CA2126441C - Microcrystalline cellulose spheronization composition - Google Patents
Microcrystalline cellulose spheronization compositionInfo
- Publication number
- CA2126441C CA2126441C CA002126441A CA2126441A CA2126441C CA 2126441 C CA2126441 C CA 2126441C CA 002126441 A CA002126441 A CA 002126441A CA 2126441 A CA2126441 A CA 2126441A CA 2126441 C CA2126441 C CA 2126441C
- Authority
- CA
- Canada
- Prior art keywords
- hydrocolloid
- microcrystalline cellulose
- drug
- spheronizing agent
- spheronizing
- 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.)
- Expired - Fee Related
Links
- 235000019813 microcrystalline cellulose Nutrition 0.000 title claims abstract description 52
- 239000008108 microcrystalline cellulose Substances 0.000 title claims abstract description 52
- 229940016286 microcrystalline cellulose Drugs 0.000 title claims abstract description 52
- 229920000168 Microcrystalline cellulose Polymers 0.000 title claims abstract description 48
- 238000005563 spheronization Methods 0.000 title claims description 21
- 239000000203 mixture Substances 0.000 title abstract description 46
- 239000000416 hydrocolloid Substances 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 35
- 229940079593 drug Drugs 0.000 claims abstract description 33
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- 239000002002 slurry Substances 0.000 claims abstract description 14
- 239000001923 methylcellulose Substances 0.000 claims abstract description 13
- 235000010981 methylcellulose Nutrition 0.000 claims abstract description 13
- 229920000609 methyl cellulose Polymers 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 25
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 9
- 239000007909 solid dosage form Substances 0.000 claims description 9
- 238000005469 granulation Methods 0.000 claims description 8
- 230000003179 granulation Effects 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 5
- 238000001694 spray drying Methods 0.000 claims description 4
- 239000011236 particulate material Substances 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 2
- 238000011068 loading method Methods 0.000 abstract description 4
- 235000010980 cellulose Nutrition 0.000 description 25
- 229920002678 cellulose Polymers 0.000 description 23
- 239000001913 cellulose Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000000306 component Substances 0.000 description 11
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 10
- 229960002900 methylcellulose Drugs 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- RZVAJINKPMORJF-UHFFFAOYSA-N N-acetyl-para-amino-phenol Natural products CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229960000278 theophylline Drugs 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 229960005489 paracetamol Drugs 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 241000275031 Nica Species 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229920002301 cellulose acetate Polymers 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
- 239000002552 dosage form Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 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
- 239000006186 oral dosage form Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000012798 spherical particle Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- UOTMYNBWXDUBNX-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinolin-2-ium;chloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 UOTMYNBWXDUBNX-UHFFFAOYSA-N 0.000 description 1
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- WYUYEJNGHIOFOC-VVTVMFAVSA-N 2-[(z)-1-(4-methylphenyl)-3-pyrrolidin-1-ylprop-1-enyl]pyridine;hydrochloride Chemical compound Cl.C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C\CN1CCCC1 WYUYEJNGHIOFOC-VVTVMFAVSA-N 0.000 description 1
- ZAMLGGRVTAXBHI-UHFFFAOYSA-N 3-(4-bromophenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical class CC(C)(C)OC(=O)NC(CC(O)=O)C1=CC=C(Br)C=C1 ZAMLGGRVTAXBHI-UHFFFAOYSA-N 0.000 description 1
- JBMKAUGHUNFTOL-UHFFFAOYSA-N Aldoclor Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O JBMKAUGHUNFTOL-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Natural products O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- 244000287680 Garcinia dulcis Species 0.000 description 1
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 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 1
- DYWNLSQWJMTVGJ-KUSKTZOESA-N Phenylpropanolamine hydrochloride Chemical compound Cl.C[C@H](N)[C@H](O)C1=CC=CC=C1 DYWNLSQWJMTVGJ-KUSKTZOESA-N 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfate Natural products OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229940057282 albuterol sulfate Drugs 0.000 description 1
- 235000015107 ale Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- -1 amino- Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940106135 cellulose Drugs 0.000 description 1
- 229920006184 cellulose methylcellulose Polymers 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013267 controlled drug release Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229960003782 dextromethorphan hydrobromide Drugs 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 description 1
- MZNZKBJIWPGRID-UHFFFAOYSA-N diphenylphosphorylmethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)CP(C=1C=CC=CC=1)C1=CC=CC=C1 MZNZKBJIWPGRID-UHFFFAOYSA-N 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960004842 ephedrine sulfate Drugs 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000004083 gastrointestinal agent Substances 0.000 description 1
- 229940127227 gastrointestinal drug Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229960002146 guaifenesin Drugs 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- PGYPOBZJRVSMDS-UHFFFAOYSA-N loperamide hydrochloride Chemical compound Cl.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 PGYPOBZJRVSMDS-UHFFFAOYSA-N 0.000 description 1
- 229960002983 loperamide hydrochloride Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000013081 microcrystal Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 1
- 229960004255 nadolol Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003207 papaverine hydrochloride Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960004227 phensuximide Drugs 0.000 description 1
- 229960002305 phenylpropanolamine hydrochloride Drugs 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229960003253 procainamide hydrochloride Drugs 0.000 description 1
- ABTXGJFUQRCPNH-UHFFFAOYSA-N procainamide hydrochloride Chemical compound [H+].[Cl-].CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 ABTXGJFUQRCPNH-UHFFFAOYSA-N 0.000 description 1
- 229960002244 promethazine hydrochloride Drugs 0.000 description 1
- XXPDBLUZJRXNNZ-UHFFFAOYSA-N promethazine hydrochloride Chemical compound Cl.C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 XXPDBLUZJRXNNZ-UHFFFAOYSA-N 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- XHKUDCCTVQUHJQ-LCYSNFERSA-N quinidine D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 XHKUDCCTVQUHJQ-LCYSNFERSA-N 0.000 description 1
- 229960002454 quinidine gluconate Drugs 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 229960001593 triprolidine hydrochloride Drugs 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/005—Processes for mixing polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
- C08L1/02—Cellulose; Modified cellulose
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2300/00—Characterised by the use of unspecified polymers
- C08J2300/14—Water soluble or water swellable polymers, e.g. aqueous gels
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
- C08L1/08—Cellulose derivatives
- C08L1/26—Cellulose ethers
- C08L1/28—Alkyl ethers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Processes Of Treating Macromolecular Substances (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Compositions Of Macromolecular Compounds (AREA)
Abstract
A particulate co-processed unattrited microcrystalline cellulose: hydrocolloid composition wherein the respective components are present in a weight ratio of from about 99:1 to 70:30. The composition is useful as a spheronizing agent for producing spheroids of uniform size and sphericity and having high drug loadings. The composition is produced by drying a slurry of the microcrystalline cellulose in an aqueous solution of the hydrocolloid. The preferred hydrocolloid is methyl cellulose.
