LU85058A1 - SUSTAINED-RELEASE PHARMACEUTICAL TABLETS, THEIR PREPARATION AND THEIR USE - Google Patents
SUSTAINED-RELEASE PHARMACEUTICAL TABLETS, THEIR PREPARATION AND THEIR USE Download PDFInfo
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- LU85058A1 LU85058A1 LU85058A LU85058A LU85058A1 LU 85058 A1 LU85058 A1 LU 85058A1 LU 85058 A LU85058 A LU 85058A LU 85058 A LU85058 A LU 85058A LU 85058 A1 LU85058 A1 LU 85058A1
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- tablet according
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- active principle
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- 238000013268 sustained release Methods 0.000 title claims description 5
- 239000012730 sustained-release form Substances 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 4
- 239000000126 substance Substances 0.000 claims description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- 239000011159 matrix material Substances 0.000 claims description 12
- 229920002678 cellulose Polymers 0.000 claims description 10
- 239000001913 cellulose Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 8
- 239000008101 lactose Substances 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 7
- 229920000058 polyacrylate Polymers 0.000 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- 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 claims description 4
- 229920003134 Eudragit® polymer Polymers 0.000 claims description 4
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 239000012634 fragment Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 3
- RPZANUYHRMRTTE-UHFFFAOYSA-N 2,3,4-trimethoxy-6-(methoxymethyl)-5-[3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[3,4,5-tris(2-hydroxybutoxy)-6-[4,5,6-tris(2-hydroxybutoxy)-2-(2-hydroxybutoxymethyl)oxan-3-yl]oxyoxan-2-yl]methoxy]butan-2-ol Chemical compound COC1C(OC)C(OC)C(COC)OC1OC1C(OC)C(OC)C(OC)OC1COC.CCC(O)COC1C(OCC(O)CC)C(OCC(O)CC)C(COCC(O)CC)OC1OC1C(OCC(O)CC)C(OCC(O)CC)C(OCC(O)CC)OC1COCC(O)CC RPZANUYHRMRTTE-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 2
- 239000005662 Paraffin oil Substances 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 230000003556 anti-epileptic effect Effects 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
- 239000001961 anticonvulsive agent Substances 0.000 claims description 2
- 239000000935 antidepressant agent Substances 0.000 claims description 2
- 229940005513 antidepressants Drugs 0.000 claims description 2
- 229960003965 antiepileptics Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229940049706 benzodiazepine Drugs 0.000 claims description 2
- 150000001557 benzodiazepines Chemical class 0.000 claims description 2
- 239000002876 beta blocker Substances 0.000 claims description 2
- 229940097320 beta blocking agent Drugs 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 235000001465 calcium Nutrition 0.000 claims description 2
- 239000000480 calcium channel blocker Substances 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 0.000 claims description 2
- OCHFNTLZOZPXFE-JEDNCBNOSA-N carbonic acid;(2s)-2,6-diaminohexanoic acid Chemical compound OC(O)=O.NCCCC[C@H](N)C(O)=O OCHFNTLZOZPXFE-JEDNCBNOSA-N 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 239000002934 diuretic Substances 0.000 claims description 2
- 229940030606 diuretics Drugs 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 238000013265 extended release Methods 0.000 claims description 2
- 238000005194 fractionation Methods 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- -1 pain relievers Substances 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229920002545 silicone oil Polymers 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 229930003799 tocopherol Natural products 0.000 claims description 2
- 239000011732 tocopherol Substances 0.000 claims description 2
- 235000019149 tocopherols Nutrition 0.000 claims description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 claims description 2
- 241000928106 Alain Species 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229940088597 hormone Drugs 0.000 claims 1
- 239000005556 hormone Substances 0.000 claims 1
- 229940124641 pain reliever Drugs 0.000 claims 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 6
- 229960000278 theophylline Drugs 0.000 description 6
- 229920003148 Eudragit® E polymer Polymers 0.000 description 4
- 229920003091 Methocel™ Polymers 0.000 description 4
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 3
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 2
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- FSXVSUSRJXIJHB-UHFFFAOYSA-M ethyl prop-2-enoate;methyl 2-methylprop-2-enoate;trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CCOC(=O)C=C.COC(=O)C(C)=C.CC(=C)C(=O)OCC[N+](C)(C)C FSXVSUSRJXIJHB-UHFFFAOYSA-M 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- IQSHMXAZFHORGY-UHFFFAOYSA-N methyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound COC(=O)C=C.CC(=C)C(O)=O IQSHMXAZFHORGY-UHFFFAOYSA-N 0.000 description 2
- 229960001722 verapamil Drugs 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229920003139 Eudragit® L 100 Polymers 0.000 description 1
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 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 1
- 238000005470 impregnation Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- DNKKLDKIFMDAPT-UHFFFAOYSA-N n,n-dimethylmethanamine;2-methylprop-2-enoic acid Chemical compound CN(C)C.CC(=C)C(O)=O.CC(=C)C(O)=O DNKKLDKIFMDAPT-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Description
* 2* 2
La présente invention est relative à - des comprimés pharmaceutiques à administrer par voie buccaleet dont le ou les principes actifs se libèrent de façon lente et régulière, à leur préparation et 5 à leur utilisation.The present invention relates to - pharmaceutical tablets to be administered by the oral route and the active ingredient (s) of which are released slowly and regularly, to their preparation and to their use.
