cellulose, and lactose were weighed and mixed. After kneading in a mortar using the mixture and an aqueous hydroxypropylcellulose solution, the mixture was sufficiently dried. Thereafter, the entire amount of the obtained dried product was passed through a sieve having an opening of 710 μm to obtain a granulated product. Corn starch, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose and magnesium stearate are added to the granulated product, mixed, and then tableted using a tabletop simple tableting machine to give a tablet hardness of about 10 kgf A 9.5 mm tablet was obtained.
（実施例２）
比較例２と同様に造粒物を得た後、造粒物にリン酸水素カルシウム、軽質無水ケイ酸、低置換度ヒドロキシプロピルセルロース及びステアリン酸マグネシウムを加え、混合した後、卓上簡易錠剤成型機を用いて打錠し、錠剤硬度が約１０ｋｇｆとなる錠剤径９．５ｍｍの錠剤を得た。
(Example 2)
After obtaining a granulated product in the same manner as in Comparative Example 2, after adding calcium hydrogen phosphate, light anhydrous silicic acid, low-substituted hydroxypropylcellulose and magnesium stearate to the granulated product, mixing them, a tabletop simple tablet molding machine Was used to obtain tablets having a tablet diameter of 9.5 mm and a tablet hardness of about 10 kgf.
（比較例３）
比較例２と同様に造粒物を得た後、造粒物にリン酸水素カルシウム、低置換度ヒドロキシプロピルセルロース及びステアリン酸マグネシウムを加え、混合した後、卓上簡易錠剤成型機を用いて打錠し、錠剤硬度が約１０ｋｇｆとなる錠剤径９．５ｍｍの錠剤を得た。
(Comparative Example 3)
After obtaining a granulated product as in Comparative Example 2, calcium hydrogen phosphate, low-substituted hydroxypropyl cellulose and magnesium stearate were added to the granulated product, mixed, and then tableted using a tabletop simple tablet molding machine. As a result, a tablet with a tablet diameter of 9.5 mm and a tablet hardness of about 10 kgf was obtained.
（実施例３）
比較例２と同様に造粒物を得た後、造粒物にメタケイ酸アルミン酸マグネシウム、軽質無水ケイ酸、低置換度ヒドロキシプロピルセルロース及びステアリン酸マグネシウムを加え、混合した後、卓上簡易錠剤成型機を用いて打錠し、錠剤硬度が約１０ｋｇｆとなる錠剤径９．５ｍｍの錠剤を得た。
(Example 3)
After obtaining a granulated product in the same manner as in Comparative Example 2, magnesium aluminometasilicate, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose and magnesium stearate were added to the granulated product, mixed, and then tabletop simple tablet molding Tableting was performed using a machine to obtain a tablet having a tablet diameter of 9.5 mm and a tablet hardness of about 10 kgf.
（実施例４）
比較例２と同様に造粒物を得た後、造粒物に水酸化アルミニウムゲル、軽質無水ケイ酸、低置換度ヒドロキシプロピルセルロース及びステアリン酸マグネシウムを加え、混合した後、卓上簡易錠剤成型機を用いて打錠し、錠剤硬度が約１０ｋｇｆとなる錠剤径９．５ｍｍの錠剤を得た。
Example 4
After obtaining a granulated product in the same manner as in Comparative Example 2, after adding aluminum hydroxide gel, light anhydrous silicic acid, low-substituted hydroxypropylcellulose and magnesium stearate to the granulated product, mixing them, a tabletop simple tablet molding machine Was used to obtain tablets having a tablet diameter of 9.5 mm and a tablet hardness of about 10 kgf.
＜評価方法＞
比較例及び実施例の錠剤について、以下の各試験方法により、錠剤硬度の測定と溶出試験を行った。結果を表４に示す。
（１）錠剤硬度
錠剤硬度計（シュロイニゲル社製）を用いて測定した。それぞれの錠剤の硬度を３回ずつ測定し、その平均値を求めた。
（２）溶出試験
得られた錠剤２錠につき、第十七改正日本薬局方の溶出試験法パドル法に従い、３７℃、パドル回転数５０ｒｐｍの条件で試験を行い、１５分後のプソイドエフェドリンの溶出率を算出した。試験液は溶出試験第１液で行った。なおプソイドエフェドリンの試験開始１５分後の溶出率が８５％以上を許容とした。
<Evaluation method>
About the tablet of a comparative example and an example, measurement of a tablet hardness and dissolution test were done by the following each test methods. The results are shown in Table 4.
