EP0491911A1 - A controlled-release pharmaceutical composition for the oral use containing non steroidal anti-inflammatory drugs - Google Patents
A controlled-release pharmaceutical composition for the oral use containing non steroidal anti-inflammatory drugsInfo
- Publication number
- EP0491911A1 EP0491911A1 EP19910912626 EP91912626A EP0491911A1 EP 0491911 A1 EP0491911 A1 EP 0491911A1 EP 19910912626 EP19910912626 EP 19910912626 EP 91912626 A EP91912626 A EP 91912626A EP 0491911 A1 EP0491911 A1 EP 0491911A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- release
- units
- active ingredient
- sub
- 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- Withdrawn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
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 238000013270 controlled release Methods 0.000 title claims abstract description 13
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 title claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 7
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 8
- 229960000991 ketoprofen Drugs 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 6
- 239000007903 gelatin capsule Substances 0.000 claims description 3
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 2
- 239000007902 hard capsule Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 7
- 239000002775 capsule Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000008119 colloidal silica Substances 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 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 4
- 238000000034 method Methods 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 108010001267 Protein Subunits Proteins 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 235000019759 Maize starch Nutrition 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000004898 kneading Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 1
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical compound C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 description 1
- SYCHUQUJURZQMO-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,1-dioxo-n-(1,3-thiazol-2-yl)-1$l^{6},2-benzothiazine-3-carboxamide Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=CS1 SYCHUQUJURZQMO-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 229920003094 Methocel™ K4M Polymers 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 229960004892 acemetacin Drugs 0.000 description 1
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229920003064 carboxyethyl cellulose Polymers 0.000 description 1
- 230000027288 circadian rhythm Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- 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
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229950002252 isoxicam Drugs 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229950005175 sudoxicam Drugs 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 208000016686 tic disease Diseases 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
Definitions
- the present invention relates to pharmaceutical compositions for the controlled release of non steroidal anti-inflammatory drugs.
- This kind of formulations can be classified in : - single-unit dosage forms
- Single-unit dosage forms are generally easier and safer to be prepared, but sometimes they can suffer from the drawbacks of lacking release of the active in- gredient, or a "burst effect" due to a too fast release of the active ingredient.
- Multiple-dosage forms provide an improvement in bioavailability of the active ingredient and lower incidence of side-effects (such as gastrolesivity) .
- the present invention relates to a pharmaceutical composition for the controlled-release of non steroidal anti-inflammatory drugs which assures safety and repro- ducibility of the preparation, a precise control of drug plasmatic levels after the administration, a com ⁇ plete bioavailability and an extremely reduced incidence of side-effects.
- Said pharmaceutical composition is characterized in that the drug total dosage can be divided into 2,3 or 4 sub-units, consisting each of a small size tablet, which sub-units can be placed in a hard gelatin cap- sule.
- Sub-units can either be identical as far as the release characteristics are concerned, or they can be different from each other, depending on the desired du ⁇ ration of the therapeutical effect. Particularly, since symptomatology of the rheuma ⁇ tic disease can show exacerbations also depending on circadian rhythms, it sometimes is preferable to make use of dosage forms which can give rise to an initial high plasmatic concentration, followed by a slower re- lease of the drug, thereby lasting for a long time (for example overnight) .
- the dosage form of the invention has the following advantages :
- Plasmatic levels and bioavailability the con- trolled-release form administered to healthy volunteers gave rise to active plasmatic levels during a 12-24 hour period, with a complete bioavailability. Variability of the plasmatic level values turned out to be extremely reduced. - Side-effects: no healthy volunteer participating to the tests showed side-effects.
- 1 or 2 sub-units can give rise to a quick release of the active ingredient
- the re ⁇ maining 1, 2 or 3 sub-units can consist of hydrophilic matrices (based on hydrophilic polymeric materials and/or hydrogels) which can release gradually the active ingredient.
- hydrophilic matrices include cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium carboxy ethyl cellulose or polyvinyl alcohols of different molecular weights.
- Said alcohols or polymeric substances are present in the sub-units at percentages ranging from 5 to 80%, depending on the desired release characteristics.