L'intérêt qui se manifeste actuelle- > ment en thérapeutique vis-àr-vis de ces formes galéniques dites "à libération prolongée" provient des avantages qu'elles présentent par rapport aux formes 10 conventionnelles, lesquelles libèrent leur principe actif de façon plus rapide ou plus brutale.The interest which is currently manifested in therapeutics with respect to these so-called "sustained-release" dosage forms comes from the advantages which they have over conventional forms, which release their active principle more rapidly. or more brutal.
Parmi ces avantages, on citera, notamment : - leur aptitude à produire dans 1'organisme des 15 concentrations en principe actif plus uniforn^ dans le temps en éliminant les effets "en dents de scie" caractérisés par des pics où la concentration en médicament excède le niveau thérapeutique et engendre des effets secondaires et des vallées où cette même 20 concentration s'abaisse en dessous de la zone efficace.These advantages include, in particular: - their ability to produce 15 active principle concentrations in the body over a longer period of time by eliminating the "jagged" effects characterized by peaks where the drug concentration exceeds the therapeutic level and generates side effects and valleys where this same concentration drops below the effective zone.
- la possibilité qu'elles offrent d'assurer une imprégnation médicamenteuse suffisante de l’organisme pendant les périodes où les prises de médicament sont irrégulières voire absentes, par exemple pendant 25 les périodes nocturnes et pour des médicaments à .- the possibility that they offer to ensure a sufficient drug impregnation of the organism during the periods when the medication is irregular or even absent, for example during the night periods and for medications.
/1 ht 3 courte durée d'action./ 1 ht 3 short duration of action.
- la diminution des variations interindividuelles des taux sanguins en médicament, obtenue par la prolongation et la régularisation de la résorption.- the decrease in interindividual variations in blood levels of medication, obtained by prolonging and regulating absorption.
5 - la réduction du nombre de prises journalières, ce qui simplifie la posologie et entraîne une meilleure observance du patient vis-à-vis de cette posologie.5 - the reduction in the number of daily intakes, which simplifies the dosage and results in better patient compliance with this dosage.
- la possibilité d'utiliser des doses élevées de médicament tout en minimisant le risque d'atteindre • 10 les concentrations toxiques, particulièrement dans le cæ de médicamentsdont 1'indice thérapeutique est peu élevé.- the possibility of using high doses of drug while minimizing the risk of reaching toxic concentrations, particularly in the case of drugs whose therapeutic index is low.
La réalisation de comprimés pharmaceutiques à libération prolongée fait actuellement appel 15 à plusieurs techniques galéniques telles que : - matrices hydrophiles : le principe actif est libéré lentement d'un support insoluble et gélifiable au contact des fluides digestifs. Cette matrice peut être érodable ou non.The production of prolonged-release pharmaceutical tablets currently makes use of several galenical techniques such as: hydrophilic matrices: the active principle is slowly released from an insoluble and gellable support in contact with digestive fluids. This matrix can be erodible or not.
20 - matrices inertes : le principe actif diffuse au- travers des canalicules d'un support inerte poreux.20 - inert matrices: the active principle diffuses through the canaliculi of an inert porous support.
