CA1328614C - Preservative system for ophthalmics formulations - Google Patents
Preservative system for ophthalmics formulationsInfo
- Publication number
- CA1328614C CA1328614C CA000576880A CA576880A CA1328614C CA 1328614 C CA1328614 C CA 1328614C CA 000576880 A CA000576880 A CA 000576880A CA 576880 A CA576880 A CA 576880A CA 1328614 C CA1328614 C CA 1328614C
- Authority
- CA
- Canada
- Prior art keywords
- nsaid
- vol
- formulation
- ophthalmic
- surfactant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
ABSTRACT OF THE DISCLOSURE
Stable, clear, antimicrobially effective, ophthalmic formulations include an ophthalmologically effective amount of a drug, especially a -COOH group-containing drug or a NSAID, and a preservative system formed of a quaternary ammonium preservative and a nonionic surfactant, all in an aqueous vehicle. These formulations are useful for treating diseases that are either caused by, associated with or accompanied by inflammatory processes, including, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy, and conjunctivitis, or any trauma caused by eye surgery or eye injury.
Stable, clear, antimicrobially effective, ophthalmic formulations include an ophthalmologically effective amount of a drug, especially a -COOH group-containing drug or a NSAID, and a preservative system formed of a quaternary ammonium preservative and a nonionic surfactant, all in an aqueous vehicle. These formulations are useful for treating diseases that are either caused by, associated with or accompanied by inflammatory processes, including, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy, and conjunctivitis, or any trauma caused by eye surgery or eye injury.
Description
~i ~328614 - . .
~.
...
~ 5 . .
.
PRESERVATIVE SYSTEM_FOR OPHTHALMIC FORMULATIONS
. ,.
BACKGROUND OF THE INVENTION .
The present invention: cela~es..t.o`.imp-rove~o'phthaim~c~-.
ormulat~ons, particularL~ t= ophth~aimié~r~r.mulàti-o~s-for ~-anti-in~lammatory drugs',-':an:d speci~ical ~ t~'''an'i-mpr~ve.d'~
preservative system ror-ophthalmic-~formulàtions''of~
carboxyl ( n-COOHn ) group-containing-~ru'g~s~,~'ëspecLa~ y~
~-~ .---= ...:._-~ _-~~non-s.te~f~3oC~anti-fn~la ~ drugs-t'~NS'A~
- ;~ The invention also r~lates t~o-methods ot usin~ thesé . ............... ~ ' ~20 :~ormulations ~or treating-'d~se'ases-that' are~-'either caused ~':'--~` ' _ _ _ . b.y,'~ssoc~i~ c-~th or ~ '~ ' ~processes,-including, among'otne.rs-,-'g~aucoma,-~cystoid ~
:` macular`edema, uveitis~ diabetic`:retinopathy,~and '~'-~~---=.~ ~~ .
conJunctivitis, or any trauma caused by eye surgery or eye inJury.
.'`The topical use ~ot-~ AID~s,~-particu~àr y~
:'pyrrol-e~ ~ the treatme ~ phthatmic.d-~ e'asés-~was-'''~ -.'~
first~taught in U.S. Patent~No~--4~:454~15.1, where NSAID
compounds ~suc:h as those described in U.S. Patents :.
~: : 30 -4j-089-,969; 4,23290~8; 4,087,5~9 and; 4-~097:,519) weré ~~ '~~ ' :.' ': exempli~ied in ~ormuIation:with:NaH2~04-H20, ~:~ .-~'~'''~ ~- ~ .-.
' N-a2HP04~-H20, NaCl, benzalk~oni~um~chloride `(n~AC~ ~ ~~ ~` ~ ~ ` -. and sterilized water. While the formulations described~
-: : : - .
~: 35 ~ ~.
.
~ ~ 8408Y 26280-FF
~328614 --2-- ...
in the '151 patent were efficacious, an insoluble complex was ~ound to form between the NSAID and the BAC. The -formulations became cloudy or turbid and did not, therefore, have the stability desired for shelf life in ' 5 commercial applications. A reasonable m~nimum shelf li~e .~:
(that is, the time during which a solution remains clear ~ -and retains its pharmaceutical activity) is at least ~-about one year, representing su~ficient time to package, ,~
ship, and store a formulation~'without havLng-to replace 10 expired stock too frequently. The solutions of the .. ' present $nvention have shown a shelt life of at least one year. Thus, the present invention entails an improvement over the tormulations desc-~bed Ln the .'151~patent.
