AU777330B2 - Analgesic with controlled active substance release - Google Patents
Analgesic with controlled active substance release Download PDFInfo
- Publication number
- AU777330B2 AU777330B2 AU10107/00A AU1010700A AU777330B2 AU 777330 B2 AU777330 B2 AU 777330B2 AU 10107/00 A AU10107/00 A AU 10107/00A AU 1010700 A AU1010700 A AU 1010700A AU 777330 B2 AU777330 B2 AU 777330B2
- Authority
- AU
- Australia
- Prior art keywords
- preparation according
- release
- microtablets
- analgesic
- preparation
- 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.)
- Ceased
Links
- 230000000202 analgesic effect Effects 0.000 title claims description 32
- 239000013543 active substance Substances 0.000 title description 27
- 238000002360 preparation method Methods 0.000 claims description 41
- 238000013270 controlled release Methods 0.000 claims description 24
- 238000000576 coating method Methods 0.000 claims description 19
- 239000011159 matrix material Substances 0.000 claims description 16
- 239000011248 coating agent Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 239000002775 capsule Substances 0.000 claims description 12
- 229920002678 cellulose Polymers 0.000 claims description 11
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 claims description 9
- 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 9
- 235000010980 cellulose Nutrition 0.000 claims description 8
- 238000007906 compression Methods 0.000 claims description 8
- 230000006835 compression Effects 0.000 claims description 8
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 8
- 239000001856 Ethyl cellulose Substances 0.000 claims description 7
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 7
- 229920001249 ethyl cellulose Polymers 0.000 claims description 7
- 229960004380 tramadol Drugs 0.000 claims description 7
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 claims description 7
- 239000001913 cellulose Substances 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 5
- 239000004925 Acrylic resin Substances 0.000 claims description 4
- 229920000178 Acrylic resin Polymers 0.000 claims description 4
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims description 4
- 150000002191 fatty alcohols Chemical class 0.000 claims description 4
- 229960005181 morphine Drugs 0.000 claims description 4
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- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 claims description 2
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 claims description 2
- IJVCSMSMFSCRME-KBQPJGBKSA-N Dihydromorphine Chemical compound O([C@H]1[C@H](CC[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O IJVCSMSMFSCRME-KBQPJGBKSA-N 0.000 claims description 2
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 2
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims description 2
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 claims description 2
- 229960001736 buprenorphine Drugs 0.000 claims description 2
- 229960004126 codeine Drugs 0.000 claims description 2
- WDEFBBTXULIOBB-WBVHZDCISA-N dextilidine Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WDEFBBTXULIOBB-WBVHZDCISA-N 0.000 claims description 2
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 claims description 2
- 229960000920 dihydrocodeine Drugs 0.000 claims description 2
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 claims description 2
- 229960002428 fentanyl Drugs 0.000 claims description 2
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims description 2
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 2
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims description 2
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- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 claims description 2
- 229960004715 morphine sulfate Drugs 0.000 claims description 2
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 claims description 2
- 229960002085 oxycodone Drugs 0.000 claims description 2
- 229960000482 pethidine Drugs 0.000 claims description 2
- IHEHEFLXQFOQJO-UHFFFAOYSA-N piritramide Chemical compound C1CC(C(=O)N)(N2CCCCC2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 IHEHEFLXQFOQJO-UHFFFAOYSA-N 0.000 claims description 2
- 229960001286 piritramide Drugs 0.000 claims description 2
- 229920000193 polymethacrylate Polymers 0.000 claims description 2
- 229960001402 tilidine Drugs 0.000 claims description 2
- 229960003107 tramadol hydrochloride Drugs 0.000 claims description 2
- 229920003176 water-insoluble polymer Polymers 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims 2
- 239000000194 fatty acid Substances 0.000 claims 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
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- 238000009472 formulation Methods 0.000 description 4
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- 239000000014 opioid analgesic Substances 0.000 description 4
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- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 3
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
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- UNZIDPIPYUMVPA-UHFFFAOYSA-M Sulpyrine Chemical compound O.[Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 UNZIDPIPYUMVPA-UHFFFAOYSA-M 0.000 description 1
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- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
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- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- PXWLVJLKJGVOKE-UHFFFAOYSA-N propyphenazone Chemical compound O=C1C(C(C)C)=C(C)N(C)N1C1=CC=CC=C1 PXWLVJLKJGVOKE-UHFFFAOYSA-N 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
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- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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Description
S&F Ref: 487637
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT
ORIGINAL
.6 Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Grunenthal GmbH Zieglerstrasse 6 D-52078 Aachen Germany Dr Johannes Bartholomaus Dr Jurgen Betzing Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Analgesic with Controlled Active Substance Release The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c Patent Application, GrOnenthal GmbH, D-52078 Aachen Internal ref.: G 2710 Analgesic with controlled active substance release The present invention relates to a pharmaceutical formulation from which the analgesic active substance is released in a controlled manner.
