CA2066313C - New pharmaceutical composition - Google Patents
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- CA2066313C CA2066313C CA 2066313 CA2066313A CA2066313C CA 2066313 C CA2066313 C CA 2066313C CA 2066313 CA2066313 CA 2066313 CA 2066313 A CA2066313 A CA 2066313A CA 2066313 C CA2066313 C CA 2066313C
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- pharmaceutical composition
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- methyl
- glioma
- treatment
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Abstract
8-carbamoyl-3-methyl-(3H)-imidaro(5,1-d]-1,2,3,5-tetrazin-4-one for use in the treatment of glioma or mycosis fungoides.
Description
~~~~rj~~
This invention ralatas~ to a n~a~r uaa o2 tamoz~lomide, which is s~carb~smoyl-3-methyl-(3~1-imidazo(6,1-d]-1,2,3,5-tetrazi:n-~~-one, and to pharmaceutical compooitions containing it.
Temozolomlda is a lens>wn compound. zta pr~paration is demoribad in Cananian Patent Pte. 1,197,257.
The group of campounde digcloaed in that patent wer~ generally deecrib~ed ag possessing valuable antinaoplgatic activity, Ear a~cample dgsinat csrcinomag, malanomaa, aarCOmnd, lymphomas and 1~ukaseraise. 'Chat' ware generally da~cribad as particularly active in miss at daily doe~s bet~w~on 0.5 and is mg/kg~ e~t11ma1 body w~ight, administered intra~peritan~ally, against 1°L~tS (s) lymphoma according to th~ ~arocedure ~~ doschar ,~ ,~,r Bioohom.
Ph4rmaCOl. (1981), ~.Qe ~~e ~19d AIyJ/l~iC6A and 15076 (rsticulum call ~arcoma). Against lnuka~mia L1210, q~ra~Eted in~trapezitoTl~ally, intracar~bxally and intrawenouely, and p38~, according to th~ pr~cadur~ described in "898thoda of Deaelopmgnt ~! Near An'tiaan~or Bxuga~~ (PTCZ M~nograpn ~~, 2b 348rch 1977, g~8~99 147"149a Nat~CII~I ~C~tnA~x Tn~tlttdte, Betheedae unit~d stet~~)e the compounds t~~r~ described as active both intrrspsriton~ally and orally at degas of betty~en 2.5 and to mg/kg animal body weight. inhibition o~
both primary tumour and metastasis vase obtainmd against the a~ ~ewi~ lung carcinoma by similar dosage regimes. Against the 816 melanoma and c38 tumo~rr in mica (ldc~ Monograph 45, g~ chi ,) ~th~ compounds. ware d~acri.mad a~ being activ~
intraparitonoally at doses of between 6.25 and z5 mg~xg animal body weight.
Tna tetrazina 4~rivativaa war~ also states to .
possess valuabl~ immunomodulatory activity and to ha oz use in the tr~atment of organ grants and ~kin grafts and in the treatment of immunological Qi6eases.
Tamozolomida is clog~ly related in structure to anoth~r known compound, mitozolomide from whioh it lift~rs in having a methyl group rath~r than a 2-ohloroethyl group at the ~-poaitian. Hitoaolomida has ba~n axtengiv~ly studied and is believed to ~xart its sffoat by oross-linking DNA. ~itozelomida ha~ bean shown to bs active againot° for ~~ample° small fall oaroinoma of the lung and in malignant melanoma but can aaus~ unpradiotablo 1~ myeloauppression.
Ia contrast and daspitg the very aloes struotural similarity, tamoaolomida whioh has be~n found to possess good axparimRntal anti-tumour activity and g~nArally lower taxi~ity has b~an found to ba 1~a~ lik~ly to give rise to unpxadictable myalosupprea~ion.
Temozol~mida has, surprisingly. bean found to arose the bl~od brain barri~r in mica and it ig believed that the compound°s ~~?eetivanass against giioma may b~
aaaocast~d with this ability.
~t has saw b~an dieoov~r~d that tamoxolomid~ is unaxpaCta4ly useful in the treatment of two particular eanditiona, nam~ly giioma and mycosis lungotdas.
b a The present invention acGOrdingly provides a pharmaceutical composition for the tic~atmsnt of glioma or mycosis fungoides ~hlch compriaso tamo2olomids in aasociatian with a pharmaceutiaa:lly acceptable carrier or .s casting.