(1) Tablet hardness It measured using the tablet hardness meter (made by Schleunigel). The hardness of each tablet was measured three times and the average value was determined.
(2) Dissolution test Two tablets obtained were tested under the conditions of 37 ° C and paddle rotation speed 50rpm according to the 17th revised Japanese Pharmacopoeia dissolution test paddle method, and the dissolution rate of pseudoephedrine 15 minutes later Was calculated. The test solution was the first dissolution test solution. The elution rate of pseudoephedrine 15 minutes after the start of the test was allowed to be 85% or more.
無機金属塩を配合していない比較例２ではプソイドエフェドリンの速やかな溶出は得られず、試験開始１５分後の溶出率は８５％を上回ることができなかった。一方、リン酸水素カルシウムを配合した実施例２では、プソイドエフェドリンは速やかに溶出し、試験開始１５分後の溶出率は８５％以上となった。しかしリン酸類素カルシウムを配合し、軽質無水ケイ酸を配合していない比較例３では、速やかな溶出の効果は得られなかった。無機金属塩であるメタケイ酸アルミン酸マグネシウム及び水酸化アルミゲルを配合した実施例３、４においては、プソイドエフェドリンの速やかな溶出が得られ、試験開始１５分後の溶出率は８５％以上であった。 In Comparative Example 2 in which an inorganic metal salt was not blended, pseudoephedrine was not rapidly dissolved, and the dissolution rate after 15 minutes from the start of the test could not exceed 85%. On the other hand, in Example 2 containing calcium hydrogen phosphate, pseudoephedrine eluted quickly, and the dissolution rate 15 minutes after the start of the test was 85% or more. However, in Comparative Example 3 in which calcium phosphates were blended and light anhydrous silicic acid was not blended, the effect of rapid elution was not obtained. In Examples 3 and 4 in which magnesium metasilicate aluminate and aluminum hydroxide gel, which are inorganic metal salts, were blended, pseudoephedrine was rapidly dissolved, and the dissolution rate 15 minutes after the start of the test was 85% or more.
本発明によれば、フェキソフェナジン又はその塩及びエフェドリン類を配合した固形製剤に関し、エフェドリン類の溶出性に優れ、エフェドリン類の即効性の高い製剤の提供が可能となる。 ADVANTAGE OF THE INVENTION According to this invention, regarding the solid formulation which mix | blended fexofenadine or its salt, and ephedrines, it is excellent in the elution property of ephedrines, and provision of the highly effective formulation of ephedrines is attained.
Claims (6)
The solid dosage form according to any one of claims 1 to 5, wherein the dosage form is a tablet.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2002255816A (en) * | 2001-03-05 | 2002-09-11 | Taisho Pharmaceut Co Ltd | Composition for treating cold |
| JP2003048834A (en) * | 2001-08-01 | 2003-02-21 | Taisho Pharmaceut Co Ltd | Pharmaceutical composition |
| JP2003532671A (en) * | 2000-05-05 | 2003-11-05 | アベンティス・ファーマスーティカルズ・インコーポレイテツド | Standardization of packaging for pseudoephedrine hydrochloride and fexofenadine hydrochloride |
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| JP2003532671A (en) * | 2000-05-05 | 2003-11-05 | アベンティス・ファーマスーティカルズ・インコーポレイテツド | Standardization of packaging for pseudoephedrine hydrochloride and fexofenadine hydrochloride |
| JP2002255816A (en) * | 2001-03-05 | 2002-09-11 | Taisho Pharmaceut Co Ltd | Composition for treating cold |
| JP2003048834A (en) * | 2001-08-01 | 2003-02-21 | Taisho Pharmaceut Co Ltd | Pharmaceutical composition |
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| JP2019147797A (en) * | 2018-02-26 | 2019-09-05 | ロート製薬株式会社 | Granule containing fexofenadine hydrochloride |
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