- matrices lipidiques : la matrice imprégnée du principe actif s'érode plus ou moins rapidement en fonction des conditions physiologiques du tractus 25 digestif.- lipid matrices: the matrix impregnated with the active principle erodes more or less rapidly depending on the physiological conditions of the digestive tract.
- comprimés enrobés î le comprimé est revêtu d'une ou plusieurs couches de substances insolubles et poreuses au travers desquelles diffuse le principe actif.- coated tablets: the tablet is coated with one or more layers of insoluble and porous substances through which the active principle diffuses.
30 Ces techniques sont donc pratiquement basées sur le même mécanisme : le solvant pénètre i 4 dans le comprimé et y dissout une quantité de principe actif; il se crée un gradient de concentration qui tend à expulser du comprimé la solution du principe actif. La sortie de cette solution hors du com-5 primé, et donc la mise du principe actif à la dispo sition de l'organisme est réglée soit par la viscosité du milieu, soit par les dimensions des canali-cules formés dans la matrice.These techniques are therefore practically based on the same mechanism: the solvent penetrates i 4 into the tablet and dissolves an amount of active principle there; a concentration gradient is created which tends to expel the solution of the active ingredient from the tablet. The exit of this solution out of the award-winning com-5, and therefore the placing of the active principle at the disposal of the organism is regulated either by the viscosity of the medium, or by the dimensions of the canaliculi formed in the matrix.
Lorsqu'il s'agit de matrices érodables, 10 qu'elles soient lipidiques ou non, la libération du principe actif est réglée par la vitesse d'érosion et par les volumes à éroder.In the case of erodible matrices, whether lipid or not, the release of the active principle is regulated by the rate of erosion and by the volumes to be eroded.
Dans tous les cas, la surface apparente du comprimé ou la continuité de l'enrobage influencent 15 . directement la libération du principe actif.In all cases, the apparent surface of the tablet or the continuity of the coating influence 15. directly release the active ingredient.
En dépit de leurs avantages, les formes galéniques susmentionnées présentent par conséquent l'inconvénient de modifier de façon importante la cinétique de libération du principe actif lorsque 20 l'on fait varier leur surface ou porte atteinte à leur enrobage.Despite their advantages, the above-mentioned dosage forms therefore have the drawback of significantly modifying the kinetics of release of the active principle when the surface is varied or the coating is affected.
Ce phénomène est particulièrement préoccupant lorsque, pour des raisons d'adaptation de la posologie, il s'avère nécessaire de fragmenter les » 25 comprimés.This phenomenon is particularly worrying when, for reasons of adjustment of the dosage, it is necessary to fragment the »25 tablets.
Cette pratique est néanmoins indispensable dans de nombreux cas; chez l'adulte lorsqu·' une posologie doit être instaurée graduellement ou adaptée avec précision et, de façon plus impérieuse 30 encore chez l'enfant, lorsque la posologie est tribu taire du poids corporel et de la grande et continue ijl I variabilité de celui-ci.This practice is nevertheless essential in many cases; in adults when a dosage must be gradually or precisely adjusted and, even more imperatively 30 in children, when the dosage is dependent on body weight and the large and continuous ijl I variability of that -this.
La présente invention a pour but de remédier à cet inconvénient majeur en prévoyant un comprimé à libération prolongée dont la cinétique ne 5 varie pas selon qu'il est entier ou fragmenté, par exemple en deux ou même en quatre parties suivant les nécessités.The object of the present invention is to remedy this major drawback by providing an extended-release tablet whose kinetics do not vary according to whether it is whole or fragmented, for example in two or even in four parts as required.
, A cette effet, suivant l'invention, la matrice constituant le corps du comprimé comprend un 10 mélange d'au moins une substance inerte avec au moins une substance hydrophile pharmacologiquement acceptables· .To this end, according to the invention, the matrix constituting the body of the tablet comprises a mixture of at least one inert substance with at least one hydrophilic pharmacologically acceptable substance.
Avantageusement, la substance inerte est constituée par un polymère acrylique ou par un mélange 15 ' de tels polymères et la substance hydrophile est constituée par un dérivé cellulosique ou par un mélange de tels dérivés.Advantageously, the inert substance consists of an acrylic polymer or of a 15 'mixture of such polymers and the hydrophilic substance consists of a cellulose derivative or a mixture of such derivatives.