Th~ compositions of the invention may be adm,iniatar~d to patients sug~~ri;ng ~trom, or. sub~act to, glioma or mycosis tungoidaa to soaurs~ an improvement in the condition ofi the patient. =t gill b~ understood that the i0 oompo~aitiona compri~a an amount o~ tamo2olomide sltoctive to secure ouch an improvement.
xhs invention also provides tamoaolomid~ for ua0 in the treatm~nt or gliama ~r ~nycoaia fungoidea.
Mothod~s of presentation of phar~aGSUtiaally 15 active compounds era w~11 knor~n in th~ art and a ouitable v~hic~.o ~aay bs datezmln~d by the physician or p'harmaciot, dsp~nding upon such factoro as the ~ffset aoue~ht, the size, age, sat and condition of the patient. The compositions may also oontain, a$ in uau~l in the art, such materials as ~0 solid or liquid diluente, t~stting ag~nts~, prssservatives, glavouring and ~olousing agents and the like.
solid compositions !or oral administration include comprmasod tablets, pill~, diaporsibl~ powders, a.nd granules. In much solid Gompositiona one or more of the 25 aotive oompounda ia, or ag~, admixed with at least one in~rt diluent ~uch ao calcium carbonate, potato starch, alr~inic acid, or lactose. Th~ ooanpoaitiona zsay also 20~~~~~
w~-campxi~e, as is normal practice, additional gubstaneas other than inert diluenta, a.g. lubricatsng agents, such as magnesium etsarata. Liquid Compositions Eor oral admsnetration snoluds pharmaoeutically-acceptable emulsions, solutions, suepeneionsa, eyrugs and elixirs containing inert dilusnts co~onlY used in the art, such as water and liquid parn~fin. P~sidsa inert diluents such compositions may also camgriss adjuvnnts, su~h as wetting and suspending agents, s.g. polYvinyipyrxolidona, and to sweetening, tlavousing, perfuming and preserving agents.
~hs compositions according to the inventson, for oral adminietretion, alas include capsul~a oI abaorbatle material euoh as gelatsn Containing one ar more o~ th~
active subetanoee with or without the addition o? dilusnta i5 or oxcipi~nts.
Solid oomposstions t~r vaginal acminiatration include pessariee Lormulat~d in a manner known ~e and containing one or moss o~ the active compounds.
Solid composition~ for r:etal administration 2o incluQa suppositories formulated in a mane~r known ~
and containing on~ or more o~ the active compounds.
preparations a~oording to the invention ror paranteral admini~tration include sterile aqueous or non-aguaoua solutions, guspenaione or emulsions. examples of 25 nan-aqueoum solvents or suspending modia ar~ polyethylene glycol, dimethyl gulphoxide, vegetable oils such a~ olive oil, and in~actable organic eaters such as ethyl oleate.
Thas~ compositions may aloo inaludo adjuvanta such as pre~orving, ~sttinq, emulsifying and dispersing agents.
They may ba storilia~d, !or Buampls, by filtzation through a bacteria-retaining tiltor, by incorporation of sterilising ag~ntB in the compositions, or by irradiation.
They may also be manufactured in the form of sterile solid compositions, which oan b~ digaol.vsd in sterile water or some oth~r sterile in~ectabls meiiium immediately before us~.
l0 ~hs p~rcontag~ of aotiv~ iagrndiant in the compositions of the invsntiAn may bs varied, it being naoeseary that it should constitutR a proportion such that a sultablo dosage fmr the tharap~utic effect dgsirad sriall be obtained. ~bviouely several unit doaag~ forms may ba administ~r~d a~t about th~ same time. Iri general, the preparations should normally gontain at Toast o.025x by wefght as aotiv~ ~ubatancs when required Eor administration by injection; Eor oral administration the preparation will normally contain at lea~t 0.1% by voight og activ~
substance. Tha dos~ employed depends upon the desired tharapautio stf~ct, the routs of administration and th~
duzation of the treatment.