- the capsule can also contain 2, 3 or 4 identical sub-units (of either the quick-release type or the sustained-release one) depending on the desired therapeutical effect.
- non steroidal anti-inflammatory drugs which can advantageously be used as active ingredients in the compositions of the invention include arylacetic acids such as diclofenac, alclofenac, acemethacin, in- do ethacin; arylpropionic acids, such as ketoprofen, ibuprofen, naproxen, flurbiprofen, suprofen; salicylic derivatives, such as diflunisal; benzothiazine deriva ⁇ tives such as piroxicam, isoxicam, sudoxicam and the like.
- arylacetic acids such as diclofenac, alclofenac, acemethacin, in- do ethacin
- arylpropionic acids such as ketoprofen, ibuprofen, naproxen, flurbiprofen, suprofen
- salicylic derivatives such as diflunisal
- benzothiazine deriva ⁇ tives such as piroxicam, is
- Ketoprofen is particularly preferred, in form of 4 50 mg sub-units, one of which being immediately relea ⁇ sed, whereas the other ones are gradually released during time, thus assuring effective plasmatic levels for 12-24 hours.
- Controlled-release pharmaceutical formulation con ⁇ taining 200 mg ketoprofen, consisting in a capsule in ⁇ cluding 4 dosage units, each containing 50 mg ketopro ⁇ fen and being designed for a controlled-release of the active ingredient.
- Dosage units were prepared as fol ⁇ lows : a) Preparation of sub-units (single units) The following material were used to prepare 1.000.00 cores : ketoprofen 50.00 kg hydroxypropylmethyl cellulose (Methocel K4M) R -(Colorcon) 37.50 kg mannitol 20.00 kg polyvinylpyrrolidone 7.500 kg colloidal silica 0.25 kg magnesium stearate 0.5 kg
- the active ingredient is mixed with hydroxypropyl- methyl cellulose and mannitol in a suitable mixing- kneading apparatus.
- the homogeneous mixture is wet with a 5% polyvinylpyrrolidone alcoholic solution, then kneaded, the resulting homogeneous humid mass is forced through a 400 micron screen and dried in an air- circulation oven.
- a pharmaceutical composition for example, a single tablet
- organoleptic characteri ⁇ stics and with uniform diffusion into the dissolution medium after the capsule disintegration, giving no aggregation, can be obtained by means of a typical film coating operation, for example, using an aqueous suspension having the following composition:
- the controlled-release formulation was administered to a healthy volunteer, recording the plasmatic concentration of the active ingredient at fixed time intervals.
- the results were as follows :
- Controlled-release pharmaceutical formulation con ⁇ taining 200 mg ketoprofen, consisting in a capsule in ⁇ cluding 4 dosage units, each containing 50 mg ketopro ⁇ fen and being designed for a controlled-release of the active ingredient.
- Dosage units were prepared as fol ⁇ lows : a) Preparation of sub-units (single units) The following materials were used to prepare 1.000.000 cores : ketoprofen 50.00 kg maize starch 40.00 kg methyl cellulose 0.65 kg polyvinylpyrrolidone 10.00 kg colloidal silica 0.25 kg magnesium stearate 0.5 kg
- the active ingredient is mixed with maize starch in a suitable mixing-kneading apparatus.
- the homogene ⁇ ous mixture is wet with a 2% methyl cellulose alcoholic solution, then kneaded, the resulting homogenous humid mass being forced through a 400 micron screen and dried in air-circulation oven.
- the dried granulate is added with cross-linked polyvinylpyrrolidone, Mg stearate and colloidal silica and it is compressed, according to the known technique, with 7 mm d. convex punches, to obtain 3.0-3.2 mm height tablets.
