CN106794142A - 核心组合物 - Google Patents
核心组合物 Download PDFInfo
- Publication number
- CN106794142A CN106794142A CN201580053828.6A CN201580053828A CN106794142A CN 106794142 A CN106794142 A CN 106794142A CN 201580053828 A CN201580053828 A CN 201580053828A CN 106794142 A CN106794142 A CN 106794142A
- Authority
- CN
- China
- Prior art keywords
- sodium ibuprofen
- mixture
- inert absorbent
- sodium
- added
- 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.)
- Withdrawn
Links
- 239000008358 core component Substances 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 85
- 238000000034 method Methods 0.000 claims abstract description 54
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 33
- 239000000463 material Substances 0.000 claims abstract description 33
- 239000002250 absorbent Substances 0.000 claims abstract description 32
- 230000002745 absorbent Effects 0.000 claims abstract description 31
- 239000007787 solid Substances 0.000 claims abstract description 20
- 239000000758 substrate Substances 0.000 claims abstract description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 33
- 238000009472 formulation Methods 0.000 claims description 32
- -1 silicon Magnesium aluminate Chemical class 0.000 claims description 25
- PTTPUWGBPLLBKW-UHFFFAOYSA-M sodium;2-[4-(2-methylpropyl)phenyl]propanoate Chemical compound [Na+].CC(C)CC1=CC=C(C(C)C([O-])=O)C=C1 PTTPUWGBPLLBKW-UHFFFAOYSA-M 0.000 claims description 24
- VTGPMVCGAVZLQI-UHFFFAOYSA-M sodium;2-[4-(2-methylpropyl)phenyl]propanoate;dihydrate Chemical group O.O.[Na+].CC(C)CC1=CC=C(C(C)C([O-])=O)C=C1 VTGPMVCGAVZLQI-UHFFFAOYSA-M 0.000 claims description 17
- 239000000377 silicon dioxide Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 10
- 235000019640 taste Nutrition 0.000 claims description 10
- 239000002002 slurry Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 206010006784 Burning sensation Diseases 0.000 claims description 7
- 239000001506 calcium phosphate Substances 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- 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 claims description 5
- 229960001680 ibuprofen Drugs 0.000 claims description 5
- 238000007873 sieving Methods 0.000 claims description 5
- 230000000873 masking effect Effects 0.000 claims description 4
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000000440 bentonite Substances 0.000 claims description 3
- 229910000278 bentonite Inorganic materials 0.000 claims description 3
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 claims description 3
- 239000000378 calcium silicate Substances 0.000 claims description 3
- 229960003340 calcium silicate Drugs 0.000 claims description 3
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 3
- 235000012241 calcium silicate Nutrition 0.000 claims description 3
