Note: Descriptions are shown in the official language in which they were submitted.
~~~~rj~~
1
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:-
19
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.