Suivant une forme de réalisation particulièrement avantageuse de l'invention, le polymère 20 acrylique est du type Eudragit et le dérivé cellulosique est choisi dans le groupe comprenant l'êthyl-cellulose, 1'hydroxyéthylcellulose, l'hydroxypropyl-cellulose, l'hydroxypropylméthylcellulose, l'hydroxy-butylméthylcellulose, la carboxyméthylcellulose et 25 ses dérivés et les mélanges de deux ou plusieurs de ces dérivés.According to a particularly advantageous embodiment of the invention, the acrylic polymer is of the Eudragit type and the cellulose derivative is chosen from the group comprising ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutylmethylcellulose, carboxymethylcellulose and its derivatives and mixtures of two or more of these derivatives.
L'invention se rapporte également à la préparation de ces comprimés pharmaceutiques du type à libération prolongée ainsi qu'à leur méthode d'utili-30 sation, qui consiste à administrer par la voie buccale ledit comprimé contenant une quantité thérapeutique- 6 ment efficace de principe actif, en entier ou sous forme d' un ou plusieurs de ses fragments.The invention also relates to the preparation of these pharmaceutical tablets of the sustained release type as well as to their method of use, which consists in administering by the oral route said tablet containing a therapeutically effective amount of active ingredient, in whole or in the form of one or more of its fragments.
Ainsi qu'on l'a déjà mentionné précédemment, la matrice du comprimé pharmaceutique de la 5 présente invention est constituée, à la fois, d'au moins une substance du type polymère acrylique et d ' un d érivé cellulosique. Ce nouveau type de matrice est caractérisé en ce qu'il confère, à la fois,les propriétés des matrices inertes (poly-10 mères acryliques) et les propriétés des matrices hydrophiles (dérivés cellulosiques).As already mentioned previously, the matrix of the pharmaceutical tablet of the present invention consists of both at least one substance of the acrylic polymer type and of a cellulose derivative. This new type of matrix is characterized in that it confers, at the same time, the properties of inert matrices (acrylic poly-10 mothers) and the properties of hydrophilic matrices (cellulose derivatives).
Bien que, suivant ces mêmes propriétés, la cinétique de libération du médicament paraisse devoir être influencée par toute augmentation de la 15' surface en contact avec le milieu de dissolution, la nouvelle matrice ainsi obtenue a permis d'obtenir, \ de façon inattendue, une cinétique ne se modifiant pas de façon significative lors de la fragmentation du comprimé .Although, according to these same properties, the kinetics of drug release appear to be influenced by any increase in the surface area 15 'in contact with the dissolution medium, the new matrix thus obtained made it possible to obtain, unexpectedly, kinetics do not change significantly during the fragmentation of the tablet.
20 Pour faciliter la fragmentation, le comprimé peut comporter sur une de ses faces au moins une rainure servant de guide à son fractionnement.To facilitate fragmentation, the tablet may have on one of its faces at least one groove serving as a guide for its fractionation.
Le comprimé suivant 1'invention est constitué d’une quantité de principe actif comprise 25 de préférence entre 1% et 88% du poids du comprimé , d'une quantité de matrice comprise de préférence entre 11,5% et 98,5% et de la quantité nécessaire d'excipient pharmaceutiquemant acceptable.The tablet according to the invention consists of an amount of active ingredient preferably between 1% and 88% of the weight of the tablet, an amount of matrix preferably between 11.5% and 98.5% and the necessary amount of a pharmaceutically acceptable excipient.
Comme principe actif utilisable, on 30 peut citer toutes les substances solides, ou rendues telles, administrables par la voie orale 4 / * ! if ' 7 dont les caractéristiques pharmacologiques ét/ou pharmacocinétiques sont telles qu'il y a avantage à les présenter sous une forma à libération prolongée, et telles, par exemple, que les dérivés xanthiques, les 5 antiinflammatoires, les ß-bloquants, les inhibiteurs calciques, les antiépileptiques, les benzodiazépines, les diurétiques, les analgésiques, certaines substances hormonales, les antidépresseurs, cette énumération étant non limitative.As active ingredient which can be used, mention may be made of all solid substances, or made such, which can be administered orally 4 / *! if '7 whose pharmacological and / or pharmacokinetic characteristics are such that it is advantageous to present them in a sustained-release forma, and such, for example, as xanthic derivatives, anti-inflammatories, β-blockers, calcium channel blockers, antiepileptics, benzodiazepines, diuretics, analgesics, certain hormonal substances, antidepressants, this list being nonlimiting.
