DE19901040A1 - Controlled release dosage forms containing active ingredients which are readily soluble in water - Google Patents
Controlled release dosage forms containing active ingredients which are readily soluble in waterInfo
- Publication number
- DE19901040A1 DE19901040A1 DE19901040A DE19901040A DE19901040A1 DE 19901040 A1 DE19901040 A1 DE 19901040A1 DE 19901040 A DE19901040 A DE 19901040A DE 19901040 A DE19901040 A DE 19901040A DE 19901040 A1 DE19901040 A1 DE 19901040A1
- Authority
- DE
- Germany
- Prior art keywords
- active ingredients
- dosage forms
- water
- active ingredient
- methacrylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000004480 active ingredient Substances 0.000 title claims description 17
- 239000002552 dosage form Substances 0.000 title claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims description 8
- 238000013270 controlled release Methods 0.000 title description 5
- 238000001125 extrusion Methods 0.000 claims abstract description 9
- 239000011159 matrix material Substances 0.000 claims abstract description 9
- 229920000058 polyacrylate Polymers 0.000 claims abstract description 7
- 229920001577 copolymer Polymers 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 8
- 229920000642 polymer Polymers 0.000 claims description 7
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 229960001300 metoprolol tartrate Drugs 0.000 claims description 4
- WUBVEMGCQRSBBT-UHFFFAOYSA-N tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)C(F)(F)F)=CC1 WUBVEMGCQRSBBT-UHFFFAOYSA-N 0.000 claims description 4
- 238000003490 calendering Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 2
- 238000007493 shaping process Methods 0.000 claims 2
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 6
- 239000013543 active substance Substances 0.000 abstract 1
- RGHAZVBIOOEVQX-UHFFFAOYSA-N Metoprolol succinate Chemical compound OC(=O)CCC(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 RGHAZVBIOOEVQX-UHFFFAOYSA-N 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 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
- 238000002156 mixing Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 2
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 238000000576 coating method Methods 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
- 238000009472 formulation Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229960002237 metoprolol Drugs 0.000 description 2
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 2
- 229960000939 metoprolol succinate Drugs 0.000 description 2
- 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 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000005096 rolling process Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000006104 solid solution Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 1
- 229920003148 Eudragit® E polymer Polymers 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003153 Eudragit® NE polymer Polymers 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 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 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZAFFWOKULJCCSA-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate;trimethylazanium;chloride Chemical compound [Cl-].C[NH+](C)C.CCOC(=O)C(C)=C ZAFFWOKULJCCSA-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- XPNLOZNCOBKRNJ-UHFFFAOYSA-N ethyl prop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C=C.COC(=O)C(C)=C XPNLOZNCOBKRNJ-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229920003087 methylethyl cellulose Polymers 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- WBHHMMIMDMUBKC-XLNAKTSKSA-N ricinelaidic acid Chemical class CCCCCC[C@@H](O)C\C=C\CCCCCCCC(O)=O WBHHMMIMDMUBKC-XLNAKTSKSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
Description
Die vorliegende Erfindung betrifft Arzneiformen mit gesteuerter Freisetzung, enthaltend Wirkstoffe mit einer Wasserlöslichkeit gemäß USP von bis zu 30 in einer Matrix auf Basis von Acrylat- Polymeren, welche durch Schmelzextrusion erhalten werden.The present invention relates to drug forms with controlled Release containing active ingredients with water solubility according to USP of up to 30 in a matrix based on acrylate Polymers obtained by melt extrusion.
Es ist allgemein bekannt, daß die gesteuerte Freisetzung, ins besondere eine retardierte lineare Freisetzung, bei gut wasser löslichen Wirkstoffen problematisch ist. Insbesondere Metoprolol- Tartrat ist auf konventionelle Weise schwer zu retardieren.It is well known that controlled release, ins in particular a delayed linear release, with good water soluble active ingredients is problematic. In particular metoprolol Tartrate is difficult to retard in the conventional way.
Aus der EP-A 240 904 ist bekannt, daß man Arzneiformen nach dem Schmelzextrusionsverfahren herstellen kann.From EP-A 240 904 it is known that one can use dosage forms the melt extrusion process can produce.
Aufgabe der vorliegenden Erfindung war es, Arzneiformen zu finden, die eine gesteuerte Freisetzung von gut wasserlöslichen Wirkstoffen ermöglichen.The object of the present invention was to provide dosage forms find a controlled release of well water-soluble Enable active ingredients.
Demgemäß wurden die eingangs definierten Arzneiformen gefunden.We have found that this object is achieved by the dosage forms defined at the outset.