Many formulations of analgesic painkillers which provide controlled release of the active substance are known from the prior art.
EP-A-0647448 inter alia has thus already described an S 15 analgesically active preparation with delayed active substance release which consists of a plurality of substrates containing opioid in controlled release form having a diameter of 0.1 to 3 mm as a single daily dose.
Substrates suitable for this purpose may assume the form of 20 spheroids, microbeads, pell.ets or granules. The production of this type of substrate entails relatively elaborate formulation methods, such as for example layer accretion agglomeration processes for pellets or the extrusion/ spheronisation process for spheroids.
There is furthermore a requirement in many therapeutic applications to provide individual doses of a pharmaceutical containing an analgesic, as is possible with orally administered, liquid dosage forms in the form of drops and to be able to make use of conventional, uncomplicated formulation methods, such as tabletting, during the production thereof.
The object of the present invention was accordingly to provide an orally administered preparation w.ith controlled release of at least one analgesic, which preparation permits individual, precise dosing, comparable to the administration of drops, for example from storaae containers or makes it possible to subdivide a certain quantity of active substance into a readily and accurately controllable number of substrates, and which may be produced using standard, straightforward formulation methods.
According to an embodiment of the invention, there is provided an orally s administered preparation with controlled release of at least one opioid as an analgesic from a microtablet with a diameter of 1 to 3 mm.
These microtablets preferably have diameters of 1.5 to 3mm.
The microtablets according to the invention preferably contain at least one opioid as the analgesic active substance. Hydromorphone, oxycodone, morphine, levorphanol, methadone, dihydrocodeine, codeine, fentanyl, dihydromorphine, pethidine, piritramide, buprenorphine, tilidine, tramadol, the particular salts thereof or mixtures thereof are preferably used as the opioid.
Tramadol, tramadol hydrochloride, morphine, morphine hydrochloride and/or morphine sulfate are very particularly preferably used as the analgesic.
Apart from the stated opioid analgesics, the preparation according to the invention may contain non-opioid analgesics which optionally exhibit a synergistic action with the opioid analgesics. These non-opioid analgesics include ibuprofen, ketoprofen, flurbiprofen, paracetamol, naproxen, propyphenazone, acematacin, acetylsalicylic acid, metamizol and/or the salts thereof.
20 The microtablets used according to the invention are distinguished by controlled release of the analgesic.
[R:\LIBZZ]487637spci doc gym Controlled release of the analgesic is taken to mean both non-delayed and delayed release. The opioid active substance is preferably released in a delayed manner.
Release may be achieved by immobilising the active substance in a controlled release matrix. Incorporation into a matrix material ensures that controlled, delayed release of the active substance is achieved over the desired period of time. It is preferably endeavoured to adjust the release of the active substance in such a manner that it is sufficient to take the preparation twice, preferably only once, per 24 hours.
Suitable matrix materials are pharmaceutically compatible hydrophilic materials which are known to the person skilled in the art. Polymers, such as for example cellulose ethers, S* cellulose esters or acrylic resins are preferably used as hydrophilic matrix materials. Ethylcellulose, hydroxypropy].methylcellu lose, hydroxypropylcellu lose, hydroxymethylcellulose, poly(metlh)acry ic acid and/or the derivatives thereof, such as the salts, amides or esters, are very particularly preferred as matrix materials.
