WO1997034585A1 - Gelules transparentes dures - Google Patents
Gelules transparentes dures Download PDFInfo
- Publication number
- WO1997034585A1 WO1997034585A1 PCT/EP1997/001352 EP9701352W WO9734585A1 WO 1997034585 A1 WO1997034585 A1 WO 1997034585A1 EP 9701352 W EP9701352 W EP 9701352W WO 9734585 A1 WO9734585 A1 WO 9734585A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oil
- capsule
- particles
- dosage form
- oral dosage
- Prior art date
Links
- 239000007902 hard capsule Substances 0.000 title description 2
- 239000002245 particle Substances 0.000 claims abstract description 85
- 239000002775 capsule Substances 0.000 claims abstract description 84
- 239000007788 liquid Substances 0.000 claims abstract description 61
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 24
- 230000009286 beneficial effect Effects 0.000 claims abstract description 21
- 239000007903 gelatin capsule Substances 0.000 claims abstract description 20
- 239000006186 oral dosage form Substances 0.000 claims abstract description 19
- 229940079593 drug Drugs 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 23
- 239000011324 bead Substances 0.000 claims description 17
- 239000003921 oil Substances 0.000 claims description 15
- 235000019198 oils Nutrition 0.000 claims description 15
- 239000003981 vehicle Substances 0.000 claims description 15
- 108010010803 Gelatin Proteins 0.000 claims description 11
- 239000008273 gelatin Substances 0.000 claims description 11
- 229920000159 gelatin Polymers 0.000 claims description 11
- 235000019322 gelatine Nutrition 0.000 claims description 11
- 235000011852 gelatine desserts Nutrition 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 7
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 claims description 7
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 claims description 7
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 5
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 5
- 239000008158 vegetable oil Substances 0.000 claims description 5
- 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 4
- 235000019486 Sunflower oil Nutrition 0.000 claims description 4
- 239000003240 coconut oil Substances 0.000 claims description 4
- 235000019864 coconut oil Nutrition 0.000 claims description 4
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 4
- 229960001680 ibuprofen Drugs 0.000 claims description 4
- 239000002600 sunflower oil Substances 0.000 claims description 4
- 229920000642 polymer Polymers 0.000 claims description 3
- BANIDACEBXZGNK-UHFFFAOYSA-N 2-(diethylamino)ethyl 1-phenylcyclopentane-1-carboxylate;ethane-1,2-disulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O.C=1C=CC=CC=1C1(C(=O)OCCN(CC)CC)CCCC1.C=1C=CC=CC=1C1(C(=O)OCCN(CC)CC)CCCC1 BANIDACEBXZGNK-UHFFFAOYSA-N 0.000 claims description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 2
- 244000068988 Glycine max Species 0.000 claims description 2
- 235000010469 Glycine max Nutrition 0.000 claims 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 claims description 2
- 235000019482 Palm oil Nutrition 0.000 claims description 2
- 235000019483 Peanut oil Nutrition 0.000 claims description 2
- DYWNLSQWJMTVGJ-KUSKTZOESA-N Phenylpropanolamine hydrochloride Chemical compound Cl.C[C@H](N)[C@H](O)C1=CC=CC=C1 DYWNLSQWJMTVGJ-KUSKTZOESA-N 0.000 claims description 2
- 240000000528 Ricinus communis Species 0.000 claims description 2
- 235000004443 Ricinus communis Nutrition 0.000 claims description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 2
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 claims description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 2
- 235000021302 avocado oil Nutrition 0.000 claims description 2
- 239000008163 avocado oil Substances 0.000 claims description 2
- 235000021324 borage oil Nutrition 0.000 claims description 2
- 239000000828 canola oil Substances 0.000 claims description 2
- 235000019519 canola oil Nutrition 0.000 claims description 2
- 229960001071 caramiphen edisylate Drugs 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 235000008524 evening primrose extract Nutrition 0.000 claims description 2
- 239000010475 evening primrose oil Substances 0.000 claims description 2
- 229940089020 evening primrose oil Drugs 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- -1 glycerol ester Chemical class 0.000 claims description 2
- 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 claims description 2
- 229960000991 ketoprofen Drugs 0.000 claims description 2
- 239000002480 mineral oil Substances 0.000 claims description 2
- 229960002009 naproxen Drugs 0.000 claims description 2
- 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 claims description 2
- 239000002736 nonionic surfactant Substances 0.000 claims description 2
- 239000003346 palm kernel oil Substances 0.000 claims description 2
- 235000019865 palm kernel oil Nutrition 0.000 claims description 2
- 239000002540 palm oil Substances 0.000 claims description 2