10 Comme substances aptes à former la ma trice, on peut citer : - d'une part, les polymères acryliques tels que, par exemple, les Eudragit, qu'ils soient utilisés soit sous forme sèche, soit en dispersion ou émulsion ou solu- 15 tion dans un véhicule aqueux ou organique.As substances capable of forming the matrix, mention may be made of: on the one hand, acrylic polymers such as, for example, Eudragits, whether they are used either in dry form, or in dispersion or emulsion or solu- 15 tion in an aqueous or organic vehicle.
- d'autre part, les dérivés de la cellulose tels que, par exemple, les hydroxyêthycellulosejs (Natrosols), les carboxymêthylcelluloses sodiques, les hydroxypropyl-celluloses(Klucels), les hydroxyprppylméthylcelluloses 20 (Méfchocels E, F, J et K, Pharmacoat, Metolose), les hydroxybutylméthylcelluloses (Méthocels HB), les éthylcelluloses (Ethocel, Aquacoat).on the other hand, cellulose derivatives such as, for example, hydroxyethylcellulose (Natrosols), sodium carboxymethylcelluloses, hydroxypropylcelluloses (Klucels), hydroxyprppylmethylcelluloses (Mefchocels E, F, J and K, Pharmacoat, Metolose), hydroxybutylmethylcelluloses (Methocels HB), ethylcelluloses (Ethocel, Aquacoat).
Le rapport entre ]e ou les polymères acryliques d'une part et les dérivés cellulosiques d'autre 25 part, est de l'ordre de 0,05/1 à 20/1, de préférence de 2/1 à 10/1.The ratio between the acrylic polymers on the one hand and the cellulose derivatives on the other hand is of the order of 0.05 / 1 to 20/1, preferably from 2/1 to 10/1.
Comme excipients pharmaceutiquement acceptables, on peut citer : - des diluants, solubles ou insolubles, comme par 30 exemple, le saccharose, le sorbitol, le lactose, le phosphate calcique, diverses formes de cellulose.As pharmaceutically acceptable excipients, mention may be made of: - diluents, soluble or insoluble, such as, for example, sucrose, sorbitol, lactose, calcium phosphate, various forms of cellulose.
i 9 8 - des modificateurs de pH : l'acide citrique, l'acide tartrique, le bicarbonate de soude, le carbonate de lysine.i 9 8 - pH modifiers: citric acid, tartaric acid, baking soda, lysine carbonate.
- des antioxydants : l’acide ascorbique et ses dérivés, 5 les tocophérols.- antioxidants: ascorbic acid and its derivatives, 5 tocopherols.
- des agents conservateurs : méthyl et propylparabens, l'acide sorbique et ses sels.- preservatives: methyl and propylparabens, sorbic acid and its salts.
. - des antistatiques : l'oxyde d'aluminium colloïdal.. - antistatic agents: colloidal aluminum oxide.
- des lubrifiants : stéarate de magnésium, calcium, 10 laurylsulfate de sodium, huile de silicone, huile de paraffine.- lubricants: magnesium stearate, calcium, sodium lauryl sulfate, silicone oil, paraffin oil.
On donne ci-après des exemples non limitatifs de préparation de comprimés suivant l'invention : Exemple 1 î 15' Théophylline : 200 mgNon-limiting examples of preparation of tablets according to the invention are given below: Example 1: 15 'Theophylline: 200 mg
Lactose fin : 46 mgFine lactose: 46 mg
Eudragit E 30 D : 46 mg Méthocel K lOO s 17 mgEudragit E 30 D: 46 mg Methocel K lOO s 17 mg
Stéarate de magnésium : 1,5 mg 20 On mélange et tamise la théophylline, le lactose, le Méthocel, et on granule en ajoutant 1'Eudragit E 30 D. On sèche le granulé, on le calibre sur tamis n° 1, on ajoute le stéarate de magnésium, mélange et comprime au poids voulu. La dureté du 25 comprimé terminé est supérieure à 10 Kp.Magnesium stearate: 1.5 mg 20 Theophylline, lactose, Methocel are mixed and sieved, and granulated by adding Eudragit E 30 D. The granulate is dried, it is calibrated on a No. 1 sieve, it is added magnesium stearate, mixes and compresses to the desired weight. The hardness of the finished tablet is greater than 10 Kp.