The matrix material may, however, also consist of 25 hydrophobic materials, such as for example hydrophobic polymers, waxes, fats, oils, long-chain fatty acids, fatty alcohols or corresponding esters or mixtures thereof. Monoor diglycerides of and/or fatty alcohols and/or waxes are preferably used as hydrophobic materials.
It is also possible to use a mixture of the stated hydrophilic and hydrophobic materials as a controlled release matrix material.
The microtablets according to the invention may furthermore contain pharmaceutically conventional auxiliaries as additional constituents, such as extenders, for example lactose, microcrystalline cellulose or calcium hydrogen phosphate, as well as slip additives, lubricants and flow control agents, such as for example highly disperse silicon dioxide, talcum, magnesium stearate and/or stearic acid.
A particularly preferred pharmaceutically compatible matrix material comprises at least one cellulose ether and/or cellulose ester, a 2 wt.% aqueous solution of which has a viscosity at 20 0 C of 3000 to 150000 mPas, preferably of 10000 to 150000 mPas, optionally in combination with an extender which is not swellable in an aqueous medium, such as for example calcium hydrogen phosphate, or with an insoluble extender swellable in an aqueous medium, such as for example microcrystalliLne cellulose, or an extender soluble in aqueous media, such as for example lactose.
15 The content of analgesic, preferably of opioid analgesic, is adjusted as a function of the desired duration of release and quantity of analgesic to be released. The active substance content is preferably between 10 and particularly preferably between 25 and 70 wt.', 20 relative to the complete mixture. On the basis of the action of opioid and non-opioid analgesics, the person skilled in the art is aware of the mixing ratios in which these should be used in order to achieve the desired release of active substances.
In the case of the preparations according to the invention, which comprise microtablets, controlled release of the active substance may also be achieved by coating the individual tablets with at least one coating which permits controlled, generally delayed, release of the active substance in an aqueous medium. Suitable controlled release coatings comprise water-insoluble waxes or polymers, such as for example acrylic resins, preferably poly(meth)acrylates or water-insoluble celluloses, preferably ethylcellulose. These materials are known from the prior art, for example Bauer, Lehmann, Osterwald, Rothgang "Uberzogene Arzneiformen", Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998, pages 69 et seq., and are hereby included by way of reference.
In addition to the water-insoluble polymers, it is optionally possible to adjust the active substance release rate by preferably also using quantities of up to 30 wt.
of non-controlled release, preferably water-soluble polymers, such as for example polyvinylpyrrolidone or water-soluble celluloses, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose, and/or known plasticisers.
In addition to the controlled release coating, the microtablets according to the invention may additionally be provided with further coatings. It is thus possible to apply a coating containing the active substance, from which 15 coating the active substance is released in a noncontrolled manner after oral administration. Such multilayer microtablets may after administration very rapidly provide an initial dose of the analgesi.c for alleviating the pain, wherein the level of the analgesic may be maintained by the subsequent delayed release of the active substance.
Apart from the controlled release coating, the microtablets may furthermore also additionally have a coating which 25 dissolves in a pH-dependent manner. It is thus possible, for example, to ensure that a certain number of the microtablets of a preparation pass undissolved through the gastric tract and are not released until they reach the intestinal tract.
Another preferred embodiment of the preparations according to the invention consists in the microtablets', which are provided with a controlled release and optionally further coatings, already containing the active substance i.n a matrix which ensures controlled, delayed release of the active substance, or in the matrix controlled release microtablets' having no controlled release coating, but at least one of the stated coatings which ensure an initial dose and/or pH-dependent release.
The microtablets are produced using known methods, as are described, for example, in EP-A-0166315. The corresponding disclosure is hereby included by way of reference.
The microtablets are preferably produced by screening all the tablet constituents, preferably through a 0.6 mm screen, and then homogeneously mixing them. The mixture may be converted into granules, wherein the screening step is then preferably performed after granulation. Where granulation is performed, slip additives and/or lubricants are preferably incorporated before compression. The homogeneous mixture is compression moulded in a tablett.Ing press, preferably a rotary tabletting press, to form 15 tablets having a diameter of 1 to 3 nun, preferably of so. to 3 mm. This method is preferably also performed when producing microtablets with matrix controlled release, wherein melt granulation is a preferred production process for hydrophobic matrix materials fusible at 100 0 C. Methods suitable for this purpose are known to the person skilled in the art.