- 229960005489 paracetamol Drugs 0.000 claims description 2
- 239000000312 peanut oil Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229960002305 phenylpropanolamine hydrochloride Drugs 0.000 claims description 2
- 239000004417 polycarbonate Substances 0.000 claims description 2
- 229920000515 polycarbonate Polymers 0.000 claims description 2
- 229920005862 polyol Polymers 0.000 claims description 2
- 150000003077 polyols Chemical class 0.000 claims description 2
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims description 2
- 229950006451 sorbitan laurate Drugs 0.000 claims description 2
- 235000011067 sorbitan monolaureate Nutrition 0.000 claims description 2
- 239000012798 spherical particle Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 claims description 2
- 239000001069 triethyl citrate Substances 0.000 claims description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000013769 triethyl citrate Nutrition 0.000 claims description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 2
- 244000042295 Vigna mungo Species 0.000 claims 1
- 235000010716 Vigna mungo Nutrition 0.000 claims 1
- 235000011453 Vigna umbellata Nutrition 0.000 claims 1
- 235000010446 mineral oil Nutrition 0.000 claims 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims 1
- 229920000053 polysorbate 80 Polymers 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 claims 1
- 239000002552 dosage form Substances 0.000 abstract description 10
- 239000000463 material Substances 0.000 description 16
- 238000000576 coating method Methods 0.000 description 15
- 239000011257 shell material Substances 0.000 description 15
- 239000011248 coating agent Substances 0.000 description 14
- 235000019484 Rapeseed oil Nutrition 0.000 description 6
- 239000007887 hard shell capsule Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000013268 sustained release Methods 0.000 description 5
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- 230000008901 benefit Effects 0.000 description 4
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- 231100000252 nontoxic Toxicity 0.000 description 4
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- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000002939 deleterious effect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 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 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 239000006096 absorbing agent Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 1
- QZCLKYGREBVARF-UHFFFAOYSA-N Acetyl tributyl citrate Chemical compound CCCCOC(=O)CC(C(=O)OCCCC)(OC(C)=O)CC(=O)OCCCC QZCLKYGREBVARF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
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- 206010037660 Pyrexia Diseases 0.000 description 1
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- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
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- YVPYQUNUQOZFHG-UHFFFAOYSA-N amidotrizoic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YVPYQUNUQOZFHG-UHFFFAOYSA-N 0.000 description 1
- 235000005550 amino acid supplement Nutrition 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
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- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003782 dextromethorphan hydrobromide Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
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- 229940066493 expectorants Drugs 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 230000027950 fever generation Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000021474 generally recognized As safe (food) Nutrition 0.000 description 1
- 235000021473 generally recognized as safe (food ingredients) Nutrition 0.000 description 1
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
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- 239000010410 layer Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000020786 mineral supplement Nutrition 0.000 description 1
- 239000000133 nasal decongestant Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
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- 238000003672 processing method Methods 0.000 description 1
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- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
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- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
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Classifications
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
Definitions
- This invention relates to an oral dosage form comprising a partially or wholly transparent swallow capsule which contains particles suspended or dispersed in a liquid vehicle, characterised in that the capsule is of the hard-shelled type, typically a hard-shell gelatin capsule.
- the capsule fill is a combination of a pharmaceutically acceptable liquid and pharmaceutically acceptable particles.
