CA2142817A1 - Ophthalmological preparation - Google Patents

Abstract

2142817 9404134 PCTABScor01 The present invention relates to an eye drop formulation, which, in combination, comprises pilocarpine and a further agent for the treatment of ocular hypertension, as well as an ophthalmologically acceptable carrier and optionally further, ophthalmologically acceptable adjuvants. The formulation is characterized in that the pH thereof is from 3.5 to 5.8 and the viscosity is from 10 to 25000 mPas. The invention also relates to the preparation of the said formulation, as well as its use for the treatment of ocular hypertension and glaucoma.

Description

~ 2 ~ 1 7 WO94/~1~ PCT~F193~00326 ,''"
Ophthalmological preparation : The object of the:present invention is an ophthalmological preparation, specifically an eye drop formulation, which, in combinationl comprises pilocarpine and a ~urther agent for the trea~ment of ocular hypertension, ;such as a ~_ blocking agent, ~e~g. timolol, as well as an ophthalmolo~
gically accepta~l:e carrie~ and op~ionally ~urther, opn~
: thalmologically~acceptable adjuvan~s. ~he invention ~urther conce.rns a process ~or the preparation o~ the said ~ormula-;tion, as well ~ai~ ~he ~se th2reo~ ~or ~hi treatment o~
:: intraocular hypertension and glaucoma.

From the EP-patent:application~253 717 i~ is known to administer into the eye ;simultaneously a ~-blocker and pilocarpine in the~ ~orm of:an eye drop combina~ion ~Ormt ation which is~buf~ered to a pH~of 6.0 to 6.8. The use of a combina~i.on form~l~tion rather than administering the two dirugs s`eiparately has, in addition to beneficial therapeuti~

2:0: ~ cal efre~cs, also t:he ~urtnar; ad~antase ~ o~ i~pro~ n~
atient compliance.

owever,:the formul:a~ion ~ico~rding to ~he EP-Fatent appli-: cati:on 253 ~717 has the~:disadvantage that~the solu~ion 25~ :formed~:remains~usable only~for a short:period of time, wh2rerore it has to: be ~adi~sho~ly be_ ~~ fi~st use, either~by combining~a solid substance;and a solution, or : two separate solutions. Thu~the formulation according to ; this EP-patent,application cannot be pa~~ked and delivered ~; : 30 to the user in the traditional bottle package or as a unit~
: : dcse~:package, ~as~ both package::forms require that the : solution contained therein is:ready~for administr~ticn:into the eye, and;also~that~it~is sùfficiently~stable.

3s ~ The formulation~dis~losed in the~EP-patent 253 717 places : strict demands on:the packaging~ technology used, and a~so : on pa~ient acceptanoe. Further~, the highly complicated }

WO ~i~l~ PCT/F193/00 ~ 81r~' 2 packages are substantially more expensive than the trad~
:~ tional ones:because:they have to b~ constructed so as to .
: allow the preparation to be ~prepared shortly before ;
administration. The dif~erent components of the ~ormula- ., : 5 tion are combined by somebody eIse than:the manufacturer ~ `''"
and thus;there is a:de~inite risk ~for~dosage mistakes:. In order to ensure~steril~ity also a~ter ~mixing o~ the com- 1;.
ponen~s,~he rormula~ion con~ains an~1miGro~ial ~reser~a- , tives.

owe-~er, i~ h~s~r a~long time been Xnown that antimic-robial~pre~ervatives;exhlbit;a;number~ o~ side ~ffects on :the cornea. In:eye therapy,:preser~ati~e-free ormulations, ;.:~
packaged in unit-dose orm, thus gain increasingly more 5 use.iAnother reason for:abandoning mu:lti-dose containers is ., that~, ~especi211y~in~ hospital u:se,: the same container is used;for~adminlstering~drug ~to :several: patients, which ~;
increa~es~the~risk for :contamination o~:the ~drug and the .'.:
';:spread~ing of~Gontagious~diseases by means o~ the eye d~op 2~0~ sol~ution.~

According: to::~t~e~ invention ;~we ~have now :surprisingly ~,;, iscovered tha~ it~;~is~possible to~ma~e~a combination:eye drop formulation,;~whiah~ in :the same solution contains .:`.
25~ pi~1OGarpine and~a;:further~:agentifor the~treatment of ocular hypert2nsion,~espi` ial~ly~a ~-bloGXer/ and which is su~fi-: :
ciently~stable~:to be:~packaged and delivered in ready-t~
uae-f;ormi~ in~;~;traditional eye~;drop bottles~or in unit-dose 'l `
: containers. : : : ..

Th~is~is achieyed~acaording to the invention;:by providing a ,'~
formulation~which~has a pH of~between;3.5 and 5.8, and ~ i VisGOSity of 10~to~2;5000 mPas~ r'''/ .