Description
.:.;. : .::. :.. ,.,.~ . :: .: ,:;. .. .. ;, ., . :: ;;.. ~::. : .;..::-.
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r '1 ~' i '~
WO 93/12768 ~ ~ ~ ~ f~3 :~ ~ .J. PCT/US92/09983 :;.w U O A O O O O
This invention relates to spheronization compo-sitions and solid pharmaceutical dosage forms based thereon. More particularly, the invention pertains to a microcrystalline cellulose:hydrocolloid spheronizing composition capable of yielding a high percentage of spheroids of uniform size and sphericity and containing highly elevated drug levels.
In the food and pharmaceutical arts, it has long l0 been the practice to prepare and utilize particulate formulations in which the individual particles are of a spherical configuration. Such contoured particulates afford a number of advantages. The sphere has the low-est surface to volume ratio. Spheres pack evenly in containers for ease of accurately measuring quantities of particulate materials by volume. In the field of pharmaceuticals, the sphere is the ideal geometric solid for~the application of film coatings to effect control-led release of drugs and/or medicinals.
A number of methods have been developed for pro-ducing spheronized pharmaceutical compositions. For instance, the preparation of spherical oral dosage forms in pill molds and pellet presses dates back many years.
Since these early times, many improvements have been made in the technology.
In recent years, a method of producing spherical particulates that is attracting increased attention of the pharmaceutical community is that of spheronization.
The essential features of this technique typically in-volve the steps of: forming a dry blend of powdered components; wetting the dry blend with a liquid, usually aqueous, in the presence of a binding agent to give a plastic-like mass or granulation: extruding the mass through a screen or dye to form a spaghetti extrudate;
cutting the extrudate into short cylinders followed by a rounding stage in which the cylinders are rolled on a grooved surface into spheres. For more detailed in--formation on the process reference is made to "A New Technique for the Production of Spherical Particles" by .
A. D. Reynolds in Manufacturing Chemist & Aerosol News, June 1970.
Much of the interest in spheronization as a means of producing spherical particulates, or spheroids as they are commonly known, comes in the wake of the ever growing use of multiparticulate controlled-release oral dosage forms. These pharmaceuticals consist of drug bearing spheroids, generally about 0.8 to 1.2 mm in diameter, contained in capsules or compressed into tab-lets. By using a combination of spheroids having dif-ferent drug release characteristics, a dosage form can be tailored to provide the desired drug delivery system.
In carrying out the spheronization, microcrystal-line cellulose is included in the fonaulation as a pre-- ferred carrier or matrix medium for the active compo-nents.
Microcrystalline cellulose (MCC) is a partially purified depolymerized form of cellulose and is obtained by treating pulps derived from fibrous plant material with mineral acid. The acid preferentially attacks the less ordered or amorphous regions of the cellulose poly-mer chain, thereby exposing and freeing the crystalline sites which form cellulose crystallite aggregates. The reaction mixture is washed to remove the degraded by-products, the resulting wet-cake freed of water and the dried cellulose crystallite aggregates, or more commonly microcrystalline cellulose, recovered.
Microcrystalline cellulose is a white, odo~less,tasteless, relatively free-flowing powder, insoluble in water, organic solvents, dilute alkalies and dilute acids. It finds wide use as a pharmaceutical excigient, being particularly effective as a binder in the manufacture of tablets by direct compression.
.In formulating a drug delivery system in which the drug composition is composed of spherical particulates, WO 93/2768 ~ ~! i ~' t~ ~t ~ PCT/US92/09983 certain properties for the spheroids are desirable.
These include low friability, uniformity of size and sphericity or roundness and surface smoothness. Such characteristics ensure that on being coated, a film layer of even thickness will be deposited on the spher-olds for precise rata of drug release.
Drug bearing spheroids, exhibiting the character-istics aforesaid to a considerable degree can be real-ized using microcrystalline cellulose as the excipient for the drug carrier and spheronizing agent. A small amount o! other cellulose derivatives that absorb water (at hydratable cellulose) may be included in combination with the microcrystalline cellulose. Examples of such cellulosic derivatives are sodium carboxymethyl cellu-lose, hydroxy lower alkyl (C1-C6) cellulose, e.g., hy-droxypropyl cellulose and hydroxypropylmethyl cellulose.
A typical spheroid preparation involves forming a dry blend. of microcrystalline cellulose, a hydratable cellulose derivative and drug. Water is then added to the blend until a densely granulated mass is obtained.
This is then passed through a cylinder (usually 1 mm) on an extruder adjusted to give a uniform, free flowing extrudate which is then spheronized. Representative de-scriptions of these formulations can be found in U.S.
Patent Nos. x,844,910; 4,867,985 arid 4,867,987.
Although such formulations and procedures can yield a high percentage of even sized spheroids at low to moderate drug levels, size distribution of the spher-oids begins to widen as drug levels exceed about 60%.
As drug loadings are further increased above about 80%, the spheroids become even more varied in size and spher-icity thereby diminishing their utility as components in controlled release formulations.
Spheroids exhibiting good uniformity of size and sphericity and containing elevated drug levels, upwards of 80%, can be produced by carrying out the spheroni-nation process with a mixture of drug and a highly modi-t~ -1 C1 ~ ,~
Ir ~ ; ~~ ~~ ;~i 1~ .~
fied microcrystalline cellulose of the type described in U.S. Patent No. 3,539,365.
This cellulosic derivative is prepared by subject-ing the washed filter cake containing about 40% micro-s crystalline solids from the acid degradation of cellu-lose, to intense attritive forces. The result is a further break up of the cellulose crystallite aggregates and an increase in submicron particles. As the attri-tion proceeds, a sufficient amount of sodium carboxy-methyl cellulose is added to the aqueous mixture in order to coat the separated microcrystals. Upon com-pletion of the attrition, the mixture is dried and re-covered. The dried product is readily redispersible in aqueous media to give gels. It contains about 5% to 15%
by weight of sodium carboxymethyl cellulose.
The material is made and sold by the FMC Corpor-ation in several grades under the Avicel~ RC and CL
trademark. Its application in spheronization processes is disclosed in FMC Technical Bulletin "Avicel Spheres.'°
Although the attrited microcrystalline cellulose:-sodium carboxymethyl cellulose composition yields gener-ally satisfactory spheroids, it forms a sticky granu-lation which clings to the spheronization equipment. In order to maintain spheroid output, the equipment must be periodically disassembled and cleaned. This detracts from the practicality of such microcrystalline cellulose composition for commercial scale production and use as a spheronizing agent.
A microcrystalline spheronizing composition has now been found that is surprisingly superior to the prior art compositions.