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 3
- 239000004927 clay Substances 0.000 claims description 3
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 3
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims description 3
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 229940094522 laponite Drugs 0.000 claims description 3
- XCOBTUNSZUJCDH-UHFFFAOYSA-B lithium magnesium sodium silicate Chemical group [Li+].[Li+].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Na+].[Na+].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3 XCOBTUNSZUJCDH-UHFFFAOYSA-B 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000006072 paste Substances 0.000 claims description 3
- 238000005549 size reduction Methods 0.000 claims description 3
- 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 claims description 3
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 3
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 3
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 3
- 229910052570 clay Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims 2
- WZWGGYFEOBVNLA-UHFFFAOYSA-N sodium;dihydrate Chemical compound O.O.[Na] WZWGGYFEOBVNLA-UHFFFAOYSA-N 0.000 claims 1
- 239000011343 solid material Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 description 16
- 229940013181 advil Drugs 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- 238000001035 drying Methods 0.000 description 9
- 239000007941 film coated tablet Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000000306 component Substances 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 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 7
- 238000004090 dissolution Methods 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000000730 antalgic agent Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 230000001387 anti-histamine Effects 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 239000000739 antihistaminic agent Substances 0.000 description 4
- 235000019658 bitter taste Nutrition 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 4
- 229960000520 diphenhydramine Drugs 0.000 description 4
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 4
- 229960000991 ketoprofen Drugs 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000003444 anaesthetic effect Effects 0.000 description 3
- 229940124584 antitussives Drugs 0.000 description 3
- 239000002830 appetite depressant Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000004040 coloring Methods 0.000 description 3
- 239000000850 decongestant Substances 0.000 description 3
- 229960001985 dextromethorphan Drugs 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 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 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000003172 expectorant agent Substances 0.000 description 3
