IT8148090A1 - Stable concentrated solutions of cisplatin, useful as pharmaceutical compositions, and their production process - Google Patents

Description

DOCUMENTATION

BOUND

. SERIES NUMBER. 135373

Series Number: 0 6/1 35.373

? EXPOSED DATE ; 31/0 3/? 980.

Class : 424 UruOTO No . : 125 Applicants : MURRAY A. KAPLAN. SYRACUSE . NY. ; _

ALPHONSE P. GRANATEK, BALDWINS VILLE, NY.

. .CONTINUATION SIDES. . .

^CERTIFICATES

.FOREIGN APPLICATIONS/PCT. . .

- CEH?H??ATI - . . - - -- t-HOW TO DEPO SITATA - fr-St-a-to? or? Pae-se-:HNY-Tavo-?e? Bfse-gn-jr:?'- -Total claim. :7-Riven dicaz.

- i - In dip. : ? 5 -Tax- de-pos i to? receipt-; -$ 105 - Attorney Practice No. RL-1617

^ADDRESS 1 JffiRBEET _W_. TAYLOR, JR. _

BRISTOL "LABORATORIES

DIV. OP BRISTOL-MYERS 00 .

" P. 0 . 'BOX' 657 "

SYRACUSE, NY 1320 1_

^Title I PHARMACEUTICAL EMULATIONS. -

It is hereby certified that the enclosed is a true copy from the files of the United States Patent and Trademark Office of the application as originally filed which is identified above.

By authorization from

COMMISSIONER OF PATENTS AND TRADEMARKS

f.to) C. W. Smith - Rogant Officer

-(Seal) Date: February 18, 1981

Date stamp

135373

PHARMACEUTICAL EMULATIONS

_ |_ _ __ SUMMARY _ _ r --_ |__ The present invention relates to solutions!

_ ini -cnncentrat e .statils of cisplatin in a solvent^-. - .

i

_ ^comprising polyethylene glycol or methoxy- ... _ _ polyethylene glycol or a mixture thereof, plus water.

_ ,_ ,and a non-toxic, pharmaceutically acceptable source- _ i

_ chloride ion table, . _ -_ _ _ _ _ _ ..

I

l

1 . ? _ :_ DESCRIPTION -OF.THE.INVENTION_ :. . _ -The_present..intention.refers _to_solutions_ _

! _ stable_and concentrated_platin.in polyglycol.- _

l ! - ^ethylene glycol, methoxypolyethylene glycol, or ;? - - -_ |mixtures thereof,..containing a -source, of chloride ions. . . . - -_ Platinum compounds are a unique group of compounds in the field of antineoplastic agents.

- .. 35 were noticed first of all for the fact

_ to. .have. .an. effect., antibiotic .by ..Rosenberg .and., his...

_c_o II ab oratoti. in.JL.965. .(.Pp.senb.erg, _B_,_ ..et. al ...v dature.

(XoncJra) .2 05-*- ~69&=5.99 196 5?-) ..and is subsequently.. from

st e s s o .. Ro s enb er e_suol~co llaborat ors? ? . state, trora-

. t o- -die. _es si _s ono .po_t en.ti_.ag.ent i..ant i.tui?or.aLL_iiegl.i i_

! .animalL.CHos.erLb.erg,..-3-._e.t^alJ_,,._Iiat.UJie.?London).,._222.( i JS5--5S6 _.(1969.) X _ |_ 4 I _ Structurally they represent a complex? e ss o_ 1 . . . . ? ? _! formed by a platinum atom in the central position

-e?ci-rc wave t o -da.-sv.ari at e._di c ?r ib.u zi on i?d i .a inm i __di

_ LcXor.o _o_ ammonia groups in planar relationship

Luis. ..Q_Jrrans .. Two of the most coma- platinum compounds

^n?mentn_-S,tudla-tl.^SQno exposed schematically oui

-J-SOttO _ _

tl _

/.*?-__

THERE

Pt Pt

J!1 i'TH??

01 __

Cis-platinum ClI) Cis-olatin (IV)

:...d iamino.d i _c1.oride diaminot etrachloride

How. is UDUG..see the 1 compound indicated with

term ._di_ci s -pi atin _?il) diaminodichloride pos-

-a-iede-irutti-i _ its chlorine and amino groups in a sin-

pol o_p i an o. .Qne.st-0_c_o.mn o.sio_,_.nt I know then

: ?nnme of cisplatin adopted in the United States, g was synthesized according to the following reaction scheme

...?|ptCl^j 2 ???^ ? - ? ^ - > eis-jpt ClTH^ > 2CI2] 2 KC1

-- - - (see Iiauf?**fman, G. B. et al. , in Inorganic Svnthe-? - -sis, J. Kleiber^ (Ed.), pap;. 239-245, McGraw-Hill .

.Book Co., Ine., ITew York, 1963).

Breusova-Baidala, Y. ,G. et al., in Akademia ITauk .SSSR, Ilo. 6 pag. 1239-1242 (ciurmo 1974), discuss the slow isomerization of cis-platinum(II) diamine bichloride in solution to form the trans-compound.

Reishus, J. Y., and Martin, D. S., in Journal of the American Chemical Society, 83, 2457-2462 (1961), describe the acid hydrolysis of cisplatin at temperatures of 25°C and 35°C. These studies were carried out in aqueous solutions at concentrations of 1.5 x 10-3 M, 2.5 x 10-5 M, and 5.0 x 10-5 M, which correspond to 0.45, 0.75, and 1.5 mg/ml, respectively. The authors state that there was some ambiguity in placing the origin (i.e., the so-called "zero point") for the hydrolysis curves because the csm-- --pions required 10 to 30 minutes to dissolve completely even at such moderate concentrations? ozencuelg.,? M..-_ei_al., ,._.in.Jlrm.als_ of .Internai .Medicine ,__6??_?.03^812._.(.?97?7-?,? - pass, in -r.asj3.egna.-i.-i ! .ri su lt at i ? og l.i_ _s var i at i .?s t.udi_ _nr.e din._e.._c Unici. de Illuso ..della?' - c i splat ina.ne i..?.speri2ient ali. ..human-._Dss.i-jn.e.t_t.ono_in_ey_iden?a?c.he- _the .Edicationp . -sub-tto-test?d-io is? raesso-at_ disposition,?ione? di- -three qualified creators through the 1 Investigational Dr! i 13r aneli ?the__ Cancer Therapy Evaluation Program of , .-tliCL_Ntional?Canc.er_Instituti5 ,_ar.a supplied. .as_p.ol.-vRTfi white lyophilized in vials containing 10 mg -di_c?splat.in^_EQ-jag_of_dodecyl_chloride, 100 mg -samitnlo? (USP-X_ed_ ..hydrochloric acid for the regulation; i Do<1-, i -ne-de 1-pH .-When the product is manufactured ^with a volume of i_l.Q__nil_djL_3 c can be sterile for lessons. ' (IIS_P3_c iasc.un mil 1 i 1 i t no_dc 1 la_ri_sult ante solu ti on e -C_QntioiLe_un-_mg-j?i_cjLspl.at ina 10_..mg_ diesami t_olo_... and 9 ? mg? of KaCl?.

.Such ey., R_._iL_e_t. al.._v_in._C.ance.n_What rio.t_he.rapy -Be.nor.ts,-5.Z,? 16-5^Mk71? C19-7-3-) , . describe.-.!.. results: _ -of.- -the.- -first-phase? -of- -their--clinical-studies. -of--the-use--_of? these pills in? the? treatment .of .human .patients .with--a--wide--variety? .neo-plastic.formations.^__CoEic _ :also -in--the--1st--previous--publication., ...the. .medium _ ..was?provided._to. these s t i_ r.i.c or c.a.t_Qri_-d al. Hat. i pnal Cancer Institute in vials containing 10 ml of cis-- - -na,~-90-raq;sodium chloride and 100 mg of marmitel, - for. reconstitution with. a volume of 10 ml of sterile water.- - - - - . ... - . - ;? J? Rossof, A.-J?._et_al.._,.in.Cancer,..30,.1451-1456-_ ? _ ..(1972) describe. ?- results,of their use of..

- .cisp Latin, in the treatment..of .51_human_patients with a . . _ - ? variety? .of_tiny-of..tumors...They claim that the me-- ...

-? . ? -. information provided by the National Cancer Institute was- --_ _ . .produced.by Ben.Venne Laboratories, Inc. and contains-. _ .. - ? - va - per vial 10-mg; of cisplatin, 10 mg; (sic)-- - -- di-mannit-ol-and -Smng-Cnic-X-di-1TaCl , _and that the opulvere

- of a yellowish-white color. It dissolved easily in a volume of 8-10 ml of sterile water. - _ _ -. .- _ Certain information, concerning the chemistry of

_ __ cisnlatine?and_.its_pharmaceutical_modulation.are._ _ _ - given on pages 1-5 and 51-52 of the publication entitled -... _ "CLINICAL BROCHURE, CIS=ELMUiIUM.(II) DIAL21I -_ NEDICHLORIDS. (1TSC 119275-)'% -H. Haldelsman ..et _al. In- _ _ . _ :v.e.s ti National. Drug 3r.anch., . Cancer.: Chemot ber apy 3evaluation. _ ._ - - - , ...

. ... .. ? _ ..Pages 51 and 32 of this publication concern . _ . . _._ the formulation of cisrlatin supplied free of charge by

N.C.I. to clinicians for their clinical assessment in

..-.ciie miter anla_d_s l_cnn_cr.o. , .. ed., in _es c e . Yes. JL reads .how many ; i -continues; j ; i - Eoglio..of...Pharmaceutical..Data._

HSC-r11$875 - CLis-diamminodicl.or-op1alino...(II)-_ L -Formula?ion of?do

.sagelo_10._ag/?:Lala_.:_JEl_.contained._of..each_lial.an _ transparent-of..20 ml__appears.like.1?a whitish_iophilized_mass.Each-.lial...contains...1Ol? <?. of__N?5C-?119S.75; 90 mg of sodium chloride; 100 mg; of mannitol and hydrochloric-acid.for?the,..pH-regulation,_

Pr_enarazione ofIla

-Solution

LO.ung/iiala. __?_Guanio_v_en.ga?_r.icostituito with

.-10 .nl__.di.accu.a.._ster.ile per__ini.ezioni, .USP_,_c.iascurL_ml?de1.the._ resulting solution contains_1 mg_ of_.USC-Il9.675., 10.jmg_di_mannito-__lo-e-9-mg?di-c-1or?ro-di?sodium___ with pH range from 5,.5__a_L, 1S-5

_C.ons.storage. The dry, non-anerted Piale should be stored at the refrigerator temperature of C4-

- 8?C?)..

Stability: __The intact vials have a temporary shelf life.

_ of.a_year when they .are _ stored .at .the .temperature .from.... _ -_ refrigerator_(4-&.?0)-._The recommen= . _ ....stability.mandas? can...

. . . be adjusted during the completion of a shelf-life study of the . ..-duration.of.two.years. Reconstitution. carried out, as recommended, gives as a result a yellow solution. From the liquid, the solution is stable for no more than one hour at room temperature (22 °C). provided it is exposed to normal ambient illumination and no more than eight hours at room temperature. (22 ?H) while the solution is protected from light, the reconstituted solutions can form a precipitate within an hour.

at the temperature of the refrigerator i?i.f and-

ro . (4--8?C) .. . _ !

! Cautions The liquid dosage formulations do not contain any agents.

.preservatives and therefore?, of consi-j._

I told him to throw away the solutions..-! _

.same ottO- 0.re gift_ their. ?l- _

- ...constitution

_ [August,

ClinicaUDrug Distribution S.ection _ _

i

jBmag _P.evelop.ment . Br.ancb _

! _The short question. Britons c o -public and sultry

coL.number ..202194-6A..I describe aqueous solutions.,sta-?;

bili .di , cisplatin having..concentration of. _cisp.la-

i.t ina- c ompr e s a_tra? .aire a- 0 . 1 _ed _1 .0 mg /ml ed. a pii ? _ ? [variable in the range from 2T0 to 5.0. The solutions !i j r -[also_may_also_contain_a_source_of_io~ ' i : | imL. chloride,_as_an_inorganic,_non-toxic, ^

1 acceptable pharmaceutical, for example chloride

. ..'.of sodium, and an excipient composition, such as for example -gannitol.._ __ _ _

_ . .This.instruction.refers.to.stable.and-concentrated.solutions.of.cisplatin.having.concentrates:

concentrations of from about 2.5 to about 2.5 mg/ml. More specifically, the present invention relates to stable and concentrated solutions of cisplatin in a solvent medium comprising from about 30 to about 95% of polyethylene glycol having an average molecular weight of from about 150 to about 5,000 or a methoxypolyethylene glycol having an average molecular weight of from about 500 to about 6,000, or a mixture thereof, and from about 5 to about 70% of water, said solutions further also containing at least one ..non-toxic and pharmaceutically acceptable source.

...of chloride ions in an amount that is at least approximately _ _ equivalent to the quantity of cisplatin present in the solution, and the said solutions having a concentration of cisplatin ranging from approximately 2.5 to approximately 25 mg/ml. . . . . _. _ _ _ ... _ .

Stable aqueous solutions of cisplatin have been described in British patent application No. 20219.46A. Although stable solutions containing concentrations of cisplatin

_ .up.to.about.1.mg/ml.can.be.obtained-installized. ? -zi.acoustic.at.room.temperature,.can?occur.by? _the_re-installation?of.cisplatin.in.the.cold,. .

_ cisplatin concentrations substantially higher than .... _...about 0.5 _mg/ml. Distal redissolution of crystallized cisplatin does not occur readily by stirring at room temperature, although re-solution can be obtained by reheating to approximately 57°C. Since transport and storage temperatures, or after sale, cannot be controlled, crystallization of cisplatin in vials would create an undesirable problem for medical administration. The maximum practical concentration of cisplatin in aqueous solutions is approximately 0.3 µg/ml. _ __Le_s CLIOS i on i_d i_c isplat ina.. d e 1

solution-can contain up to about 25 ml of solution per liter, although the preferred maximum solution is about 15 ml. Solutions of this invention contain 1.5 ml.

na.-for me, they have been ixanthanufce__at the..temperature of?_J _ _ L4?CL?for 12.nesi.__without._cb._sive_verificasse_alimentation._of_cisplatin._ These_solutions_were. -l.o. cooled..to_~60_?C and_pol._heated up to_ - ^room_temperature._without,_any_formation._eyid.enj i

r

.. _ Ite _of ..cisplatin precipitate. Thus, the solutions _ for - Practical. Use. prepared . according to the present invention? _ Ltion. _ may ..have .concentrations .of .cisplatin .at .least .thirty- .times .greater .than .the .aqueous .solutions .for .practical .use . prepared .according .to .the .previous .art?.- -- - - . 1? It will be appreciated that the concentrated solutions of cisplatin provided . by the present invention . will .require .lower .transportation, .storage, .and .other .costs. per unit dose can be compared with known solid solutions. Although even the known freeze-dried solid form has lower transport and storage costs, this saving is more than offset by the time and costs involved.

lyophilization comprises?... __ __ _ _ . . . In a preferred embodiment of the present invention, the solvent medium comprises from about 1% to about 95% (and more preferably from about 1% to about 90%) diglycerides of fatty acids having a molecular weight of about 250 to about 1600 C, and more preferably from about 250 to about

? 650).and.._from about_.1]_ 5-^-a^_sirca_U _2.0 f;? (and more preferably ? .ribably_ from..about..10_5' to..about.15 JO _of_water. In _..a.preferred.embodiment._the_medium_ _often_ comprises..about..90%_of_polyethylene_glycol_having_an average molecular weight_from about_35.0_to..about.45Q_and_about..10 ?'_of_water.. _ _ _

Preferably, the solution contains from about 5 mg to about 20 mg of cisplatin per ml and more preferably from about 10 to about 15 mg/ml. The non-toxic, pharmaceutically acceptable source of chloride ions is preferably present in a concentration of at least about two equivalents per equivalent of cisplatin in the solution. Concentrations of at least two equivalents or more of chloride ions per equivalent of cisplatin may be used. These concentrations are given, depending on the concentration of cisplatin, the percentage of water present, and the amount of water present. lare-source,.of-chloride-ions,.but-such.concentrations.. .

jI I ? high: of -chloride ions- normally, are not..neither necessary-.? . Pari- nor?..desirable..-.Experts in the relevant branch.---

' !