The tstrazine 4erivativss of general f~rmula I
era armful in the treatment of glioma and mycosis fuhgoides at doses which are generally between o.i and a00, pra~erabiy batty~an 1 and 20, mg/~g body weight per day.
~sss~~
Tn particular, temozolomide may be adntiniatere4 as era in~ravanou~ lYt2ueion (ot, for ~xampla, y hour). The compound oan ba Pora~ulatad as a 2~ (w/~r) solution in Aimathyl eulphoxido (DMBO) and st:orad, prior to use at low tAmperaturae o~, for ~xample, minus 20°C. The oompound is generally diluted in, for example, normal ealino prior to use.
Trio compound can also bo foarmulat~d ia~ 'the Form of hard gelatin capaulQS containing, for exempla, 20, 50, 100 or 250 mg. Doers of t~moEOl~omida up to 200 mg/°mz or mars can be administered, for exempla, intravsnouely. ~h~
compound Gan also beg administered oxaily at such doses and e~ood bio-awa~.labili~ty is shown. i~refaarred doses aro up to 1200 mg/ma, adminiet~rad orally.
~,5 Symptomatic toxicity ixaa~~temezolomida may be encour~te'~~d but is generally mild at doeB~ up to 700 ~ag/ma:
high~r doses may also bo umed and toxicity in most caress may D~ Controlled with ,standaxd anti~~mntica.
The oompeund may b~ administered to human patients as n e~ingln dose or, for exempla, on a Piv~ day ~cheduis nn a Eour weak cycle, using, Por eaeample, doses of 750, 9AA, 1000 or 1200 mg/m~. In addition it can alto ba given in a continuous sohsdulo orally in doses of 100 to 150 mg per day Tar ~ight weeks or more.
5 Tn gonaral, t~mozolomide (uniik~ mitoaolotaide) Can b~ readily administered orally, Par example on a five day schedule. l~yelosuppreeeion rdhich may ba e~noountgrad is 20~6~~~
-~-generally ptesdiotabie and r~versibl~. The Compound shown little evidence of cumulative toxicity at doses up ~o, got example, 1 gjmi. h pretarrea Qosaga aGh~duls ie of 1 g/ma divld~d over Zivs days in o~sasl dense, adminiatareC orally arid repeated On a lour wa~Dc cycl~.
Th~ fellowing Composition ~xaanpl~a illu~trate ph~tx'~naGautical compositions aocox~ding 'to th~ pre8ed3t invention.
~MFQ1~ v N ~ p A solution ouitable for petsnfare1 administration may be prepared frees the following ingrodionte:-8-carbamoyl-3-m~thyl-(3gi]-imidazoEg,1-d)-1,x,3,5-tatrazin-4-on~ 1.0 g ~ia.~nothyl aulphoxidg 18 ml Arachia oil 9~ ml ~y aia~~lving th~ g-carbam~yl-~-methyl-[~~)°
imidazo[5,1-d)°1,2,3,5-tot~ea~in-4-one in the dim~'thyl aulphexic~e and adding the arachis oil. Th~ resulting solution away b~ divided, ardor aseptic conditions, into a~tpoulas at an amount of 10 ml per ampoul~. The amp~ulea a5 may be sealed, to give to amp~uloa each containing 10~ mg of 6-oarbaanoyl-3-(2-chi~roethyl)-(3~]°imida~o(5,1-d) 1.Z.3~s°totrazin-~-one.
,. g ..
~aM~O~~~A~( ~ ~I~~ ~, Capaul~e auil~abla tc~z~ ~~al adminiatratian array be prepared Jay placing ~-aarbatna~rlm3-methyl- [ 3~~ °
imi8aao[5,1-4~°1.2,3,5rtetraain-rl-cne inta g~la~tln ~hells ai numbe~e 2 sia~ a~ a rate ~i 10 ~g par ~capaule.
This invention ralatas~ to a n~a~r uaa o2 tamoz~lomide, which is s~carb~smoyl-3-methyl-(3~1-imidazo(6,1-d]-1,2,3,5-tetrazi:n-~~-one, and to pharmaceutical compooitions containing it.
Temozolomlda is a lens>wn compound. zta pr~paration is demoribad in Cananian Patent Pte. 1,197,257.