- 230000003419 expectorant effect Effects 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000000936 intestine Anatomy 0.000 description 3
- 229960003088 loratadine Drugs 0.000 description 3
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 3
- 239000003158 myorelaxant agent Substances 0.000 description 3
- 229960005489 paracetamol Drugs 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- OMDMTHRBGUBUCO-IUCAKERBSA-N (1s,5s)-5-(2-hydroxypropan-2-yl)-2-methylcyclohex-2-en-1-ol Chemical compound CC1=CC[C@H](C(C)(C)O)C[C@@H]1O OMDMTHRBGUBUCO-IUCAKERBSA-N 0.000 description 2
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 description 2
- GNXFOGHNGIVQEH-UHFFFAOYSA-N 2-hydroxy-3-(2-methoxyphenoxy)propyl carbamate Chemical compound COC1=CC=CC=C1OCC(O)COC(N)=O GNXFOGHNGIVQEH-UHFFFAOYSA-N 0.000 description 2
- KHOITXIGCFIULA-UHFFFAOYSA-N Alophen Chemical compound C1=CC(OC(=O)C)=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OC(C)=O)C=C1 KHOITXIGCFIULA-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 2
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 235000010724 Wisteria floribunda Nutrition 0.000 description 2
- HUCJFAOMUPXHDK-UHFFFAOYSA-N Xylometazoline Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCCN1 HUCJFAOMUPXHDK-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 230000000954 anitussive effect Effects 0.000 description 2
- 230000003474 anti-emetic effect Effects 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 2
- 229960005370 atorvastatin Drugs 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- CNBGNNVCVSKAQZ-UHFFFAOYSA-N benzydamine Chemical compound C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 CNBGNNVCVSKAQZ-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- FDSDTBUPSURDBL-LOFNIBRQSA-N canthaxanthin Chemical compound CC=1C(=O)CCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C(=O)CCC1(C)C FDSDTBUPSURDBL-LOFNIBRQSA-N 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
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- 229960001803 cetirizine Drugs 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
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- WRCHFMBCVFFYEQ-UHFFFAOYSA-N clofedanol Chemical compound C=1C=CC=C(Cl)C=1C(O)(CCN(C)C)C1=CC=CC=C1 WRCHFMBCVFFYEQ-UHFFFAOYSA-N 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- JURKNVYFZMSNLP-UHFFFAOYSA-N cyclobenzaprine Chemical compound C1=CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 JURKNVYFZMSNLP-UHFFFAOYSA-N 0.000 description 2
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- 238000009826 distribution Methods 0.000 description 2
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 2
- BZEWSEKUUPWQDQ-UHFFFAOYSA-N dyclonine Chemical compound C1=CC(OCCCC)=CC=C1C(=O)CCN1CCCCC1 BZEWSEKUUPWQDQ-UHFFFAOYSA-N 0.000 description 2