35~:~PreferabLy :the pH~is from 4.5~to~5.5 and~ the viscosity not ~1;
:: more than:150 mPas,~espci:ally 15~to~:50 mPas. :

~ ~2817 ~
W094/~134 PCT/F193/00326 :
,: ..

3 ..
~he viscosity is measured wi*h a Brookfield-viscosimeter :(type LVDV-III) at a temperature of 22 C, and a shear ~ .
rate (D) of l s l ~or viscosities in the range of lO0 to l ;~
25000 mPas, and a shear rate o~ 8 5 1 for viscosities in : S the range o~ lO:to lO0. ~ ~ 1.. ;

It is known that the st~bil~ty o~ pilooarpine decreases ~.
~:~when the pH approaahes neu~ral. At:a pn of 6 or ov~r, pilocarpine is stable only for a: ~ew weeks, or even a ~ew days.~However,~by lowering~the pH:below 6 the degradation : ::;: of pilocarpin~ 2duced markedly and it i5 3u~iciently ~.:
: stable for aommercia} purpos~

However,~when the pH is lowered the bivavailability o~ the j lS; active agents are~ reduced compàred to almost neutral : soîutions.: Accordin~ to the invention, the reduction in bioavailablity~ is~`;:compensated~ for by increasing the viscosity of the~ oxmulàtion, thus providing for a product allowing a longer contact time on the eye sur~ac0.

The~agents to~ be~ used ~according to the invention in; : !~
::: : combination with~pilocarpine for:~the treatment of ocular hypertension~are~ generally :speaking carbonic anhydr~s2 inhib;itors,:~prostag;landins~or any:agent known in the art 5~ for~blocking~or~ activating the: adrenergic receptors, such ~ : .
as~ ~-blocXing ~agen~s~, o~ which ~ypic~l ex~ples ar~ ~ .
carteolol, be~unolol,::metipronalol, pindoloI~, betaxolol, ,~.
levobutanol and espeaially~;t;imolol, and their ophthalmolo-gically acceptable salts and prodrugs. :~
0 :~
The ophthalmologically ~acceptable~ aarrier vehicle is ~ ~.
a~va~tàgeously`~water, or:a mixture of water and an oph~
: ;tha;lmologically acceptable organic solvent, which as such are known in the art. The;~preparation according ~to the !`;~
3~5~ invention may :also contain :further ophthalmologically acceptable adjuvants.

WO941~41~ PCT/FI93/003~'~
21 4~ ~1 7l 4 In order to regulate or stabiliæe the pH, convention~l pH-regulating agents such as acids or bases may be used, or suitable bu~fers, such aæ phosphate buf~er, borate bu~er, ~: acetate buf~er, or citrate bu~fer. To regulate the tonicity of the produc~, substances conventionally used for this : ~purpose may. be used, such `as sodium chloride, potas~ium ch1Oride, glyaerol, mannito1,~ sorbitol, sodium borate, iU~ 2~ Yr ~a 1~ k~
;
Th~:viscosity is adjust~d by using~ in the ~rmulation, a sul~able visco~ty e~h~nci~g 2g t in an ~mou~t to ~iv ~he des~lr~d viscosity:1evel. Typiaal examples are the cellulo~
e deriva~i~es, such as hydroxyprspyl meth-~lcellulose (HPMC; e.g. Methocel by Colorcon, UK), sodium carboxymet~
hylcellulose (e.g. Blanose by Aqualon, UKj, methylc~llulose ~x~e.g. ~ethocel A by Colorcon UK), poly~inylpyrrolidone (e.g. Plasdone by GAF, UK), pol~ inylalcohols (e~g.
Polyviol by Wacker Chemiaal~ UK), dextrans (e.g. Dextran by Si~a, US~), polyacrylia acids ~e.g. Carbopol by Goodrich, U~ etc . Th~ amaunt o~ ~olymer to ~e added d~ps~.ds in ~: a~ai~ion ta ~he desired viscosity ievel, a~so on the pol~mer used,~and can be :easily determined by `a person skillQd in '~h~ art. Tn additisn:tQ raising the viscosity OL
the:formulation, the use o~ the said polymers may have 2~5 ~ ~additional advantages such as a 1ubricating effect on the~
eye,:~as well as a stabilizing e~fect on~the tear film, which~are beneficial effects for patients suffering e.g.
from~dry eyes.

30~ In case an antimicrobial agent is necessary, as is the case when packaging the preparation in multi-dose-containers, : but not when packaging the same in unit-dose-contàiners, : agents known for::this~purpo5e may be used, such as quater~
::nary ammonium:compo~nds, e.g. benzalkonium chloride, benzyl ~: 35 alcohol, mercury salts, thiomersal, chlorhexidine, chlo-robutanol or the like, as such or in combination.