- the particles are of a size and are present in the dosage form in a quantity such that whilst the liquid fills the internal capsule space, the particles do not, so mat when the capsule is moved the particles will shift position in the liquid. Such a presentation makes tampering more evident.
- WO 95/00125 discloses a soft-shelled gelatin capsule containing particles in a liquid vehicle.
- This invention provides a novel capsule preparation wherein a partially or wholly transparent hard-shelled capsule contains a mixture which comprises particles containing at least one beneficial agent and a non-toxic, transparent or translucent liquid carrier which may also contain a beneficial agent, wherein the particles fill less than the internal volume of the capsule.
- a beneficial agent such as a vegetable oil may be used as the liquid carrier and particles comprising or containing a beneficial agent are present at a concentration such that when the particles settle, there remains a portion of the oil which does not contain particles.
- Capsule preparations according to the present invention offer an advantage over soft gel capsules with respect to easier processing conferring reduced manufacturing costs and a smaller product which is easier to swallow. Processing methods available for filling hard-shell capsules also avoid potential damage to the particles containing the beneficial agenf which may impair performance.
- this invention relates to a method for providing a tamper- evident dosage form which method comprises filling a partially or wholly transparent hard-shelled capsule with a mixture comprising particles which contain at least one beneficial agent and a translucent or transparent non-toxic liquid carrier which may also contain a beneficial agent and wherein the particles fill less than the internal volume of the capsule.
- this invention relates to an oral dosage lorm comp ⁇ sing a partially or wholly transparent hard-shelled capsule, preferably a hard-shelled gelatin capsule, containing a translucent or transparent liquid in which particles are suspended which are insoluble in the liquid and wherein the particles are not so numerous as to fill completely the capsule.
- a translucent or transparent liquid in which particles are suspended which are insoluble in the liquid and wherein the particles are not so numerous as to fill completely the capsule.
- the partially or wholly transparent capsule and the translucent or transparent liquid allow the moving particles to be seen. Visible, moveable particles make it easier to detect capsules which have imperfections such as capsules where extraneous material has been introduced into the capsule or where the fill has leaked out for some reason.
- Such a system is particularly useful for ale ⁇ ing the end user to the fact there may be some imperfection in the capsule, such as might occur when capsules are tampered with.
- this dosage form Three parts make up this dosage form, the hard-shelled capsule, a compatible non ⁇ toxic liquid for suspending the particles, and particles containing a beneficial agent, sized so that numerous particles are contained in the finished dosage form without interfering with their movement in the suspending liquid and which do not adhere to the capsule wall or coagulate in die suspending liquid.
- all of the capsule wall will be transparent or translucent. In another embodiment, a portion of the capsule wall will have a different refractive index or will transmit more light than another portion of the capsule.
- one portion of the capsule may be opaque whilst another portion may be transparent or translucent.
- a preferred formulation comprises a hard gelatin shell containing a light oil of moderate viscosity and particles which do not dissolve in the oil, form aggregates or adhere to the gelatin capsule wall. Particles will be present in numbers such that a portion of the oil will be particle-free when the capsule is at rest. The particles will be visible to the naked eye through the capsule wall in normal lighting conditions irrespective of capsule orientation. The viscosity of the suspending agent will be such that the particles can move readily widiin the capsule when it is tipped or rolled out of its resting plane.
- any suitable material known to me an may be used to form me shell.
- Hard-shell capsules made from natural and synthetic materials are known in the art.
- gelatin examples include gelatin, starch and cellulose etiiers such as methyl cellulose.
- gelatin is the preferred material.
- Hard-shelled gelatin capsules are well documented in me literature and are well known to manufacturers and technicians alike. They may comprise, in addition to gelatin, materials such as cross-linking or polymerising agents, plasticisers, stabilisers, antioxidants, light absorbing agents for protecting light-sensitive fills, preservatives and me like. Any non-toxic liquid that is pharmaceutically acceptable and compatible wim me chosen capsule material and me particles suspended in it may be used. It should be flowable at or about ambient temperature to a degree which does not interfere with particle movement.