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- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 2
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- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
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- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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Abstract
本发明提供了一种用于将活性药物成分吸附到底物上的方法，包括以下步骤：(a)将惰性吸附剂添加并混合到包含活性药物成分的非固体形式，从而形成混合物；以及(b)干燥该混合物以形成固体易碎材料。
Description
相关申请的交叉引用
本申请要求2014年8月1日提交的美国临时申请序列号62/032,029的优先权，该申请的内容据此全文以引用方式并入本文。
背景技术
技术领域
本发明涉及将活性药物成分吸附在惰性吸附剂上的组合物和方法。
已使用了各种方法来改善剂型的药物递送。例如，已尝试了各种聚合物体系。最终结果并不总是有利的，并且有时导致活性成分的溶解或释放不足。
例如，对改善抗炎剂和止痛药物诸如甾体抗炎药、非甾体抗炎药(NSAID)的药物递送存在很大的期望。通常这意味着快速起效和/或持久的疼痛缓解。然而，实现这些特性是困难的。
因此存在对将活性成分加载到不妨碍该活性成分的释放的惰性底物上的改进方法的需要。本发明提供此类方法。
发明内容
本发明涉及将活性药物成分吸附到底物上的方法，包括以下步骤：(a)将惰性吸附剂添加并混合到包含活性药物成分的非固体形式，从而形成混合物；以及(b)干燥该混合物以形成固体易碎材料。
在一个实施方案中，本发明涉及将布洛芬钠二水合物吸附到底物上的方法，包括以下步骤：(a)将惰性吸附剂添加并混合到包含布洛芬钠二水合物的非固体形式，从而形成混合物；以及(b)干燥该混合物以形成固体易碎材料。
本发明还包括对布洛芬钠剂型进行掩味的方法。该方法包括将布洛芬钠二水合物吸附到底物上的步骤，包括以下步骤：(a)将惰性吸附剂添加并混合到包含布洛芬钠二水合物的非固体形式，从而形成混合物；以及(b)干燥该混合物以形成固体易碎材料。
本发明还包括当吞咽布洛芬剂型时，降低受试者口或喉咙中灼烧感的方法。方法包括以下步骤：(1)为受试者提供布洛芬钠剂型，其中该布洛芬钠剂型通过将布洛芬钠二水合物吸附到底物上制成，包括以下步骤：(a)将惰性吸附剂添加并混合到包含布洛芬钠二水合物的非固体形式，从而形成混合物；以及(b)干燥该混合物以形成固体易碎材料；以及(2)指导受试者吞下步骤(1)的布洛芬钠剂型。
附图说明
图1为示出核心制剂A对比膜包衣片剂(由Advil Ion CoreTM Technology支持)在0.25％SLS/0.1N HCL中的溶解结果的图；
图2为示出核心制剂B和核心制剂C对比膜包衣片剂(由Advil Ion CoreTMTechnology支持)在FaSSGF Biorelevant pH 1.6介质中的溶解结果的图；
图3为示出核心制剂B和核心制剂C对比膜包衣片剂(由Advil Ion CoreTMTechnology支持)在FaSSGF Biorelevant pH 1.6介质中的平均溶解结果的图；
图4为示出核心制剂D和核心制剂E对比膜包衣片剂(由Advil Ion CoreTMTechnology支持)在FeSSGF Biorelevant pH 5.0介质中的溶解结果的图；并且
图5为示出核心制剂D和核心制剂E对比膜包衣片剂(由Advil Ion CoreTMTechnology支持)在FeSSGF Biorelevant pH 5.0介质中的平均溶解结果的图。
具体实施方式
本发明涉及将活性药物成分(例如布洛芬钠二水合物)吸附到惰性吸附剂上的方法。具体地讲，本发明涉及将活性药物成分吸附到底物上的方法，包括以下步骤：(a)将惰性吸附剂添加并混合到包含活性药物成分的非固体形式，从而形成混合物；以及(b)干燥该混合物以形成固体易碎材料。
用于混合的任何合适装置能够被用来将惰性吸附剂混合到非固体形式。例如，可使用叶轮混合器在混合釜中将惰性吸附剂添加到非固体的干燥形式。
另外，如果确实需要，该方法可包括在干燥混合物之前将附加的活性药物成分添加到混合物的步骤。该可选步骤还将添加到药物负载。
所得的混合物还可经受湿法筛分步骤。湿法筛分步骤有助于分散混合物从而促进干燥，并且还可有助于减小所得的固体易碎材料的混合物的粒度。
使用任何合适的装置来执行混合物的干燥。例如，混合物可为风干的、烘干的或流化床干燥的。
此外，还可对固体易碎材料进行处理以减小材料的粒度。可使用任何合适的方法来减小粒度。
例如，粒度减小装置可为干法筛分装置。
此外，在粒度减小步骤之前、之后或期间可添加助流剂诸如胶体二氧化硅。
之后，可压缩所得的材料以形成核心。
非固体形式可为例如溶液、悬浮液、乳液、糊剂或浆液。另外，非固体形式可为基于水的、基于溶剂的或基于脂类的。
在一个实施方案中，在约50℃至约80℃、优选地约50℃至约60℃的温度范围内执行该吸附。药物效能的范围为40％-95％。
该活性药物成分(“API”)可为任何活性药物成分。例如，止痛剂、抗炎剂、退热剂、抗组胺药、减充血剂、镇咳剂和祛痰剂、肌肉松弛剂、兴奋剂、镇静剂、食欲抑制剂、麻醉剂、斯达汀等等。
活性成分可为例如对乙酰氨基酚、阿司匹林、萘普生、酮洛芬、氟比洛芬、双氯芬酸、环苯扎林、美洛普康、罗非考昔、赛来考昔以及它们药学上可接受的盐、酯、异构体和混合物以及它们的组合。用作本发明中第二活性成分的其它合适的活性成分包括：止痛剂、抗炎剂、抗关节炎药、麻醉剂、抗组胺药、镇咳药、抗生素、抗感染剂、抗病毒剂、抗凝血剂、抗抑郁药、抗糖尿病剂、止吐药、抗气胀药、抗真菌剂、解痉药、食欲抑制剂、支气管扩张剂、心血管剂、中枢神经系统剂、中枢神经系统兴奋剂、减充血剂、口服避孕药、利尿剂、祛痰剂、胃肠剂、偏头痛制剂、运动病产品、黏液溶解剂、肌肉松弛剂、骨质疏松制剂、聚二甲基硅氧烷、呼吸剂、睡眠助剂、尿道剂、以及它们的混合物。