In accordance with the present invention, a microcrystalline spheronizing composition useful in the production of spheroids having high drug loadings, is provided by a particulate co-processed nonattrited microcrystalline cellulose and a non-ionic hydrocolloid, the two components being intimately associated with one WO 93/12768 ;~ -~~. a:~ a ~r. ~: ~. PCT/US92/09983 another. The invention further includes a process for producing the spheronizing composition, a method of producing solid dosage forms based on the spheronizing composition, and the resulting solid dosage forms.
The particulate co-processed spheronizing compo-sition of the invention contains as its two ~ssential components, microcrystalline cellulose and a pharma- .
ceutical grade, non-ionic hydrocolloid. As understood herein, hydrocolloid means a hydrophilic resin or poly-mer. Although the percentage of these two components can vary considerably, the weight ratio of microcrystal-li~ne cellulose to hydrocolloid is desirably held to a range of from about 99:1 to about 70:30, or, when the hydrocolloid is methyl cellulose, preferably from about 97.5:2.,5 to about 90:10 and most preferably from about 96:4 to 94:6.
The source of the microcrystalline cellulose is preferably wet cake from a conventional microcrystalline cellulose manufacturing process. Wet cake Which has not yet been dried is sometimes referred to as "never dried"
or hydrocellulose. The dried microcrystalline cellulose can be used but it must be vigorously agitated in aque-ous media to reconstitute the cellulose crystallite aggregates.
An economic advantage of the spheronization compo-sitions invention is that it can be manufactured without having to employ the more expensive highly attrited microcrystalline cellulose of the prior art composition.
The micro~rystalline cellulose component of the compo-sitions of the invention, whether in the wet cake or dried stage is understood to be unattrited microcrystal-line cellulose.
The concentration of the non-ionic hydrocolloid solution should be sufficient to permit interaction of the microcrystalline cellulose with the hydrocolloid.
Such interaction is believed to involve adsorption of hydrocolloid molecules on the surface of the cellulose crystallite aggregates which constitutes the structure of nonattrited microcrystalline cellulose.
The affinity or attraction or other property of the hydrocolloid for the cellulose crystallites appears to vary from one member to another, as evidenced by ,.
differences in spheronization properties.
A hydrocolloid which has been found exceptionally effective for preparing the microcrystalline spheroni-zation compositions of the invention is methyl cellu-lose: Granulations containing this hydrocolloid process very cleanly in the sgheronization equipment with no evidence of sticking while giving a high percentage of spheroids having excellent uniformity of size distri-bution'and sphericity.
A number of non-ionic hydrophilic polymers are known and have been described in the technical liters-tore: many are available commercially as etherified or esterified celluloses and in other synthetic or deriva- .
tive form. In addition to methyl cellulose, other pre-ferred classes and examples of these polymeric entities are the modified (semisynthetic) gums including hydroxy - lower alkyl (C1-C6) celluloses such as hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxy-propylmethyl cellulose, and the synthetic gums including vinyl polymers such as polyvinylpyrrolidone. For other examples of modified and synthetic gums, see Glicksman, "Gum Technology in the Food Industry°' (1969), page 8.
To the extent that they may be non-ionic, the water soluble cellulose acetates are also useful. These are the partially hydrolyzed derivatives of cellulose ace-tate having an acetyl content in the range of about 1?-2?% (calculated as combined acetic acid - U.S. Patent 3,482,011) or 13-19% (Eastman Chemical Products Publi-cation No. E-1408, February 1981, "Eastmane Cellulose Acetate For Coatings").
In preparing the spheronizing compositions of the WO 93/12768 ~a ~. ~.'.a i ~'~ ~'~. ', PGT/US92/09983 _7_ invention, microcrystalline cellulose is added to an aqueous solution of the non-ionic hydrocolloid and the mixture formed into a slurry under high energy shear.
The microcrystalline cellulose is preferably wet cake formed in the conventional acid hydrolysis of cellulose pulps. Dried microcrystalline cellulose can also be used provided the high shear blending is sufficient to redisperse the cellulose crystallites.
Mixing of the microcrystalline cellulose and aque-ous hydrocolloid is continued until interaction of the hydrocolloid with the cellulose crystallites is complete o~.has reached equilibrium. Normally, this takes about 10 to about 60 minutes. As previously noted, the hydro-colloid is believed to form an adsorbed layer on the cellulose crystallite surface.
The concentration of microcrystalline cellulose and hydrocolloid in the aqueous slurry is such that the weight ratios of these components in the dried solid will fall within the specified ranges of 99:1 to 70:30, microcrystalline cellulose:hydrocolloid. Generally speaking, total amounts by weight of slurry solids will vary from about 5% to about 25%.
Certain of the hydrocolloids may form viscous solutions or even gels in aqueous media making it dif-ficult or impossible to produce a flowable slurry. This can usually be circumvented by employing a more dilute solution of the hydrocolloid: also increasing the tem-perature may increase fluidity. For example, methyl cellulose is available in various viscosities, ranging from about 10 to 400 centipoise or higher in aqueous solution. When using~the higher viscosity material, lesser concentrations can be employed.
After the blending is complete, the slurry is dried, preferably by spray drying. Conventional spray drying equipment and operating procedures are employed.
Drying gas outlet temperature is ordinarily used to control residual moisture content of the co-processed ~~.r~~~~:
_ _8_ particulate material. Moisture levels of about 0.5% to about 8.0% are satisfactory with preferred levels being about 3.0% to about 5.0%.
The particle size of the dried spheronizing compo-sition approximates that of the microcrystalline cellu-lose, although some of the crystallite aggregates may form clumps of larger particles.
Spheroids are produced from the spheronizing mi crocrystalline cellulose compositions of the invention following known spheronization procedures, including extrusion spheronization and'rotogranulation/rotopro-c~ssing techniques. A dry blend of the composition and drug is first prepared. Water is then added slowly, with continuous mixing until a granulation of the requi-site consistency is obtained. Alternatively, the drug, if it is water soluble, can be dissolved in the water, and this solution added to the MCC:hydrocolloid particu-late composition. The amount of the drug to be added is fixed by the loadings to which the spheres are suscepti-ble and may be predetermined by routine testing.
The wet granulation is extruded using suitably sized pierced screens and spheronized using a rotating disk having a ground surface. The spheres are then dried in a fluidized bed or other drying means to a suitable moisture level, typically about 0.5% to 5%.
As understood in the pharmaceutical art, the term "sphere" or "spheroid°~ means spherical particles having a diameter in the range of about 0.1 to 2.5 mm, more preferably from 0.5 to 2 mm and most preferably from 0.8 to 1.4 mm.
The co-processed microcxystalline cellulose:-hydrocolloid composition of the invention affords a surprisingly higher percentage of spheroids in the nar-row 0.8-1.4 mm range than when the spheronization is carried out using a three component granulation of mi-crocrystalline cellulose, hydrocolloid and drug as called for in the prior art; see cited U.S. Patent Nos.