They will appreciate that, with a high concentration of cisplatin and a large amount of water, it will not be possible to obtain a sufficient amount of a chloride ion source, such as sodium chloride, so as to give 50 equivalents of the chloride ion per equivalent of cisplatin. Furthermore, a saturated solution -or-almost-saturated-with-a-salt-of-crystall!-or-in-organ?GO-.would-not....be-desirable_.because_.of_the_possibility_j... -?'l-l-it?--of-crystallization.from-the-solution-in-the-cold.-_ JIe.l.the.situation.established.above, 50 equivalents of ;

-ions, chloride .per.equivalent..? cisplatin^_it_could_be_obtained.--However. -Obtained by mixing ..hydrochloric..acid.. with..source? _chloride ions, but this_ could_ give_ an_undesirably_ very acidic_ solution,_ that is, _ with._ a_ low_ pH. It?s_ found_ that_ excessively_ acidic_ solutions_ are_ somehow_ less_ stable_ than_ more_ moderately_ acidic_ solutions. The range of pI of - . . . solutions preferably is between about 1.5 . . . . _about 4.5? Preferably, they are used from about . . __ _ _ __2.a._about .10..equivalents of chloride ions per ec.uiv.a~ . - ?-,lens-of-cisplatin,...and.more?.preferably from-about - :_ 3?a..about ? .equivalents._of?chloride_ions per ec.uiv.a~ . - - -- .lens-of-cisplatin._

_ _ .Chloride ions.can.be.supplied.to.a.hydrochloric.acid,.a.non-toxic.pharmaceutically.metal.halide,.such.as.sodium.chloride,.potassium.chloride,.calcium.chloride,.or.an.addition.salt.of.-hydrochloric.acid?with.a.non-toxic.pharmaceutically.acceptable.tertiary.amine,.such.as.

?- - triethylamine, or their mixtures? The... source of sodium chloride... is preferred to hydrochloric acid, sodium chloride, or a mixture thereof. _ _ _ ? - _ __ _ _ - Polyethylene glycols and methoxypolyethylene glycols have the general formulas _ _

_ _ __ _ _H:C0CH2GH2)n0H _ and . .

- _ CHpz(0CIio dCH do)nOCHp,_ _ _ __ _ _ ;_ respectively, _e._sonq_available, on the market as-_ _ as Carbouar Eolvetlivlene .Glrcols and Carbowax l'ethoxy . . . . .. ?Polyethylene Glycols . It is preferred to use the _ ._ _ Sentry Grades of Carbowax Polyethylene Glycols, which are ? are .produced, according to the standard for_ aolications of the madicamenti-de^li .Isti-I

U.S.P. pipes , 1T.F_. .and 1 ,G ,C.. . Gl ^intervals of_nesi ..! _ j ??molecular-typical oer-a-variety-ofCarbowax. Polye--i!-thylene- Glycols_ and- Carbowax Methoxy Powder thylene _Gly iicols.-are given..in the _tables.,l_e__2 _

Table 1

? ICarbov/ax- Interval.

J? ly and thylene _ typical .of _.p_e-_ Olycols" _(>*9. so molecular.

.200 _4a 2L.9Q_ 3. 210_ 3P0 281 to 519

. . . 4.0Q _ from 580 to 4-20

- 4 1500 from 570 to 630

1000 d a^SpO _a_ 105.0

154-0 from 1300 to 1600

.4-000. _from 3_00p to_3 700 _ 600CL from -7,000 to

_ ? .(.jfc ) . Gl i c o 1 i : no 1 i e t i 1 e n i c i _ .6 arbqwax.

_ Table 2

."Carbowax . Range .. -4 . iiethoxy . _ typical of pe-1-Polyathylene

_ GlycolsvW

550 from 355 to 565

...._ 550 . . . from 525 to 575

. 750 _ _ _ _ _ from 715 to . 785 . .

2000. . from 1850 to. 2150 _ ... .. _ (.+).-Methoxypolyethylene glycols .Carbpwax.. - --_ _ It is known. that polyethylene glycols form co.m-.

_ __ complexes with certain inorganic salts...Thus, the reaction - . _ _ _ _ -of polyethylene glycols with ammonium cobaltthiocyanate - . -- -born.to form a blue complex.? the basis of a.

? - - colorimetric procedure for determining the concentration of non-ethylene glycols in various mixtures. It is believed that the truly unique stability of cisplatin in the solutions of the present invention may be due to a complex formed between cisplatin and the glycol.

_ .polyethylene, . but this is .only. a .theoretical .hypothesis .and .it .does .not .form .part .of .the .present .invention. . - .evidence.-of-the-formation.of .a .complex ? has _ _ been _ noted _ in _ the _ thin _ layer _ _ _ _ chromatography _ technique _ followed _ in _ the _ present _ invention. Using _ the _ techniques _ described _ below, _ cisplatin _ acouo-_ ..

_ _ sa produces a_m_acohia at an Rf value of about 0.65.

.. _ ....However, a..solution of cisplatin in 90% ethylene glycol-^00? .- acaua at 10 (i.e.

. ...10% of HC10,5-K).provides a stain to a vaio

- re Rf.of-about-.Qv3-which_extends_in.a.strip.u_ ..up-to-about-0.65-..-The-dilution_with-how-many!?_.s_ostan-' !

- biali-di...water appears.Gp.ejszar.e._..irmnediai:anient.e_.the__co.in-_ _ .plex.,-after_the_dilution_-.of?the_sol.uzi..one_.41_-c.uii_ _ sound._of PEG-Ii^0 (or HCl) with_5_^Plumi of water_ .shows.'aljor.a_.solo_o__a.cisplatin.stain.at_such_o_of_ RU J.__c.irc.a__0_V6JL

Thin-layer chromatography. Apparatus and reagents.

5a) Thin-layer chromatography plates - plates _str.e^ EIvL_iahoratories_silic.a_gel_6Q-__number_of_caia! og o_5_76. J, _ o_e mix v.ale n ti ..

0}.)__Lluerte: acetone/UTO^ 1li?(-9/l). To be prepared freshly daily.._ :_

_C_c X JSdevup pa?_or e^_di.s ci.o., gl. 5.6 g of stanrin chloride in 10 ml of concentrated HG1. Add 90 ml of distilled water and 0.2 g of EI. Mix well...Pre.u_ararc_<}L_?r_e_sco_daily._ :

I

(d) Laboratory oven set to 100?0.__

J_ Technique followed_

Xa_)_Divide__the__sample__with_5.volumes_of_dieti1forj_mamide (PHP) (Burdick and Jackson, distilled.in glass.}.

Ch) Stain a thin-layer chromatography plate with 5 microliters of the sample and 5 microliters of a standard solution containing cisplatin (and translatin and datin S, if appropriate) at a concentration approximately identical to that expected in the sample to be analyzed. Develop to a height of 10 cm in a thin-layer chromatography container previously equilibrated with the eluent. Spray the dried plate with the freshly prepared developer solution and then place the plate in an oven at 100°C for 10 minutes. Observe the purple zone.

(c) Approximate values of Rf:

_ .? _..-0165^cisplatin . . -. _ ... . 0.76-transplatinum.

_ - - .0,9-platinum B , . . . - _

_ ...Tests carried out by chromatography on .. _ ?_liquid of.solutions of the present invention _ _ for the content of: cisplatin may be carried out in accordance with the technique described in UK Patent Application _ _ _ No. 202194-6A. The step .

? Preferred mobile standard is ethyl acetate/-methanol/dimethylformamide/distilled water (25/16/5/5). Preferably the standard is cislatine dissolved in dimethylformamide at a concentration of ..1 mg/ml,-.?. Samples for analysis. come- _ ;

. gono.-diluted-.with. dime tilt ormamraide until. ..to _ obtain and _

\

an approximate concentration of cisplatin equal to 1.

_ J_ Although. ..it is not possible to keep _ any.. particular _ __

t |

_ advantage today o_.d to _lo.ro_ _pr.e s.enz a,._l e._ solutions .eie Ila _; _

I i

) *

_ present-invention can., s.e_s i .denide r.a ,_c.ont ene.- _

! !

_ _ _ re., an excipient among those usually used, fi- _ _ _

| !

- - B io 1 o g ic a m e n t e- acceptable _ as ad_..e sciani o__il .-mannio.- _ j _

! ' ' !

i_ - lo.. - : _ _ _ : _ l _

i *

_ I - Based on stability studies carried out so far _

1

? _ you a ti , . the -ut abili. t??pr e vistr.-d elle .s o lu t ioni__del.la-: _

? . I ' I

_ present? invenziane_(.de.f irritates ?How -re.rd.ita di__p_oten- _

j j

_ z a. equal to -10- ?') ? ...greater? than....two ... years? a _t e mpe ra t u- _ :

i ? i

_ r.a amb ientO-. _ _ :_

There

f ;

_ _ In a preferred embodiment of this ?__

t ~~ t

i I

_ inve ns i ore. , le_ e o lu t ioni- s ,o no.. sterile- e.d_.e feel, .dai _ - _

- hydrogen, and are they packaged? in-containers? starili -

_ es ent i-da-_pir.agen.o_. _ Such _. I know lu.sioni__p.o.ss ono . .Then? and sae- _

- r e -of 1uit e for r?es empio _c on _Water . st.e ri le ..per _:ln ie?^ _

_ zi oni. USP-? o_Yv.er.o_is olution._.s.alina_n normal, yes erile _ _

- __USE"? and -are-they-administered?by. -the-intramuscular-route _

- p -ln.trar.en osa,.? X_aez.zi-per_s.t erilize these? s.olm- _ _

? \ J.

_ z i on i_ s ono_gi ?_be.n ..not i_n eJL_ram o_re lativo . . If ll.a.._p_rer- _ , _

_ _ _ sent_in.vention _it_ is_ preferred. .pass_the_-?olU? _ : sions through a sterile 0.22 micron Millipore pyrogen-free filter, using aseptic techniques under sterilized nitrogen pressure. ".Millipore" is a registered trademark of Millipore Corporation for membrane filters. The sterile filtrate is collected in sterile pyrogen-free containers and is finally introduced, in the desired quantity, into suitable sterile pyrogen-free vials and tanned with sterile pyrogen-free tannins (preferably Teflon-lined) and sealed with sterile aluminum seals. -?? For use in cancer treatment, concentrated solutions are diluted to the desired concentration (typically 1 mg cisplatin per ml) with, for example, so-called "sterile water for injection USP," "sterile normal saline USP," or "sterile glucose solution." They are then used by intramuscular or intravenous injection, or by intravenous infusion as is known from prior art cisplatin preparations. Doses currently used with mild to moderately acceptable toxicity are in the range of 60 to 100 mg/ml intravenously as a single dose or as a dose divided over a period of 3 to 5 days, then repeated at intervals of 4 weeks. A safe dose _6Q jns/Mf ..??gr.QS: .nolan.ly ..equivalent. to__l , 5. .mg/kg;.. which_ in_its_ turn!-i ! ? :?- tiOEs.O-lanamen.te _e5uale._.a_lQ>-nig/panlen.te_..of. pesol of . 70-las.._-I)_i_.f.reqxie.n_t_e__sl?i'in_lDipief:.o_.dl. .unaJ;exapial_ -concomitant_CDn-...aLtri-_a^nfel.._ohe,!ni.Qtarapicl._p.er__o-t-.. - tender. imi pilo ri results .

As used herein in the claims, the "chloride ion equivalents per mole of cisplatin" means "chloride ion equivalents per mole of cisplatin". Thus, for example, when using the range of approximately 5 to approximately 7 mol of chloride ion equivalents per mole of cisplatin, one uses an amount of about 5 to about 7 moles of WaCl per mole of cisplatin, but an amount of about 5 to about 7 mol of chloride ion equivalents per mole of cisplatin. from ima _L, 5 to about 3, 5 moles of CaCl per mole of c ys -iplatin, ?accelerates..?

The_nla?the?O__B _? .an arbitrary name here .impi.e.? at,a_p er_un . prodoil or . _d i_._reazi on&-ac_i?_o. of and i s.- . .platin a_r he _?_one half? d.e.l_no me? c_o mp l.e.sao? mas or ._di iagrus ..ed? alruial. ?. s t ata_asa.egnata.-in_via_di _ip o-? the?sasmanta? structure

-H 4i JC1- _ ci _

Pt

. K3IL JCLL

- 1

-.the. present_ invention__.??illustrated by -the. .examples that follow without, however, being limited in any way .. .by them,.

_ _ . . . Example X .. . .

_ _ .. Stable concentrated solution of

. - cisplatin (10 mg/ml) in mixture

_ _ of polyethylene glycol 400 (90#.)/

_ _ - KC11N._.(10/ ?o) . _ ... . . . . 500 mg of cisplatin were suspended in a solution of 5 ml of 1N HCl and 45 ml of polyethylene glycol 400. After 2.5 days of shaking at room temperature (with the container protected from light by aluminum foil), a clear yellow solution was obtained. Portions of the solution were placed in 17 ml amber vials, tanned with Teflon-coated stoppers, sealed with aluminum caps, and subjected to a storage stability test at high temperatures. After two weeks of storage at 45°C, thin-layer chromatography indicated the presence of a trace of transplatin and approximately 1% of platinum B. After two weeks of storage at 56°C, thin-layer chromatography indicated the presence of a trace of less than ?% transplatin and approximately 3% of platinum B. Samples stored for two weeks at 56°C showed a slight increase in transplatin concentration.

.o 19_v:Qlu?i..di.. acciua in- miod.o.. d.a_dare.. s ol_u.? i_oni . 1 wrath-. ...hypid. which .contained re s p e 11 iy.aman t e_2.,..,! .. ,e_0 , .5.jng/rsl. . -Of? cisplat ina-A-mild-turbidit? it-developed-into _ ! , the __ _|each_d.ei__samples.ions- diluted .1???-??;???..?_?.??- about 18 .hours ..a? temperature. environment... _ _ _ I I..2

Solution with stable concentration of dialysate (10 mg/ml) in glycol

..then ethylene 400 _(_9Q_i ZH010.5N

_(.10_..?i)

5 ml of USP purified water and 5.0 ml of 1N HCl were mixed and to them was added 90.0 µl of ethylene glycol 400. To 50 ml of the solution was added 1 µg of cisnatine and the mixture was protected from light with an aluminum foil and stirred at room temperature for 24 hours to produce a clear solution.

Thin-layer chromatography of the freshly prepared solution showed only a single area of cisplatin with a possible trace of translating agent. The solution was placed in 1-ml amber-coated vials, coated with Teflon-lined stoppers, sealed with aluminum caps, and subjected to storage stability tests at various temperatures. A sample vial was frozen in a dry ice-acetone bath for one hour and then allowed to return to room temperature. A clear solution was obtained without any trace of precipitate. After storage for three months at 37-?-C and ? ?

,at 45?C, thin layer chromatography indicated: the presence of platinum J3 at concentrations from 1 to 1

2? and a possible trace of transplatin. After one month of storage at 56°C, thin-layer chromatography indicated the presence of more than 5% but less than 10% platinum B and a trace of transplatin. The samples, stored at 37°C and 45°C for three months and at 56°C for one month, were diluted with 4 volumes of USP purified water to give clear solutions containing 2 mg/ml cisplatin. The diluted solutions remained clear after 24 hours at room temperature.

. . --rat?tra environment. _ _ _ __ _ --.Example 3 . .

Stable concentrated solution of cisplatin (10 mg/ml) plus CaCl^

(20 mg/ml) in polyethylene glycol

400 (90 ?J)/HC10,5N (10 ?)

2 g of anhydrous CaCl2 of quality? "reagent" came: i j

- .vain. disaiol.ti..in_a__mixture..of _5 ? ral gods. accua ourij - :^cata_USP_e_5-inl-di_HGl_.lN* .89 -Dii- -di_.;-;l.ic_ole._polie-..

- itilenic or 400 .arano .animiti .cos.?_da_?ori are_il voJLu-! i - 'Me., a. 1GQ 50._ml_di._Quest.a__s-Qlu.z:LQ.na_y_eniv-an.Q _ L_

added- .5-50- .mg: _ of._ c_ispl at ina., _ _e._ Xa_jois ce la_rra_prp-; i i ? jtejfci.a__.da II a_luce_.c_Qn an aluminum leaf and acti-

? |tata_a_tesperatura.-ambierite..for .2.4__hours..In_way_.from__d.to-_.