合适的止痛剂、抗炎剂和退热剂的示例包括但不限于：非甾体抗炎药物(NSAID)，诸如丙酸衍生物(例如，布洛芬钠、布洛芬、萘普生、酮洛芬、氟比洛芬、芬布芬、非诺洛芬、吲哚洛芬、酮洛芬、氟洛芬、吡洛芬、卡洛芬、丙嗪、普拉洛芬、苄达明和舒洛芬)和COX抑制剂诸如塞来考昔；对乙酰氨基酚；乙酰水杨酸；乙酸衍生物诸如吲哚美辛、双氯芬酸、舒林酸和托美丁；芬那酸衍生物诸如甲芬那酸、甲氯芬那酸和氟芬那酸；联苯甲酸衍生物诸如二氟尼柳和氟苯柳；和昔康类诸如吡罗昔康、舒多昔康、伊索昔康和美洛昔康；它们的异构体；以及它们的药学上可接受的盐和前药。
抗组胺药和减充血剂的示例包括但不限于：溴苯那敏、氯环嗪、右溴苯那敏、溴己新、苯茚胺、非尼拉敏、美吡拉敏、松齐拉敏、pripolidine、麻黄碱、去氧肾上腺素、伪麻黄碱、苯丙醇胺、氯苯那敏、右美沙芬、苯海拉明、多西拉敏、阿司咪唑、特非那丁、非索非那丁、萘甲唑林、羟甲唑啉、孟鲁斯特、丙已君、苯丙烯啶、克立马丁、阿伐斯汀、异丙嗪、奥索马嗪、美喹他嗪、布克力嗪、溴已新、酮替芬、特非那丁、依巴斯汀、苯咪唑嗪、赛洛唑啉、氯雷他定、脱羧氯雷他定和西替利嗪；它们的异构体；以及它们的药学上可接受的盐和酯。
止咳剂和祛痰剂的示例包括但不限于：苯海拉明、右美沙芬、诺司卡品、氯苯达诺、薄荷醇、苯佐那酯、乙基吗啡、可待因、乙酰半胱氨酸、羧甲半胱胺酸、氨溴索、颠茄生物碱、索布瑞醇、愈疮木酚和愈创甘油醚；它们的异构体；以及它们的药学上可接受的盐和前药。
肌肉松弛剂的示例包括但不限于：环苯扎林和美他沙酮、奥芬那君和美索巴莫；它们的异构体；以及它们的药学上可接受的盐和前药。
兴奋剂的示例包括但不限于：咖啡因。
镇静剂的示例包括但不限于：安眠药诸如抗组胺药(例如苯海拉明)、艾司佐匹克隆和唑吡旦以及它们的药学上可接受的盐和前药。
食欲抑制剂的示例包括但不限于：苯丙醇胺、苯丁胺和二乙基卡西酮以及它们的药学上可接受的盐和前药。
麻醉剂(例如，用于治疗咽喉痛)的示例包括但不限于：达克罗宁、苯佐卡因和果胶以及它们的药学上可接受的盐和前药。
合适的他汀类药物的示例包括但不限于：阿托伐他汀、罗苏伐他汀、氟伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀、普伐他汀以及它们的药学上可接受的盐和前药。
合适的胃肠剂的示例包括：抗酸剂诸如碳酸钙、氢氧化镁、氧化镁、碳酸镁、氢氧化铝、碳酸氢钠、二羟基铝碳酸钠；刺激性泻剂诸如双醋苯啶、波希鼠李皮、二羟蒽醌、番泻叶、酚酞、芦荟、蓖麻油、蓖麻油酸和脱氢胆酸以及它们的混合物；H2受体拮抗剂诸如法莫替丁、雷尼替丁、西咪替丁、尼扎替丁；质子泵抑制剂诸如奥美拉唑或兰素拉唑；胃肠细胞保护剂诸如硫糖铝和米索前列醇；胃肠促动药诸如普卢卡必利；用于幽门螺旋杆菌(H.pylori)的抗生素诸如克拉霉素、阿莫西林、四环素和甲硝唑；止泻剂诸如地芬诺酯和洛哌丁胺；甘罗溴铵；止吐药诸如昂丹司琼；止痛剂诸如美沙拉嗪，和消旋卡多曲以及它们的衍生物。
在本发明的一个实施方案中，活性成分可以选自：伪麻黄碱、去氧肾上腺素、苯丙醇胺、氯苯那敏、右美沙芬、苯海拉明、阿司咪唑、特非那丁、非索菲那丁、氯雷他定、地氯雷他定、西替利嗪、它们的混合物和药学上可接受的盐、酯、异构体、对乙酰氨基酚、尼古丁、雷尼替丁、布洛芬、酮洛芬、洛哌丁胺、法莫替丁、碳酸钙、二甲基硅油、美索巴莫、氯苯达诺、抗坏血酸、果胶、达克罗宁、苯佐卡因和甲醇、它们的药学上可接受的盐及前药以及它们的混合物。
在一个实施方案中，API具有大于约1mg/ml的溶解度。在另一个实施方案中，API具有大于约20mg/ml的溶解度。在另一个实施方案中，API具有大于约50mg/ml的溶解度。在另一个实施方案中，API具有大于约100mg/ml的溶解度。在另一个实施方案中，API具有大于约200mg/ml的溶解度。在另一个实施方案中，API具有大于约250mg/ml的溶解度。所有上述的溶解度均以室温为参考。
可压缩所得的材料以形成核心。该核心中API的量将取决于API自身和期望的剂量水平。优选地，核心含有约1mg至约500mg的API，并且更优选约1mg至约400mg的API。甚至更优选地，核心含有约50mg至约400mg的API，并且还更优选约150mg至约400mg的API。
惰性吸附剂为例如合成锂皂石、膨润土、粘土、硅铝酸镁(由VanderbiltMinerals,LLC供应的)、偏硅酸铝镁多孔硅酸钙、以及磷酸二钙和磷酸三钙、中孔二氧化硅以及它们的混合物。
在一个实施方案中，惰性吸附剂为中孔二氧化硅，相比于具有独特形态的热解法二氧化硅，其具有更高的堆积密度和均匀的粒度分布。中孔二氧化硅可来源于Maryland的W.R.Grace and Company，该公司以商品名出售其产品。
在另一个实施方案中，惰性吸附剂为偏硅酸铝镁，诸如 US2。 US2为偏硅酸铝镁的超轻细小颗粒，并且为可用于药物的多功能赋形剂。其具有较大表面积和多孔性，并能够吸附大量的油或水。Tokyo,Japan的Fuji ChemicalIndustry Co.,Ltd.出售 US2。
核心包含约5重量％至约95重量％(wt.％)的惰性吸附剂。
在一个实施方案中，核心包含约5重量％至约90重量％的惰性吸附剂。优选地，核心包含约5重量％至约75重量％的惰性吸附剂。更优选地，核心包含约5重量％至约50重量％的惰性吸附剂。甚至更优选地，核心包含约5重量％至约20重量％的惰性吸附剂。
在另选的实施方案中，核心包含约50重量％至约95重量％的惰性吸附剂。优选地，核心包含约50重量％至约90重量％的惰性吸附剂。更优选地，核心包含约75重量％至约90重量％的惰性吸附剂。
在一个实施方案中，可在核心中使用本发明的干燥固体易碎材料。可以片剂形式或作为多层片剂的至少一个层来压缩核心。在另一个实施方案中，干燥固体易碎材料可存放在胶囊形式中。在另一个实施方案中，可将干燥固体易碎材料用于从小袋直接给药。
任选地，其它成分可以包含在本发明的组合物或剂型中。
例如，助流剂还可包含于核心组合物中以有助于组合物的流动特性。合适的助流剂包括例如二氧化硅诸如胶体二氧化硅、热解法二氧化硅、它们的混合物等。
在一个实施方案中，核心可包含约0.01重量％至约3重量％的助流剂。在另一个实施方案中，核心包含约0.05重量％至约2重量％的助流剂。在另一个实施方案中，核心包含约0.1重量％至约1重量％的助流剂。
可添加至组合物的其它成分或组分包括但不限于：超级崩解剂、润滑剂、芳香剂；甜味剂诸如山梨醇、糖，以及高强度甜味剂诸如三氯蔗糖、天冬甜素与糖精等可以包括在其中。