In the event that the preparations according to the invention contain microtablets with coatings, these may be 25 applied using conventional methods, such as for example by sugar coating, spraying witl solutions, dispersions or suspensions, by melt processing or by powder application processes.
The orally administered preparations according to the invention consisting of microtablets moreover have the major advantage that the desired dose of analgesic may be subdivided into a straightforwardly countable number of units. In this manner, it is possible to fornmil-ae t-he orally administered preparation in accordance with individual patient requirements by, for example, taking the desired number of microtablets from a supply of microtablets using a metering unit, preferably a dispenser, in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved.
The present invention accordingly also provides individually meterable, orally administered preparations, the number of microtablets of which is determined in accordance with the individually desired duration of release and quantity of analgesic for release.
The present invention also provides the orally administered preparations according to the invention in capsules which contain a defined number of the microtablets with controlled release of the analgesic in accordance with the individual duration of release and quantity of analgesic S15 for release which are to be achieved. The number of microtablets in a capsule is preferably selected such that the dose is sufficient for administration once or twice daily. It is advantageous in this dosage form too for the dose of the analgesic to be subdivided between a 20 straightforwardly countable number of microtablets, but the patient is relieved of the task of counting by the dose being determined in a capsule.
The orally administered preparations according to the 25 invention may furthermore assume the form of a so-called macrotablet, i.e. a tablet of conventional dimensions, into which a defined number of microtablets in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved are compression moulded with conventional tablet auxiliaries and additives to form a tablet. In this case, too, it is advantageous if the number of microtablets constituting the macrotablet is selected such that the duration of release and quantity of analgesic for release is suff-icipnt for administration once or twice daily.
The present invention accordingly also provides orally administered preparations with controlled release of at least one analgesic comprising microtablets, wherein a 8 certain number of microtablets in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved are compression moulded with conventional auxiliaries and additives to form a tablet.
Soo.
*g *oooo Examples The release profile of the preparations produced in the Examples was determined as follows: The preparations were placed in 600 ml of artificial gastric juices (pH 1.2) in a rotating basket apparatus (according to the European Pharmacopoeia) at a temperature of the release medium of 37°C and a rotational speed of the rotating basket of 100 min After 120 minutes, the pH value of the release medium was raised to pH 7.2 by addition of phosphate buffer solution. This pH- value was maintained until the end of the testing. The quantity of actLive substance released at a particular point in time is 15 determined spectrophotometrically.
Example 1: Composition: per tablet per capsule containing tablets *2 0 Components of Tramadol HC1 10.0 mg 100 mg the micro- Microcrystalline 4.0 mg 40 mg tablets cellulose Povidon® K30 0.8 mg 8 mg Magnesium stearate 0.2 mg 2 mg Total 15 mg 150 mg The tramadol salt and microcrystalline cellulose were granulated with an aqueous solution of Povidon® K30, dried, screened, mixed with magnesium stearate, compression moulded to form tablets having a diameter of 3 mm and a height of approx. 2 mm and packaged in capsules each containing 10 tablets.
The release profile was as follows: after 15 minutes 80% active substance release.
Example 2:
S
S
S
S
Composition: per tablet per capsule containing tablets Components of Tramadol HCI 10.0 mg 100 mcq the micro- Microcrystalline 4.0 mg 40 mg tablets cellulose Povidon@ K30 0.8 mg 8 mg Magnesium stearate 0.2 mg 2 mg Coating Ethylcellulose 0.8 mg 8 mg components (Aquacoat®) Dibutyl sebacate 0.2 mg 2 mg Total 16 mg 160 mg The tramadol salt and microcrystalline cellulose were granulated with an aqueous solution of Povidoti® K30 (polyvinylpyrrolidone), dried, screened, mixed with magnesium stearate, compression moulded to form tablets having a diameter of 3 mm and coated with an aqueous ethylcellulose/ dibutyl sebacate dispersion in a 4:1 quantity ratio in a fluidised bed apparatus by spraying on the dispersion with continuous drying. 10 microtablets were packaged in each capsule.