: : : :
':;

.....

4 ~I 4 S gl 7 PCT/F193/00326 .'.
An advantageous eye drop formulation according to the invention is made in sterile water as the carrier vehicle .;~.
and has the following composition (% w/~): pilocarpine HCl :1-5 %j preferably 2-4 %, in combination with a ~-blocker, 5 especially timolol, in an amount of 0.1-1 ~, pre~erably l.
0.25-0.5 %, HPMC as the ~isc~sity enhan~er in an amount of I
0.3 to 1 % to give a~iscos~ity o~ ~0 to 150 mPas, pre~era-bly 1~ to 50 mPa~, and ci~rat~ a pu c ,.5- l"~,~
5.5~ In addition the formulation may contain an acceptable microbial pr~servativ~, such as benzalkaniu~ chloride, typically in n a~ount o Q.04-O.Z ~Jml. .;~;~

The invention aiso concerns a process for the pr~paration '''~''`''!"'~''``' of an eye drop formulation as defined, which comprises `
5 combining pilocarpine and a further agent for the treatment ;~.
o~ocular hyp7ertension: with an ophthalmologically ~ccepta- ~
; ble carrier, adjusting the pH to~a va~ue o~ 3.5 to ~.8 and : ,.;
:the viscosity to a value of 10 ~o 25000 mPas, and possibly adding further ophthalmologically acc~ptabl~ adjuvants.
~: 2 0 ; The~; invention:also concerns ~he use :of the ey~ *rGp formulation for the ~reatment of ocular hypertenslon and glaucomar : 25 : The invention: is illustrated: with the:following examples : withaut l~mit~ng~the.same.~: 1.

.:

~ 35~
..

' . . .
:

~0 ')4/C4134 2 1 ~ 2 8 1 7 PCr/Fl93/0o3-f `

6 . .:, .
~L ~,i'~

~ulti-dose formulation :, 5 composltion ~ A ~ B ;

Piloca~pine HCl ~ ~0.0 ~ : 40.0 ii~;,;
$imolol maleate : 6.84~ ~ 6.84 : 10 citr1c acid monohydr.: 1.~2 0.8~
sodium citrat2 di~ydr ~ ~.73 : 6.13 .i Benzalkon. ch1orid ~ 0.1 ~ 0.1 .PM~ 5~0 5,o ~Steril~ water ad ~ 1.0 ml 1.0 ml : 15 The~eye drop so1ution according t,o this ~xample is made in ; three stages.~In the `~lrs~ step the hydroxypropyl methylcellulosc is st;irred in sterile water. The solution ; is~ster~ilized~ in ~n autocla~e. The autoclav~d solu~ion is :20 co~izd tO room temperature wnile:s~irr1ng.

In the`second stcp the benæalkonium chloride, citric aci~
odlum~citrate,~pilocarpine hydrochloride and tne timolol l .
maleate are dissolved in sterile wa~er at room temperature.
2~5:~ he soluti~n is;:s~crilizcd by ~iltration on filter with a :2ore~size o~ o.

In~ thc~:third~and~last~step~thc:solutions ~rcpared in the ; :;~
~:two steps above are combined aseptically and mixed until ,.
they ~orm homogenous solution. ~he pH of the solution ; :: obtained is 5.3~and lts viscosity:2~5:mPas. The solution is :packed in traditionaI:cyc drop~bottlcs.

1: . ., 214;~817 ~`
PCT/FI93/00326 ,;:
WO 94~4t34 , i 7 :~

Unit~dose formulation 5 Co~iposition ~ A~

.:Pilocarpine HCl : : ~0.0 ~4 ~0 imolol maleate : : 6.84: G.~4 , .
10~itxic acid monohydr.~ : 1.12 : 0.88 Sodium citrate~dihydr.~ 9 ~ 6~13 :
PNC : ~ : 5.0~ ~ 5.0 Steriie~water ad ~ l.O:ml ~ ~ 1.0 ml lS~ The solutions~a$e~ prepaxed according~to the Exampl~ 1. The pH;~or the s~lution~ obtàined~:is ;5.3 and :the ~isco~ity 25 :mPas. The~so:l~tion~is packed in unit-dose-~ontainers. .

xam~le 3 Tt~ A~5Q-r ~rmUlation~

Composition ;:;~

Pilo~arpin~C~ 20.0 imolol:~:;hemihydr. ~ 5.12 Citric acid~:monohydr.~ 2.40 Sodium cltrate dihydr.~ 4.00 :30 ~PMC
Sterile~;water~ ad~ 0:ml ~:

The solution:ls:~prepared accordin~ to the Example 1. The ~
~ ~ . pH~ or~the~soluti~on ~obtai`ned is 5.3 and~ the viscosity 25 I ~;
35~ mPas:.;~ The so~lution~is packed in~ unit-dose-containers. ~y `:adding to the~formulation~benzalkonium~chloride O.lO mg/ml, :a corresponding:multi-dose~formulation is~obtained.