;re_a_clear_solution. Crosatography_on_stratb

-- :thin-of-the-freshly-prepared_solution indicated I " i _ ..only..a_xoiia_of..Latin_C?sp__with a trace pos-__

;

- i|hissable. of _trans.n "l at in a. Ali au.o.t and ile 1_ volume of 2 mi j

_ The._solution were placed in staining vials! i I i _ ln.P_-j?m~hra__1.volume of 17 ml, tanned with caps re-

t i _ iv-estiti_di_t.e-fl.on,_sigil.lat_e_ con_eaorucci di alumi-I1 ? iI _ _ rio?e_sattoposie_r.ller stability problem? to conservation

_ lv.azipne_a...avari_t.emp_erature. A sample vial__

! ^ ?i _ -was-p-os.t.a in..a bath of dry ice-acetone _

_ pe-p ?? &7.7, 'now and frozen until it forms a transparent gel-

_ ?rentn. It was then allowed to return to the temperature

? ra? I love i e n t e__e_ y es ...obtained a_solu ti on_1. Do-

ino conservation lasting three months at the tera?

ppratrm of 57?C, thin layer chromatography

-indicates?the--presence_of.a.conc.en.txation from__l.to 2 %

t?i platinum B and a possible tiaccia of transplati^.*-

After three months of storage at 45°C, thin-layer chromatography indicated the presence of approximately 5% platinum B and a possible trace of trasnlatin. After one month of storage at 56°C, thin-layer chromatography

A thin film indicated the presence of 8 to 10 µg of platinum B and a trace amount of transolatin. Samples stored at 37°C and 45°C for three months and at 56°C for one month were diluted with 4 volumes of USP purified solution to give clear solutions containing 2 mM/ml cisplatin. The diluted solutions remained clear after standing for 24 hours at room temperature. . . .

__ 1 . . Example 4

Stable concentrated solution d.i.

: . _ tea isplatin (about 22 mg/ml) more _

CaCl^.(25 mg/ml) in polyethylene glycol.(90 ?)/HCl 0.5I\T (10 ?) _ . . To a volume of 3 ml of a solution of polyethylene glycol 400 (.90 1') and HCl 0.5I\T (10 ?') were added 45 mg of cisplatin, and the mixture was stirred for about an hour at room temperature to obtain a clear solution. A quantity An additional 30 ml of cisplatin was added (for a total of 25 mg/ml) and the mixture was stirred at room temperature, approximately 45°C, for one hour and then in the usual natural state. The solution was to be produced in a nearly complete solution. The small amount of insoluble material was removed by filtration. The chromatography on a thin layer of the filter was performed.

j-to mo s t r ava . only ament and . a_zone of_c i spi at.ina_ . with one? the possible trace sdi _tr_a;a.s.p latin o..,JC;a__part remaining.. of the filtrate was stored in a color vial, [amber. d e 1 _ v o lurae .. a ' i_? V/L m 1 .f.Q.rni.ta._di_un_tappo: rive i-. ... Stito. of ..teflon, .seals.t.a..with_an._capppccio_ of_allup_. mino-e_msntenu.ta_alla_.tanip_eraiJura_di._t5--^.-l)er._tjre._ i _ m e si . After aging for three months at 45°C, chromatography on a thin substrate indicates the presence of

I

- i-za-di -a -concentration? from ~al-_2??i-di? nlatino-S ? ' [ '

. _ |e.._ne ss.un._qu antit at. ivo. Of. . trans p latin o . _the_of 1 uiz i o.ne.

! ? _ of the... solution - placed- acLinv.e echi are ron_acuuarpuri-^ ficaia USP .filio .at.a concentration ..of .2_mg/ml._of. cisplatin, .clear solutions._that_remained_so._even, after standing at? room temperature? for _24_ hours..

-Example- -5 ?

Concentrated stable solution of

i

i

X cisplatin .(12 mg/ml).pi?-NaCl?

(10. mg/ml) _in .ethylene glycol.

400 ..(90 il) /HC1 ..0 , 5N- (10 #)-- -

100 mg of sodium chloride was dissolved in a 5 ml solution of USP purified water and 5 ml of HCl-12. To this solution was added 9.0 ml of 0.0 ml of polyethylene glycol and the mixture was stirred for 1 minute. 5 ml of this last solution was added. 50 mg of cisplatin was added, and the mixture was stirred at room temperature for three days to produce a solution. _ clear._-Thin-layer chromatography of the freshly prepared solution showed only a single,...late cisp spot.,._Liquid chromatography. high efficiency test carried out on a freshly prepared solution showed that it contained 12 mg of cisplatin per ml. Aliquots were sealed in amber vials of 17 ml volume as described in example 3 and subjected to stability tests at various temperatures and observation at 57°C for a period of three months. Thin layer chromatography indicated the presence of a quantity less than 12 mg. 1% platinum B and no significant trans-platinum concentration. After storage at 56°C for one month, thin-layer chromatography showed the presence of 1 to 29% platinum B and no significant trans-platin concentration. Dilution of the aged samples using purified water (USI! ? I) to a concentration of 2 mg/ml of cisplatin gave clear solutions which remained

such even after resting at room temperature for,... - *24 hours,_ _ _?_ ..:_ _ _

Tests carried out using high-efficiency ointment on samples stored for three months at a temperature of 45°C, for several months at 37°C, and for eight months at room temperature showed power losses of 6.6g and 2g, respectively. Example 6. _ _ _ _ Solution.

__ cisplatin_C.11,4.mg/rol) plus..NaCl_

? -(10?mg/ml)?in.polyethylene.glycol-_

:o-400 (90 -%)/water (10 fi)_ __

- To a solution of 50 mg of NaCl in 5 ml of purified USP water and 43 ml of polyethylene glycol 400 mg were added, and the mixture was stirred in the dark at room temperature for 6 hours to give a thin solution. Thin-layer chromatography of the freshly prepared solution showed only one fflac-j ^ ! ' ' ' .. ?" "T" cisplatin. The test carried out by high-efficiency liquid chromatography showed that this solution contained 11.4 mg of cisplatin per milliliter. Aliquots were sealed in 17 ml amber dye vials as described in Example 3 and subjected to chromatography tests.

_ _ stability, to, .storage. .at various temperatures. . .

- After storage at temperatures of 37°C and 45°C for three months, thin-layer chromatography indicated the presence of 12' jif-jiLatino B and no traces of

. - - transolatine litative. The .dilution .of the samples . .

. . aged .with USP purified water until obtaining _ a .concentration .of .. .2_mg/ml_of _c_.ispl at ina dava _

_ _ transparent solutions, the. .aualilre.stava no such also

. _ after resting at room temperature and for 24 hours . . . _ _ The . tests, carried out by means of high-efficiency chromatography on samples stored for three months at a temperature of 45-?.0°C for six months at a temperature of _

_ _ 37-?-C and. ..seven .months. at room temperature showed _ _ no.. power losses compared to?_iyamgnte_ of 6.1 #., 7?_0r _

_ _ _ _ Example. _7_ _ _ _ _ _ _ Stable concentrated solution of _ _ _ ; _ cisplatin (10 mg/ml)_.iii -glycol . _ _

. . _ _ polyethylene 6.00 .C90-^)/ECl 0.5 N .

. _ . do ro _ . - _ _ .' . _ _ _ __ To a solution of 2.5 ml of purified water.

_ ESP, 2.5 ml of H31 IN and 45 ml of polyethylene glycol

-to 600 mg of cisplatin was added, and the mixture was stirred in the dark at room temperature for 5 hours to obtain a clear solution. ; _ ! Thin layer chromatography of the freshly prepared solution was performed. Only one spot of cisplatin was tested. Samples of the freshly prepared solution were diluted with 1, 2, 3, 4, 5, and 9 volumes of purified water.USPj?these..dilute solutions did not_ - show any_crystallization_phenomenon_for_

-rest of-ISrore-at_temperatureaixhient_a__ovvero.a 'HI? ^waxing of- 4-?C.._Parts alinuo-te-from-saluaione?.prer

-freshly prepared? were they? s igi 11 at and _ ..in vials._.of.. . co-1ore-.abra with a lumen of 17 ml as shown in example 3 - and Jeran.o.oi._so.ttjoppste_tests_of -- ? !stability?-to storage_at_various_temperatures_ _ !*Bo-oo-Oonserv..-at_3xatupa_of_32?C_and_of_45?C! * ' . | 1 _ jjer?si, thin layer chromatography indicated the presence of 1% of Platinum B__and_absence_of_

1

_ ... -transplatin.. . After storage at 56? C for a while, thin-layer achromatography indicated the presence of:.3,4 of .platinum 3 and no Quantity -of?transplatin...the dilution of the samples ages-|

i

?ti_with purified water.USP until_a con-?' -j contraction -of 2 mg/ml-of. cisplatin _gave_.clear_ solutions-, the. .which remained. the same_even_after_ resting at room temperature for 24 hours.

..._ _. _ _ _ Example .6

- - Concentrated..stable solution of.. . _ - - - Lcisplatin (.10.jag/ml) pi? I'Ia.C]_ ..__ __ _ ,_ (1.0_ng/ml)_in.giico1e_ppiie tile-_ _

- nico 400 -C-90 HCl_0t2E _(1.0l)- - . . ? _ ;_ To a splur3?Qne of C,5:% of N,aGl in 4 ml of USP purified water, 1 ml of EOI IR and 45 ml of polyethylene glycol 4-0.0 were added 250 mg of cisplatin, and the mixture was stirred in the dark at room temperature for 4 hours to give a clear yellow solution. Chromatography on a thin layer of the prepared solution. freshly showed _ . _ only. a. spot ... of ci splatin. .The. dilutions.. _ of the freshly prepared solution. with. 1., 2., 3., 5. and 9 volumes. of.. purified water gave clear solutions which remained clear after 24 hours at room temperature. The dilutions with 1, 2, 3, 4. and 5 volumes showed no sign of crystallization and were kept at 4?C for 24 hours. Aliquots of the prepared solution. The fresh samples were sealed in 17 ml amber vials as described in Example 3 and were subjected to storage stability tests at various temperatures. After storage at 37°C for three months, thin-layer gray chromatography indicated the presence of 1% platinum B with a possible trace of transplatin. After storage at 5°C for three months, thin-layer chromatography indicated the presence of 5% platinum B with a possible trace of transplatin. After storage at ?S-0-CLps temperature, nm_ mene la_ctomatography, .on a layer. .sub_i_ j

-ti le., indicated the presence of 2.^ 3_ ?i_di. -platinum...B .and _ I j absence of, transplatin._ The dilution of the .samples L__ i( !t -aged -with purified USP aqueous solution...up to a concentration of .2..mg/ml_.cisplatin..gave 3-comp.ic solutions that..remained..clear after resting for 2 hours _?-room temperature._

_ Example._9

Stable concentrated solution of

- ciapia.tina..(2,5.mg/mi ..HaC.1(9....mg/mi).

a.-marmi.to.lo_(12.5.mg/ml)._in _pQli.ethylene_glycol_.SOOO '.acidifiedat__ 1_.'31 % -(weight/volume).aqueous_

(1 i Sodium chloride (0.9 g), mannitol (1.25 g) and ethylene glycol 6000 (51.5 g) were dissolved in a sufficient volume of purified water. I prepared 100 ml of solution and then the solution was acidified to a pH of 2.2 with HCl B 4 (0.7 ml). Isolatin (255 ml) was added and the mixture was kept in the dark for three days at room temperature to obtain a clear solution. Chromatography, on a thin layer thin..of the solution. _ _. _ freshly prepared. showed, only..an .area.of_

-- ,- cisplatin. Portions of the freshly prepared solution were sealed in 17 ml amber jars as described in Example 5 and subjected to stability tests at storage temperatures of 5°C and 56°C.

_ After .storage for two.months at temperatures of .

_ _ 45-?..C and 56?C,.the.mo- thin-layer.chromatography.

_ ?_ strava .la.nredenaa-jminPJ9...dell.,JLil..di _p.latinq._B ed_

_ ! absence . of .transplatin . The. dilution . of . the . samples .

- - aged-, with .an. equal. volume.. of .purified. water. -_ _ _ _ USP gave limoid solutions that . remained .clear ... . _ . _ : _ after . resting, at . room . temperature for .24?. hours. ? ..

_ __ __ Example._lQ_ _

_ __ Concentrated, stable solution of_

... - - cisplatin .(15.8 mg/ml). plus ITaCl . -_ _ (10 mg/ml) in polyethylene glycol . _ . ... ___ __ _ _ _ 4.00.aqueous al.90 Si._ . . . ..

Polyethylene glycol 400 (90 ml) was dissolved in a solution of 1.0 g NaCl in 10 ml USP purified water. A 60 ml solution was

, many__.were added._900_rags .of_oisp].at ina .and. the. _; The mixture was stirred in the dark for ..five..hours_at_room_temperature_to_obtain-a-clear-.._ 1 I ?pical. Thin-layer chromatography-of-the-..only.-... _ t tion. freshly prepared .indeed...only a zo-_ _ I

! ? solution of _cisplatin_; the chromatogram of a liquid with a high efficiency, carried out as a test, showed that Os- _ _ i sa.. contained 15% of cisplatin_.per ml, the dilution?-_ .. !tion_. of the solution..prepared,.of.?re3cp_with _quat_H. .

The volumes of water-based solution were found to be rapid and liquid, which remained liquid after standing for 2 hours at room temperature. Portions of the freshly prepared solution were sealed in amber-colored bottles with a volume of 17 ml as described.

! ? _ in example 3 _.e_were_subjected to stability tests suitable for storage at various temperatures. ;

p - ? ~ i _ _After_two_months.of_storage_at_a_temperature_of_14-5_C,_the_thin_layer_chromatography_indicated_J_

\

. _ '111., 5- %- ?i - platinum B .e d _a s. cren 0.a__di_ t r an s p 1 a t_in o . ; _

i _ ...JAfter a month of -.storage.. at-_t.e.mperatur.a.-_of___[ _ _ ?560C,-the-chromatography_siL-thin_layer_indicated

_ the presence of the 2. of latin B and the absence of trans- . - .platinum. The sample .aged ?at 56?C was diluted to a .. concentration of 2_mg/ml _ [with water, sterile .. for .injections, and _the _sample .aged .at 45?C was diluted to the .

? -contractions of 2.5..and 5.0 mg/ml -of cisplatin with .

_ sterile water...for injections. Each formed a solution...

- clear, which remained clear after resting at room temperature for 24 hours.. _ _ _ _ _ High-efficiency liquid chromatography tests were performed on samples stored for 3 months at a temperature of 5°C for 6 months at a temperature of 37°C and for 8 months at room temperature. _ showed losses of 1 7^ S S:, 7.6 .# . _

_ .and -O.ii,-respectively _ _._ _ -_ _ __ _ _ -Example?11_ _ _ _

_ Solution._ji.oiicentra_3?iLb.lle_di_ ;_ ?. _ ..._ cisplatin (15^mg/ml) .pi?..CaCl?^ _ _ _ :_ C?5-ms/mL)_.in_slicole_polietileni-_ _ . _ .co_4r00-aqueous_al_ _

J_ Note: Cisplatin is a possible carcinogen. Protective gloves, masks, goggles, and respirators must be worn during the entire procedure. All work areas and equipment must be thoroughly cleaned to avoid further future contamination. . _ _ _ . ...

.sodium_chloride.? 0.0.15 ; ..._0.150.?:?

i

acid, hydrochloric 0,pyr('"2)

.0.10 mi. _ 1.0 mi_ ethylene glycol...A.OQ?

- Cprodot to.Sentry)_ .Glove,. -C-uarto:.

..enough,to _l_,.CLjnl enough to 10.,.Q.rnl_ ,_ _ (.1.) This...weight..of .cisplatin .assumes.a?power of 1

- 1jOOQ_mc.g/mg.-.To ..determine the quantity?_of cdsplatin__.

I ;

! j

- if you are someone who loves the errruent, ask me to: _ i

I ? !

_ ?0Q0_x_Qr015-* _

= g of cisplatin ??i?

! .Power. of _ ci.splat ina _in.. nieg /rag. .asked _ i _

.(_2 )_A ..1 it.ro._of? acid....c 1 oridric 0 , 5 IT . comes? cracked r?-r_

;o? c CHIC _ angue :

??

._. Eo r re_057 , 25Vo.i_ a c qua.. s.t er ile., .por _inle.zicni ,

- . USP_An_um ball? di.._Erlenme.y_e:r_pulit_o_ .d.el volume.? Of.

-un_li-t.ro .