Gut wasserlösliche Wirkstoffe sind erfindungsgemäß solche, die eine Wasserlöslichkeit gemäß USP 23 von 1 bis 10 (leicht löslich) oder 10 bis 30 (löslich), bevorzugt kleiner 1 (sehr leicht löslich), aufweisen. Die Zahlenangaben beziehen sich darauf, wieviel Teile Lösungsmittel pro Teil zu lösender Substanz benötigt werden.According to the invention, active ingredients which are readily soluble in water are those which a water solubility according to USP 23 from 1 to 10 (easily soluble) or 10 to 30 (soluble), preferably less than 1 (very easily soluble). The figures relate to how many parts of solvent per part of substance to be dissolved are needed.
Bevorzugte Wirkstoffe sind Metoprolol und seine Salze, besonders bevorzugt Metoprolol-Tartrat.Preferred active ingredients are metoprolol and its salts, especially preferably metoprolol tartrate.
Die Wirkstoffe werden bei der Schmelzextrusion in einer Matrix auf Basis von Acrylat-Polymeren homogen dispergiert oder im Sinne einer festen Lösung gelöst. Bevorzugt liegt der Wirkstoff in der Matrix in röntgenamorpher Form vor. Besonders bevorzugt werden feste Lösungen des Wirkstoffs erhalten.During melt extrusion, the active ingredients are in a matrix based on acrylate polymers homogeneously dispersed or in the sense dissolved in a solid solution. The active ingredient is preferably in the Matrix in X-ray amorphous form. Are particularly preferred receive solid solutions of the active ingredient.
Als Acrylat-Polymere eignen sich insbesondere quellbare Polymere vom Eudragit®-Typ. Geeignete Polymere sind beispielsweise Meth acrylsäure-Copolymere (Eudragit L-Typen) wie Methacrylsäure-Ethyl acrylat-1 : 1-Copolymere M 250.000, Methacrylsäure-Methylmeth acrylat-1 : 1-Copolymere M 135.000, Methacrylsäure-Methylmeth acrylat-1 : 2-Copolymere M 135.000 oder Dimethylaminoethylmethacry lat-Copolymere (Eudragit E) wie Poly(butylmethacrylat(2-dimethyla minoethyl)methacrylat)-1 : 2 : 1 Mt 150.000. Bevorzugt sind die pH-un abhängig quellenden Methacrylsäureester-Copolymere (Eudragit NE) wie Ethylacrylat-Methymethacrylat-2 : 1-Copolymer M 800.000, beson ders bevorzugt Methylmethacrylat-Ethylacrylat-2 : 1-Copolymer mit 5 oder 10% Trimethylammoniumethyl-methacrylatchlorid (Eudragit RS und RL-Typen) M 150.000.Swellable polymers of the Eudragit® type are particularly suitable as acrylate polymers. Suitable polymers are, for example, methacrylic acid copolymers (Eudragit L types) such as methacrylic acid / ethyl acrylate 1: 1 copolymers M 250,000, methacrylic acid / methyl methacrylate 1: 1 copolymers M 135,000, methacrylic acid / methyl methacrylate 1: 2 Copolymers M 135,000 or dimethylaminoethyl methacrylate copolymers (Eudragit E) such as poly (butyl methacrylate (2-dimethyla minoethyl) methacrylate) -1: 2: 1 M t 150,000. Preference is given to the pH-independent swelling methacrylic acid ester copolymers (Eudragit NE) such as ethyl acrylate-methymethacrylate 2: 1 copolymer M 800,000, particularly preferably methyl methacrylate-ethyl acrylate 2: 1 copolymer with 5 or 10% trimethylammoniumethyl methacrylate chloride (Eudragit RS and RL types) M 150,000.
Es können auch Mischungen der genannten Polymere verwendet werden.Mixtures of the polymers mentioned can also be used will.
Die Mengen an Wirkstoff und Acrylat-Polymeren werden so gewählt, daß die Arzneiformen 1 bis 50 Gew.-%, bevorzugt 10 bis 30 Gew.-% Wirkstoff enthalten. Insbesondere eignen sich Formulierungen, die 1 bis 80, bevorzugt 10 bis 40 Gew.-% Eudragit RL und 1 bis 50, bevorzugt 5 bis 20 Gew.-% Eudragit RS enthalten.The amounts of active ingredient and acrylate polymers are chosen so that the dosage forms 1 to 50 wt .-%, preferably 10 to 30 wt .-% Contain active ingredient. Particularly suitable are formulations that 1 to 80, preferably 10 to 40% by weight Eudragit RL and 1 to 50, preferably contain 5 to 20% by weight of Eudragit RS.