任何适合用于食品或药品中的着色剂均可用于本发明组合物。典型的着色剂包括例如偶氮染料、喹酞酮染料、三苯甲烷染料、呫吨染料、靛青类染料、铁氧化物、铁氢氧化物、二氧化钛、天然染料以及它们的混合物。更具体地讲，合适的着色剂包括但不限于专利蓝V、酸性艳绿BS、红2G、偶氮玉红、丽春红4R、苋菜红、D&C红33、D&C红22、D&C红26、D&C红28、D&C黄10、FD&C黄5、FD&C黄6、FD&C红3、FD&C红40、FD&C蓝1、FD&C蓝2、FD&C绿3、亮黑BN、炭黑、氧化铁黑、氧化铁红、氧化铁黄、二氧化钛、核黄素、胡萝卜素、花青素、姜黄、胭脂虫提取物、叶绿素、角黄素、焦糖、甜菜苷以及它们的混合物。
相似地，组合物或固体剂型中可包含风味剂。添加到组合物中的风味剂的量将取决于所需口感特性。
在一个实施方案中，组合物包含吸附在惰性吸附剂上的布洛芬钠二水合物。惰性吸附剂可为例如二氧化硅(63FP、 XDP 3050、 XDP 3150等)和硅酸镁铝( US2)。胶体二氧化硅同样可与活性吸附剂和惰性吸附剂共混。
本发明还包括对布洛芬钠剂型进行掩味的方法。该方法包括将布洛芬钠二水合物吸附到底物上的步骤，包括以下步骤：(a)将惰性吸附剂添加并混合到包含布洛芬钠二水合物的非固体形式，从而形成混合物；以及(b)干燥该混合物以形成固体易碎材料。
本发明还包括当吞咽布洛芬剂型时，降低受试者口或喉咙中灼烧感的方法。方法包括以下步骤：(1)为受试者提供布洛芬钠剂型，其中该布洛芬钠剂型通过将布洛芬钠二水合物吸附到底物上制成，包括以下步骤：(a)将惰性吸附剂添加并混合到包含布洛芬钠二水合物的非固体形式，从而形成混合物；以及(b)干燥该混合物以形成固体易碎材料；以及(2)指导受试者吞下步骤(1)的布洛芬钠剂型。
提供以下实施例来进一步说明本发明的组合物和方法。应当理解，本发明并不限于所描述的实施例。
实施例1
表1
布洛芬钠二水合物在水中的溶解度：
| 温度 | 室温(约25℃) | 40℃ | 50℃* | 60℃ |
| 溶解度(mg/mL) | 250 | 551 | 653 | 676 |
*选择该温度是为了作为吸附过程的一部分使用(参考：步骤1)
悬浮液/浆液过程：
1.使用水浴将23mL无菌水加热至50℃的温度。
2.向加热的水中添加45克布洛芬钠二水合物并让其溶解大约4分钟。因材料处于饱和点上方，所以其为粘性的并且颜色为白色。
表2
核心制剂A：
吸附过程：
1.在添加5克中孔二氧化硅( XDP 3150)的同时，使用叶轮混合机在可能的最低混合速度下混合悬浮液/浆液。所得的混合物为更粘性的并能够发泡。总混合时间不超过30秒。
2.通过30目筛网对材料进行湿筛。材料从筛的下侧垂下，并且看起来为具有挤出外观的小管。
3.使挤出物风干大约6分钟，然后从筛上刮下并过夜干燥约20小时，从而得到干燥的固体易碎材料。
4.通过60目筛网对圆柱体进行干筛并与二氧化硅共混。
表3
分析结果：
- US2–来自Fuji Chemical Industry Co.Ltd.的偏硅酸铝镁
- XDP 3050和 XDP 3150为来自W.R.Grace的中孔二氧化硅
本发明的方法展示了配制流动特性良好的布洛芬钠二水合物颗粒的能力。
表4
负载有药物的颗粒B、C、D和E的制剂：
表5
负载有药物的颗粒B、C、D和E的粒度分布：
表6
B、C、D和E的核心制剂：
- PH102–Philadelphia,PA的FMC BioPolymer供应的微晶纤维素
- SMCC 90–Rosenberg,Germany的JRS Pharma供应的微晶纤维素(98％)和胶体二氧化硅(2％)的共混物
-63FP为来自W.R.Grace的二氧化硅
制剂B、C、D和E的吸附过程：
1.使用水浴将无菌水加热至50℃的温度。
2.在聚乙烯袋中预混 XDP 3150和 SMCC90或 PH102。
3.向加热的水(44.6ml)中添加布洛芬钠二水合物的“溶液”部分(29.15g)并让其溶解大约4分钟。所得的药物溶液澄清且含有较多水。
4.将药物溶液从水浴移除，并向步骤3的药物溶液添加步骤2的预混干燥材料。使用金属刮刀混合所有材料并确保被打湿。
5.用铝箔盖紧步骤4的中间产物批料，并于室温下在实验室工作台上浸渍不超过30分钟。
6.将中间产物批料返回到水浴中并使用金属刮刀混合以确保所有未吸附的药物处于溶液中。
7.添加布洛芬钠二水合物的“粉末”部分(见表6中粉末的含量)的同时，使用叶轮混合器混合步骤6的浆液不超过40秒。材料比步骤6的更粘性并能够发泡。总混合时间不超过30秒。
8.通过30目筛网对材料进行湿筛。材料从筛的下侧垂下，并且看起来为具有挤出外观的小管。
9.使挤出物风干大约6分钟，然后从筛上刮下并散布在托盘纸上，并将其置于实验室通风橱中，于环境温度下干燥约20小时，从而得到干燥的固体易碎材料。
10.通过60目筛网对圆柱状物进行干筛并与63FP和硬脂酸镁共混。
11.使用以下过程将步骤10的共混物压缩成片剂。
片剂的压缩：
A：冲压机-5/16"倒圆平面斜边缘型
力-0.75吨
剂量-256.24mg布洛芬钠二水合物(相当于200mg布洛芬酸)
B、C、D和E：
冲压机-5/16"倒圆平面斜边缘型
力-1.0吨
剂量-128.12mg布洛芬钠二水合物(相当于100mg布洛芬酸)
实施例2
对比由Advil Ion CoreTM Technology支持的膜包衣在0.25％SLS(月桂基硫酸钠)/0.1N HCL介质中的溶解结果。
在220nm桨叶并且桨叶转速为50rpm条件下使用HPLC方法。0.1mg/mL至0.3mg/mL范围内的样品注入体积为10μL(100mg的IBU钠片剂在1000mL溶解容器中为0.1mg/mL，此时无任何其它稀释剂注入)。
表7
核心制剂A在0.25％SLS/0.1N HCL中的溶解结果
图1提供了结果的图形化展示，其示出在10分钟时，制剂A样品至少50％被释放，而由Advil Ion CoreTM Technology支持的膜包衣产品少于23％被释放。在20分钟时，制剂A样品至少75％被释放，而由Advil Ion CoreTM Technology支持的膜包衣产品少于54％被释放。
相比于膜包衣片剂(由Advil Ion CoreTM Technology支持)在FaSSGF(模拟空腹状态时的胃液)Biorelevant pH 1.6介质中的溶解结果。
在220nm桨叶并且桨叶转速为75rpm条件下使用HPLC方法。0.1mg/mL至0.3mg/mL范围内的样品注入体积为10μL(100mg的IBU钠片剂在1000mL溶解容器中为0.1mg/mL，此时无任何其它稀释剂注入)。
表8
核心制剂B和C在FaSSGF Biorelevant pH 1.6介质中的溶解结果