11 The average release profile was: Time after Active substance release in of original active substance concentration minutes 1% 240 minutes 18% 480 minutes 29% Example 3: Microtablets of a diameter of 2 mm and height of approx.
2 mmu of the following composition were produced and coated in a similar manner to Example 2. 20 microtablets were packaged in each capsule.
per tablet per capsule containing tablets Components of Tranadol IfC.1 5.0 ing 100 ing the micro- Microcrystalline 2.0 mrg 40 mg tablets cellulose Povidon® K30 0.4 Img 8 mg Magnesium stearate 0.1 mg 2 img Coating Ethylcellulose 0.4 Ing 8 Img components (Aquacoat®) Dibutyl sebacate 0.1 mg 2 mg Total mIg 160 mg Example 4: Matrix controlled release microtablets were produced by screening tramadol HC1 (5 ing/Lablet) and glyceryl behenate (Compritol 880 atoO) (5 ing/tablet) through a 0.6 nun mesh screen. The homogenised mixture was then compression moulded with 2 mm punches to form corresponding microtablets. These exhibited the following release profile: Time after Active substance release in A of original active subs tance concentratLion minutes 120 minutes 240 minutes 480 minutes 8 V00.* 00..
Claims (17)
1. An orally administered preparation with controlled release of at least one opioid as an analgesic from a microtablet with a diameter of 1 to 3 mm.
2. The preparation according to claim 1, wherein the microtablet has a diameter of 1.5 to 3 mm.
3. The preparation according to claim 1 or 2, wherein hydromorphone, oxycodone, morphine, levophanol, methadone, dihydrocodeine, fentanyl, codeine, dihydromorphine, pethidine, piritramide, buprenorphine, tilidine, tramadol, the particular salts thereof or mixtures thereof are used as the at least one opioid. o0 4. The preparation according to claim 3, wherein tramadol, tramadol hydrochloride, morphine, morphine hydrochloride and/or morphine sulfate are used as the at least one opioid. The preparation according to any one of claims 1 to 4, wherein the microtablets contain the analgesic uniformly distributed in a controlled release matrix.
6. The preparation according to claim 5, wherein the matrix comprises at least one polymer, a wax, a fat, an oil, a fatty acid, a fatty alcohol or a corresponding ester.
7. The preparation according to claim 6, wherein cellulose ethers, cellulose esters and/or acrylic resins are used as the polymers.
8. The preparation according to any one of claims 5 to 7, wherein ethylcellulose, 20 hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, mono- and/or diglycerides of C 12 -C 30 fatty acids and/or C 12 -C 30 fatty alcohols are used as the matrix material.
9. The preparation according to any one of claims 1 to 4, wherein the microtablets are provided with at least one coating.
10. The preparation according to claim 9, wherein the coating provides controlled release.
11. The preparation according to claim 9 or 10, wherein the coating is based on a water-insoluble polymer or wax.
12. The preparation according to claim 11, wherein an acrylic resin or cellulose derivative is used as the nnlvmer
13. The preparation according to claim 12, wherein the cellulose derivative is alkylcellulose.
14. The preparation according to claim 12 or 13, wherein ethylcellulose and/or a poly(meth)acrylate is used as the coating material. [R.\LIBZZ)487637specidoc gym 14 The preparation according to any one of claims 1 to 14, wherein the microtablets are in a capsule.
16. The preparation according to claim 15, wherein the capsules each contain a defined number of microtablets in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved.
17. The preparation according to claim 16, wherein the number of microtablets in the capsule is sufficient for administration once or twice daily.
18. The preparation according to any one of claims 1 to 14, wherein the microtablets are taken from a supply of microtablets using a metering unit in a countable 0o number in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved.
19. The preparation according to claim 18, wherein the metering unit is a dispenser The preparation according to any one of claims 1 to 14, wherein a certain number of microtablets in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved are compression moulded with conventional auxiliaries and additives to form a tablet.