WO 93/12768 ~ ~ ~ ~ ~~ ~~ '~ PGT/US92/09983 _g_ 4,844,910; 4,867,985 and 4,867,987 supra. For some reason not presently understood, the interaction or affinity between the microcrystalline cellulose and hydrocolloid is not evident in the aforesaid three com-ponent system.
Because of their excellent uniformity of size and sphericity, the spheroids produced with the spheronizing compositions of the invention can be evenly coated for precise controlled drug release.
A further advantage of the invention is that the granulation of the herein co-processed composition is 1-ess susceptible to overwetting than is normally the case. This "forgiving feature" means that fewer batches of unacceptable granulated material will be produced, even with less experienced operators.
Still another advantage is that the coprocessed compositions of the invention are not sticky, that is;
do~not stick to spheronization equipment, and therefore are adaptable to large, commercial scale, multi-batch spheronization operations.
The spheronizing compositions of the invention can be used to form spheres with virtually all phanaa-ceutical preparations and drugs, including combinations .
of drugs, and whether the drugs are water soluble or water insoluble. Typical of such drugs are the follow-ing a o Analgesics - acetaminophen, ibuprofen, keto-profen and the like, indomethacin, naproxen, acetaminophen with codeine and acetaminophen with propoxyphene napsylate.
o Antibiotics - erythromycin, cephalosporins,~
minocycline IiCl.
o Antiepileptics - phensuximide, phenytoin sodi-um and valproate sodium.
o Antihistamines - chlorpheniramine maleate, diphenhydramine hydrochloride, triprolidine hydrochloride.
WO 93/12768 PCT/US92/a9983 ~-' ~ ~ 'w . . .e o Cough and Cold Drugs - dextromethorphan hydro-bromide, ephedrine sulfate, guaifenesin, phenylpropanolamine hydrochloride, prometha-zine hydrochloride, and pseudoephedrine hydro-chlorade.
o Cardiovascular Drugs - captopril, chlor-thiazide and hydrochlorthiazide, diltiazem, nadolol, papaverine hydrochloride, procain-amide hydrochloride, propranolol hydra-chloride, quinidine gluconate, qiiinidine sul-fate.
~ Gastrointestinal Drugs - cimetidine, loper-amide hydrochloride and ranitidine.
o Respiratory Drugs - albuterol sulfate, amino-' phylline,, theophylline.
The following examples illustrate the invention in greater detail.
Example 1 PREPARATION OF SPHERONIZING COMPOSITION
?0 Methylcellulose (6.3 lb (2.86 kg) at 4% moisture) having a viscosity of 15 centipoise (Dow Chemical Co.
Methocel~ A-15LV) Was hydrated with 9°7.9 lb (44.4 kg) of water to form a solution containing 5~ solids. The hydrocolloid was added slowly to the water with overhead stirring using a commercially available variable speed mixer. In a separate slurry tank, microcrystalline cellulose (2'74.7 lb (124.f kg) of a 41.5 wet cake) was diluted with 287.8 lb (130.5 kg) of water. The ' microcrystalline cellulose was added to the water and dispersed using a high energy dispersator such as a Co~ales mixer at 1500 RPM until a smooth cream-like slurry was formed. The methylcellulose solution was added to the microcrystalline cellulose with continued stirring for 40 minutes using the high energy mixer to form a uniform dispersion. The final slurry had a solids content of 18%. The slurry was then spray dried using a single fluid nozzle for atomization. The con- .
WO 93/12768 ~ ~, r~ c~ :, ,: ..~
ditions used during the drying were 1500 psi (10.342 x 103 KPa) line pressure and a flow rate of 0.5 gpm. An outlet temperature of 230oF-240oF (110oC-115.6oC) was maintained. The production rate at these conditions was 46 lbs/hr (20.87 kg/hr: ) .
Example 2 A co-processed material containing 95% microcrys-talline cellulose and 5%.hydroxypropylmethyl cellulose was prepared using process and conditions similar to l0 those described in Example 1.
Example 3 _ A, pRFP~R~TTON OF SPHEROTDS OF PRESEh~' ~'h' ~~h'TTON
The co-processed material described in Example 1 (95/5 microcrystalline cellulose/methylcellulose - w MCC/MC) was used in the preparation of spheres contain-ing 80% theophylline using the process commonly referred to as extrusion/spheronization. The co-processed 95/5 MCC/MC (200 gj along with 800 g of anhydrous theophyl-line was charged into a 12 quart planetary mixer and allowed to mix for a period of 5 minutes until a homo-geneous mixture was achieved. To this mixture 600 g of water was added slowly with continued mixing for a periad of 15 minutes allowing for sufficient distri-bution of the water throughout the mass. This process of wetting powders is commonly referred to as granula-tion. The so-obtained wet mass was then charged into the hopper of a Nica extruder. It was extruded through screens having 1.0 mm openings, at a speed of 14-16 RPM
to form a pellet-like extrudate having an approximate length between 0.25 and 1.0 cm. The extrudate was then charged into the Nica spheronizer. This piece of equip-ment consists of a bowl having stationary side walls and a rotating bottom commonly referred to as the disk. The extrudate was processed in the spheronizer for a period of 8 minutes at a disk speed of 650 RPM. At the end of 8 minutes, the spheres were discharged into an appro-priate receptacle. The spheres were then transferred WO 93/12768 c~ ;~ ~, ,.~ ~ PCT/US92/09983 F,~ ~ rd ~ ',t ~, onto trays of a conventional forced air oven and dried at 50oC for a period of 6 hours. 90% of the so obtained spheroids were within the range of 0.8 to 1.4 mm.
B. PRIOR ART S~~R~ OID, S, Non-attrited microcrystalline cellulose (Avicel~
PH-101, FMC Corporation, 190 g), methyl cellulose (10 g) and 800 g of anhydrous theophylline were dry blended and subjected to spheronization following the procedure of Example 3A. 73% of the so-obtained spheroids were within the size range of 0.8 to 1.4 mm. This Example illustrates the spheronizing procedure in which all three components aforesaid are spheronized as disclosed in cited U.S. Patent Nos. 4,867,985 and 4,867,987.
C . PRIOR ART ~~~iEROI DS
Non-attrited microcrystalline cellulose (Avicel~
PH-101, FMC Corporation, 200 g) and 800 g anhydrous theophylline were dry blended and subjected to spheronization following the procedure of Example 3A.
68% of the resulting spheroids were within the size w range of 0.8 to 1.4 mm. This Example illustrates the spheronizing procedure in which microcrystalline is the sole spheronizing agent.
As is readily apparent from the foregoing compara-tive Example 3, the percent of spheroids in the desired range of 0.8 - 1.4 mm is surprisingly greater using the spheronizing composition of the invention (Example 3A) than is obtained with the prior art compositions (Ex-amples 3B and 3C).