图2和图3提供了结果的图形化展示，其示出在10分钟时，制剂B和C样品至少22％被释放，而膜包衣片剂(由Advil Ion CoreTM Technology支持)产品少于13％被释放。在20分钟时，制剂B和C样品至少35％被释放，而膜包衣片剂(由Advil IonCoreTM Technology支持)产品少于35％被释放。
相比于膜包衣片剂(由Advil Ion CoreTM Technology支持)在FeSSGF(模拟进食状态时的胃液)Biorelevant pH 5.0介质中的溶解结果。
在220nm桨叶并且桨叶转速为75rpm条件下使用HPLC方法。0.1mg/mL至0.3mg/mL范围内的样品注入体积为10μL(100mg的IBU钠片剂在1000mL溶解容器中为0.1mg/mL，此时无任何其它稀释剂注入)。
表9
核心制剂D和E在FeSSGF Biorelevant pH 5.0介质中的溶解结果
Biorelevant缓冲剂的制备
FaSSGF Biorelevant pH 1.6介质-将0.42g牛磺胆酸钠和溶于3.2mL二氯甲烷中的0.32g卵磷脂溶于10L水中。添加2g胃蛋白酶和40g NaCl。将混合物加热至40℃并用水适量至20L。
表10
参考：Karuppiah,V.；Kannappan,N.；Manavalan,R.In-vitro an。Simulated In-vivo Dissolution of Dipyridamole Extended ReleaseCapsules.Intl.J.Pharm.Sciences Review and Research.13(1),68-72.(2012)
FeSSGF Biorelevant pH5.0介质-在10L水中溶解277.0g NaCl和80.08g乙酸钠。添加20mL乙酸并用水适量至20L。
表11
参考：Karuppiah,V.；Kannappan,N.；Manavalan,R.In-vitro an。Simulated In-vivo Dissolution of Dipyridamole Extended ReleaseCapsules.Intl.J.Pharm.Sciences Review and Research.13(1),68-72.(2012)
实施例3
味道测试
使用表12中的制剂制备负载有布洛芬钠活性药物成分(API)的颗粒以供味道测试。该吸附过程与实施例1所述的相同。
表12
用于味道测试的颗粒制剂
*理论上已在干燥步骤的通风橱中完全去除
然后测试包含布洛芬钠的颗粒的味道。将该颗粒与纯布洛芬钠API(活性药物成分)相比较。每个样品含有50mg布洛芬钠。指示四个受试者摄取各个样品，并基于包括苦味、咸味和口/喉咙灼烧感的若干标准评估感觉。级别为基于0-10的评分，其中0＝无(无苦味、咸味或喉咙/口灼烧感)，并且10＝高水平(高水平的可感知苦味、咸味或喉咙/口灼烧感)。结果示出于表13中。
表13
味道测试的结果
苦味的平均感觉改变为1.25；咸味为1.25；并且口/喉咙灼烧感为3.25。
在所有的标准中，纯API表现出了比负载有40％API的颗粒更高的水平，表明该颗粒提供了对感觉的掩味。
虽然上文已结合具体实施方案描述了本发明，但显而易见的是，在不脱离本文所公开的发明构思的条件下，可作出多种变化、修改和变型。因此，本文旨在涵盖属于所附权利要求书的实质和广义范围内的所有此类变化、修改和变型。本文引用的所有专利申请、专利以及其它出版物均全文以引用方式并入。
Claims (23)
1.一种用于将活性药物成分吸附到底物上的方法，包括以下步骤：
(a)将惰性吸附剂添加并混合到包含所述活性药物成分的非固体形式，从而形成混合物；以及
(b)干燥所述混合物以形成固体易碎材料。
2.根据权利要求1所述的方法，其中所述非固体形式为溶液、悬浮液、乳液、糊剂或浆液。
3.根据权利要求2所述的方法，其中所述非固体形式为基于水的、基于溶剂的或基于脂类的。
4.根据权利要求1所述的方法，其中所述惰性吸附剂为合成锂皂石、膨润土、粘土、硅铝酸镁、偏硅酸铝镁、多孔硅酸钙、磷酸二钙和磷酸三钙、中孔二氧化硅、二氧化硅以及它们的混合物。
5.根据权利要求4所述的方法，其中所述惰性吸附剂为中孔二氧化硅。
6.根据权利要求1所述的方法，还包括步骤(a)之后的湿法筛分步骤。
7.根据权利要求1所述的方法，其中所述固体易碎材料在粒度减小装置中被进一步处理。
8.根据权利要求1所述的方法，其中所述活性药物成分为布洛芬钠二水合物。
9.根据权利要求1所述的方法，还包括在步骤(b)之前将附加的活性药物成分添加到所述混合物的所述步骤。
10.一种用于将布洛芬钠二水合物吸附到底物上的方法，包括以下步骤：
(a)将惰性吸附剂添加并混合到包含所述布洛芬钠二水合物的非固体形式，从而形成混合物；以及
(b)干燥所述混合物以形成固体易碎材料。
11.根据权利要求10所述的方法，其中所述非固体形式为溶液、悬浮液、乳液、糊剂或浆液。
12.根据权利要求10所述的方法，还包括步骤(a)之后的湿法筛分步骤。
13.根据权利要求10所述的方法，其中所述固体易碎材料在粒度减小装置中被进一步处理。
14.根据权利要求10所述的方法，其中所述惰性吸附剂为合成锂皂石、膨润土、粘土、硅铝酸镁、偏硅酸铝镁、多孔硅酸钙、磷酸二钙和磷酸三钙、中孔二氧化硅、二氧化硅以及它们的混合物。
15.根据权利要求10所述的方法，其中所述惰性吸附剂为中孔二氧化硅。
16.根据权利要求10所述的方法，其中所述悬浮液在添加所述惰性吸附剂之前处于约50℃至约60℃的温度。
17.根据权利要求10所述的方法，还包括在步骤(b)之前将附加的布洛芬钠二水合物添加到所述混合物的所述步骤。
18.一种通过权利要求10所述的方法制得的剂型。
19.根据权利要求18所述的剂型，其中约50％的所述布洛芬钠二水合物是使用HPLC方法在约10分钟内释放在0.25％SLS/0.1N HCL介质中的。
20.根据权利要求18所述的剂型，其中约22％的所述布洛芬钠二水合物是使用HPLC方法在约10分钟内释放在FaSSGF Biorelevant pH 1.6介质中的。
21.根据权利要求18所述的剂型，其中约35％的所述布洛芬钠二水合物是使用HPLC方法在约20分钟内释放在FaSSGF Biorelevant pH 1.6介质中。
22.根据权利要求10所述的方法，其中所述方法用于生产提供所述布洛芬钠的掩味的布洛芬钠剂型。