Zusätzlich können weitere Polymere in der Matrix enthalten sein, beispielsweise Homo- oder Copolymere des N-Vinylpyrrolidons wie Povidon oder Copovidon-6 : 4 oder bevorzugt Celluloseether wie Hydroxypropylmethylcellulose, Ethylcellulose oder Hydroxypropyl cellulose.In addition, further polymers can be contained in the matrix, for example homo- or copolymers of N-vinylpyrrolidone such as Povidone or copovidone 6: 4 or preferably cellulose ethers such as Hydroxypropyl methyl cellulose, ethyl cellulose or hydroxypropyl cellulose.
Weiterhin können weitere übliche pharmazeutische Hilfsstoffe zur zusätzlichen Retardierung zugesetzt werden. Hierzu zählen ins besondere hydrophobisierende Hilfsstoffe wie Lipide oder deren Salze, zum Beispiel Stearinsäure, Palmitinsäure, hydrierte Ricinolsäure oder ähnliche, bevorzugt Magnesiumstearat.Furthermore, other common pharmaceutical excipients can be used additional retardation can be added. These include ins special hydrophobizing auxiliaries such as lipids or their Salts, for example stearic acid, palmitic acid, hydrogenated Ricinoleic acid or the like, preferably magnesium stearate.
Zusätzlich können die Zubereitungen noch weitere übliche Pharma hilfsstoffe in den hierfür üblichen Mengen enthalten, beispiels weise Stabilisatoren, Antioxidantien, Farbstoffe, Aromastoffe, Füllstoffe oder Stabilisatoren wie beispielsweise hochdisperses Siliciumdioxid oder Gleitmittel.In addition, the preparations can also contain other common pharmaceuticals Contain auxiliaries in the usual amounts, for example wise stabilizers, antioxidants, colorings, flavorings, Fillers or stabilizers such as, for example, highly dispersed Silicon dioxide or lubricant.
Die Herstellung der erfindungsgemässen Zubereitungen erfolgt durch Vermischen der Komponenten unter Einsatz von Scherkräften und Zufuhr thermischer Energie. Bevorzugt erfolgt das Mischen in einem Ein- oder Mehrschneckenextruder, besonders bevorzugt einem Zweischneckenextruder. Durch Zufuhr thermischer Energie wird eine Schmelze der Mischungskomponenten erzeugt. Dies geschieht üblicherweise durch Aufheizen des Extrudermantels auf Temperaturen im Bereich von 50 bis 180, vorzugsweise 80 bis 130°C. Das Vermischen des Wirkstoffs mit den anderen Komponenten kann vor oder nach dem Schmelzen des polymeren Bindemittels erfolgen. The preparations according to the invention are produced by mixing the components using shear forces and supply of thermal energy. Mixing is preferably carried out in a single or multi-screw extruder, particularly preferred a twin screw extruder. By supplying thermal energy a melt of the mixture components is produced. this usually takes place by heating up the extruder jacket Temperatures in the range from 50 to 180, preferably 80 to 130 ° C. Mixing the active ingredient with the other components can take place before or after melting the polymeric binder.
Die Schmelzen sind lösungsmittelfrei. Damit ist gemeint, dass kein Wasser oder organische Lösungsmittel zugesetzt wird.The melts are solvent-free. This means that no water or organic solvents are added.
Die geschmolzene Mischung der Komponenten wird durch die Schneckenbewegung in Richtung auf den Extruderauslass, der vorzugsweise aus einer Düse besteht, gefördert. Nach Extrusion durch die Düse wird die noch plastische Masse zu geeigneten Arzneiformen verformt.The melted mixture of the components is through the Screw movement towards the extruder outlet, the preferably consists of a nozzle, promoted. After extrusion the still plastic mass becomes suitable through the nozzle Deformed drug forms.
Geeignete Arzneiformen sind bevorzugt Tabletten, insbesondere Bolustabletten, linsenförmige Tabletten oder Oblongtabletten.Suitable dosage forms are preferably tablets, in particular Bolus tablets, lenticular tablets or oblong tablets.