2. Shaking rapidly, slowly add

_e_cnn-caute1a !?,_75_.nl...of .concentrated hydrochloric acid-_ to-_A.gi.tare_nar-lQ_L'iinu.t.i..__larnar-e.._with^a_cap_of_

_ go ramalo ut ilica_p3_ul i to....

L, Instructions for preparing one litre

_ of _ solution _ s t e rii e _

i_ 2__Put 1G0.ni of hydrochloric acid_0.51L h

in a clean, calibrated Erlenneyer flask

!

of a liter containing a suitable stirrer, such as._

i

i

'for example, a magnetic rod-dweller, 6cm long, coated with Teflon._ _ -_ -I

t__ _ 2. Add, with moderate stirring, 1.5*0 g 1

I of sodium chloride...It is stirred until the salt is dissolved.

!completely-melted . _ _ _ _ -?

4)_ 5?._Si__a.g. arrive with rapid,.agitation..750 ml; polyethylene glycol 400 (product_S.enirv)_.e._si_ t

shake for five minutes, :- --_ _4 ,_Si__r imu py e_l * stirrer _a . magnetic rod _ La_si . drains, the excess fluid into!?? flask... _ : j

i

_.J_ _ 5-?-The_15-,0_.g. of active_ ?t-?-cisnlatine_ is_added_with_caution._

6?..Add_polyethylene glycol 400 (JSentry product.)-up to the liter mark...(-a._total_of- -f

880 ml of polyethylene glycol 400 ml - - 7. Add the shaken Teflon rod to the mixture and stopper it with a clean butyl rubber stopper. 8. Wrap the flask in aluminum foil to completely exclude light. 9. Shake rapidly for 24-48 hours at a time.

- datura - ambient. A clear solution should be obtained. If a clear solution is not obtained within 48 hours, the mixture can be heated until ?

. .at ..37-40?C for _2-6 hours in the absence of_.air and.light so as to facilitate the rapid dissolution.of the cis-_

? - remaining platina .-_Yes-.cold. -up to _-23-27? C... ?L

__ !_ 10. _Using an ase11ic technique you can get through:_

- the.-solution-of..yellow_oil_acuro?under..alappr?-, .

i ! ? -priata-pressure-of...sterile nitrogen.,--through--an _adat-

i \ - to-f-il-tro?sterile-free_from_thermogens_.Millin.hours_from_ ?_ i ? '? ? I - " Q!,.22__micron._-S?i-collect_.the.-_filtered__s.t.aryl^LrLini;!_

_ pi'a'llone_di_Er1enueyer...sterile and .esente.dn.pir.Qgcnij'

! t ?. _ It is closed with a sterile butyl rubber stopper and 1_

..free?from-pyrogens...The.solution.-preceded_with..on.s.e.rv_a-; | -ta.-in.the.dark,._

11. Enter the required quantity of the

JS-olnzinne sterile in sterile co1ora tion vials

-ambra es?nti__da_piromeni. It caps with tanni of tea-? : 1 . ? t 1on-Starili?esanii_da pyrogens. It is sealed with ele-1; Sterile _:nen.t.i__sigillant.i_.di...siluminium.

__ 12. The vials should contain the following?

-et-iehetta_.a_tit.olo_di._precauzione.j_.

NOT FOR DIRECT INTRAMUSCULAR USE 0

INTRAVENOUS *

^PEG-4-00 solution can be diluted with

H sterile water drops for injections USP

_op.p.ure__so.Luzion.e..-sa_Lina_norriale___ste_rile_ IS_P_

J_ in order to give a solution of cisplatin j ; J_ at a concentration of 1 ras;/??-1.?If higher concentrations are necessary, one can use: i

- - ?? juna-nuantit? proportionally-lower than.water.

i

_ sterile or saline solution. Diluted solutions.

_ ,- 'they can be used for intravenous use..^ -They are. _

|

- stable at room temperature (22-25 °C) for at least

- -- 48 hours and...Do not cool diluted solutions,...because?

_ jpotrebh.erosformarsi.,cristalli... __ _ >.

!

_ !!_ __13.-The vials are kept in the dark. _ .......

_ ^_ |_ ._ _ _ Example 13_ _ ]

_ j_ _ Stable _ concentrated _ solution of _ ^ _

_ I _ , _ ci splatin .(2 , 5. ng/ml) _NaCl (9_ mg/ml.)_ ; _ ?

_ CaClp_.(1-5?mg/ml)..and_raannitol._(_10_mg/ml) _

_ _ j_:_ in .polyethylene glycol .400.in_ _

_ !_ solution.causal_at 31.-?...acidified- . .

i

!

- :- j?- cata. - :_ -_

- _ _ j _ Q,9-g- of.. sodium chloride, 1 , 5 a of _CaCl _ed -.l , 0 st ..

I ? ^ _ : _ Idi-manni bolus were dissolved in_a mixture of 31 .25 ml j

_ Ldi-polyethylene-glycol -400__e_4CLnil.di_acqua_pure-. ..

- ficata.USE._Iia s.olution...was acidified up to_pH?

_ -_ ,?,? with a volume of 0.4_ml_of_HCl IN, then_add-

_ lgevano-255-mg.of ..cisplatin,-_the volume.was brought

_ _ i_a.100 ml with USE purified water.and the mixture was

_ 1 stirred in the dark for five hours at room temperature

_ Environment-so as to obtain a clear solution. The

|

_ _ , thin-layer chromatography_of the prepared solution. _of._ _fresh_sc_o...mos ti ava. _s_o.lt breath, .a..zone.of.platinum. - - -

_ Example . 14-

The general technique...skies.example .1 comes....r.ipe_-

_ i.'_all_except_that_the_sodium_chloride_used_there__?_ i

}substituted Aa an equivalent amount of chloride

magnes and_in this way a solution is produced

_i n e--.-C.anc.e ntrata .states of ci a platina.

1

-l_ Example_._15_

The general technique of example 5 is repeated

except that the sodium chloride used therein is

from an equivalent quantity of hydrochloride

Jj-Q?deIla trieti1mira and thus a solution is produced

stable cisplatin concentrate

_Exam.i>io_lS_

The general technique of example 5 is repeated.

and>r.cept that polyethylene glycol 4-00 is used therein-

zato .is replaced by an equal volume of the ^lico-

the pnlioti1anici 200 and ^00 respectively, and yes

thus producing stable concentrated solutions of cis-

_platina,

Example 17

The general technique of example Q is repeated.

except that polyethylene glycol 6000 is substituted

t o ria an equal weight of polyethylene glycols

1000 and 4000 respectively, and...concentrated and stable solutions of...cisplatin are thus produced.

. . . . . RIVEHDICAZIOHI_ _

.. ..1..Stable concentrated solution of cisplatin

iin -a solvent medium.comprising?from about -30 to .

f

approximately..95-$-of..polyethylene glycol..having, yield .mo-I

medium molecular weight from about 150 to 9000 c, i.e. a methoxypolyethylene thread having a molecular weight of

-hilar, medium or_. from__ about 300- to .about 35,000, or a lo-

- __;ro_mis.cela, . e.. from ..eir.G.a_5 -% a. circ_a.J7_Q_?.._di._acjqusL,__._ _

i

_ Ldet_t a. solution^ also contains at least one source

!

- oion .pharmaceutically toxic..acr_et.tab.il.e_.di_i.oni_

you '

? _ \ chloride _in_ cmantit?.ch.e ?_at least _all 1 approximately__eauivat

t

- - Smelly ..at the -quantity? of ..cisplat ina_present_. in, so-_ ...

- - ? solution, .and ..called _s.alution-avendjQ_ima_cjonc.entrazio~ .

4ne .of. _cis platina ranging._from.approximately_2.5...to. approx. at _25_mm/m 1 . -_ 2 Concentrated solution _ .stari i1 e__di jc i.splatina _

- in a solvent medium comprising approximately 80...?La_ - approximately 95? of a polyethylene glycol having an average molecular weight of approximately 25? to approximately

_ i-1600-.or. . a ..methoxypolyethylene glycol. having

_ ? an average molecular weight ranging from 30Q to 80.0, ^or

? - - iuna -loro miscela, e da circa. 5 ?L.a . circa. 20 3 di ac?

_ Lq.ua,?said?solution also containing .at least uria

i

- _ The source is non-toxic and pharmaceutically acceptable.

j

{

- ;d?_ ion... cloTt?ro__iii_ q.u ant i t a ...c.he . ?_ v .ari ab.il e _ne_X 1_| in- .? . l ; ..it.er.vallo_da .about an o_ equivalent. to approximately- 10 .e.quiva-_ilenti_p.er-eauivalent.e_ of -.ci splatina in.. solution., _ _ j e__cle.t t a_s o Inzion e._c untene ndo_Jla._ci rea 5 a c i rea.- 20_jag . I ; idi?cisplatina-per?mi.- :_ \ _ !_ o1u tion of cisp_latina-as -claimed in the-.jl.u_.riYendicn.iii.Qne__2._in.which the non-toxic source ! % ? i -?? armac eut i.c ameni a .acce.tt abil?_di.i on.e__c l.oruro__ .?__a.cjL~ ?do., hydrochloric, __cJ.orur_o_di_l? odium-, calcium chloride , : I i . Ic?magnesium chloride or <31 or hydrate of. triethylam- _ i ? j 1 d1mina- or ro- their o-ini s is hidden. _ _i! ; i _?_ 4 .-Stable concentrated solution of c?spiatina ? Iin un-renzo.._s.o.lvente._eariiprendinte?_d.a clr_cfL__85/n.a._ci ir--ica--90-- te n1icole._po1ieti1enico._avente pe.s.Q.-ULO1eco-ILare-medio_da_circ.a_2.50-r.circa?650_e da circa 10 % i

of about 15 t/l of water, said solution containing also a source of chloride ions selected from chlorohydric acid, chloride ions, hydrochloric acid, and chloride ions, in an amount ranging from about 2 to about 7 equiv/l per equivalent of cis-Linyl in the solution, said solution having a concentration of cis-Linyl in the solution varying from about 10 to about 15 t/l.

5.?__S_oJ.ution of cisnlatine according to the claim-?dieato-in._claim_4_inurui_l_a__det1a_solu-!

i

j.tion??-S?erile.ecLe contained_j,n a si--- - pilled container such as a vial. . - ? -- .

. . . :- 1- 6. Stable, sterile, concentrated solution of cis~

f

? t

_ _ slatina- in a sealed container like e.g. I'm wrong

? I

_ ,a vial,?. the. said.. solution containing. one. how many?

_ _ t?. variable from about -10 to about 15 mg of cisplatin

. - - - per-ml? and -about- 10- to -about 15 mg of NaCl ? per mi -? ? .

i

- - -in -a -solvent -medium -consisting -of - approximately - -90 - of - a -

I

- - - - polyethylene glycol having -average molecular weight

i

_ various abilities_from_. about 350 to about .450. .and .about .10. ?Ldi

. i :

* '? iacqua . '?

?

_ _ i ? _ 7..?.Solution._c.oncenf rat ?L_st able. sterile ci..c.is-!

- -p3.atina-.in -a_ container, sealed-as . acL esempio _

- a._formalized.solution..containing, a Quantity?!..

f

- varying-from-about -10-to-about -15-0g -of -cisplatin _ _

- per-.ml _.e_da- approximately -lQ_a_. approximately. 15 .mg of Nudi per jnl_.in. _ !

- - a solvent medium consisting of a corresponding quantity

- - corresponding_to_about_9Q_^ ..of_a_polyethylene_glycol_.

- having a variable average molecular weight. from_circ.to_3 50. _

. . _a-_about A50- and.d. a..Glove corresponding to_j:approximately .. _ _

. -. diluted lQ-^-di_acidQ -hydrochloric-, having c.oncentration- _

- ne. up. to .about _0.5 H. _ _ _

IN VER TO RI. IN COM3 DECLARATION, POWER OF ATTORNEY AND. APPLICATION

We, MURRAY ARTHUR KAPDAN and ALPHONSE PETER, GRAND ATEK, hereby declare that we are citizens of the United States of America, residing at 1026 Glencove Road, Syracuse, New York and 8323 Oswego Road, Baysville, New York, respectively; that we have read the foregoing description and claims and truly believe that we are the original, first and joint inventors of the invention in PARMACEUTICAL FORMULA (RD-16-17) described and claimed therein; that we do not believe and do not inherit the present invention, whether was never known or used prior to our invention thereof, or has been patented, or has been described in any printed publication in any country prior to our invention thereof, or for a period exceeding one year prior to this application; or has been in public use or on sale in the United States for a period exceeding one year prior to this application; or has never been patented or made the subject of an inventor's certificate in any country outside the United States in an application filed by us or our legal representatives or assigns for a period exceeding twelve months prior to this application; or that we recognize it is our duty to furnish information of which we are aware which is material for the examination of this application.

^this application; and that no application for patent or inventor's certificate^ on this invention has ever been filed by us or our legal representatives or assigns in any country outside the United States. _

And we hereby appoint Herbert J. Taylor, Jr., Registration No. 18,177, David M. Morse, Registration No. 25,742, Richard R. Lloyd, Registration No. 22,632, and Robert H. Uloth, Registration No. 26,041, of Bristol Laboratories, Division of Bristol-Myers Company, Post Office Box 657, Syracuse, New York 13201, as our agents and/or legal representatives to prosecute this application and to perform all Patent and Trademark Office transactions in connection therewith.

WHEREAS, we pray that a Patent Certificate may be issued to us for the invention or discovery described and claimed in the foregoing description and claims, and we hereby sign our names to the foregoing description and claims, to the Declaration, to the Power of Attorney and to this Application.

The undersigned applicants further declare that all statements hereinbefore made are true to the best of their knowledge, and that all statements made in accordance with information and opinion they believe to be true, and further that such statements were made with knowledge that intentionally false and similar statements so filed are punishable by fine or imprisonment, or both, under Section 1001 of 118, United States Code, and that such intentionally false statements may impair the validity of said application or any patent issued thereunder.

Inventor^: f._to Murray Arthur Kaplan

Date: March 25, 1980

Post Office Address: 1026 G-lencove Road,

Syracuse, New York

Inventor signed ) Alphonse Peter Granatek

Date: May 27, 1980

Address: Post Office: 8323 Oswego Road,

Baldwin's ville, New York.

, THIS FORM CAN? 1 BE EXECUTED! ONLY WHEN .ATTACHED TO A COMPLETE ??) SEND AS THE LAST PAGE BEAUTIFUL SAME

HYPER TRANSLATION OF THE RME COINAGE.

4?.. ENG. JBARZANO & Z Ali ARDO S .p.A.

6898

H --.4*'

A&

. Cl '

\>

VA-

Oh?

P

?

48U90A/8

?, SY-I617

_ BISSO RI.21 OHE .

a ..corrosion of_.a. patent. application. for. an. invention

the iavante per titolo..: _ _ . _ ? _ _? !

4.'.'Solutions. c.onn.entrat e. stable of c useful isolates.

. - - - icome- pharmaceutical compositions,. and., related .procedi-[

- - Production .ment'/ ? - - - - ? _ ..

!

- ja- name :_BRISTOL .. -KYERS .C OMPANY rJ-yfv?1;

Description changed

(art 49 Presidential Decree no. 333/1979) |

application filed on _ _ _ SUMMARY _ _ _ ; .. .

The present invention relates to s?luzio-

.?ni?concentrate? stabili- of which I spied ina.. in .a. solvent. _ [

I

4c comprising_glycol ..polyethylene. o_glycol_jnetos- .

ns ipolie t il enic o. or, .a ..their _mixture the ,__.more?_ water.

-odmra. non-toxic source, pharmaceutically. accept-

-1 able to le. of i oni ^c lo rur.o. . _ _

L?

_ DESCRIPTION OF THE INVENTIONS

- The present invention refers to solutions.

. _ stable . concentrates . of. .cisplatin. in polyglycol

- .ethylene . aqueous glycol, methoxypolyethylene , or .

_ _ ,1 gold .mixtures .containing__a_source_of_chlorine_ions~

._... . ;rq. _ .. _ . _ .... _ _ _

_ __ Platinum compounds.. are._ a_ criminal group

-of compounds in the environment or of antineoplastic agents. I

They were first noted for having an antibiot. effect by Rosenberg and his colleagues in 1965 (Rosenberg, B. et al., T. Jatupe, and C. Londr., 20.5, 69.8, 699, (1-96.5-)-). and subsequently by

The same. -Rosenberg. and. his _ collaborators-? ..been. informed? that. _they. are. _potential__ tumor] _ n e g 1 _ ; animals (Rosenberg, B . e t_ _.al_._, ... Natu r e..-.( Londr_a) 222 , i ; ? L3-8-5-^38S?C19&? )- L ..Utru_t_t_ura1mente..they represent a comp?es o .Liorimated by a platinum atom in the central position i j a and?nircondato?da.s\rariate_dis.tribuzi.oni_b.i__aiomi_..di.._ j chloro_o_.groups_of ammonia in planar relation _ ?__ _cis o_brans. Two of the most platinum compounds? comu-:.nement s.t.udia11..s.??.?.__?_??o_S_ti_scbematically here under.o_

1 . ;7

THERE ??