The group of campounde digcloaed in that patent wer~ generally deecrib~ed ag possessing valuable antinaoplgatic activity, Ear a~cample dgsinat csrcinomag, malanomaa, aarCOmnd, lymphomas and 1~ukaseraise. 'Chat' ware generally da~cribad as particularly active in miss at daily doe~s bet~w~on 0.5 and is mg/kg~ e~t11ma1 body w~ight, administered intra~peritan~ally, against 1°L~tS (s) lymphoma according to th~ ~arocedure ~~ doschar ,~ ,~,r Bioohom.
Ph4rmaCOl. (1981), ~.Qe ~~e ~19d AIyJ/l~iC6A and 15076 (rsticulum call ~arcoma). Against lnuka~mia L1210, q~ra~Eted in~trapezitoTl~ally, intracar~bxally and intrawenouely, and p38~, according to th~ pr~cadur~ described in "898thoda of Deaelopmgnt ~! Near An'tiaan~or Bxuga~~ (PTCZ M~nograpn ~~, 2b 348rch 1977, g~8~99 147"149a Nat~CII~I ~C~tnA~x Tn~tlttdte, Betheedae unit~d stet~~)e the compounds t~~r~ described as active both intrrspsriton~ally and orally at degas of betty~en 2.5 and to mg/kg animal body weight. inhibition o~
both primary tumour and metastasis vase obtainmd against the a~ ~ewi~ lung carcinoma by similar dosage regimes. Against the 816 melanoma and c38 tumo~rr in mica (ldc~ Monograph 45, g~ chi ,) ~th~ compounds. ware d~acri.mad a~ being activ~
intraparitonoally at doses of between 6.25 and z5 mg~xg animal body weight.
Tna tetrazina 4~rivativaa war~ also states to .
possess valuabl~ immunomodulatory activity and to ha oz use in the tr~atment of organ grants and ~kin grafts and in the treatment of immunological Qi6eases.
Tamozolomida is clog~ly related in structure to anoth~r known compound, mitozolomide from whioh it lift~rs in having a methyl group rath~r than a 2-ohloroethyl group at the ~-poaitian. Hitoaolomida has ba~n axtengiv~ly studied and is believed to ~xart its sffoat by oross-linking DNA. ~itozelomida ha~ bean shown to bs active againot° for ~~ample° small fall oaroinoma of the lung and in malignant melanoma but can aaus~ unpradiotablo 1~ myeloauppression.
Ia contrast and daspitg the very aloes struotural similarity, tamoaolomida whioh has be~n found to possess good axparimRntal anti-tumour activity and g~nArally lower taxi~ity has b~an found to ba 1~a~ lik~ly to give rise to unpxadictable myalosupprea~ion.
Temozol~mida has, surprisingly. bean found to arose the bl~od brain barri~r in mica and it ig believed that the compound°s ~~?eetivanass against giioma may b~
aaaocast~d with this ability.
~t has saw b~an dieoov~r~d that tamoxolomid~ is unaxpaCta4ly useful in the treatment of two particular eanditiona, nam~ly giioma and mycosis lungotdas.
b a The present invention acGOrdingly provides a pharmaceutical composition for the tic~atmsnt of glioma or mycosis fungoides ~hlch compriaso tamo2olomids in aasociatian with a pharmaceutiaa:lly acceptable carrier or .s casting.
Th~ compositions of the invention may be adm,iniatar~d to patients sug~~ri;ng ~trom, or. sub~act to, glioma or mycosis tungoidaa to soaurs~ an improvement in the condition ofi the patient. =t gill b~ understood that the i0 oompo~aitiona compri~a an amount o~ tamo2olomide sltoctive to secure ouch an improvement.
xhs invention also provides tamoaolomid~ for ua0 in the treatm~nt or gliama ~r ~nycoaia fungoidea.