23.一种在吞咽布洛芬剂型时降低受试者的所述口或喉咙中灼烧感的方法，包括以下步骤：(1)为所述受试者提供布洛芬钠剂型，其中所述布洛芬钠剂型是通过将布洛芬钠二水合物吸附到底物上制成的，包括以下步骤：(a)将惰性吸附剂添加并混合到包含所述布洛芬钠二水合物的非固体形式，从而形成混合物；以及(b)干燥所述混合物以形成固体易碎材料；以及(2)指导所述受试者吞下步骤(1)的所述布洛芬钠剂型。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US201462032029P | 2014-08-01 | 2014-08-01 | |
| US62/032,029 | 2014-08-01 | ||
| PCT/US2015/043127 WO2016019252A1 (en) | 2014-08-01 | 2015-07-31 | Core compositions |
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| CN106794142A true CN106794142A (zh) | 2017-05-31 |
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| CN201580053828.6A Withdrawn CN106794142A (zh) | 2014-08-01 | 2015-07-31 | 核心组合物 |
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| US (1) | US20160030345A1 (zh) |
| EP (1) | EP3174527B1 (zh) |
| CN (1) | CN106794142A (zh) |
| BR (1) | BR112017001958A2 (zh) |
| CA (1) | CA2956947C (zh) |
| RU (1) | RU2017106094A (zh) |
| WO (1) | WO2016019252A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114452262A (zh) * | 2022-03-03 | 2022-05-10 | 成都恒瑞制药有限公司 | 一种盐酸西替利嗪片及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10245284B2 (en) * | 2015-08-19 | 2019-04-02 | Alpex Pharma S.A. | Granular composition for oral administration |
| DE102016218604A1 (de) | 2016-09-27 | 2018-03-29 | Constantin Adams | Partikuläres Stoffgemisch, vorzugsweise zur Verwendung bei der Prophylaxe und/oder Behandlung einer Atemwegsstörung |
| US11439595B2 (en) * | 2018-07-18 | 2022-09-13 | Glatt Gmbh | Immediate release formulations of cannabinoids |
| CN112107694B (zh) * | 2020-10-30 | 2022-07-22 | 黄山中皇制药有限公司 | 一种喜炎平干混悬剂 |
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2015
- 2015-07-31 CN CN201580053828.6A patent/CN106794142A/zh not_active Withdrawn
- 2015-07-31 RU RU2017106094A patent/RU2017106094A/ru unknown
- 2015-07-31 EP EP15751191.6A patent/EP3174527B1/en active Active
- 2015-07-31 US US14/814,795 patent/US20160030345A1/en not_active Abandoned
- 2015-07-31 BR BR112017001958A patent/BR112017001958A2/pt not_active Application Discontinuation
- 2015-07-31 WO PCT/US2015/043127 patent/WO2016019252A1/en active Application Filing
- 2015-07-31 CA CA2956947A patent/CA2956947C/en active Active
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| WO2008104852A2 (en) * | 2007-02-26 | 2008-09-04 | Wockhardt Research Centre | Pharmaceutical compositions comprising adsorbate of fenofibrate |
| CN101380474A (zh) * | 2007-09-06 | 2009-03-11 | 北京大学 | 用于口服制剂的pH敏感性固体药物组合物及制备方法 |
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Also Published As
| Publication number | Publication date |
|---|---|
| BR112017001958A2 (pt) | 2017-11-21 |
| RU2017106094A (ru) | 2018-09-04 |
| CA2956947A1 (en) | 2016-02-04 |
| CA2956947C (en) | 2022-11-08 |
| EP3174527A1 (en) | 2017-06-07 |
| US20160030345A1 (en) | 2016-02-04 |
| EP3174527B1 (en) | 2021-02-17 |
| WO2016019252A1 (en) | 2016-02-04 |
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