Pt

Pt

TTH

Cis-platinum (II). Cis-platinum(IV)

.d.iamiminodicypruro_ diamminetetrachloride As can be seen, the compound indicated by the term...di...c Ls-platinum(II) diamminedichloride possesses all of its chloro and amino groups in a single plane. This compound, currently known as cisplatin, adopted in the United States, has been synthesized according to the following reaction method.

?.JVtci4j NH4C1

. c.i<? I-t(I;H3)2Gl2] 2 ICC1

? ( si _ueda. .ICauff man , . _G . R.-_e.fc_ al- ,_.in Inorganic. -Svnthe-? sis ,? J?- Kleiberg (Ed . )-,--pag . 239-245, - McG-raw-H?ll -_ Boolt-C.o Ine . , ..iiew-Y.ork, .1963) * _

.1 _ Breusova^Baidala, _Y. . G-_. et__al . .in Akadamia ITauk J3SSRv_Ko .. 6 .pag 12 39^*1242 (June _ 1974) ..-discuss _ _ the slow _isomerization ...of. .cis-p.lail ino. XI I ) ..of aJM^?5s^ -noh i chloride- in- taccmosal solution__c.os? to-form the :.ll : V,? ?' .compound, -trans . _ _ _ - _ :... , _ Reishus ,_<J ,_W ,.._e_Jiartin , D.,__S in _ Journal_ of _ -the_ . American _Chemical] _ Society _ 83 , ._24_57-2 4S2 _ (.1961.).? _ -describe the acid hydrolysis _of_ cisplatin at .

_ _temperatures of 25?C and 35?C. _ These- st?di ...ver ivano... ..

conducted in aqueous solutions at concentrations of 1.5 x 10?5 K, 2.5 x 10?5 M, and 5.0 x 10?5 II, which correspond to 0.45, 0.75, and 1.5 mg/ml, respectively. The authors state that there was a certain difference in the concentration of the hydrolysis curves, since the

? Spies? required 10 to 30 minutes to dissolve completely with such intense concentration? Ho.zanc?eig M. et al. in Annals of Internal

..Medicine.,? 86 ,...803-812.. (1977)-?) . pass-in...rns.s.egna 1

? <

'fei.su Ita. ti_d e.g l? . .several, st.udi._pr0clin she . and _c 1 inici.

? :

..from the U-uao? of the; ' - ci splat ina me i-.turoor i_sp e r imeni al i. ;

j i

..in, .animals.; as__ancihe. .in .s.varia ti. _t_lni_d i-_t_umo ri .

..humans.?.?Es.si_m.e_ti .0no__1n evid e.mz_a__c.he_Jl_medi .camento..

-under -study,? made available?to?researchers?

iiualif tcati. through the 1Inve stigational Lrug

's ? ?

Br ano h.. o1 ?t h.e.._C.anc_an?The rapv Evaluati on Pr 0 gr am_._o.f_

S\-ile. _.Kuti onal_C.anaermIns.t i tute., ...era .f orni t o_...c_Qm&_??1_-_.v.er.e._branca? lio_f.il ?z.zat a __in_ vials containing IO ms;

rii rvi spi atn.na, .1 sodium chloride, 100 mg of

-mann it olo- (??1 P )..ad? aeido._cl orid r i c o _p.e j__la_me g o la?l _Q?

in e-d e l_oH.. .Ou and o the...prodo.fc..t_cmYie.no_E?constituted with

1 ml of sterile water for injections

YUSP) m'asniin milliliter of the re su 1tante s ol action .comt_i.en.emjJL.iiL?_di_O?i2_'pi]m_t.ina.v-.1.0...mp; of gannitol e

-9 ? mg? of-Had-.

JTalle y., R . ? . _.e_t_al.? , in ..C ance r_._Cie motte, r.ap.y.

_ Re p? r t a ^57^ - 165 - t?l ....(197 3 ) ?> describe. 3 results _

_ from 11 a.m. -Before ? phase..d and 1-1 gold -? tudio_ clinic or .dell empie.-.

!

.-ugo?di- cisplatin.. in the treatment of-65-human_patients_and

_,a -large, varied age-, of? formations, .neo.plasticih and... . Like___ .

?also-in the previous publication.,? the. medicine.

iv e n i v a? fo rn i.t 0 _ amu e s ti., r i c. e r c a t o r i ._ d a 1. Jia.t i.Qna 1_ . C an

cer -Institute? in-vials- containing-10-mg- of spied ci- ?

. na,-_ $0_rag_di? -cl-orur-o- di? sodium-e-100-ra.g di-mannitol, J.p.er.la_nicostitution_eon.-un._ volume. Of? 10-ml-of sterile water.

_Rossof-,_A.._H.... et _al.. in-Cancer.,? 30, - -1251?1156 .(.197.2-)? _do.s_c ri v.ono. the results. de ] _ 1 or r0_irapiego_d and I la

|

nisplatin_._in.the.care-of._5-l-ura.ni_patients? with_a

pm di-tioi di? tumors..? They-affirm-that-the-rae-?die-catment_provided_by_the_Iffational? Caacer? Institute era-, Iproduct? from? Ben Vanue. _Laboratori.es, ..Ine ... e... c o n t e ? d- ? go? oer -every -f ialsu-10-mg. -tell- us sp la t ina, -I- -rag? ? s-i c ) v~ di_m years to Lo.? e--9-.ma . (yes to) _ of _NaCl., _ and? that 1 a_ dust er e _

I

1 ' 1 .

,of_ color? diane o_.yellowish _yes_of melt and go_?ac-i Iraen

I

t e._.in_a_Jvolum.e.-of.- 8- 10 mi-.. di_ac a ua_s? eri le.. - _

_ Certificates and information regarding the chemical composition of ...

la_s.ua. f orraul az iona_i.arra.ac enti ca sono.

d at e_ a 1-1 e- -pag ine- I~5- e? Jl? -^2? from the? pub n ] 1 c a ti on - -dal- -l-tit Ol-O-LCLIITLCAL BROCHURE ,... CLS^RLAlimii-1. ( ??)_.?)???1?? ? HSDICHLORIDS (NRO 11_98_75)? t? H..._ Haldelsman _et_al . ,_lnjmeot ignt ional _Brug? Brune h., _C anc er._Gh.e rao. t ber apx. _Eva- _ -luation tErogram,?IXivision?of- Cuocer .Treatment ,?KatLo- -er-Institute _(Rav.isionata_nell '.August .197^)? bThe?images? 31 and __32_of .this.. publication .regard.

? a _ dormimi ari one_di_.c i s.p latina provided . free... from .

,NfC .I . to clinicians for 1 y _JLo ro .. clinical estimate in 1 y

. cancer * - _ed._in_.e.ssa? you_.read_how much

I

.continued: . ~r

-He or . .de j _ Data . Pharmaceuticals _

..KSG-l 108 75 _ G.is_-^d laminino die Loropl ai ino_ _(_II_).

I

0 mnu 1 a t i on e -d i? d o -s age _l.0_.mg/ilial a _ L_ Il__c onte nu.t_o._d i _ _cxasc?na_f 1 wing

tras narent.e snnsTip nnmri

_ nneL_mas_s.a_bxancas_t32a_li??ilizza=-ta .. .There each a- vial, with nt ?ene_l O-ns _

_4i_NS_C - 1138.75 ; 9 Q mg of chloride r o_

._di_so_di o_: 1.00 mg_of mannitol and Tir -acida?c 1 or idric o_nar_4a_xexala-_ ?-?? tion. d< iJLpBL.

? ? ? Preparation of the

-Solution.

I. mg/f.iala J?uand o .. v e n gxx i co.atLiiuit o_ c p n

1 Q _nJ _ of ..ac oua_s teriLe-_O-er_inxe-.aloni , _LTSIL,_c?as c un_nil _ dal la.s.o^.

resulting solution contains 1 mg

of NSC-119875, 10 mg of mannitol? and 9 mg of sodium chloride

with pH range from 3, 5 to

F ia 1 e_._s e c he_n ope n do- , xr.ebben.o_e_s.s_e re .preserved outdoors

temperature, of the refrigerator (? i- _ &??). _ !... _ Stability?. _ le_ fi al e._int att e ..have, one. s ta bi-.

_ lit?__pr QVV?S hem. _dell_a_dur at a. ..

_ _ Of. _one_ ..year...a u an d.o....e aae .jzLe.ngona _ with s.er.vat_e._ at the time mp.er a tur a. r and v; refrigerator _ (4--31 C.) ^ He_racc o-itH <JL .mand anions. of... stability?, no ss on orsLL .ess ere.rego 1 atc ..during ? the completion of a study. of.. con-_ s ervat ion ln_sc affai e_d ella ...

-duration-of?two years,._Xa ri co sii-. turione efxettn ata as racco

. sent to_d?__come__ r i su lt.ato. a . color._solution... already at the o_p al-.

ouale-?. _.stable_ner no more than_an! hour_.aH at. ambient temperature (22?C) When ver. g a..

. and so as.ta_to__a.a. i 1 l.u"in aion.__ambien t ale. _n_qrnale and no more?.. than _ october at temo e r atura ambien t e _ .{22 fG_X..when. the. _s .o.lut i o n_. is n ga_pr_o.te ita.. .from 1 to_l_uc g_._Xe._.s.o.lut io_-po s s ono_Xo_rm a - _ ?r-e? an?oreoiox.t atcu don? a fora .

_ ..at .refrigerator temperature?-- - -ro (4-8?C). .- ?.

?

Caution!

- - L-The dosage formulations -lio-I r

- philized - do not contain - preservative - agents and __therefore? -?it is recommended to throw away the..solutions_

.stes.se_.ctto_ore after their..

& - - - ..constitution

?

.August, 1974_ _ ;_ Yes? \ J Clinic!..Drug Distribution_Sect.ion .

Dr?g JDevelopment Branch _ _

The d o rnando ? Of. short 11 o _b r i t years c o_ jpub 1 i c ata

_col .number_2021946A_describes .watery seductions_sta-!_

bili, of cisplatin?having-concentration-of?cisplatin-between..approximately-CL,1_and_1.,_Q_mg/ml_and_a ..pH .

variable in the range from 2.0 to 3.0. The solutions

Others may also contain a source of chloride, as a non-toxic inorganic source;

indefinitely accessible, for example, the _c 1 oride

Ldi .sodium,. _ecl_.an . excipient composition__such as e-^-&empio-.mannitol.

The present invention relates to solutions??

Stable and concentrated _of?cisolatina having, concentration'

1

zinnia from approximately 2.5 to approximately 2.5 mg/ml. More specifically!

I . . . i

!Lare., the present invention relates to solutions

- -stable cisplatin concentrates in a solvent medium ranging from about 30 to about 95%, or a polyethylene glycol having an average molecular weight ranging from about 150 to about 9,000, or a polyethylene glycol having an average molecular weight ranging from about 300 to about 6,000, or a polyethylene glycol having an average molecular weight ranging from about 50 to about 7,000. % of_ water,..the _:_ \ ' -The_sol.u2;ions?in0ltu?-also?containing?at?least?one--_ non-toxic-and-.pharmaceutically-acceptable-source_ _conditions of each.Jn quantities that _?_..at;eno...approximately

!? , The ,

? and quiv.ale.nte_ .alla. _q_.u antit a_.di__cis p 1 at in a. present inai - _ .the__s_o.lution_,__e_J..e_ said _??.1?.?_????1_?. I sell _un.?r roncar - ^.v /_ .? razi.o.n_e_?a. i._c is.pl at in.a__varis.h il.e.__d.a . cir.c.a_2_,_5_-3.. _cir-_ _C.EL2.5? m.g/ml ...

__ 80lnzi.o.ah.able_abqueous_cisplatin_solutions,_known_as_described_in_British_patent_application_issued_under_number_2021Q4-6A. Although_stable_solutions_containing_fine_concentrations_of_cisplatin_at_L.nir/ni]_can_be_o__o_t??and_in_tali_nez_-_-zi?acouosj_at_room_temperature,_..the_crystallization_of_cisplatin_in_the_cold_at_concBnt_rations. cisplatin is a stable solution of approximately 0.5 mg/ml. The dissolution of this crystallized cisplatin does not occur effectively with vigorous stirring at room temperature, although a solution can be obtained by heating to approximately 37°C.

\

Since... the temperatures of the transport and of the...

o;I after. the. sale_cannot. -be ..controlled,! .

I

- ?? the. ??????1??2???1??&-.1?.11?-.??3??1???? in the -vials- i i _

!

would create an undesirable problem for the administration

j

extraction, medical, ?the-maximum-concentration .practice -I

of cisplatin in -tali? me z-zi? ac.au osi ?- of. about-

? ,5-.????^1.._ ._. _

_ The ?s oLU Zi oni ?of__c.isp 1a t i na. .d eli a pr es.en t e _ inv ep-I

I

tion may contain-f.ino_a.~ci:t?ca? 25?msp?ii-Cispla-!

tina -per milliliter T_although .the concentration . ras-; _

j

sima -pref eri-ta_sia._of_about? 15-mg/ml? -Solutions, deli-^.

i j

the present -invention -.cont.enents--l5 -inS-tii -ci-sP^ati?? ??? I ' . ? !

-inal ner-ml are -atate-mantenute-.allaiteiimenataira di_[ _

? * ?

;74-.?C_for 12 years yes ..without the occurrence of s s e .crystals z- _

;zaz ione-della_ci spiai ina.. la 1 i._ _s o 1 u.z.ip n i_ s orno.. _ s_t a. te.

_ banks. .cooled .to .-60_?_C.e. then reheated .to, to_

? ^ambient-temperature. without-any-evidence-formation_

? , :

-t e? of .pr and c ipit at o of ...cisplatin ..__.What? , le., soiuzi oni _

_|for practical use prepared according to the present invention

-tion may _have razipni_ concentrations of cisplst ina _al-

-At least thirty times higher than _a.-That of the solutions

f ? ;

..aqueous 'for-use.-.practical_ prepared., according to the technique

J

^previous - - - _j ?

_ |_ It will be appreciated that the concentrated solutions of ^

- J.JL -

-.cisplatin._?ornithine--d.alla_presente-_invention-.-ricliie~. ?' ?

-will-they-have-internal-costs?of_takeaway,--of.,warehouse^-!

-gl o- - _e__d 2 _ other a e r_dQ.s e?.un iiari?Lwhen_si_p aras on ano. the

-with?l-and? aqueous-solutions, .note-.?- Sehle.na?anc?ie_la- f or- _ ma_solida._ freeze-dried^ ata__note abjHi3._c.o s. t i . ti i__t ra s p o ri o _ |

-And? dinnagaz s ina g i O? in te r i o r i.v._ caie st.o...ri a panni o_vi.ene _ -pi?-clie-.counterbalanced?by?time_and-expenses _ 1st..freeze-drying__includes

In a preferred embodiment of the present invention, the solvent medium comprises approximately

-1'-B0?4-a-.cirea_il 4)5?!n_(and more?_.pr.e?eribilraento__da..c.i? _ca 118jz. % a_c.irca_i.l_9Q. %) _di_ -glie ole... pol? e i i_le ^ nlsM: t-, having a _pa so_- noi and cular n_edi_o_..da ,.c_ir_ca 250. .a__c

1600 (and more? are f.eribi lmente__d a. _.c_irca_2.50 ..a__c_izc a _ _ _ _ 1

650) to from. around 115 ? to approximately 20 *4 (and more preferably from around 10 % to approximately 15 90 _ of acnu a_._ In _ realization oi? oreferita..ll_zezzo so.1venie nnrncontains approximately 90 % of glycol e__pol iet ile n i c .o__ay ennn ppRO.J.Q1,eco1are average.from about 550 to circ_a_450 about .il_101?dj_ water._

Preferably the solution contains from about 5 mg to about 20 mg of cisplatin per ni and oi? preferably - from? about 10? s _ about...19- ns/ral ....the.? source. j

-non-toning, pharmaceutically acceptable ions_ Llrvrnro preferably ? present -in a concentrated

JL(Z

..pione .of._at least about -two equivalents-ner.equivaler!- ?