Mothod~s of presentation of phar~aGSUtiaally 15 active compounds era w~11 knor~n in th~ art and a ouitable v~hic~.o ~aay bs datezmln~d by the physician or p'harmaciot, dsp~nding upon such factoro as the ~ffset aoue~ht, the size, age, sat and condition of the patient. The compositions may also oontain, a$ in uau~l in the art, such materials as ~0 solid or liquid diluente, t~stting ag~nts~, prssservatives, glavouring and ~olousing agents and the like.
solid compositions !or oral administration include comprmasod tablets, pill~, diaporsibl~ powders, a.nd granules. In much solid Gompositiona one or more of the 25 aotive oompounda ia, or ag~, admixed with at least one in~rt diluent ~uch ao calcium carbonate, potato starch, alr~inic acid, or lactose. Th~ ooanpoaitiona zsay also 20~~~~~
w~-campxi~e, as is normal practice, additional gubstaneas other than inert diluenta, a.g. lubricatsng agents, such as magnesium etsarata. Liquid Compositions Eor oral admsnetration snoluds pharmaoeutically-acceptable emulsions, solutions, suepeneionsa, eyrugs and elixirs containing inert dilusnts co~onlY used in the art, such as water and liquid parn~fin. P~sidsa inert diluents such compositions may also camgriss adjuvnnts, su~h as wetting and suspending agents, s.g. polYvinyipyrxolidona, and to sweetening, tlavousing, perfuming and preserving agents.
~hs compositions according to the inventson, for oral adminietretion, alas include capsul~a oI abaorbatle material euoh as gelatsn Containing one ar more o~ th~
active subetanoee with or without the addition o? dilusnta i5 or oxcipi~nts.
Solid oomposstions t~r vaginal acminiatration include pessariee Lormulat~d in a manner known ~e and containing one or moss o~ the active compounds.
Solid composition~ for r:etal administration 2o incluQa suppositories formulated in a mane~r known ~
and containing on~ or more o~ the active compounds.
preparations a~oording to the invention ror paranteral admini~tration include sterile aqueous or non-aguaoua solutions, guspenaione or emulsions. examples of 25 nan-aqueoum solvents or suspending modia ar~ polyethylene glycol, dimethyl gulphoxide, vegetable oils such a~ olive oil, and in~actable organic eaters such as ethyl oleate.
Thas~ compositions may aloo inaludo adjuvanta such as pre~orving, ~sttinq, emulsifying and dispersing agents.
They may ba storilia~d, !or Buampls, by filtzation through a bacteria-retaining tiltor, by incorporation of sterilising ag~ntB in the compositions, or by irradiation.
They may also be manufactured in the form of sterile solid compositions, which oan b~ digaol.vsd in sterile water or some oth~r sterile in~ectabls meiiium immediately before us~.
l0 ~hs p~rcontag~ of aotiv~ iagrndiant in the compositions of the invsntiAn may bs varied, it being naoeseary that it should constitutR a proportion such that a sultablo dosage fmr the tharap~utic effect dgsirad sriall be obtained. ~bviouely several unit doaag~ forms may ba administ~r~d a~t about th~ same time. Iri general, the preparations should normally gontain at Toast o.025x by wefght as aotiv~ ~ubatancs when required Eor administration by injection; Eor oral administration the preparation will normally contain at lea~t 0.1% by voight og activ~
substance. Tha dos~ employed depends upon the desired tharapautio stf~ct, the routs of administration and th~
duzation of the treatment.
The tstrazine 4erivativss of general f~rmula I
era armful in the treatment of glioma and mycosis fuhgoides at doses which are generally between o.i and a00, pra~erabiy batty~an 1 and 20, mg/~g body weight per day.
~sss~~
Tn particular, temozolomide may be adntiniatere4 as era in~ravanou~ lYt2ueion (ot, for ~xampla, y hour). The compound oan ba Pora~ulatad as a 2~ (w/~r) solution in Aimathyl eulphoxido (DMBO) and st:orad, prior to use at low tAmperaturae o~, for ~xample, minus 20°C. The oompound is generally diluted in, for example, normal ealino prior to use.
Trio compound can also bo foarmulat~d ia~ 'the Form of hard gelatin capaulQS containing, for exempla, 20, 50, 100 or 250 mg. Doers of t~moEOl~omida up to 200 mg/°mz or mars can be administered, for exempla, intravsnouely. ~h~
compound Gan also beg administered oxaily at such doses and e~ood bio-awa~.labili~ty is shown. i~refaarred doses aro up to 1200 mg/ma, adminiet~rad orally.