Exemple 2 : Vérapamil HCl : 160 mgExample 2: Verapamil HCl: 160 mg
Lactose fin : loo mgFine lactose: loo mg
Eudragit RL : 6 mg 30 Eudragit L 100 : 10 mgEudragit RL: 6 mg 30 Eudragit L 100: 10 mg
Klucel HF : 5 mg 9Klucel HF: 5 mg 9
Stéarate de magnésium : 1,5 mgMagnesium stearate: 1.5 mg
On mélange et tamise le vérapamil, les Eudragit, le Klucel, et on granule au moyen du mélange acétone-eau (96 - 4 volumes). On sèche le granulé, le 5 calibre sur tamis n° 1, ajoute le lactose et le stéara te, mélange et comprime au poids voulu. La dureté du comprimé terminé est supérieure à 10 Kp.The verapamil, the Eudragits and the Klucel are mixed and sieved and granulated using the acetone-water mixture (96 - 4 volumes). The granulate is dried, the size 5 on a No. 1 sieve, the lactose and the stearate are added, mixed and compressed to the desired weight. The hardness of the finished tablet is more than 10 Kp.
. Exemple 3 :. Example 3:
Théophylline 1 Ho : 7,3 kgTheophylline 1 Ho: 7.3 kg
ZZ
Lactose fin : 1,5 kgFine lactose: 1.5 kg
Eudragit E 30 D i 1,4 kgEudragit E 30 D i 1.4 kg
Eudragit RS : 0,4 kg Mé'thocel E5 ï 0,3 kgEudragit RS: 0.4 kg Me'thocel E5 ï 0.3 kg
Stéarate cè magnésium : 0,05 kg 15 ' a12°3 c°lloî(3al ! 0,001 kgCé magnesium stearate: 0.05 kg 15 'a12 ° 3 c ° lloî (3al! 0.001 kg
On mélange et tamise théophylline, lactose et Eudragit RS. On granule avec 1'Eudragit E 30 D, on sèche et calibre sur tamis n° 1. On ajoute le Méthocel E5, le stéarate de magnésium, 20 l'oxyde d'aluminium colloïdal et on mélange. On détermine le pourcentage de théophylline (exprimé en anhydre) dans le granulé et comprime au poids , voulu pour avoir 200 mg_de théophylline anhydre par comprimé. La dureté des comprimés doit être supé-25 rieure à 10 Kp.Theophylline, lactose and Eudragit RS are mixed and sieved. Granulate with Eudragit E 30 D, dry and size on a No. 1 sieve. Add Methocel E5, magnesium stearate, colloidal aluminum oxide and mix. The percentage of theophylline (expressed as anhydrous) in the granule is determined and compressed to the weight desired to have 200 mg of anhydrous theophylline per tablet. The hardness of the tablets must be greater than 10 Kp.
Les comprimés préparés suivant l'exemple 3 serviront à réaliser une étude pharmacocinétique approfondie chez des volontaires sains, ainsi que des études cliniques chez des patients asthmatiques.The tablets prepared according to Example 3 will be used to carry out an in-depth pharmacokinetic study in healthy volunteers, as well as clinical studies in asthmatic patients.