Die Herstellung von Tabletten erfolgt vorzugsweise gemäß dem in der EP-A 240 906 beschriebenen Verfahren durch Hindurchführen des noch plastischen Stranges zwischen zwei gegenläufig angetriebene Walzen mit einander gegenüberliegenden Vertiefungen im Walzen mantel. Durch entsprechende Wahl der Form dieser Vertiefungen können auch Tabletten mit Bruchkerben erhalten werden. Granulate oder Pellets können durch Kaltabschlag oder, bevorzugt, durch Heißabschlag gewonnen werden.The production of tablets is preferably carried out according to the in of EP-A 240 906 described by carrying out the still plastic strand between two driven in opposite directions Rolling with opposing depressions in the rolling a coat. By choosing the shape of these indentations accordingly tablets with score lines can also be obtained. Granules or pellets can be cold cut or, preferably, through Hot cut can be won.
Die Arzneiformen können zusätzlich noch mit an sich bekannten Überzügen, die keinen Einfluß auf das Freisetzungsverhalten haben, versehen werden.The dosage forms can also be known per se Coatings that have no effect on the release behavior have to be provided.
Überraschenderweise lassen sich durch die erfindungsgemäße Kombi nation des Schmelzextrusionsverfahrens mit einer entsprechenden Formulierung auf Basis von Acrylat-Polymeren auch für gut wasser lösliche Wirkstoffe Arzneiformen mit gesteuerter Freisetzung her stellen. Insbesondere war nicht zu erwarten daß sich auf einfache Weise mit Hilfe der Schmelzextrusion und einer entsprechenden Rezeptur retardierte Metoprolol-Tartrat-Zubereitungen erhalten lassen, die hinsichtlich ihrer Freisetzung bioäquivalent zu dem Metoprolol-Succinat enthaltenden Marktprodukt Beloc-ZOK® sind.Surprisingly, the combination according to the invention nation of the melt extrusion process with a corresponding Formulation based on acrylate polymers also for good water soluble active ingredients. Controlled release drug forms place. In particular, it was not expected to be simple Way with the help of melt extrusion and a corresponding Prescription retarded metoprolol tartrate preparations obtained let bioequivalent to the release in terms of their release The market product Beloc-ZOK® containing metoprolol succinate is.
Die Herstellung der Tabletten erfolgte durch Extrusion der in der nachstehenden Tabelle aufgeführten Mischungen in einem gleichsinnig drehenden Zweischneckenextruder des Typs ZKS-40 der Firma Werner & Pfleiderer und anschließender Kalandrierung zu Oblong-Tabletten mit einem Tablettengewicht von 500 mg gemäß dem in der EP-A 240 906 beschriebenen Verfahren. The tablets were produced by extrusion Mixtures listed in the table below in one Co-rotating twin-screw extruder type ZKS-40 from Werner & Pfleiderer and subsequent calendering to oblong tablets with a tablet weight of 500 mg according to the process described in EP-A 240 906.
Temperaturprofil des Extruders:
Einzug: 20 bis 25°C, Schuß 1: 80°C, Schuß 2: 110°C,
Schuß 3: 110°C, Schuß 4: 130°C, Düse: 130°C. Die Drehzahl lag
bei 110 Upm; der Durchsatz bei 15 kg/h. Die Tabletten wurden
anschließend gecoatet mit einer Menge von 15 mg per Tablette.
Zusammensetzung des Coatings:Temperature profile of the extruder:
Feed: 20 to 25 ° C, section 1: 80 ° C, section 2: 110 ° C, section 3: 110 ° C, section 4: 130 ° C, nozzle: 130 ° C. The speed was 110 rpm; the throughput at 15 kg / h. The tablets were then coated with an amount of 15 mg per tablet. Composition of the coating:
Die in-vitro-Freisetzung wurde gemäß USP 23 in einer Paddle-
Apparatur bei 100 Upm in künstlichem Darmsaft bei pH 6,8,
No-Change, 24 h, ermittelt.
The in vitro release was determined according to USP 23 in a paddle apparatus at 100 rpm in artificial intestinal juice at pH 6.8, no-change, 24 h.
In Fig. 1 ist die in-vitro-Freisetzung einer Tablette gemäß Beispiel 11 (n = 6) in Vergleich zu dem Marktprodukt Beloc-ZOK Retard (95 mg Metoprolol-Succinat) dargestellt.In Fig. 1, in comparison to the commercial product Toprol-ZOK sustained in vitro release of a tablet according to Example 11 (n = 6) (95 mg metoprolol succinate) is shown.