! . _ ' ? * I

-te-of.cisplatin in the solution.?Concentrations -co--i

-s?-elevated as 50 equivalents or more--of-chloride-ions?

_for cisplatin equivalents-can be used_

-!sate, depending on the concentration of cisplatin ia,

i

-of-the-percentage-of-water?Dresente-e of the narco1

i ' !

-lar, source of chloride ions,.but such.high.concentrations.of.chloride ions,are normally not.mnec?s-.

would be desirable? .The .experts-in the relevant branch_

! !

they will realize that, with a high concentration of cisplatin and a small amount of water, it would not be possible to dissolve a sufficient amount of chloride ions such as chloride V;

I f

I

? : - sodium rho-di, so as to give _50 ion equivalents /:

- chloride-per-equivalent-of-cisplatin..-Furthermore,_????;i'..

- saturated, or nearly saturated, solution of a chloride salt

_ :_ inorganic.-ro.-it.would.be.desirable_for_the.possi- __

? : - 5d-lit? of- crystallization- from solution _in the cold ... .

?

_ Sella, situation^.s_stability_s_qpra,_50_equivalents of

- per-equivalent chloride ions of cisplatin.

_ bero. obtain .using,hydrochloric.acid-coin?.source_

I

- of- chloride- ions, -but this - could .give, an undesirably.. very? acidic solution,. that is? with _.a low pH- _

! _ 1

- to? Yes-?? found, that _1 and...solutions.. ec_cessivanente_aci-_

- - - d I e- are_.in. -somehow less ..stable. than the solutions 1 _ t _

4 more moderate amende- -acidic Lfinterval-la-di-pH- of the . ? I . '

junlu s i o n i... p.r o f e r ibi Ime n t .e_...?_ ..c.orn.p r e .s.o.. da_ ci rea _1. ,5. _

.to.? circadl,-5-?? of-P^-ef-erenza_si-.utiliz.?ano_da^c.irca__ _

? 2 3^.c.irc.a__lD_eQ.uiv-alenti di_ions_ .chloride.- permeo ui va- ... lente-di? cisplatin,? e- -pixj.-prefcribilm.ente.-du- circa -?. a.-ci r_c.a_d - oqui va lenti d, i-i.ani_cl o_rur Q_p.e.r e cu iva

1 entity? of? there spi at ina. is uot?? Chloride ions_. .can be supplied by activating .hydrochloric acid, a., metal halide . mn_: _ it oxic? cubically-formed drug - as _for .example o-0 1 oride_.of _

: s odi o.,. -Chloride. _di_pot as.s_io.,._c 1 orar o di_cal c. io_o_ c 1 q- _ !

magnesium oxide, _ or an addition salt of

^acid or -eloridrixe- with. for example

_itr iethylamine, ? a doro? rais cele .. The preferred source of -i ori j -chloride is hydrochloric acid, sodium chloride, or a lor o .jais c e.la_,__

T rrl i c.oli_onlieiilenici-e..i glie oli m e.t o s ipo= diedi 1 e ni ci have the general formula.

_ dCOOH2CH2.)nOH _ and _

CH pZ (CCEL 2Crl 2O n OCH o, _ _ _

. rice and it ivaui e: t.e , and co-_ine_ Carbowax -.Polye.thylene _Glyc.ols and .C.arbov.xax.ilethpxy Poiy.eth are commercially available; of ve ol s . Do you prefer? if and use i

?pjprrhrv Grades of Carbowax Polyethylene Glycols, which are produced, according to ??- sjiandard for_l ' alimentazio

.ne-e Der .l? ar>t>l reactions of medicines -de^li .U.S.E.,.N.E.....and-E.G..C institutes. The?int?rvalli.-di_p.esi.

molecular--thioic pei??a-variety-of-Carbowax-Polye-! th.ylene_ Glycols^e_- Carbowax.Jletboxy .Polyetl^lene. Glycols. are.. given in the Jbab and l:le__l_e?2 _ , _

Table 1

".Carbowax _ _ Interval. - - V >

*'* Polyethylene.. . .typical of _p_e-,

Glycols" O) _ so molecular

200_ _fromJ190_.to..210_

300. from 285 to 515

from 380 to 420

.,600 from 570 to 650

1000 from 950 to 1050

15.40 from 1300 to 1600!

4000. from 5000. to 5700_ r

6000__ from 7000 to 9000 .

;(*) Glycols:eoliethylenei_6arb ov;ax

.Table_2._ _

_ !_ l'.Carbowax,. Interval.

Iiethoxy typical of pe--1,__ ^plystbylene___ ^.a .anJLecoiare

.1_ _ Glycols" (*)

I

- _j- 350 .da.335? .to. . 365 _

_5?Q__ _ from.. 525 _ .to . .. 575- -- -_ 73Q___ _ from 7.15 _ to 785 _ ...

2000 from 185.0 -a, _21 50- _ -4?#? Osaipolyctylene raet glycols -Garbowax,

It is known that the c_Qli_p. alai the ani ci_i_or.marLO_c_o.Tit?.. iplesm .con-certi-Gali-inorganici ._Cosi.T _la.-xea?ione~ i ! _.d ei ..gli ions i_ p o.l i e_t.i leni c i _ con_amtaoni ?..-C ob.alt o1; i o ci a-..

-^born to form -a. blue-complex-? _the. .base..of? a.

-procedure - metric c o l o r - d i- d e t e r min a t i o n? of 1st. ^ ? v>: . ? -C.onc e n t rasi on -of the _ gl i c.o ls. then she i l.enic i _in_s.v ari a-^ _ i

_these miseries.. ..He.. believes ..the_..ability?._of. character. _ truly ...unique-of the 1 a clapJlaiina noll-e_soluz inni -iof the present invention-may be e-sneLra_dovii-ta_ad_nn _ ; r-nmple es o__chlorEiato__between.....liL..Spl at ina__eci_i 1 glycol _ _ _ ; polyethylene, _ but this ? only a theoretical hypothesis and it does not form part of the present invention..? Work. of the formation -of .mn_ornal s so. .? .sta.-..

\ t a -no t ata me 11 a..._technique_of_chronic_nalo-gr af la _.s_u _?? r ai o_ so 11 i 1 e? s e :;ui t.a . in the present invention . Using _

Ile -te.cn i ch6-:pi.? .sotto. de aeriti e., _la_c_i spiatine, .acnuo-!

:sa produces a stain at an Rf value of approximately 0.6.5..

!Tu tta_yia,_ a_ solution of cisp lati n_a_in _poly-_ ylene _glycol-dOO--al? 90-i3_ water - al -10-^_ Cammero

!in di-HC 1-..0, 5-_E.)-provides.c e__a... stain a??d_un- go o r_ ire - Ri di -about...0.5- 11 . anal.- it _..e s t end e. i n. _ s t ri scia _

I .

-up to about 0.65? The dilution with a sufficient amount of water appears to immediately break the liquid, since the dilution of the solution

! ! koora...of.PEG-HgO...(i.e. .HClV with ? Volumes of water

.show; ? then only . a stain of_cjjspJ. at ina to a

_value.?of__Rf?of?circ.c.at_0,..65

Thin-layer gromatographs

. Echoes and reactions appear

_?ja_) Thin layer chromatography plates - pias ir e__-EM__ Lato rato rie s s Line gel 60? mimero._di- & nata!??:? 5763, or equivalent

(b) Sluent: acetone/HNQ^ 1 TST (9/1 ). To be prepared from;

-I eat-daily._

Ce )... S.vllyp p atoxe^_dl.aclois Ile r_e_5, 6_ _g_di _c.l.o.ry.r.Q?. s t an -no.so . ir.10 mi _di_HGl_concentrato_.__As.h.i 90 mi

distilled water and 0.2 g of ICI. Mix well. Prepare 4L fresh daily.._ ?_ L_

(d1) Laboratory oven set to 100?C.

Senruita technique

(a). Dilute. _the..champion- _o_on_5? mJjmi_ d.i_ dimethyl formamide (DHF) (Burdick and Jackson, distilled in

jsietro)?._ 1_ __ ^_ :_ _ ;

'b) Stain a layer chromatography plate

.s o tt ile__c o n 6 mi crolit ri.iie 1? c_aBipi-one__e__5_ni icr O^L

'?'?'?liters of a standard solution containing cis-/platinum (and transplatin and platinum, if appropriate) at an approximate concentration identical to that which would be expected in the sample to be analyzed. Develop a height of 10?cm in a chromatography vessel on a thin layer previously equilibrated with the eluent material... Spray the plate. t

- _stra_es.s located .with. the. developer.solution_ _ ? freshly prepared .and_then_place the .plate- . : in .an..oven at...10.0?C._for.10 minutes. Observe the Lev??!?

?:.? _ zones?yellow/purple.) Approximate values of__Rf il i - 0,?-5^-cispiatina_

_ 0.76~transplatinum._

-0.9^-platinum_B -tests carried out ?by_liquid_chromatography_of_the_solutions_of_the_present_invention_for_the_cisisolatin_content .may_be_conducted_in_accordance_with_the_technique_described_in_patent_application_for_the_sign_IJnitO-Ko._2.02194-6A...The_preferred_mobile_phase ?consists_of_ethyl_acetate/. .methanol/dimethylformamide/distilled.water ..(25/16/. 5/5). Preferably the_standard_consists_of_cisisolatin .dissolved_in_dimethylforminide.and_at_a_con-.

.centre .t ione., of 1..rag/ml ._1__ black-samples..1J ven-analysis.

-gono- dilu? t i _.c on..diniethylformaminide _ till? ad' _.ot keep.

-an- approximate-concentration-of-cisplatin. .equal

- .-??-.l.rag/ml._ _ i_

i !

_ i_ Seb?ene..it_is_not_possible_to_get_any_detail_

i i

I 1

; l

- yantaggi o_d at LaJ. gold present _ 1 e.._s oJLu ti on _of the _ ; _

! !

- present...invention can.,_,r5.e_._s3_ want content.?-_

| i

_ re?un...e.cci.p.len.t.e_tr.SL.ai?elli_4i_usual employees, fi-_

| 1

- ethologically acceptable-name _for_example_.the?damaged-_

j

- the.._ :_ ^_

!

__ j_ Based on stability studies? so far effective 1 A V iuati .,_1a_stabilit?.prevista_.de1Le_aoluzioni_ deJJL.a_

? .present-invention? 4def inita-Co.me? pardi t.a._ d_i_ .poter

i 4. za. equal to _al_10-?n). __? -greater ..than two ..years_.a._i ejrtpe.ratu?

ra environment,._

_ Xn_un a__preferred realization of this _

inveri zione.^? the?Solutions _ are? sterile? and.d. free, .from

pyrogen-, ? and? are? conf e z-ionat e in conte-nitori-sten the i

and feel _ from-jp_i rogen.. ?These _ solutions can then be diluted? for example- with _ sterile- black-water? in _ USP ".. or _... "_. salt _ solution.. called star

USB".?and?are-administered?by?intramuscular_route_

-Or?intravenous...I..me z zi_ to._.sterilize_these,solution-=?

.zi mri FAIR already? well known in the _r.e.1 hold. .He ll.a _pr e_j=.

fignts inveri?! one prefers -to pass- l.e_ aelu- _

tions through a sterile, nitrogen-1-free filter

r

Millipor genes and from 0.22 microns, using advanced techniques

\

filter.under-sterilized-nitrogen-pressure. MilliporeJhn - a registered trademark of Millipore Corporation for membrane filters. MilliporeJhn filter

?to .sterile . is collected in sterile containers and

you hear from-.pyrogens and..it is finally introduced,- in theS

1 \ ?the-desired-quantity,?in-suitable-sterile-vials-free

pyrogen-free and capped with sterile, pyrogen-free caps (preferably Teflon-coated) and sealed with sterile aluminum seals. For use in cancer treatment, concentrated isolation tablets are diluted to the desired concentration (typically 1 mg of solution).

piatina .per_.ml.)._for._example_with_1a._c.osi.dde11a_?acaua_ !

..sterile? for injections _ USES? ", " normal saline solution _ ..? ter ile_ USP'! ^-or J! sterile solution... of... gluconate " . therefore, administered by intramuscular or intravenous injections, ..or by intravenous infusion as already known for... cisplatin preparations of the previous technique. . doses .used __consistently_ with _toxicity _ from ..mild. to moderately acceptable are, in ..the _

J o

range .from..60.to 100?mg/M^ by..intravenous route,._as.

single dose or as a dose divided over a period of 3 to 5 days, to then be repeated at intervals.

-v.alli_.cLi_ A weeks .. JJn.. dosage? of _gr.o&-! . I

nolanamente equiv.a?ente_._a. .1 , 5 .rag /kg . cde__a._s.ua ?volta' _

._n!__gr?.ss o.1an ameni a _ equal to 1Q5 !ng/patient_?&l_ wt. i1_

j

_ ..j&i?7Q_ks..._ Hi . j?r.eAuentfi._si^?a_irap ieg o__di ..an a_t e_r.apla_ _

i ' ; i

_.c onc omitant e_. c on.. al.trl_ag.ent i_.c he.mi o t erap? cl_p_e.r_oi -!

? itene re -i miai i or t_..ri stillini i * _ : _ 1 j

As it is here. _used in claims. 1

-references to chloride ion "equivalents" for "e- j/ > ? <?./

\ uiv.al ertr't.d i_ ci s piai ln_a__sign i f ic a_e.au i v ale. nt i__mo-. fc' ? ;

?lari. So for example when using 1 1interval

i i

preferred heat setting from about 3 to 7 degrees equiva-

_lent-i- di 1 oni? chloride rpe r?eqniv.alent e__di _c i.s.p Lat ina.,

you use an amount of about 5 to about 7 moles _ ;

of NeCI for r._mo the di._c i s platina but an ou entity? from

y.i rca 1.,_5_at about 3.5 moles of CaCl^ per mole of ci s-

_pl.at in a , _e.c c.e te r a - _ !

Xl_pla.tino_B is an arbitrary name here

_imp linked pen_un_ reanion pr o d u c t e cis- acid

_p.la?ln?L__nrie_?__una. net.?__del_not_o_c ompass o_rosno_di _

laguna ed.nl _ which one?. s t aia _a sue grata .in..via_?i_ipo^_

4: e.s i_the _s e-quent? st rut ture - -

?jf 31. Gl

Ffe

_E5IL _Q1_

? t

_ The? present ?Imr.ention? ?_ll ~l.us-trat a_d agline rem.- _

_ _ _ lipi...cii:and they follow, without, for? . be limited in any way

t !

. I j _ _? _ fmodo._da questi . _ j _ _ _ _ ?._ _

_ _ ; _ JJs.enipiQ_l _ i _

!

_ _ Concentrated, stable solution of _

- -- j.- cisplatin? (10. mg/ml) .in . mix _ ! .. .

! - ;

- . _ of .polyethylene .glycol. 400_ C 90 %)/. _ . . .

r _ HCi .inXio_Ji _ | _ _

_ _ _ 5QCL-?&--di_clsplatin were suspended, in_a_

I :

- : - [solution-, of .5-?l? of.. HC1 ?N .and. 4-5 ml., of poly- _ glycol.

! ;

- [ethylene. 100 .?After 15, 5- days of.. agitation .at .e.m- _ _

_ protection. environment _(.with . the . container, protected by the

_ ila_luc.e_con. _una_?o.gl i.a ...of...aluminum) . s i. obtained 'u

i I

- in a-clear-solution, of. yellow-color.? .Earti. aliouo- .. ?

- f jte_della? solution ms/onivano placed. in vials of colo- _ . ..

[

? _ _ _ amber bottles of 17 ml volume, stoppered with Teflon-coated caps, sealed with _dj_ _ caps

' r . -- - [aluminum- and post-ali a-.proof.-dl_sta?ilit? .jalla_ con- _

? - J - ? j-storage -at -different- temperatures. After storage

- .ne? of? two- weeks to ?chrome graf ia_on_stra- . .. ..