- the density of the liquid is less than that of the particles suspended in it so diat the particles will sink or flow widiin the liquid when the capsule is tilted in normal use.
- Combinations of two or more liquids may be used and preferably mey will be miscible liquids.
- the liquid must be sufficiently translucent for observing the suspended particles. Additives such as preservatives, colouring agents, stabilisers, UV absorbing agents, processing aids and the like may be inco ⁇ orated into the liquid provided they too are compatible wim the particles and the chosen capsule material.
- the liquid may also contain a beneficial agent in which case the agent should be soluble in the liquid and should not cause the liquid to become opaque.
- Suitable liquids include oils and polyols such as glycols, poiyalkylene glycols, glycerol esters, fatty acids, polycarbonates and syrups.
- Waxes which are liquid at room temperature, e.g. Labrafac Lipophile, Labrafil M1944CS, Labrasol, Transcutol, Peceol, and Plurol manufactured by Gatefosse, Elmsford, New York, USA; non-ionic surfactants e.g.
- polyoxyemylene (20) sorbitan monooleate or sorbitan laurate; triethyl citrate, acetyl triemyl citrate, tri-n-butyl citrate, or acetyl tri-n-butyl citrate manufactured by Morflex, Greensboro, NC, USA; glycerly triacetate; polyoxyethylene-polyoxypropylene polymer; diethylene glycol monoemyl ether or any other liquids which do not solubilise either the capsule shell material or the particles can also be used. Vegetable oils or mineral oils which are GRAS materials an enjoy a long history of use in the pharmaceutical formulation arts are also preferred.
- a list of useful vegetable oils will include castor bean oil, coconut oil, peanut oil, palm kernel oil, canola oil, avocado oil, evening primrose oil, rice bran oil, borage oil, sunflower oil, soyabean oil, palm oil, corn oil, and sunflower oil. All will perform well in the context of the preferred hard-shelled gelatin capsule. This list is not intended to be exhaustive; any liquid can be used so long as it is safe for human or animal consumption and has me requisite physical properties noted above.
- any form of particle may be used in the dosage form of the invention, so long as it contains or comprises a beneficial agent, is stable in the suspending liquid, is visible to me naked eye, and moves within me capsule when it is tilted.
- beneficial agent means any compound or material which has a beneficial effect on a mammal when consumed for its intended use in me manner prescribed.
- a drug is a beneficial agent for me purposes of this definition.
- omer compounds or materials which can have a subjective or objective beneficial effect on the user and which are to be included widiin the meaning of this term.
- Nutritional agents such as vitamins, minerals, or amino acid supplements are beneficial to those needing to supplement their diet.
- Flavours and sweeteners provide a subjective benefit and a source of energy as well, and are also included.
- Drugs and drug delivery are of greatest interest herein.
- the word "drug” is used in its broadest sense and includes any agent which exhibits a pharmacological effect on me user and which can be administered orally in the form of particles as described herein. Any solid or liquid form of a drug can be used provided it can be manufactured into a particulate form, as is true for any compound or material which constitutes a beneficial agent for the purposes of this invention.
- Bom fat soluble and water soluble drugs may be used.
- Drugs for treating pain and inflammation and cough cold, and allergy symptoms are of particular interest. They include drugs for treating inflammation, pain and pyrexia; antihistamines, nasal decongestants; expectorants; sedatives as used in cough and cold remedies, and the like.
- Paracetamol, aspirin or another non-steroidal anti-inflammatory drug such as ibuprofen, naproxen or ketoprofen, phenylpropanolamine hydrochloride, caramiphen edisylate, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, and chlorpheniramine maleate are most preferred.
- particles size, density, stability, lack of adhesion to the capsule wall and lack of agglomeration are me only limiting factors. So far as size is concerned, me principal consideration will be that of creating a particle of a size such tiiat the particles are visible to the naked eye under normal lighting conditions, while making them small enough to flow in the suspending liquid and tumble over one another when the capsule is tilted.