~,5 Symptomatic toxicity ixaa~~temezolomida may be encour~te'~~d but is generally mild at doeB~ up to 700 ~ag/ma:
high~r doses may also bo umed and toxicity in most caress may D~ Controlled with ,standaxd anti~~mntica.
The oompeund may b~ administered to human patients as n e~ingln dose or, for exempla, on a Piv~ day ~cheduis nn a Eour weak cycle, using, Por eaeample, doses of 750, 9AA, 1000 or 1200 mg/m~. In addition it can alto ba given in a continuous sohsdulo orally in doses of 100 to 150 mg per day Tar ~ight weeks or more.
5 Tn gonaral, t~mozolomide (uniik~ mitoaolotaide) Can b~ readily administered orally, Par example on a five day schedule. l~yelosuppreeeion rdhich may ba e~noountgrad is 20~6~~~
-~-generally ptesdiotabie and r~versibl~. The Compound shown little evidence of cumulative toxicity at doses up ~o, got example, 1 gjmi. h pretarrea Qosaga aGh~duls ie of 1 g/ma divld~d over Zivs days in o~sasl dense, adminiatareC orally arid repeated On a lour wa~Dc cycl~.
Th~ fellowing Composition ~xaanpl~a illu~trate ph~tx'~naGautical compositions aocox~ding 'to th~ pre8ed3t invention.
~MFQ1~ v N ~ p A solution ouitable for petsnfare1 administration may be prepared frees the following ingrodionte:-8-carbamoyl-3-m~thyl-(3gi]-imidazoEg,1-d)-1,x,3,5-tatrazin-4-on~ 1.0 g ~ia.~nothyl aulphoxidg 18 ml Arachia oil 9~ ml ~y aia~~lving th~ g-carbam~yl-~-methyl-[~~)°
imidazo[5,1-d)°1,2,3,5-tot~ea~in-4-one in the dim~'thyl aulphexic~e and adding the arachis oil. Th~ resulting solution away b~ divided, ardor aseptic conditions, into a~tpoulas at an amount of 10 ml per ampoul~. The amp~ulea a5 may be sealed, to give to amp~uloa each containing 10~ mg of 6-oarbaanoyl-3-(2-chi~roethyl)-(3~]°imida~o(5,1-d) 1.Z.3~s°totrazin-~-one.
,. g ..
~aM~O~~~A~( ~ ~I~~ ~, Capaul~e auil~abla tc~z~ ~~al adminiatratian array be prepared Jay placing ~-aarbatna~rlm3-methyl- [ 3~~ °
imi8aao[5,1-4~°1.2,3,5rtetraain-rl-cne inta g~la~tln ~hells ai numbe~e 2 sia~ a~ a rate ~i 10 ~g par ~capaule.
Claims (3)
1. A pharmaceutical composition for the treatment of glioma or mycosis fungoides which comprises 8-carbamoyl-3-methyl-[3H]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one in association with a pharmaceutically acceptable carrier or coating.
2, 8-carbamoyl-3-methyl-[3H]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one for use in the treatment of glioma or mycosis fungoides.
3. Use of 8-carbamoyl-3-methyl-[3H]-imidazo[5,1-d]-1,2,3,5-tetrazin-4-one in the treatment of glioma or myoosis fungoides.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/781020 | 1991-10-18 | ||
US07/781,020 US5260291A (en) | 1981-08-24 | 1991-10-18 | Tetrazine derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2066313A1 CA2066313A1 (en) | 1993-04-19 |
CA2066313C true CA2066313C (en) | 2002-08-20 |
Family
ID=25121424
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA 2066313 Expired - Lifetime CA2066313C (en) | 1991-10-18 | 1992-04-16 | New pharmaceutical composition |
Country Status (1)
Country | Link |
---|---|
CA (1) | CA2066313C (en) |
-
1992
- 1992-04-16 CA CA 2066313 patent/CA2066313C/en not_active Expired - Lifetime
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Publication number | Publication date |
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CA2066313A1 (en) | 1993-04-19 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
MKEX | Expiry | ||
MKEX | Expiry |
Effective date: 20120416 |