30 /1 i30/1 i
Claims (15)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU85058A LU85058A1 (en) | 1983-10-24 | 1983-10-24 | SUSTAINED-RELEASE PHARMACEUTICAL TABLETS, THEIR PREPARATION AND THEIR USE |
| EP84201468A EP0142877A3 (en) | 1983-10-24 | 1984-10-12 | Pharmaceutical tablets with prolonged action, their preparation and their use |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU85058 | 1983-10-24 | ||
| LU85058A LU85058A1 (en) | 1983-10-24 | 1983-10-24 | SUSTAINED-RELEASE PHARMACEUTICAL TABLETS, THEIR PREPARATION AND THEIR USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| LU85058A1 true LU85058A1 (en) | 1985-06-19 |
Family
ID=19730159
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LU85058A LU85058A1 (en) | 1983-10-24 | 1983-10-24 | SUSTAINED-RELEASE PHARMACEUTICAL TABLETS, THEIR PREPARATION AND THEIR USE |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP0142877A3 (en) |
| LU (1) | LU85058A1 (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0205336B1 (en) * | 1985-06-11 | 1991-09-11 | Teijin Limited | Oral sustained release pharmaceutical preparation |
| LU86077A1 (en) * | 1985-09-18 | 1987-04-02 | Pharlyse Sa | NEW GALENIC FORMS OF VERAPAMIL, THEIR MANUFACTURE AND THE MEDICINAL PRODUCTS CONTAINING THESE NEW GALENIC FORMS |
| LU86099A1 (en) * | 1985-09-30 | 1987-04-02 | Pharlyse | EXTENDED RELEASE GALENIC FORMS OF VERAPAMIL, THEIR MANUFACTURE AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| US4968508A (en) * | 1987-02-27 | 1990-11-06 | Eli Lilly And Company | Sustained release matrix |
| IL85538A (en) * | 1987-02-27 | 1991-09-16 | Lilly Co Eli | Sustained release matrix tablet formulations containing hydrophilic and enteric polymers |
| GB8707416D0 (en) * | 1987-03-27 | 1987-04-29 | Wellcome Found | Pharmaceutical formulations |
| IT1222414B (en) * | 1987-07-31 | 1990-09-05 | Chiesi Farma Spa | PHARMACEUTICAL COMPOSITIONS CONTAINING TRAPIDIL, THEIR PREPARATION PROCEDURE AND RELATED THERAPEUTIC USE |
| JPH0273011A (en) * | 1988-07-28 | 1990-03-13 | Warner Lambert Co | Aqueous polymer dispersion of cellulose and acrylic polymer for preparing drug administration form |
| DE4021678C2 (en) * | 1990-07-07 | 1994-07-07 | Merz & Co Gmbh & Co | Process for the preparation of small-sized shaped articles with a high etofibrate content and controlled release of active ingredient, their use and existing orally administrable administration forms |
| IT1250654B (en) * | 1991-07-08 | 1995-04-21 | Farcon Ag | METHOD FOR THE PREPARATION OF ORAL PHARMACEUTICAL FORMS WITH EXTENDED RELEASE CONTAINING ACTIVE SUBSTANCES SOLUBILITY DEPENDENT ON THE PH VALUE. |
| DE4138513A1 (en) * | 1991-11-23 | 1993-05-27 | Basf Ag | SOLID PHARMACEUTICAL RETARD FORM |
| DE4220782A1 (en) * | 1992-06-25 | 1994-01-05 | Basf Ag | Process for the preparation of solid pharmaceutical sustained release forms |
| TR199802305T2 (en) | 1996-05-13 | 2002-06-21 | Norvartis Consumer Health S.A. | Cheek application method. |
| US6210710B1 (en) * | 1997-04-28 | 2001-04-03 | Hercules Incorporated | Sustained release polymer blend for pharmaceutical applications |
| ES2427724T3 (en) | 2006-02-03 | 2013-10-31 | Evonik Röhm Gmbh | Pharmaceutical compositions, containing mixtures of polymers and active substances hardly soluble in water |
| WO2010056564A1 (en) | 2008-11-13 | 2010-05-20 | Merck Sharp & Dohme Corp. | Quinolone neuropeptide s receptor antagonists |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1467781A1 (en) * | 1963-07-15 | 1968-12-05 | Boehringer Sohn Ingelheim | Process for the production of coated tablets with extended release of active ingredients |
| PT66201B (en) * | 1976-02-23 | 1978-11-07 | Corvi Mora E | METHOD AND COMPOSITION FOR THE THERAPEUTICS OF BRAIN CIRCULATORY DISEASES |
-
1983
- 1983-10-24 LU LU85058A patent/LU85058A1/en unknown
-
1984
- 1984-10-12 EP EP84201468A patent/EP0142877A3/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP0142877A3 (en) | 1986-10-08 |
| EP0142877A2 (en) | 1985-05-29 |
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