- Preferred particles will be in the range of about 100 to 1500 microns.
- Particle size can vary in any given capsule, just so long as the variance is not so great that the larger particles obscure the smaller ones.
- the preferred particle size is between about 420 and 840 microns (about 20-40 mesh). Sizing can be achieved by any appropriate means. Large particles can be reduced by grinding and sieving through screens until the right size cut is achieved. Small particles can be built up to a desired size by conventional coating technologies. All these processes are well known in the formulation arts.
- Particles may for example be round, irregular, oblong, elliptical, or square. Particles can have different shapes so long as the particles can flow freely over one another when the capsule is tilted. Round or spherical particles in the form of beads are preferred.
- Particles can comprise pure agent or a mixture of pure agent and excipients and can be manufactured by methods well known in the art, including for example extrusion/marumerisation and prilling.
- the particle may be coated with a protective layer which may or may not affect how fast the particle dissolves and releases the active ingredient. Coating may be included for functional and/or aesthetic reasons and may be effected by methods well known in the art.
- Pan coating for example, is a well established technology that provides a basic pellet. Another approach is to create a core or seed and then to add one or more layers of a coating to the core.
- red, white and blue particles will be much more apparent than what will be observed if all the particles are white.
- Dyes or lakes of any sort may be used provided they are non-toxic and do not have an untoward or deleterious effect on the user.
- particles will be manufactured to be heavier than the carrier liquid.
- the liquid carrier may have higher density than the particles so that when the capsule is tilted, the liquid will shift and push the less dense particles to another location within the capsule.
- Particle stability as well as intrinsic stability of the beneficial agent are factors which must be taken into consideration when matching particle and liquid, and the composition of the capsule wall-forming material.
- the particle should remain chemically inert when in contact with the liquid and the capsule wall-forming materials and should not dissolve in the suspending liquid to any significant extent.
- the particle will be insoluble in the suspending liquid.
- Particle coatings known to be soluble in a given carrier liquid should accordingly be avoided when formulating coated beads.
- gelatin materials used to make hard-shell gelatin capsules contain substantial amounts of water which may have a deleterious affect on the particles .
- liquid vehicles containing substantial amounts of water could have a deleterious effect on gelatin capsules.
- Each formulation must be addressed on a case-by-case basis is within the skill of one trained in the formulation arts.
- Dosage forms according to the present invention provide means for delivering poorly bioavailable drugs together with absorption enhancers.
- Absorption enhancers may be dissolved in the liquid vehicle whilst the drug is contained in particulate form.
- a further variation can be to incorporate a drug substance in solution or as a very fine suspension in the liquid vehicle.
- a drug substance incorporated in this manner may function as a loading dose which will be rapidly absorbed into the blood stream to provide immediate therapeutic benefit.
- continuous release of drug substances over an extended time period may be achieved from beads suspended in the liquid vehicle.
- the liquid vehicle may be modified to solubilise the drug.
- the liquid vehicle may comprise two or more phases, namely a component in which a drug is soluble and a component which a drug is insoluble.
- drugs having different solubility profiles may be incorporated.
- Dosage forms of the invention may also be used to deliver drug substances which interact with one another by dissolving one drug in the liquid vehicle and confining a second drug to particulate form.
- different drugs can be contained in separate particles or beads.
- a hard-shell capsule according to the invention will be a capsule filled with a liquid which contains particles where the volume of the particles does not amount to more than about 90% of the internal volume of the capsule.
- the particles will be present in an amount which fills between about 40 to 80% of the capsules' internal volume.
- Hard-shell capsules of any form or shape can be used in this invention, limited only by the availability of manufacturing methods and the requirement that when in use the shape does not have a restriction point which interferes with particle or liquid movement to a degree that obviates the benefits of this invention.
- a suitable capsule is the commercially available hard-gel capsule which is formed from two co-operating parts.