21. The preparation according to any one of claims 1 to 4, wherein more than 75% of the analgesic is released within 30 minutes. 20 22. An orally administered preparation with controlled release of at least one analgesic, said preparation being substantially as hereinbefore described with reference to any one of the examples. Dated 16 March, 2004 Grunenthal GmbH 0 Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0 [R:\LBZZ]487637speci doc:gym
Applications Claiming Priority (2)
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|---|---|---|---|
| DE19901683A DE19901683B4 (en) | 1999-01-18 | 1999-01-18 | Controlled-release analgesic |
| DE19901683 | 1999-01-18 |
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| JP (1) | JP2000212069A (en) |
| KR (1) | KR20000071245A (en) |
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| CA (1) | CA2295469A1 (en) |
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| SK (1) | SK652000A3 (en) |
| ZA (1) | ZA200000171B (en) |
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| DE19901687B4 (en) * | 1999-01-18 | 2006-06-01 | Grünenthal GmbH | Opioid controlled release analgesics |
| SK285128B6 (en) * | 1999-12-28 | 2006-07-07 | Zentiva, A. S. | A remedy with controlled release comprising tramadol hydrochloride and method for preparation thereof |
| US20020044962A1 (en) * | 2000-06-06 | 2002-04-18 | Cherukuri S. Rao | Encapsulation products for controlled or extended release |
| UA81224C2 (en) * | 2001-05-02 | 2007-12-25 | Euro Celtic S A | Dosage form of oxycodone and use thereof |
| AU2002314968B2 (en) * | 2001-06-08 | 2006-12-07 | Endo Pharmaceuticals, Inc. | Controlled release dosage forms using acrylic polymer, and process for making the same |
| PE20030527A1 (en) | 2001-10-24 | 2003-07-26 | Gruenenthal Chemie | DELAYED-RELEASE PHARMACEUTICAL FORMULATION CONTAINING 3- (3-DIMETHYLAMINO-1-ETHYL-2-METHYL-PROPYL) PHENOL OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME AND ORAL TABLETS CONTAINING IT |
| US8487002B2 (en) | 2002-10-25 | 2013-07-16 | Paladin Labs Inc. | Controlled-release compositions |
| TWI319713B (en) | 2002-10-25 | 2010-01-21 | Sustained-release tramadol formulations with 24-hour efficacy | |
| MY135852A (en) | 2003-04-21 | 2008-07-31 | Euro Celtique Sa | Pharmaceutical products |
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| US6984403B2 (en) * | 2003-12-04 | 2006-01-10 | Pfizer Inc. | Azithromycin dosage forms with reduced side effects |
| PT1931346E (en) | 2005-09-09 | 2012-08-14 | Angelini Labopharm Llc | COMPOSITION OF TRAZODONE FOR ADMINISTRATION ONCE A DAY |
| WO2007048219A2 (en) | 2005-09-09 | 2007-05-03 | Labopharm Inc. | Sustained drug release composition |
| DE102006006532B4 (en) | 2006-02-10 | 2007-11-08 | Biogenerics Pharma Gmbh | Pharmaceutical preparation |
| SA07280459B1 (en) | 2006-08-25 | 2011-07-20 | بيورديو فارما إل. بي. | Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic |
| RU2363451C2 (en) * | 2007-09-14 | 2009-08-10 | Общество С Ограниченной Ответственностью "Технология Лекарств" | Composition for making dosage form with prolonged effect and method of making said form |
| RU2354358C1 (en) * | 2007-12-25 | 2009-05-10 | Зао "Биоком" | Solid medicinal form of matrix type, which has anti-inflammatory, analgesic, febrifugal activity, with prolonged release and method of its obtaining |
| DE102008056312A1 (en) | 2008-11-07 | 2010-05-12 | Biogenerics Pharma Gmbh | Use of micro-tablets as food and feed additive |