U~94J04l34 ~1 4 ~ 81 7 PCT/FI93tO03 -~

8 ;
`:'.',''`.
~, .. ....
ExamPle 4 , . . .
Composition :~
(mg) : '~
1.,.,,.': ., : Pilocarpine HC~. ~ 20.0 ~;: Timolol maleate 6.84 ~.~.;, Citric acid monohydr. 1.~2 l.
10 Sodium citrat~ d~hydr. 5.79 ~, nzalkon. chloride: 0.10 .
: Polyvinylal~ohol 115000 40.00 :~ ~ St~ile wat~r ad~ 1.0 ml : l~

15: Th~ solution is p~epared according to the Exampl~ 1. The :i;
; pH~ o~ the solution obtained is 5.3 and th~ viscosity 35 mPas.

3~ L~2 :2G
Composition (mg) Pilocarpine HC:l ~O.O mg :
25 Betaxolol HCl ~ 5~6 mg MC ~ : 5.0 m~
, NaOH/HCl : ad pH 5.3 : .
Sterile water ~: :ad ~1.0 ml The solutlon is prepared according to the Example 1. The ~;
pH of ~he solution; obtained is 5.3:and the viscosity 25 mPas.

ExamPle 6 ~ ~ , In~ the following the preparation of~ two high-viscosity ~i products is described. ;
, ;-, PCT/F193J00326 ~;
W~1041~

Comp~sition ~mg) ` ~ f','.''~i;.~' 5 Pilocarpine HCl 20.0 Timolol maleate 6.84 Citria acid monohydr. 1.1 Sodium ci~ra~a;diny~r. 5.7 Benz~alkon. ahloride 0.10 1;~
Carbopol0 941 ~ 9.0 Natr.hy~r. ~s . ad pr 5.0-a.5 Sterile~water~ ad~ ` l.O g The solution is prepared according to the Example 1. The :.
pH o~ the solution o~tained is 5.2 and the ~iscosity 24000 mPas.~

Pilocarpine HCl ~ 20.0 imolol hemihydr. 5.12 Z~ Ci'ri- ac~d~Q~hyd . ~ 1.12 S~odium~citr~ee dlhyar. 3./~
Benza~kon.`chloride;~ ~ 0.10 carDop~ 7 . 5 Natr.hydr. ~ q.s~ ad pH 5.~0-5.5 ~ 1;
Sterile~water~ ad~ l.O g The~`solution;isi~;prepared according to the Example 1. The ; ! ':
pN~of~the solution~obtained is 5.5~and th~ viscosity 13700 ;~ , mPas. ~ ;

Claims (11)

Claims

1. Eye drop formulation, which, in combination, comprises pilocarpine and a .beta.-blocking agent, as well as an ophthal-mologically acceptable carrier and optionally further, ophthalmologically acceptable adjuvants, characterized in that the pH of the formulation is from 2.5 to 5.8 and the viscosity is from 10 to 25000 mPas.

2. Formulation according to claim 1, characterized in that the pH is from 4.5 to 5.5.

3. Formulation according to any one of the preceeding claims, characterized in that the viscosity of the prepara-tion is from 10 to 150 mPas, preferably from 15 to 50 mPas.

4. Formulation according to any of the preceeding claims, characterized in that pH has been adjusted with a suitable buffer, especially citrate buffer.

5. Formulation according to claim 3, characterized in that as the viscosity enhancer, hydroxypropyl methylcellulose is used.

6. Formulation according to claim 1, characterized in that the concentration of .beta.-blocking agent is from 0.1 to 1 %
(w/v), and that of pilocarpine from 1 to 5 % (w/v), preferably 0.23 to 5.5 % (w/v) of .beta.-blocking agent and 2-4 % (w/v) of pilocarpine.

7. Formulation according to claim 6, characterized in that the .beta.-blocking agent is a timolol compound, such as timolol base, timolol hemihydrate, a pharmaceutically acceptable timolol salt, e.g. timolol maleate.

8. Formulation according to any one of the preceeding claims, characterized in that it is in unit dose form.

9. Process for the preparation of an eye drop formulation according to claim 1, characterized in that it comprises combining pilocarpine and a further agent for the treatment of ocular hypertension with an ophthalmologically accepta-ble carrier, adjusting the pH to a value of 3.5 to 5.8 and the viscosity to a value of 10 to 2500 mPas, and possibly adding further ophthalmologically acceptable adjuvants.

10. Process according to claim 9 for the preparation of an eye drop formulation according to any one of the claims 2 to 8.

11. Use of an eye drop formulation according to any one of the preceeding claims for the treatment of ocular hyperten-sion and glaucoma.