,:;:;, . ::;:. .., ..;., ;;, .. .. ..., ., ,,. ~.. . .; . ,,." ,. ,,._ . . , ,. . , . . ; . .
r '1 ~' i '~
WO 93/12768 ~ ~ ~ ~ f~3 :~ ~ .J. PCT/US92/09983 :;.w U O A O O O O
This invention relates to spheronization compo-sitions and solid pharmaceutical dosage forms based thereon. More particularly, the invention pertains to a microcrystalline cellulose:hydrocolloid spheronizing composition capable of yielding a high percentage of spheroids of uniform size and sphericity and containing highly elevated drug levels.
In the food and pharmaceutical arts, it has long l0 been the practice to prepare and utilize particulate formulations in which the individual particles are of a spherical configuration. Such contoured particulates afford a number of advantages. The sphere has the low-est surface to volume ratio. Spheres pack evenly in containers for ease of accurately measuring quantities of particulate materials by volume. In the field of pharmaceuticals, the sphere is the ideal geometric solid for~the application of film coatings to effect control-led release of drugs and/or medicinals.
A number of methods have been developed for pro-ducing spheronized pharmaceutical compositions. For instance, the preparation of spherical oral dosage forms in pill molds and pellet presses dates back many years.
Since these early times, many improvements have been made in the technology.
In recent years, a method of producing spherical particulates that is attracting increased attention of the pharmaceutical community is that of spheronization.
The essential features of this technique typically in-volve the steps of: forming a dry blend of powdered components; wetting the dry blend with a liquid, usually aqueous, in the presence of a binding agent to give a plastic-like mass or granulation: extruding the mass through a screen or dye to form a spaghetti extrudate;
cutting the extrudate into short cylinders followed by a rounding stage in which the cylinders are rolled on a grooved surface into spheres. For more detailed in--formation on the process reference is made to "A New Technique for the Production of Spherical Particles" by .
A. D. Reynolds in Manufacturing Chemist & Aerosol News, June 1970.
Much of the interest in spheronization as a means of producing spherical particulates, or spheroids as they are commonly known, comes in the wake of the ever growing use of multiparticulate controlled-release oral dosage forms. These pharmaceuticals consist of drug bearing spheroids, generally about 0.8 to 1.2 mm in diameter, contained in capsules or compressed into tab-lets. By using a combination of spheroids having dif-ferent drug release characteristics, a dosage form can be tailored to provide the desired drug delivery system.
In carrying out the spheronization, microcrystal-line cellulose is included in the fonaulation as a pre-- ferred carrier or matrix medium for the active compo-nents.
Microcrystalline cellulose (MCC) is a partially purified depolymerized form of cellulose and is obtained by treating pulps derived from fibrous plant material with mineral acid. The acid preferentially attacks the less ordered or amorphous regions of the cellulose poly-mer chain, thereby exposing and freeing the crystalline sites which form cellulose crystallite aggregates. The reaction mixture is washed to remove the degraded by-products, the resulting wet-cake freed of water and the dried cellulose crystallite aggregates, or more commonly microcrystalline cellulose, recovered.
Microcrystalline cellulose is a white, odo~less,tasteless, relatively free-flowing powder, insoluble in water, organic solvents, dilute alkalies and dilute acids. It finds wide use as a pharmaceutical excigient, being particularly effective as a binder in the manufacture of tablets by direct compression.
.In formulating a drug delivery system in which the drug composition is composed of spherical particulates, WO 93/2768 ~ ~! i ~' t~ ~t ~ PCT/US92/09983 certain properties for the spheroids are desirable.
These include low friability, uniformity of size and sphericity or roundness and surface smoothness. Such characteristics ensure that on being coated, a film layer of even thickness will be deposited on the spher-olds for precise rata of drug release.
Drug bearing spheroids, exhibiting the character-istics aforesaid to a considerable degree can be real-ized using microcrystalline cellulose as the excipient for the drug carrier and spheronizing agent. A small amount o! other cellulose derivatives that absorb water (at hydratable cellulose) may be included in combination with the microcrystalline cellulose. Examples of such cellulosic derivatives are sodium carboxymethyl cellu-lose, hydroxy lower alkyl (C1-C6) cellulose, e.g., hy-droxypropyl cellulose and hydroxypropylmethyl cellulose.
A typical spheroid preparation involves forming a dry blend. of microcrystalline cellulose, a hydratable cellulose derivative and drug. Water is then added to the blend until a densely granulated mass is obtained.
This is then passed through a cylinder (usually 1 mm) on an extruder adjusted to give a uniform, free flowing extrudate which is then spheronized. Representative de-scriptions of these formulations can be found in U.S.
Patent Nos. x,844,910; 4,867,985 arid 4,867,987.
Although such formulations and procedures can yield a high percentage of even sized spheroids at low to moderate drug levels, size distribution of the spher-oids begins to widen as drug levels exceed about 60%.
As drug loadings are further increased above about 80%, the spheroids become even more varied in size and spher-icity thereby diminishing their utility as components in controlled release formulations.
Spheroids exhibiting good uniformity of size and sphericity and containing elevated drug levels, upwards of 80%, can be produced by carrying out the spheroni-nation process with a mixture of drug and a highly modi-t~ -1 C1 ~ ,~
Ir ~ ; ~~ ~~ ;~i 1~ .~
fied microcrystalline cellulose of the type described in U.S. Patent No. 3,539,365.
This cellulosic derivative is prepared by subject-ing the washed filter cake containing about 40% micro-s crystalline solids from the acid degradation of cellu-lose, to intense attritive forces. The result is a further break up of the cellulose crystallite aggregates and an increase in submicron particles. As the attri-tion proceeds, a sufficient amount of sodium carboxy-methyl cellulose is added to the aqueous mixture in order to coat the separated microcrystals. Upon com-pletion of the attrition, the mixture is dried and re-covered. The dried product is readily redispersible in aqueous media to give gels. It contains about 5% to 15%
by weight of sodium carboxymethyl cellulose.
The material is made and sold by the FMC Corpor-ation in several grades under the Avicel~ RC and CL
trademark. Its application in spheronization processes is disclosed in FMC Technical Bulletin "Avicel Spheres.'°
Although the attrited microcrystalline cellulose:-sodium carboxymethyl cellulose composition yields gener-ally satisfactory spheroids, it forms a sticky granu-lation which clings to the spheronization equipment. In order to maintain spheroid output, the equipment must be periodically disassembled and cleaned. This detracts from the practicality of such microcrystalline cellulose composition for commercial scale production and use as a spheronizing agent.
A microcrystalline spheronizing composition has now been found that is surprisingly superior to the prior art compositions.
In accordance with the present invention, a microcrystalline spheronizing composition useful in the production of spheroids having high drug loadings, is provided by a particulate co-processed nonattrited microcrystalline cellulose and a non-ionic hydrocolloid, the two components being intimately associated with one WO 93/12768 ;~ -~~. a:~ a ~r. ~: ~. PCT/US92/09983 another. The invention further includes a process for producing the spheronizing composition, a method of producing solid dosage forms based on the spheronizing composition, and the resulting solid dosage forms.