- the junction is suitably provided wid a seal to preclude leakage of the carrier liquid.
- Suitable means for sealing hard-shell capsules are known in the art.
- Capsule-filling apparatus are available which can fill capsules with liquid vehicle and particles, either sequentially or simultaneously to provide a dosage form according to the invention.
- Ibuprofen beadlets were prepared as described in WO 93/00991. Beadlets are sugar coated and introduced into a standard hard-shell gelatin capsule (size 0) together with corn oil to provide 400mg ibuprofen per capsule. The two halves of the capsule shell are sealed by applying a gelatin band to the junction between the body and the cap of the capsule.
- Sugar starch beadlets (approximate diameter 0.5mm) are sprayed with an ethanolic solution of dextrometiiorphan hydrobromide in a suitable coating column, to give white spherical beads containing approximately 10% dextrometiiorphan hydrobromide. These beads are then sprayed with an aqueous suspension containing ethyl cellulose, hydroxypropylmethyl cellulose and triethyl acetate in the same coating column to give white spherical beads containing approximately 9% dextrometiiorphan hydrobromide and 10% polymeric coating.
- the beads are then filled into the bodies of transparent colourless hard gelatin capsule shells (size 1) together with an aliquot of edible rape seed oil which substantially fills the body of the capsule shell, the capsule shell caps are subsequently fitted to the capsule body and the two halves of the capsule are sealed with a band of transparent gelatin to give transparent colourless hard gelatin capsules containing rape seed oil and dextrometiiorphan hydrobromide sustained release beadlets, whereby each capsule contains approximately 40mg dextrometiiorphan hydrobromide.
- Sugar starch beadlets (approximate diameter 0.5mm) are sprayed with an aqueous solution of chlo ⁇ heniramine maleate in a suitable coating column, to give white spherical beads containing approximately 1 % chlo ⁇ heniramine maleate. These beads are then sprayed with an aqueous suspension containing ethyl cellulose, hydroxypropylmethyl cellulose and triethyl acetate in the same coating column to give white spherical beads containing approximately 0.9% chlo ⁇ heniramine maleate and 10% polymeric coating.
- the beads are then filled into the bodies of transparent orange hard gelatin capsule shells (size 1) togetiier with an aliquot of edible rape seed oil which substantially fills the body of the capsule shell, the capsule shell caps are subsequently fitted to the capsule body and the two halves of the capsule are sealed with a band of transparent gelatin, to give transparent orange coloured hard gelatin capsules containing rape seed oil and chlo ⁇ heniramine maleate sustained release beadlets, whereby each capsule contains approximately 4mg chlo ⁇ heniramine maleate.
- Sugar starch beadlets (approximate diameter 0.5mm) are sprayed with an ethanolic solution of pseudoephedrine hydrochloride in a suitable coating column, to give white spherical beads containing approximately 10% pseudoephedrine hydrochloride. These beads are then sprayed with an aqueous suspension containing ethyl cellulose, hydroxypropylmethyl cellulose and triethyl acetate in the same coating column to give white spherical beads containing approximately 9% pseudoephedrine hydrochloride and 10% polymeric coating.
- the beads are then filled into the bodies of transparent colourless hard gelatin capsule shells (size 0) togetiier with an aliquot of edible coconut oil which substantially fills the body of the capsule shell, the capsule shell caps are subsequently fitted to the capsule body and the two halves of the capsule are sealed with a band of transparent gelatin, to give transparent colourless hard gelatin capsules containing coconut oil and pseudoephedrine hydrochloride sustained release beadlets, whereby each capsule contains approximately 120mg pseudoephedrine hydrochloride.