- the thin one? indicated the _presence_of .a|crack_of _ _

_ _ _ _ ! _ ? transplatinum . and. about 1 di? platin o.JB . _After _with se ir-

_ vation of two...weeks at 56?C, the chromat??r_af ia

?- !_ _ ;on a thin layer indicated the presence of a quan-

_ __ 1_ [title?-minor .of?'!.# of_transplatinum _and_about .3. % 'of . .

i

_ [platinum .B. I. samples - stored for_two weeks

t

f

i

_a.l the _t crup e r a t ur a__ of . .56 ? C ^came, d the mourners with A, 9. BL1S .volnAi d? _acqu.a_^in_mod_o^d_a_.give _spluzioni_ li.m laughelle ..containing_ respectively 2.,.__l.. and .0, 5 mg/ml of cispla.tin? -Una-lie.ve_t orbitit?? did-it-develop-into_ ? c i as c_ a o.._d.e i_.c campi on ? ..of him later. rt_pos_o___pe.r about 18 hours...at _t.emper.aiura_ambi.ente_._

i Example 2_ __ i _S ol u tio n.e__c .oncentrats.. _s_t_ab ile. _Of .

_ cis.pl.aiina.(IO.mg/ml)_in_glic_ole_

_ polle file nic..Q_ 400 ( 90 ?0/HC 1 jO, 5N _41GL?S.)_._

5 ml of purified water USP and 5 ml of HC1 IN 1 were mixed and to them were added 90 ml of 400 μL ylene glycol. To 5 ml of the solution containing 5 ml of 5 ml of chlorella solution, 50 ml of chlorella solution were added.

The mixture was protected from light with aluminum foil and stirred at room temperature for 1 hour to produce a clear solution.

i

-1Thin layer chromatography of the freshly prepared solution showed only one area of C-splatin__with a possible trace of trans ?_1?-_ I .

I

The solution was placed in amber-colored vials of 17 ml each, capped with Teflon-coated caps, sealed with aluminum caps, and subjected to storage stability tests at various temperatures. A sample vial was frozen in a dry ice-acetone bath for an hour and then allowed to return to room temperature. A clear solution was obtained without any trace of precipitate..._After.storage.for.three.months?at.3.7°C.and.at.-45°C,?sublayer.chromatography.indicated___ the -presence_of_platinum_B..at.concentration_of.1.2_ and_a_possible_trace_of_transplatin. After -one.month,storage_at.temperature.. dd^SJLCU..

}-thin-layer-chromatography, indicated, the. _p.re4 I

-without more than 5% but less than 10% of Latin_B__ and a trace of,transp_latinq_.,The samples retain?

\ti_at ^3-7--C--and at 45-?-C.._for three months-and_at temperatures, of_ i

56?C..for_a-month^jwere diluted with 4 volumes of_ j

XaCQ ua..purified__USP__cos?..to give_limnide solutions I x

containing .2-mg/ml_of..cisplatin._.?and_.diluted_succlusions-. -ite._restavano-lithoide gift,riooso..of 24 ox.e_.a_tejiper-.. and attracts environment.

JCexample .3-Stable concentrated solution, _of

?cisplatin (10 mg/ml) plus CaCl^ _ (20.mg/ml) in polyethylene glycol

AOO (90 ?)/H01 Or5N .(10 #)

.2..g._of CaCl^ anhydrous quality?J'reagentJL.veni- :V.ano. dissolvedHn. one _DILSC eia-di.. 5 'ml of pure water-- -j?icata-.USP_e-_5--ml . 1?_?01.1??.^_-8$--??? of _ glycol., noli and-.

I . v

- itylenic. . AQ Q _ _there are ... additions. c o s i da pori are_.il _y_olu-.

_:ine__a_ l.QQ. ml . A. 50 mi of this a oluz :Lone._ven?vano

added . 550 .mg _cl i_ci.s_pl ali a?_e_ 1 a_ mi s cela... era pr?

t e_t.ln.Hall a.lu c e with an aluminum leaf.. and agi

nanny-at-temperature. .amb.i.entc^pnr_21r ._ar.e_lii_mod,o da da-,

J

r.e - a clear solution. Layer chromatography _

s ot.t il e_ de 1 1st_~s.o.lu tion prepared.. by . _f.r_e_sc_o_._indicated .

!

only. a dic.ic.tLlatina sound with a t>os- trace Ad . s ib il e_ di__ t r ans r 1 at ino.. Ali a u .o.t e. He _1 _Y.O monday__of_. _2_ _ mi

_ 'dell a.__s olution_.yeniyan_o_.placed in amber-colored vials _of] _ volume... . , corked and with tannins ri-'

[teflon suits, _sigil_l_ni_e_ with,.. hoods _of _alium.i-.

?nio--e--s.ot-t-op-ostc a.lle_proye of stability? to conservation, to various at_e__tpmp erature . One sample vial

J?vp.nriva_ pQ&ta_in.- a dry ice-acetone whine

for half an hour and frozen until it formed a transparent gel. It was then allowed to return to room temperature and a clear solution was obtained. It was then stored for three months at room temperature.

p aratura di. 37? C, la_cr ornai ography on a thin layer

indicated-the-presence.. of _a._c.onc.e.ntm zione_Hp^_l_.._a 2 %

of latin B and a possible trace of transplauirn, T)r>rn three months of storage at temperature

- ? of 45?C,.thin layer chromatography indicated

!

----_ ,;the..presence.of.about.5.platinum.B.Odes.and.a..track..

?

- LD.O.Ssibila.di_trahsplat.ino. After m me3e_d?..conserva- ..

Reading at a temperature of 56?C? the .chromatography- on -

- - Thin layer indicated the presence of a quantity?

i

f

?from -8?to-10- %.of platinum B and..a trace of..transplatin JL samples stored at a temperature of 57?C

?and.of_45^C for three months and at a temperature of_3.6?C_.

i

[for a month they were diluted with 4 volumes of water

Jp?r?f?cata.-USJ?. so as to give clear solutions. with?

Jnenti--2--mg/ml -of -cisplatin. -The_diluted_solutions

They remained clear after a 24-hour rest at the Jfc.empe.- 7 t

plowing the environment. _ _ _

.Execration i.o_.4 _

... S.o luz io n e_ . cone en t r a_ t a_. s t ab i le di _

_ cisp1atina_(c.irea..22 mg/ml_)_pi?_

- :- !- .CaCl _-(25-mg/ml)?J.n vlicol_._polyeth.ile-- [_ nico _(90 il)/EOI...Q,5IL (10.?)_ ..

i

_ ;_ To_a_volume_of_5 ml_of_a_grlic0- solution

_ :_ ._ Polyethylene 400...C.9CL&)-.and H01.Q,5N .(1050.were-- - -- ;45..ras .of..cisplatin,.and the mixture

?- -^was-shaken for about an hour at room temperature

- -- ,1_ to obtain a clear solution. A quantity of 50 mg of cisplatin was then introduced.

_ _ Ita (for a total of 25 mg/ml) and the mixture was agi-If

i

- - itata .at. temperature. of about. _4-5?CL for_Lm' hour. and then _

| ? , ' i - . the. ambient. temperature, nar 18 hours so_da .x>r.od.U3?re.j. _

! ^ " ' i . juna-.soluzione_almost cormleta.._The small... auanti.ta _

\ !

- idi-material -insoluble --era_rim.oasa_-mediante JTil tra-?

! I - ? ii-ssione?. Ln chromat?gra?ia.-S.u - thin layer -of the filter 1a

- .ito showed- only one.-area. of _cisp latina- with_a

? - ? ! !possible . tr , i r accia ..sdi_ transplatinum .-from jpart and .remaining _ ;of_the_filtrate was placed _in_ a staining vial j

- The iamb.ra .of -v :olum :e , of ..17. mi, - f.Drni .ta_di ' .u .n. cap., ri ;ve ]- _

! ! - Teflon lining, sealed with an aluminum cap

. . |mino-e-inrntenuta__alla. temperatura di 450C ner tre

_ |uie yes. I give aging for three months at 4-5?C, the i

i

_ ?chromatography_.on _thin_layer 1 1i indi cated the presence;

! T f --za_ of- a conc entra tion-from HI -to_2_?-of? nlat-ino B

_.e. no amount . of i.i.ransOlatino . The dilution

- ideal, solution, post- acLinve addi are. .con_.acoua puri- _

; i - jficata .USP .up to ui?- concentration __ eli.2_ng/?nl _cLi_ _

_ - risplatina gave, -clear- solutions _that -remained. -such _

.and_ after, rest .at. .room. temperature? for. 24? - _

? ?... hours . _ _

- - ? Example -5- ? - [ -

Concentrated stable solution of _ i_

cispl&tin (1.2 mg/mi) plus?iTaGl _ _

)

i (.10.mg/ml) in .ethylene glycol _ _ T i

-L 4-00 (90 ?J)/.HC1 0.5N (10 ?) - _ _ _ ! . .. (

I I

J _ 10.0- .mg_.of _ chloride- dl_. sodium hydroxide._was dissolved_; _ in a 3-part solution...of_5_ml---of_. water...pure_.USP_and _ _ -1^ Ml-of-HGl-.IN..To_.this_solution..were..added_

,?_9-0_JH ] _ di __gl i.co 1 a_p.ol le ti l.en_ico_ 4_Q0 _e_ 1 a_ ini s cela Q ?? _ _!????.?^?^-??^-.15-??1?^^._?^_50.-.??1- .di _Qua stlult ima_s olu- _ 4_zione_Jvenivano...add.ti._iQQ_mg._di_. cis.platin.,. and the; _ i

mixture was stirred at room temperature to produce a solution.

_j.clearL?. Thin-layer chromatography of the freshly prepared solution showed only a small amount of smear..Liquid-layer chromatography;_ and not sufficiently performed as a test on the substance __ ?

A freshly prepared solution showed that it contained 12 mg of cisplatin per ml. Aliquots were sealed in amber vials of 17 ml volume as described. The sample was then subjected to stability tests at various temperatures after storage at 5 °C for a period of three months. A chromatograph on a thin film indicated the presence of less than 11% platinum B and no trans-; platinum- -After _consery.ation_. at 56?C for _one month, chromatography_ on_ a thin layer .indicated .the _pr.es.erL- _, \

...l-zu-di.unaviuantit?_dallil_al..2?5i_cLi_platino_3__e..nes~_ iRim quantitative transplatin, the dilution of _ - aged samples using purified water. USP_

- - .until.a.concentration.of.2.mg/ml__of_. j

- --!ici.splatina. gave . clear solutions which remained..

?such also- after- rest at -room..temperature. for. i.

24?._hours?? _ _ _ :_ _ _ '

?t" .' _ The tests carried out by chromatography.

jal.ta - efficiency on . samples_stored for three months

i

the temperature of 45?C,-For the months at.37?Q_,e_oer

! '

Eight months at room temperature showed leaks!

Idi .power respectively, of 6.6 6;l__#_and 2.3 J?

Example -6

_ __ Stable concentrated solution of_ /

_ cisplnt.ina._(ll,4 mg/ml) more? NaCl _

?

- (lCL.mg/ml) -in glycol, polyethylenes--_ i_

- :- co-400 -(90-5a)/water-(10-?0_

- To. a. solution. of..5)fLmg_di-.HaC.l..J-n?5?mi?di r

USP water_and_45 ml of_glycole_polyeth_i1eni-

.:co 400-50.0 mg of cisplatin were added, and the

-the mixture was stirred in the dark at room temperature.

I

- ' !

-hiente -for_6 hours in order to give a ^limited_solution-

pida. .The?chromatography.thin substrate of the solution

?zioneprepar.ata_.di fresca showed only upa mac-

_ |chia. di-cisplatin.II. test performed by ^

i j

_ jchromat?grafia..on_liquid, high efficiency show-

\ '

_ Jva-.che .tale,solution contained 11.4 mg of cisplats

,_..na? per. .milliliter^_.Then_.alive_articles._were sealed - _ _ in .amber_coloring .vials_ of .1.7- min-. ? ? _ me. described. ..ne LUes and leathers o._ 5 ..and ..subjected _ to _storage stability tests? at various, .temperatures -After. .storage -at a_ temperature? of 37-0-C_and? of. ..45 _C.. . j ?

for _three_, months, _ thin layer chromatography in- _ _dl5rava_dLa_.pr.esa.nzs._di_ 1? _di_4nl.aiin.0i8__e._ne s.sun_. _euantitative . di_ .transplat in o.*_.The_dilution_.of the ...aged camoioni __con__ac_qua..ou r i f i c a.t a. USP until you get-I .

a concentration of 2 ine;/ml of cisplatin gave

?% " ? ' ?t - ? -r A -transparent solutions., _le._auali . rssJ;.ayano__tali_ancjb?Vi.i__,:? after, rest _ at. lampe r at urn__i ent and for .24. .hours .

The tests carried out by high-speed chromatography? efficiency? on? ion wagon? stored for ?ner..-.three months. al~_ . there. .tome and portrait_. Of? 4 Ij?dil,.. six.. ..of _ _37?_-CL_e__s ette-months to 1 a_ t e mp.e r atur a_amb lente _cio.s brava- _ _no_p.erdite_.di. power, ris_p_e_t??iiyntLerte_. del_6_,.l_?L, _7

? ) O of-Esemnio

Stable concentrated solution of

cisplatin _( 10... mg/ml ) in ..gli or le

.then ethylene 600 (90 1') /HC1_. 0 , 5_JL

. C.1Q.J$)_ ,_

To a solution of 2.5 ml of purified water USP_,. 5_ml _of.__KC1_XIT_and 45 ml of glial and polyethylene

? I ?

jco -600_500 mg of cisplatin were added, and the ani---i t

- Iscela . was agitated - in the .dark ... at .room temperature _

i . ;

-- . ber 3 .hours so as to _obtain _a _clear .solution., _

?

- Chromatography.on..-S.o.t.ile.layer_.of.the.solution.

freshly prepared, it showed only a stain of

cisplatin..Samples -of-.the-prepared_solution_of._

-:fresh were diluted-with 1,-3,-3,-4,_ 5?and-9 -volumes-of?.

USP purified water;_auest.and.solutions_..diluted_and_.non.

showed no crystallization phenomenon.

..?rest for.16.hours..at-room-temperature..or..at_.em-_

? |

waxing of-4?C.-Parts, aliquots.of-.:solution?create _...

? loarata di - fresco- were_both:illate? in_f.iale. di_co~

? / _ llore. .ambra d.el volume. At 17 I as_fgi? described

? .p ?example -3 and .were?then subjected to tests of_ ?!

- !established..for conservation? at...various.temperatures

-I give .storage... at. .temperatures of 37?C and 45.r?_Q_

! " ~ I

r |

jnertre rnesi,.__thin layer chromatography in-._

said the presence of 1 $ of n1atino B and the absence of

'transplatin. After storage at 56?C for one month,

__thin layer chromatography indicated the pre-_

-.without..3,4.?'.of .platinum..B and no quantity_ _

--of.transplatin. .The.dilution,of the samples,ages

iti con.-acaua ourificata.USP.until.obtaining acon-:

centrat one of 3 mg/ml. of cisnlatine.dava,solutions

llimoide.which..remained the same even after rest

room temperature for 24 hours.

Semulo 8

. .. Stable concentrated solution eli

. ?.??cisplatin (.10 .mg/ml) plus? .EaCl.. _

.... . ..._.(.10 mp:/inl) in n;ibicol .polyethyl-_

- nico-4-00 (-90. tX - HC10.2N (10f'). _ p_ _ To a solution of 0.5 ml NaCl in 4 ml of purified water USP, 1 ml KCl 1N and 4-5 ml .... To the polyethylene glycol 4-00 were added 2.5 ml cisplatin, and the mixture was kept in the dark at room temperature for 4 hours to give a clear yellow dilution... thin layer chromatography of the freshly prepared solution showed only one cisplatin spot. Dilutions of the freshly prepared solution with 1.2 ml - 5 and 9 volumes of purified water gave clear solutions that remained clear after refluxing for 2 hours at room temperature. Dilutions of 1, 2, 3, and 5 volumes showed no evidence of crystallization and were kept at 4°C for 24 hours. Aliquots of the freshly prepared solution were sealed in 17 ml amber vials as described in Example 3 and subjected to storage stability tests at various temperatures. After storage at 37°C for three months, thin-layer chromatography indicated the presence of

of 1 c.o. platinum B with possible traces of transplatin. After storage at a temperature of 4-5?C for

indicated

three months, thin layer chromatographyYTa npresence of 5 platinum B with a possible trace'

!

-of translatable. After storage at temperature

of 56?C for one month, thin-layer chromatography indicated the presence of 2-5 C( of platinum 3 ed.

absence of transplatin. The solution of the samples,

aged with USP purified water up to a concentration of 2 mg/ml cisplatin gave clear solutions that remained clear after standing for 24 hours.

at room temperature.