The particulate co-processed spheronizing compo-sition of the invention contains as its two ~ssential components, microcrystalline cellulose and a pharma- .
ceutical grade, non-ionic hydrocolloid. As understood herein, hydrocolloid means a hydrophilic resin or poly-mer. Although the percentage of these two components can vary considerably, the weight ratio of microcrystal-li~ne cellulose to hydrocolloid is desirably held to a range of from about 99:1 to about 70:30, or, when the hydrocolloid is methyl cellulose, preferably from about 97.5:2.,5 to about 90:10 and most preferably from about 96:4 to 94:6.
The source of the microcrystalline cellulose is preferably wet cake from a conventional microcrystalline cellulose manufacturing process. Wet cake Which has not yet been dried is sometimes referred to as "never dried"
or hydrocellulose. The dried microcrystalline cellulose can be used but it must be vigorously agitated in aque-ous media to reconstitute the cellulose crystallite aggregates.
An economic advantage of the spheronization compo-sitions invention is that it can be manufactured without having to employ the more expensive highly attrited microcrystalline cellulose of the prior art composition.
The micro~rystalline cellulose component of the compo-sitions of the invention, whether in the wet cake or dried stage is understood to be unattrited microcrystal-line cellulose.
The concentration of the non-ionic hydrocolloid solution should be sufficient to permit interaction of the microcrystalline cellulose with the hydrocolloid.
Such interaction is believed to involve adsorption of hydrocolloid molecules on the surface of the cellulose crystallite aggregates which constitutes the structure of nonattrited microcrystalline cellulose.
The affinity or attraction or other property of the hydrocolloid for the cellulose crystallites appears to vary from one member to another, as evidenced by ,.
differences in spheronization properties.
A hydrocolloid which has been found exceptionally effective for preparing the microcrystalline spheroni-zation compositions of the invention is methyl cellu-lose: Granulations containing this hydrocolloid process very cleanly in the sgheronization equipment with no evidence of sticking while giving a high percentage of spheroids having excellent uniformity of size distri-bution'and sphericity.
A number of non-ionic hydrophilic polymers are known and have been described in the technical liters-tore: many are available commercially as etherified or esterified celluloses and in other synthetic or deriva- .
tive form. In addition to methyl cellulose, other pre-ferred classes and examples of these polymeric entities are the modified (semisynthetic) gums including hydroxy - lower alkyl (C1-C6) celluloses such as hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxy-propylmethyl cellulose, and the synthetic gums including vinyl polymers such as polyvinylpyrrolidone. For other examples of modified and synthetic gums, see Glicksman, "Gum Technology in the Food Industry°' (1969), page 8.
To the extent that they may be non-ionic, the water soluble cellulose acetates are also useful. These are the partially hydrolyzed derivatives of cellulose ace-tate having an acetyl content in the range of about 1?-2?% (calculated as combined acetic acid - U.S. Patent 3,482,011) or 13-19% (Eastman Chemical Products Publi-cation No. E-1408, February 1981, "Eastmane Cellulose Acetate For Coatings").
In preparing the spheronizing compositions of the WO 93/12768 ~a ~. ~.'.a i ~'~ ~'~. ', PGT/US92/09983 _7_ invention, microcrystalline cellulose is added to an aqueous solution of the non-ionic hydrocolloid and the mixture formed into a slurry under high energy shear.
The microcrystalline cellulose is preferably wet cake formed in the conventional acid hydrolysis of cellulose pulps. Dried microcrystalline cellulose can also be used provided the high shear blending is sufficient to redisperse the cellulose crystallites.
Mixing of the microcrystalline cellulose and aque-ous hydrocolloid is continued until interaction of the hydrocolloid with the cellulose crystallites is complete o~.has reached equilibrium. Normally, this takes about 10 to about 60 minutes. As previously noted, the hydro-colloid is believed to form an adsorbed layer on the cellulose crystallite surface.
The concentration of microcrystalline cellulose and hydrocolloid in the aqueous slurry is such that the weight ratios of these components in the dried solid will fall within the specified ranges of 99:1 to 70:30, microcrystalline cellulose:hydrocolloid. Generally speaking, total amounts by weight of slurry solids will vary from about 5% to about 25%.
Certain of the hydrocolloids may form viscous solutions or even gels in aqueous media making it dif-ficult or impossible to produce a flowable slurry. This can usually be circumvented by employing a more dilute solution of the hydrocolloid: also increasing the tem-perature may increase fluidity. For example, methyl cellulose is available in various viscosities, ranging from about 10 to 400 centipoise or higher in aqueous solution. When using~the higher viscosity material, lesser concentrations can be employed.
After the blending is complete, the slurry is dried, preferably by spray drying. Conventional spray drying equipment and operating procedures are employed.
Drying gas outlet temperature is ordinarily used to control residual moisture content of the co-processed ~~.r~~~~:
_ _8_ particulate material. Moisture levels of about 0.5% to about 8.0% are satisfactory with preferred levels being about 3.0% to about 5.0%.
The particle size of the dried spheronizing compo-sition approximates that of the microcrystalline cellu-lose, although some of the crystallite aggregates may form clumps of larger particles.
Spheroids are produced from the spheronizing mi crocrystalline cellulose compositions of the invention following known spheronization procedures, including extrusion spheronization and'rotogranulation/rotopro-c~ssing techniques. A dry blend of the composition and drug is first prepared. Water is then added slowly, with continuous mixing until a granulation of the requi-site consistency is obtained. Alternatively, the drug, if it is water soluble, can be dissolved in the water, and this solution added to the MCC:hydrocolloid particu-late composition. The amount of the drug to be added is fixed by the loadings to which the spheres are suscepti-ble and may be predetermined by routine testing.
The wet granulation is extruded using suitably sized pierced screens and spheronized using a rotating disk having a ground surface. The spheres are then dried in a fluidized bed or other drying means to a suitable moisture level, typically about 0.5% to 5%.
As understood in the pharmaceutical art, the term "sphere" or "spheroid°~ means spherical particles having a diameter in the range of about 0.1 to 2.5 mm, more preferably from 0.5 to 2 mm and most preferably from 0.8 to 1.4 mm.
The co-processed microcxystalline cellulose:-hydrocolloid composition of the invention affords a surprisingly higher percentage of spheroids in the nar-row 0.8-1.4 mm range than when the spheronization is carried out using a three component granulation of mi-crocrystalline cellulose, hydrocolloid and drug as called for in the prior art; see cited U.S. Patent Nos.
WO 93/12768 ~ ~ ~ ~ ~~ ~~ '~ PGT/US92/09983 _g_ 4,844,910; 4,867,985 and 4,867,987 supra. For some reason not presently understood, the interaction or affinity between the microcrystalline cellulose and hydrocolloid is not evident in the aforesaid three com-ponent system.