- Polymer coated beadlets from Example 2 and Example 3 are mixed together in a ratio of approximately 1: 1 and then filled into the bodies of transparent orange hard gelatin capsule shells (size 00) together with an aliquot of edible rape seed oil which substantially fills the body of the capsule shell, the capsule shell caps are subsequently fitted to the capsule body and the two halves of the capsule are sealed with a band of transparent gelatin, to give transparent orange coloured hard gelatin capsules containing rape seed oil, chlo ⁇ heniramine maleate sustained release beadlets and dextrometho ⁇ han hydrobromide sustained release beadlets, whereby each capsule contains approximately 4mg chlo ⁇ heniramine maleate and 40mg dextrometho ⁇ han hydrobromide.
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Abstract
Formes galéniques orales comportant des gélules à enveloppe dure partiellement ou totalement transparentes renfermant des particules qui contiennent un agent bénéfique en suspension dans un véhicule liquide. Les formes galéniques préférées comportent des gélules à enveloppe dure de gélatine.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9605948.0 | 1996-03-21 | ||
GBGB9605948.0A GB9605948D0 (en) | 1996-03-21 | 1996-03-21 | Novel formulations |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997034585A1 true WO1997034585A1 (fr) | 1997-09-25 |
Family
ID=10790782
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/001352 WO1997034585A1 (fr) | 1996-03-21 | 1997-03-17 | Gelules transparentes dures |
Country Status (2)
Country | Link |
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GB (1) | GB9605948D0 (fr) |
WO (1) | WO1997034585A1 (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7229639B2 (en) * | 2002-03-11 | 2007-06-12 | Warner-Lambert Company | Ibuprofen containing hard shell capsules |
EP1228125A4 (fr) * | 1999-09-14 | 2009-09-02 | Smithkline Beecham Corp | Procede relatif a la formation de granules a revetement aqueux |
US8957095B2 (en) | 2009-10-26 | 2015-02-17 | Sephoris Pharmaceuticals, Llc | Treatment of sunburn using analgesics and antihistamines |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995000125A1 (fr) * | 1993-06-18 | 1995-01-05 | Smithkline Beecham Corporation | Particules encapsulees dans une enveloppe souple en gelatine |
WO1995001787A1 (fr) * | 1993-07-09 | 1995-01-19 | Smithkline Beecham Corporation | Particules encapsulees dans la gelatine formant une enveloppe souple |
WO1996041622A1 (fr) * | 1995-06-09 | 1996-12-27 | R.P. Scherer Corporation | Capsules gelatineuses molles contenant un materiau particulaire |
-
1996
- 1996-03-21 GB GBGB9605948.0A patent/GB9605948D0/en active Pending
-
1997
- 1997-03-17 WO PCT/EP1997/001352 patent/WO1997034585A1/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995000125A1 (fr) * | 1993-06-18 | 1995-01-05 | Smithkline Beecham Corporation | Particules encapsulees dans une enveloppe souple en gelatine |
WO1995001787A1 (fr) * | 1993-07-09 | 1995-01-19 | Smithkline Beecham Corporation | Particules encapsulees dans la gelatine formant une enveloppe souple |
WO1996041622A1 (fr) * | 1995-06-09 | 1996-12-27 | R.P. Scherer Corporation | Capsules gelatineuses molles contenant un materiau particulaire |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1228125A4 (fr) * | 1999-09-14 | 2009-09-02 | Smithkline Beecham Corp | Procede relatif a la formation de granules a revetement aqueux |
US7229639B2 (en) * | 2002-03-11 | 2007-06-12 | Warner-Lambert Company | Ibuprofen containing hard shell capsules |
US8957095B2 (en) | 2009-10-26 | 2015-02-17 | Sephoris Pharmaceuticals, Llc | Treatment of sunburn using analgesics and antihistamines |
US9895360B2 (en) | 2009-10-26 | 2018-02-20 | Sephoris Pharmaceuticals, Llc | Treatment of sunburn using analgesics and antihistamines |
US10751331B2 (en) | 2009-10-26 | 2020-08-25 | Sephoris Pharmaceuticals, Llc | Treatment of sunburn using analgesics and antihistamines |
Also Published As
Publication number | Publication date |
---|---|
GB9605948D0 (en) | 1996-05-22 |
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