.. Example 9

Stable concentrated solution of

cisplatin (2.5 mg/ml), ITaCl (9 mg/ml)

and mannitol (12.5 mg/ml) in glycol

polyethylene 6000 ? acidified]_

'31 /.(weight/volume) aqueous

Sodium chloride (0.9 s), mannitol (1.25 ?0 e

Polyethylene glycol 6000 (31.3 g) was dissolved in a sufficient volume of USP purified water

to prepare ICO I ?i solution, and then the solution

was acidified up to a pH of 2.2 with HC11IT

(0.7 ml). Cisplatin (255 ml) was added and the mi- .

.scela was inhabited in the dark for three..days at room temperature to obtain a clear solution.. .

Thin-layer chromatography of the solution...

The freshly prepared solution showed only a trace of cisplatin. Portions of the freshly prepared solution were sealed in 17 mL amber vials as described in the example and subjected to stability tests upon storage at temperatures of 45°C and 56°C. After storage for two months at temperatures of 45°C and 56°C, thin-layer chromatography showed the presence of less than 1 mL of platinum and the absence of transplatin. Dilution of the samples

- -aged...with.an.equal.volume...!! USP purified water gave clear solutions that remained clear

. .after.resting.at.room.temperature.for.24.hours,. . , _ _ _ Example 10 _ _ _ _ _ .._ . _ Stable concentrated production of. . . . . . . . . . _ cisplatin .(15.8- mgy?al) . plus.1TaCl . _ _ _ .. . . (10. mg/ml) in polyethylene glycol _

_ 400..acnuous at 9Q %. . . . .. .. _ ..

Glycol, ethylene glycol 400 (.90 ml) was dissolved in a solution of 1.0 g of ?TaCl in 10 ml of purified U.GP water. A 60 ml of the solution resulted

many were added 900 mg of cisplatin, and the

mixture was inhabited in the dark for five hours.

room temperature to obtain a clear solution. Thin-layer chromatography of the freshly prepared solution indicated only a single area of cisplatin; high-performance liquid chromatography performed as a test showed that it contained 15.8 mg of cisplatin per ml. The dilution,

Mixing the freshly prepared solution with four volumes of USP Rare Water gave a clear solution that remained clear after standing for 24 hours at room temperature. Aliquots of the freshly prepared solution were sealed in 1 ml amber vials as described.

.in example 3 and were subjected to storage stability tests at various temperatures.

.After two months of storage at the temperature of

?5?0, the thin-layer chronography indicated _...

.l,l,5??-.of platinum B and absence__of transplatin...

After a month of storage at a temperature of ..

-56?C, thin layer chromatography indicated

the presence of 2% platinum B and the absence of transplatin. The sample aged at temperature

of 56?C was diluted to a concentration of 2 mg/ml

with sterile water for injections and the sample aged

..chiato at a temperature of 4-5?C was diluted to the con- .

Concentrations of 2.5 and 5.0 mg/ml of cisplatin with sterile water for injections. Each formed clear solutions that remained clear after standing at room temperature for 24 hours. High-efficiency liquid chromatography tests were performed on samples stored for 5 months at 4-5°C and for 6 months at room temperature.

temperature of -57?C and for 8?months at -room temperature there were no power losses of _7.6.5'-, 7.6 ?-.

and 0 /., respectively

.Example..THE .

..'..Concentrated .solution_of_cisplatin_tablet_(.15 .mg/ml) plus CaClg

(25 Aqueous polyethylene glycol 4-00, 90% al.?/?

Note: Cisplatin is a possible carcinogen. Protective clothing, gloves, masks, goggles, and face coverings must be worn throughout the entire procedure. All work areas and equipment must be thoroughly cleaned to avoid any future contamination.

Formula

per mi per 10.0 mi ?cisplatin 0.015 0.150 rr

sodium chloride .. .. 0.015 s .0.150.! ?; .. .

(2)

-- hydrochloric acid Q.5U J. 0.10 ml . 1.0 ml _ __ _ -- Polyethylene glycol 400 _ . . .. _ _ _ _ _ .... .. . : - .-Sentry Pipeline) . . . _ how much. . _ _ Glove _ ! _ _ _ - - - - enough, at 1.0 ml....enough at L.J.0..Q_ml_

_ (1).This weight of cisolatin assumes a potency of _ _ - 1000 mcg/mg. To determine the quantity of cisolatin_ _ ...

.request is used.the following formula: ... _ _ _

.1000 x 0.015 s_ _ _ _ _ '_

_ ;_ = g of cisolatin ii-Potency of cisolatin in mcg/mg _ requested._ . . .

(2) One liter of hydrochloric acid..O.5 IT.is,oropara-_ (?j_..^" _5.

? to come anmie:_ . -*/,_ _

:<hL

_ 1. Place Q57.25Y of sterile water before injections, ..

. .. .USB- In.. a -.clean .Erlenmeyer .flask- of the ..volume ..of.

?a liter

_ ..2...Dwelling .quickly,-.adding.slowly_

. and .with caution.42.75.ml.of concentrated chlorine acid.

- -to. Live.for.10.minutes...Cork.up.with.a.lot_of_ _

_ clean butyl rubber.._

_ Instructions for preparing one liter

. .. _ of .sterile solution ..._

1. Add 100 ml of 0.5N hydrochloric acid.

in a clean Srlenneyer flask, calibrated to the volume

iTi a liter containing a suitable inhabitant, such as

for example, a 6cm long magnetic rod inhabitant, coated in Teflon.

2. Add, with moderate stirring, 15.0 g of sodium chloride. Stir until the salt is completely dissolved.

5.750 mi are added with rapid habitation.

.of polyethylene glycol 400 (Sentry product) and it lasts for about 50 minutes.

4.Remove the magnetic bar dweller

???,',?5 .and the excess fluid in the balloon is drained.

5. 15.0 g of cisolatin activity is carefully added.

6.Add 400-grade polyethylene glycol (Sentry grade) to the top of the liter (a total of 880 ml of 400-grade polyethylene glycol required).

7?Replace the Teflon rod inhabitant in the mixture and seal it with a clean butyl rubber cap. .- . . _ .. . _ _.

8.Wrap the balloon in aluminum foil to completely exclude light.

, . 9. Stir rapidly for 24-48 hours at room temperature. A clear solution should be obtained. If a clear solution is not obtained within 48 hours, the mixture can be heated to

at 57-40?C for 2-6 hours in the absence of air and light

so as to facilitate the rapid dissolution of the remaining cisplatin. Cool to 23-27°C.

. - 10..-Using an aseptic technique,, one passes..

- ?the dark yellow solution under an appro-_ _

. priata -pressure-.of-sterile-nitrogen-,-through..an-adap-_ _ _ - . -to-sterile-pyrogen-free-filter-Millipore..from _ _

- 0.22 microns...It is collected-sterile filtered in a _

. . .sterile and pyrogen-free Erlenmeyer flask,

. _ It is.capped.with_a_sterile_butyl_rubber_stopper_and_

free from pyrogens. The solution can be stored in the dark.

11. The required nuance is introduced.

sterile solution in sterile staining vials

-_ ..amber, pyrogen-free. It is capped with sterile, pyrogen-free, te-.fiLon caps. It is sealed with sterile, aluminum sealants.

12. The vials -doyrebterp_cpntenere_ the_following

- et iohetta .a_titola_di_orecauzione:_

NOT FOR DIRECT IUTRAliUSCULAR USE?0

Il'TTR?VEH OSO *

ijf-PEG-400 solution can be diluted with

..14.parts of sterile water for injections USP _

or_.sterile normal saline solution USP_

in -rodo to give a risolatine solution

at a concentration of 1 mg/ml. If necessary

For higher concentrations, a proportionally lower amount of sterile water or saline can be added. Diluted solutions can be used for intravenous administration and are stable at room temperature (22-26°C) for at least 4-5 hours. Do not refrigerate diluted solutions, as crystals may form.

13. Store the vials in the dark.

/* Example 13 ... : Stable concentrated solution of cisplatin (2.5 g/ml), TaCl (9 mg/ml) X CaCl2 (15 mg/ml), and mannitol (10 mg/ml) in 400 mg polyethylene glycol in ... 31% acidified solution. 0.9 g sodium chloride, 1.5 g CaCl2, and 1.0 g mannitol were dissolved in a mixture of 31% 5 ml 400 mg polyethylene glycol and 40 ml USP purified water. The solution was acidified to pH 2.2 with a 0.4 ml volume of 1N HCl, then 255 mg cisplatin was added, the volume was made up. to 100 ml with USP purified water and the mixture was stirred in the dark for five hours at room temperature to obtain a clear solution. Thin-layer chromatography of the freshly prepared solution showed only one zone of cis-;

?platina. . _ .. .

- - - - - - .. Example 14_ .. .

- -- The general technique of example 5 is repeated?

- all.except-That sodium chloride _ivi.utili_z.zatp.?

_ _ .replaced by a puivalent quantity of chloride

_ magnesium, and in this node a concentrated, stable solution of cispiatin is produced. . . ..

PU ^ ?. . ? - _ Example 15_ _

7 . _ The general technique of example 5 is repeated_...

. .except that.J.1 sodium chloride .iyi_used is.

_...replaced by a more or less equivalent quantity of hydrochloride-_ of the ethyl amino acid Ljferietylamnine_and...a solution is thus produced-_

? concentrated-stable-solution-of-cisplatin.. .. _

.. - - .Example 16_ _ _ _

_ The general technique of example 5 is repeated.

. _ .except that the glycol p o 1 i and t_yl e ni co zl-0_0 used therein consists of .a .volume. equal _of _plicp-_ li poliethyl.enici_2.00 _ and 30_0___respect_iyament?, e. .Yes

.. producep. what? sjtabi li concentrated solutions of cisplatin...

_ __ Example 17

The general technique of example 9 is repeated.

except that polyethylene glycol 6000 is replaced by an equal cohesive of polyethylene glycols

.1000 and 4000 respectively, and thus produce concentrated and stable solutions of .cisDlatina

REVELATIONS

1. Stable concentrated solution of cisplatin: in a solvent medium comprising - from about 30% to

-about 95 /?' of polyethylene glycol, having an average molecular weight of about 150 to about 9000 or a.

methoxypolyethylene glycol having an average molecular weight of about 300 to about 6000, or a 1Q

,ro mixture, and from about 5 # to about 70 # of accua

.said solution further contains at least one non-toxic, pharmaceutically acceptable source of chloride ions in an amount that is at least approximately equal to the amount of cisplatin present in the solution.

-solution, and said solution having a concentration- .

_ of cisplatin ranging from approximately 2.5 to approximately 25 mg/m1.

_, 2. Stable concentrated solution of cisplatin

?in a solvent medium comprising from about 80 to about 95% of a polyethylene glycol having an average molecular weight of from about 250 to about

,1600 or a methoxy polyethylene glycol having

.an average molecular Deso of about 300 to 800, or

.a mixture of them, and from about 5 ?- to about 20 c;' of water, said solution also containing at least one

.pharmaceutically acceptable non-toxic source

of ion_ clo nino? in_ ci u ant i t ?_._c_h_e _ _?.-.variable_ in 1 in-SEE found 11 or from f?-ir-Cn_.unQ- equivalent leqm va- i *

1 lenti? ner_equivalent of cisplatin in the l a ?????? pns',

and this solution containing from approximately 5 to approximately 20 g

idi?cisplatin for me

3. Cisplatin solution as claimed in-

' 1st claim 2 wherein the source is non-toxic

blade ceut icame nt.e _ cloniro ? acid-

d_o_cloridrico_*?sodium chloride, calcium chloride,1

_ di.juappiesio chloride _or.fi._d1orldrate of triethylam-

-imina?or-or-a_mixture of gold?

!

4. Stable concentrated solution of cisolatin

.in__un-^e-ZZQ-_sjolv_erLte_.conprehensive__d_a_circ_a_?55? 3?c_in^

??_-90_?1_1?-4?1???1&-43ethylene glycol-having._weight.no.le.co-

I from Cyrea__25_Q-B___about .650_..e._d.a__about 10 ?'

at about 15 # of water, said solution containing i-

.Innitro a source of chloride ions chosen from acid

hydrochloric acid, sodium chloride and their mixtures as

! SEE .tit? which is in the range from about 2 to about 7 eaui- ppgjlLlA! 2 ?yr?erti per equivalent of cislatine in the solution,_

-this solution having a concentration of cis

Ir la?.ina_var i able from about 10 to about 15 nq/ml ,

5_._-So.l.ution of cisolatine according to the claim

indicated in claim .4 wherein the said solution

-tion.n .sterile and is contained in a container^ sjl?-_

of chloride ion in an amount that varies in the range from about one equivalent to about 10 equivalents per equivalent of cisplatin in the solution.

.and_.that solution .containing_from_about_5 to_about_20 mrz

-of cisplatin for..me.

3.,^Cisplatin solution.as claimed in-- _claim.._2._wherein__the_.non-toxic_source.

--pharmaceutically -aceefctabile_dl...ion.e..chloride._?.aci-_

hydrochloric acid, sodium chloride, calcium chloride, magnesium chloride, or triethylamine dichloride or a mixture thereof.

4. ..Stable concentrated solution - of cisoia t ina

.? in..a_solvent_medium_-CQKorendent.e._dA--Approximately ,?5f' to approximately 9051 of non-lylene glycol having isolec weight-.

- lare -medium .from.about.250.to.about.650 and from.about._10_?i. .

.at about 15% of water, said solution also containing a source of ions, chloride 5_selected_from acid,

.hydrochloric, -sodium chloride .and l-Oro__mixtures,..in.nuan-.tit? which is in the range from about 2 to about ? equi-__vaient per equivalent.of_cisplatin in the solution,

..and said solution, having a concentration of cis-....Dlatina varying from about 10 to about 15jTig/ml_._

5. Cisplatin solution as claimed in claim 4 wherein said solution is sterile and is contained in a container

sealed like a vial

. - 6. Sterile stable concentrated solution of cis-. ..platin in a sealed container such as ! ?

_ a vial, the said solution containing an amount varying from approximately 10 to approximately 15 mg of cisolatine

I

-per ml and from about 10 to about 15 -me; of NaCl per ml in a solvent medium consisting of about 90% of a polyethylene glycol having an average molecular weight of _ varying from about 550 to about ?50 and about 10 ?

- -waterfall. _ . . .

_ 7. Sterile stable concentrated solution of cisi-? _ . -platin in a sealed container such as . - ..a vial, said solution containing a quantity - ? .?varying from about 10 to about 15 mg of cisi-? ..per ml and from about 10 to about 15 mg of IaCl per ml in _ _ _ a solvent medium consisting of ..a quantity corresponding-,

. corresponding to approximately 90.A of a polyethylene glycol. - ?_ ?having an average molecular weight varying from approximately 350. _ n. approximately._ d50 and a quantity corresponding to approximately .. ...10-5? of diluted hydrochloric acid having a concentration? _ .. .up to approximately 0.5 H. .

8. A process for the production of a stable concentrated solution of cisplatin in a solvent medium, which process comprises dissolving a sufficient quantity of cisplatin in the solvent medium to provide a concentration of cisplatin ranging from 2.5 to approximately 25 mg/ml, said solvent medium comprising a quantity ranging from approximately 30 mg/ml to approximately 95 mg/ml. I use a polyethylene film having a molecular weight of approximately 150 mg/ml, or a glycol solution of approximately 100 mg/ml. : polyethylene methoxylate having an average molecular weight of about 300 to about 6000 or a mixture thereof, and a variable quantity from about 5 to about 70 ?l of water, the said solution further containing at least one non-toxic and formally acceptable chloride ion in such a quantity as to be at least 1% equivalent to the quantity of cisplatin present in the solution. _ _ _ _ __ . Roioa ; _ 2 4 H^R. 1981 _ _

. p : ... BRISTOL, IiTERS. COHPMiY ? _ _ . _ _ ; IMG? BARZAITO * If ZAITAUDO S ??^

lA-n- ? _ _ _ _ nn / _

68.98

Claims (1)

ANNEX A Corrections to be made to the text of the application Patent No. 48090-A/81 contained in No. 2 footnotes requested with a request for corrections of the POSTSCRIPT 1: page 42, line 2: correct "from about 1 to about 10" to "from about 2 to about 10"; POSTSCRIPT 2: page 42, line 19: correct "from about 2 to about 7" in "from about 3 to about 7" Rome 9 NCV 1982 p. : BRISTOL-MYERS COMPANY p. : ING. BARZAN0? & ZANARDO ROMA S .p.A s FM/gg-6822