Because of their excellent uniformity of size and sphericity, the spheroids produced with the spheronizing compositions of the invention can be evenly coated for precise controlled drug release.
A further advantage of the invention is that the granulation of the herein co-processed composition is 1-ess susceptible to overwetting than is normally the case. This "forgiving feature" means that fewer batches of unacceptable granulated material will be produced, even with less experienced operators.
Still another advantage is that the coprocessed compositions of the invention are not sticky, that is;
do~not stick to spheronization equipment, and therefore are adaptable to large, commercial scale, multi-batch spheronization operations.
The spheronizing compositions of the invention can be used to form spheres with virtually all phanaa-ceutical preparations and drugs, including combinations .
of drugs, and whether the drugs are water soluble or water insoluble. Typical of such drugs are the follow-ing a o Analgesics - acetaminophen, ibuprofen, keto-profen and the like, indomethacin, naproxen, acetaminophen with codeine and acetaminophen with propoxyphene napsylate.
o Antibiotics - erythromycin, cephalosporins,~
minocycline IiCl.
o Antiepileptics - phensuximide, phenytoin sodi-um and valproate sodium.
o Antihistamines - chlorpheniramine maleate, diphenhydramine hydrochloride, triprolidine hydrochloride.
WO 93/12768 PCT/US92/a9983 ~-' ~ ~ 'w . . .e o Cough and Cold Drugs - dextromethorphan hydro-bromide, ephedrine sulfate, guaifenesin, phenylpropanolamine hydrochloride, prometha-zine hydrochloride, and pseudoephedrine hydro-chlorade.
o Cardiovascular Drugs - captopril, chlor-thiazide and hydrochlorthiazide, diltiazem, nadolol, papaverine hydrochloride, procain-amide hydrochloride, propranolol hydra-chloride, quinidine gluconate, qiiinidine sul-fate.
~ Gastrointestinal Drugs - cimetidine, loper-amide hydrochloride and ranitidine.
o Respiratory Drugs - albuterol sulfate, amino-' phylline,, theophylline.
The following examples illustrate the invention in greater detail.
Example 1 PREPARATION OF SPHERONIZING COMPOSITION
?0 Methylcellulose (6.3 lb (2.86 kg) at 4% moisture) having a viscosity of 15 centipoise (Dow Chemical Co.
Methocel~ A-15LV) Was hydrated with 9°7.9 lb (44.4 kg) of water to form a solution containing 5~ solids. The hydrocolloid was added slowly to the water with overhead stirring using a commercially available variable speed mixer. In a separate slurry tank, microcrystalline cellulose (2'74.7 lb (124.f kg) of a 41.5 wet cake) was diluted with 287.8 lb (130.5 kg) of water. The ' microcrystalline cellulose was added to the water and dispersed using a high energy dispersator such as a Co~ales mixer at 1500 RPM until a smooth cream-like slurry was formed. The methylcellulose solution was added to the microcrystalline cellulose with continued stirring for 40 minutes using the high energy mixer to form a uniform dispersion. The final slurry had a solids content of 18%. The slurry was then spray dried using a single fluid nozzle for atomization. The con- .
WO 93/12768 ~ ~, r~ c~ :, ,: ..~
ditions used during the drying were 1500 psi (10.342 x 103 KPa) line pressure and a flow rate of 0.5 gpm. An outlet temperature of 230oF-240oF (110oC-115.6oC) was maintained. The production rate at these conditions was 46 lbs/hr (20.87 kg/hr: ) .
Example 2 A co-processed material containing 95% microcrys-talline cellulose and 5%.hydroxypropylmethyl cellulose was prepared using process and conditions similar to l0 those described in Example 1.
Example 3 _ A, pRFP~R~TTON OF SPHEROTDS OF PRESEh~' ~'h' ~~h'TTON
The co-processed material described in Example 1 (95/5 microcrystalline cellulose/methylcellulose - w MCC/MC) was used in the preparation of spheres contain-ing 80% theophylline using the process commonly referred to as extrusion/spheronization. The co-processed 95/5 MCC/MC (200 gj along with 800 g of anhydrous theophyl-line was charged into a 12 quart planetary mixer and allowed to mix for a period of 5 minutes until a homo-geneous mixture was achieved. To this mixture 600 g of water was added slowly with continued mixing for a periad of 15 minutes allowing for sufficient distri-bution of the water throughout the mass. This process of wetting powders is commonly referred to as granula-tion. The so-obtained wet mass was then charged into the hopper of a Nica extruder. It was extruded through screens having 1.0 mm openings, at a speed of 14-16 RPM
to form a pellet-like extrudate having an approximate length between 0.25 and 1.0 cm. The extrudate was then charged into the Nica spheronizer. This piece of equip-ment consists of a bowl having stationary side walls and a rotating bottom commonly referred to as the disk. The extrudate was processed in the spheronizer for a period of 8 minutes at a disk speed of 650 RPM. At the end of 8 minutes, the spheres were discharged into an appro-priate receptacle. The spheres were then transferred WO 93/12768 c~ ;~ ~, ,.~ ~ PCT/US92/09983 F,~ ~ rd ~ ',t ~, onto trays of a conventional forced air oven and dried at 50oC for a period of 6 hours. 90% of the so obtained spheroids were within the range of 0.8 to 1.4 mm.
B. PRIOR ART S~~R~ OID, S, Non-attrited microcrystalline cellulose (Avicel~
PH-101, FMC Corporation, 190 g), methyl cellulose (10 g) and 800 g of anhydrous theophylline were dry blended and subjected to spheronization following the procedure of Example 3A. 73% of the so-obtained spheroids were within the size range of 0.8 to 1.4 mm. This Example illustrates the spheronizing procedure in which all three components aforesaid are spheronized as disclosed in cited U.S. Patent Nos. 4,867,985 and 4,867,987.
C . PRIOR ART ~~~iEROI DS
Non-attrited microcrystalline cellulose (Avicel~
PH-101, FMC Corporation, 200 g) and 800 g anhydrous theophylline were dry blended and subjected to spheronization following the procedure of Example 3A.
68% of the resulting spheroids were within the size w range of 0.8 to 1.4 mm. This Example illustrates the spheronizing procedure in which microcrystalline is the sole spheronizing agent.
As is readily apparent from the foregoing compara-tive Example 3, the percent of spheroids in the desired range of 0.8 - 1.4 mm is surprisingly greater using the spheronizing composition of the invention (Example 3A) than is obtained with the prior art compositions (Ex-amples 3B and 3C).
Claims (17)
1. A microcrystalline cellulose spheronizing agent comprising particles of a dried slurry consisting essentially of nonattrited microcrystalline cellulose and a non-ionic hydrocolloid selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrollidone, the weight ratio of microcrystalline cellulose to hydrocolloid being 99:1 to 70:30.