Eine Tablette gemäß Beispiel 11 wurde als Einmaldosis acht gesunden männlichen Freiwilligen im Fastenzustand verabreicht. Unter den gleichen Bedingungen wurde Beloc-ZOK (mit der gleichen Menge an freier Metoprolol-Base) als Referenzsubstanz ver abreicht. In Fig. 2 ist das geometrische Mittel der Plasma konzentration dargestellt. Die Quadrate bezeichnen die er findungsgemäße Extrudatform, die Rauten die Referenzsubstanz.A tablet according to Example 11 was administered as a single dose to eight healthy male volunteers in the fasted state. Beloc-ZOK (with the same amount of free metoprolol base) was administered as a reference substance under the same conditions. In Fig. 2, the geometric mean of the plasma concentration is shown. The squares denote the extrudate shape according to the invention, the diamonds denote the reference substance.
Claims (8)
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19901040A DE19901040A1 (en) | 1999-01-14 | 1999-01-14 | Controlled release dosage forms containing active ingredients which are readily soluble in water |
| JP2000593105A JP2002534443A (en) | 1999-01-14 | 2000-01-07 | Dosage form with controlled release containing a sufficiently water-soluble active substance |
| PCT/EP2000/000053 WO2000041481A2 (en) | 1999-01-14 | 2000-01-07 | Medicament forms having controlled release and containing active substances which easily dissolve in water |
| EP00904879A EP1140030A2 (en) | 1999-01-14 | 2000-01-07 | Medicament forms having controlled release and containing active substances which easily dissolve in water |
| CA002359381A CA2359381A1 (en) | 1999-01-14 | 2000-01-07 | Medicament forms having controlled release and containing active substances which easily dissolve in water |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19901040A DE19901040A1 (en) | 1999-01-14 | 1999-01-14 | Controlled release dosage forms containing active ingredients which are readily soluble in water |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19901040A1 true DE19901040A1 (en) | 2000-07-20 |
Family
ID=7894143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19901040A Withdrawn DE19901040A1 (en) | 1999-01-14 | 1999-01-14 | Controlled release dosage forms containing active ingredients which are readily soluble in water |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1140030A2 (en) |
| JP (1) | JP2002534443A (en) |
| CA (1) | CA2359381A1 (en) |
| DE (1) | DE19901040A1 (en) |
| WO (1) | WO2000041481A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8507527B2 (en) | 2004-12-27 | 2013-08-13 | Eisai R & D Management Co., Ltd. | Method for stabilizing anti-dementia drug |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2818552B1 (en) * | 2000-12-26 | 2003-02-07 | Servier Lab | SOLID THERMOFORMABLE PHARMACEUTICAL COMPOSITIONS FOR THE CONTROLLED RELEASE OF IVABRADINE |
| JP2009523833A (en) * | 2006-01-21 | 2009-06-25 | アボット ゲーエムベーハー ウント カンパニー カーゲー | Formulations and methods for drug delivery |
| WO2008011596A2 (en) * | 2006-07-21 | 2008-01-24 | Lab International Srl | Hydrophilic abuse deterrent delivery system |
| US9226907B2 (en) | 2008-02-01 | 2016-01-05 | Abbvie Inc. | Extended release hydrocodone acetaminophen and related methods and uses thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3830353A1 (en) * | 1988-09-07 | 1990-03-15 | Basf Ag | METHOD FOR THE CONTINUOUS PRODUCTION OF SOLID PHARMACEUTICAL FORMS |
| KR100355130B1 (en) * | 1992-09-18 | 2003-01-30 | 야마노우치세이야쿠 가부시키가이샤 | Hydrogel Sustained Release Tablet |
| DE19509807A1 (en) * | 1995-03-21 | 1996-09-26 | Basf Ag | Process for the preparation of active substance preparations in the form of a solid solution of the active substance in a polymer matrix, and active substance preparations produced using this method |
-
1999
- 1999-01-14 DE DE19901040A patent/DE19901040A1/en not_active Withdrawn
-
2000
- 2000-01-07 JP JP2000593105A patent/JP2002534443A/en active Pending
- 2000-01-07 CA CA002359381A patent/CA2359381A1/en not_active Abandoned
- 2000-01-07 EP EP00904879A patent/EP1140030A2/en not_active Withdrawn
- 2000-01-07 WO PCT/EP2000/000053 patent/WO2000041481A2/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8507527B2 (en) | 2004-12-27 | 2013-08-13 | Eisai R & D Management Co., Ltd. | Method for stabilizing anti-dementia drug |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000041481A3 (en) | 2000-09-28 |
| EP1140030A2 (en) | 2001-10-10 |
| CA2359381A1 (en) | 2000-07-20 |
| JP2002534443A (en) | 2002-10-15 |
| WO2000041481A2 (en) | 2000-07-20 |
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