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02094390A IT1243341B (it) | 1990-07-13 | 1990-07-13 | Composizione farmaceutica per uso orale a rilascio modificato di antiinfiammatori non steroidei |
| IT2094390 | 1990-07-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0491911A1 true EP0491911A1 (en) | 1992-07-01 |
Family
ID=11174413
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19910912626 Withdrawn EP0491911A1 (en) | 1990-07-13 | 1991-07-04 | A controlled-release pharmaceutical composition for the oral use containing non steroidal anti-inflammatory drugs |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0491911A1 (enrdf_load_stackoverflow) |
| AU (1) | AU8186291A (enrdf_load_stackoverflow) |
| CA (1) | CA2066751A1 (enrdf_load_stackoverflow) |
| ES (1) | ES2043567T1 (enrdf_load_stackoverflow) |
| GR (1) | GR930300020T1 (enrdf_load_stackoverflow) |
| IT (1) | IT1243341B (enrdf_load_stackoverflow) |
| WO (1) | WO1992000730A1 (enrdf_load_stackoverflow) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993017673A1 (en) * | 1992-03-03 | 1993-09-16 | Top Gold Pty., Limited | Sustained release analgesics |
| US5922722A (en) * | 1996-11-12 | 1999-07-13 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
| DE19718012C1 (de) * | 1997-04-29 | 1998-10-08 | Jenapharm Gmbh | Verfahren zur Herstellung peroral anwendbarer fester Arzneiformen mit gesteuerter Wirkstoffabgabe |
| DE19901683B4 (de) * | 1999-01-18 | 2005-07-21 | Grünenthal GmbH | Analgetikum mit kontrollierter Wirkstofffreisetzung |
| EP2070520A1 (en) * | 2007-12-11 | 2009-06-17 | LEK Pharmaceuticals D.D. | Pharmaceutical composition comprising at least one active agent and a binder, which swells in an acidic media |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2021147A1 (de) * | 1970-04-30 | 1971-11-11 | Christian Brunnengraeber Chem | Kapsel mit einer Fuellung von Pharmazeutika |
| US4773907A (en) * | 1982-12-20 | 1988-09-27 | Alza Corporation | Primary delivery system comprising secondary dosage form |
| GB2176999B (en) * | 1985-06-22 | 1989-07-12 | Stanley Stewart Davis | Sustained release medicament |
| IT1230576B (it) * | 1988-10-20 | 1991-10-28 | Angeli Inst Spa | Formulazioni farmaceutiche per via orale a liberazione selettiva nel colon |
-
1990
- 1990-07-13 IT IT02094390A patent/IT1243341B/it active IP Right Grant
-
1991
- 1991-07-04 WO PCT/EP1991/001246 patent/WO1992000730A1/en not_active Application Discontinuation
- 1991-07-04 AU AU81862/91A patent/AU8186291A/en not_active Abandoned
- 1991-07-04 ES ES91912626T patent/ES2043567T1/es active Pending
- 1991-07-04 CA CA002066751A patent/CA2066751A1/en not_active Abandoned
- 1991-07-04 EP EP19910912626 patent/EP0491911A1/en not_active Withdrawn
-
1993
- 1993-04-28 GR GR930300020T patent/GR930300020T1/el unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9200730A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2066751A1 (en) | 1992-01-14 |
| AU8186291A (en) | 1992-02-04 |
| IT1243341B (it) | 1994-06-10 |
| IT9020943A1 (it) | 1992-01-13 |
| IT9020943A0 (it) | 1990-07-13 |
| WO1992000730A1 (en) | 1992-01-23 |
| GR930300020T1 (enrdf_load_stackoverflow) | 1993-04-28 |
| ES2043567T1 (es) | 1994-01-01 |
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Legal Events
| Date | Code | Title | Description |
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| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
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| 17P | Request for examination filed |
Effective date: 19920303 |
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| RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: L.C. PHARCHEM LTD. |
|
| ITCL | It: translation for ep claims filed |
Representative=s name: STUDIO BIANCHETTI |
|
| EL | Fr: translation of claims filed | ||
| TCAT | At: translation of patent claims filed | ||
| TCNL | Nl: translation of patent claims filed | ||
| DET | De: translation of patent claims | ||
| REG | Reference to a national code |
Ref country code: DE Ref legal event code: 8580 Free format text: DER ANMELDER LAUTET RICHTIG: L.C. PHARCHEM LTD., NICOSIA, CY |
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