2. The spheronizing agent of claim 1 characterized in that the hydrocolloid is methylcellulose and the weight ratio of the two components is in the range of from 97.5:2.5 to 90:10 microcrystalline cellulose:hydrocolloid.
3. The spheronizing agent of claim 1 characterized in that the hydrocolloid is methylcellulose and the weight ratio of the two components is in the range of from 96:4 to 94:6 microcrystalline cellulose:hydrocolloid.
4. The spheronizing agent of claim 1 characterized in that the source of the microcrystalline cellulose component is wet cake.
5. The spheronizing agent of claim 1 characterized in that the hydrocolloid is methylcellulose.
6. The spheronizing agent of claim 1 characterized in that the hydrocolloid component is hydroxypropyl methylcellulose.
7. A process for producing a particulate material, useful in the preparation of spheroids by spheronization, characterized by:
forming a well dispersed slurry of nonattrited microcrystalline cellulose in an aqueous solution of a nonionic hydrocolloid, the amounts of microcrystalline cellulose and hydrocolloid components being such as to provide a component ratio within the range recited below for the particulate co-processed product, and drying the aqueous slurry to yield a particulate coprocessed product wherein the weight ratio of nonattrited microcrystalline cellulose to hydrocolloid is in the range of from 99:1 to 70:30.
forming a well dispersed slurry of nonattrited microcrystalline cellulose in an aqueous solution of a nonionic hydrocolloid, the amounts of microcrystalline cellulose and hydrocolloid components being such as to provide a component ratio within the range recited below for the particulate co-processed product, and drying the aqueous slurry to yield a particulate coprocessed product wherein the weight ratio of nonattrited microcrystalline cellulose to hydrocolloid is in the range of from 99:1 to 70:30.
8. The process of claim 7 characterized in that the aqueous slurry is dried by spray drying.
9. The process of claim 7 characterized in that the microcrystalline cellulose is wet cake.
10. The process of claim 8 characterized in that the spray drying is carried out at a drier outlet temperature of from 230°F
to 240°F (110°C to 115.6°C).
to 240°F (110°C to 115.6°C).
11. A method of producing a particulate spheronized solid dosage form characterized by (a) forming the spheronization agent of any one of claims 1 to 6, (b) granulating said spheronization agent with a pharmaceutically effective amount of a drug active ingredient, (c) spheronizing the resulting granulation of said spheronizing agent and drug active ingredient.
12 A solid dosage form characterized by spheres containing, in combination, the spheronizing agent of claim 1 and a pharmaceutically effective amount of at least one drug.
13. A solid dosage form characterized by spheres containing, in combination, the spheronizing agent of claim 2 and a pharmaceutically effective amount of at least one drug.
14. A solid dosage form characterized by spheres containing, in combination, the spheronizing agent of claim 3 and a pharmaceutically effective amount of at least one drug.
15. A solid dosage form characterized by spheres containing, in combination, the spheronizing agent of claim 4 and a pharmaceutically effective amount of at least one drug.
16. A solid dosage form characterized by spheres containing, in combination, the spheronizing agent of claim 5 and a pharmaceutically effective amount of at least one drug.
17. A solid dosage form characterized by spheres containing, in combination, the spheronizing agent of claim 6 and a pharmaceutically effective amount of at least one drug.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US81602791A | 1991-12-30 | 1991-12-30 | |
US816,027 | 1991-12-30 | ||
PCT/US1992/009983 WO1993012768A1 (en) | 1991-12-30 | 1992-11-18 | Microcrystalline cellulose spheronization composition |
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CA2126441A1 CA2126441A1 (en) | 1993-07-08 |
CA2126441C true CA2126441C (en) | 1999-12-21 |
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CA002126441A Expired - Fee Related CA2126441C (en) | 1991-12-30 | 1992-11-18 | Microcrystalline cellulose spheronization composition |
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US (1) | US5725886A (en) |
EP (1) | EP0619731B1 (en) |
JP (1) | JP2628230B2 (en) |
CN (1) | CN1074228A (en) |
AT (1) | ATE196733T1 (en) |
AU (1) | AU663146B2 (en) |
BR (1) | BR9206996A (en) |
CA (1) | CA2126441C (en) |
DE (1) | DE69231499T2 (en) |
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FI (1) | FI943121A (en) |
IL (1) | IL104087A (en) |
MX (1) | MX9207438A (en) |
NO (1) | NO942457D0 (en) |
WO (1) | WO1993012768A1 (en) |
ZA (1) | ZA929161B (en) |
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US20100055180A1 (en) * | 2007-10-10 | 2010-03-04 | Mallinckrodt Baker, Inc. | Directly Compressible Granular Microcrystalline Cellulose Based Excipient, Manufacturing Process and Use Thereof |
US20110288146A1 (en) * | 2008-11-19 | 2011-11-24 | Nandu Deorkar | Directly compressible granular microcrystalline cellulose based, excipient, manufacturing process and use thereof |
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1992
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- 1992-11-18 JP JP5511647A patent/JP2628230B2/en not_active Expired - Fee Related
- 1992-11-18 EP EP93900553A patent/EP0619731B1/en not_active Expired - Lifetime
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- 1992-11-18 CA CA002126441A patent/CA2126441C/en not_active Expired - Fee Related
- 1992-11-18 WO PCT/US1992/009983 patent/WO1993012768A1/en active IP Right Grant
- 1992-11-18 DE DE69231499T patent/DE69231499T2/en not_active Expired - Fee Related
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1994
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- 1994-09-26 US US08/311,800 patent/US5725886A/en not_active Expired - Lifetime
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US5725886A (en) | 1998-03-10 |
NO942457L (en) | 1994-06-29 |
CN1074228A (en) | 1993-07-14 |
IL104087A (en) | 1998-10-30 |
EP0619731A1 (en) | 1994-10-19 |
FI943121A0 (en) | 1994-06-29 |
WO1993012768A1 (en) | 1993-07-08 |
AU3179393A (en) | 1993-07-28 |
FI943121A (en) | 1994-06-29 |
EP0619731B1 (en) | 2000-10-04 |
ATE196733T1 (en) | 2000-10-15 |
CA2126441A1 (en) | 1993-07-08 |
EP0619731A4 (en) | 1995-05-03 |
DE69231499D1 (en) | 2000-11-09 |
DE69231499T2 (en) | 2001-05-03 |
MX9207438A (en) | 1993-06-01 |
JP2628230B2 (en) | 1997-07-09 |
IL104087A0 (en) | 1993-05-13 |
ZA929161B (en) | 1993-05-25 |
NO942457D0 (en) | 1994-06-29 |
AU663146B2 (en) | 1995-09-28 |
BR9206996A (en) | 1995-12-05 |
ES2150438T3 (en) | 2000-12-01 |
JPH06511255A (en) | 1994-12-15 |
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