| RU2426541C1 (en) * | 2010-05-11 | 2011-08-20 | Государственное образовательное учреждение дополнительного профессионального образования "Новокузнецкий государственный институт усовершенствования врачей Федерального агентства по здравоохранению и социальному развитию" | Method of preventing post-operation nausea and vomiting in children in otolaryngological surgery |
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| IT1243341B (en) * | 1990-07-13 | 1994-06-10 | Farcon Ag | PHARMACEUTICAL COMPOSITION FOR ORAL USE WITH MODIFIED RELEASE OF NON STEROID ANTI-INFLAMMATORS |
| SE9301057L (en) * | 1993-03-30 | 1994-10-01 | Pharmacia Ab | Controlled release preparation |
| PT654263E (en) * | 1993-11-23 | 2002-06-28 | Euro Celtique Sa | METHOD FOR THE PREPARATION OF A PROLONGED LIBERTYACAO COMPOSITION |
| DE19530575A1 (en) * | 1995-08-19 | 1997-02-20 | Gruenenthal Gmbh | Rapidly disintegrating drug form of tramadol or a tramadol salt |
| PT1009387E (en) * | 1997-07-02 | 2006-08-31 | Euro Celtique Sa | STABILIZED CONTROLLED FREQUENCY FORMULATIONS OF TRAMADOL |
| US6156342A (en) * | 1998-05-26 | 2000-12-05 | Andex Pharmaceuticals, Inc. | Controlled release oral dosage form |
-
1999
- 1999-01-18 DE DE19901683A patent/DE19901683B4/en not_active Expired - Fee Related
- 1999-12-20 AR ARP990106587A patent/AR021934A1/en unknown
- 1999-12-21 EP EP99125471A patent/EP1020183A3/en not_active Withdrawn
-
2000
- 2000-01-04 PE PE2000000003A patent/PE20001453A1/en not_active Application Discontinuation
- 2000-01-05 AU AU10107/00A patent/AU777330B2/en not_active Ceased
- 2000-01-11 NZ NZ502260A patent/NZ502260A/en unknown
- 2000-01-14 CA CA002295469A patent/CA2295469A1/en not_active Abandoned
- 2000-01-14 JP JP2000006880A patent/JP2000212069A/en not_active Withdrawn
- 2000-01-14 KR KR1020000001691A patent/KR20000071245A/en not_active Ceased
- 2000-01-17 CO CO00002025A patent/CO4910117A1/en unknown
- 2000-01-17 RU RU2000101023/15A patent/RU2244541C2/en not_active IP Right Cessation
- 2000-01-17 PL PL00337868A patent/PL337868A1/en not_active Application Discontinuation
- 2000-01-17 CN CN00104185A patent/CN1270028A/en active Pending
- 2000-01-17 SK SK65-2000A patent/SK652000A3/en unknown
- 2000-01-17 HU HU0000137A patent/HUP0000137A3/en unknown
- 2000-01-17 ZA ZA200000171A patent/ZA200000171B/en unknown
- 2000-01-17 IL IL13407500A patent/IL134075A0/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1153014A (en) * | 1966-01-26 | 1969-05-21 | Andre Chambon | Improvements in or relating to An Oral Dose for the Treatment of Tuberculosis |
| EP0336621A1 (en) * | 1988-03-25 | 1989-10-11 | Canon Kabushiki Kaisha | Metal oxide material |
| EP0647448A1 (en) * | 1993-10-07 | 1995-04-12 | Euroceltique S.A. | Orally administrable opioid formulations having extended duration of effect |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0000137A2 (en) | 2001-02-28 |
| HUP0000137A3 (en) | 2001-03-28 |
| JP2000212069A (en) | 2000-08-02 |
| DE19901683B4 (en) | 2005-07-21 |
| CN1270028A (en) | 2000-10-18 |
| NZ502260A (en) | 2002-02-01 |
| PL337868A1 (en) | 2000-07-31 |
| SK652000A3 (en) | 2000-08-14 |
| RU2244541C2 (en) | 2005-01-20 |
| AU1010700A (en) | 2000-07-20 |
| CO4910117A1 (en) | 2000-04-24 |
| EP1020183A3 (en) | 2000-09-20 |
| DE19901683A1 (en) | 2000-07-20 |
| EP1020183A2 (en) | 2000-07-19 |
| PE20001453A1 (en) | 2000-12-23 |
| CA2295469A1 (en) | 2000-07-18 |
| IL134075A0 (en) | 2001-04-30 |
| AR021934A1 (en) | 2002-09-04 |
| KR20000071245A (en) | 2000-11-25 |
| HU0000137D0 (en) | 2000-03-28 |
| ZA200000171B (en) | 2000-08-07 |
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