--In-g~ral, a-n op~nth~lm~ç--~ormuLa~i~a':'~.ontai-n-~.an. --~
~ -~~~ ~ 1s active compound and various-ophth-aI-moIogi:ca:l}y accept~ble excipients, in the form of.a soI'ution, an ointment, a suspension, etc. An excipient is:ophthalmologically a~eeptable--~f---i-t is non-iTrlt-r~o to~the e~e a~C=~f-Lts~
- - active ingredient penetr~e~ ~ ~roo~-~q~ùe'ous~'b'arrier '~
20 and!or di~uses through-~he-Ya~i-ous ocu=~ar substructures : -- ' . to the_site-where it i~
excipients can include a t-an~c~ifier,. a preservativeJ'i~
surfactant, a but~ering =s.ystem,~a chelatin.g:agent', à . .~ ' viscosity agent as well as other stabilizing agents.
25 Ophthalmic ~ormulations mus-t be-sterile, and.if intende~d .
: for multlple dosing regim ~ t-bé-pr'e:serve~d "wi'~h--an~~ ~~'~.~;-''~'.
_ - .etrective anti-microbia~3:e~b~
Organo-mercurials (e~ -thimerosal,~-phenylmercuric'' acetate and phenylmercuric nitrate) have been used 30 extensively as the preservative ln ophthalmic solutions.
- These co0pounds, however,.pos:e-'~-:dif~i'cu~ties due to~
potential mercury toxicit~~~as~-:well--as-poor ch'emical~~~
stability. Benzalkonium chloride, a quaternary ammonium compound, has been widely used in ophthalmic solutions, .:~
and is considered to be the preservative o~ choice.
- , ---- .......... - , ., .......... . . _. _,_ . .. . . _ . _ ,. . .
8408Y 26280-FF ~
However, BAC has typically been considered to be incompatible with anionic drugs ~e.g., salicylates or ..
nitrates, etc.), forming insoluble complexes which cause the solution to become cloudy or turbid. Such a complex between the anionic drug and benzalkonium chloride can cause a decrease in the pharmaceutical activity of the anionic drug.
Many NSAIDs (such as ketorolac, indomethacin, ~ `
~lurbipro~en and diclo~enac) are being devel'oped ~or ,.
10 ocular use because of their activity as anti-in~lammatory ,.
agents including their ability to prevent cystoid macular edema.
., = . .-. ~ , .: .......... ..
In the past, as in the case-with-:othër-o~hthalmic .-dr~s--~tnt-eonta~n-~ a~-gr~op~~ant51nf1~m~r~
~ f5 solutions o~ NSAIDs for occ~Ia~r ûse-hav~ ven t~
incompatible with quaternary~.ammonium compounds such as,. . ,, :~
BAC. This incompatibility"-is'due to--the ~act.~:that 'the - '--~
COOH group can torm a com~,~ th ~s~e~o~r~
' ,.,- ~ -ammonium-compounds, renderi-ng.,th~-,-pre~s~Fv3Ri~e~,les's ~'~
available to serve its function,_.and re.du~n~-the- ~ ,. .m . ~
activity o~ the active i ~ ~.
ophthalmic ~ormulations have he~ prepared~oweverr~
these are suspensions, not-solutions:.- O,cù~en Ophthalmic.
solution, an NSAID (rlurbipro~en) approved by the FDA ~or : 25 ophthalmic use, incorporates thimerosal (with EDTA) as ~--, -'- its preservative system. :,I,n.a~ ,p:a~èn~t=~-l4~4~ 51~thé'ré -,~r~- ~-,, -~= 'is a :disclosure o~ an oph ~ .~
ketorolac, benzalkonium chlo~ide-~as'th:e prese'rvative) ¦: and polysorbate 80, however~the solution became cloudy or ' :
:: 30 turbid a~ter a short period o~,ti-me. .: .
- : It has remained desiréd-~-to pro'vide~a st-able,-clear, antimicrobially e~fective ophtha~$~ ormu:iation-~ith-a prolonged shel~ e ~or -COOH group containing .:
:~:: ophthalmic drugs, especially NSAIDs, using BAO as the .:
preservative. ~ '. ' ~f R ¦ 1 3 2 8 6 1 4 r SUMMARY OF THE INVENTION
It has now been discovered that stable, clear and antimic.robially effective, NSAID-containing ophthalmic j formulations can be prepared which include a quaternary 5 ammonium preservative. These solutions have an improved shelf life, exhibiting no cloudiness or turbidity over - extended,periods.
In one aspect of the inv-ention, these compositions include an ophthalmologicaLIy effective:~,amount of a 10 NSAID, a quaternary ammonium preservative ànd a stabilizing amount o~ an ethoxylated octylphenol as a .
nonionic surfactant, all in an aqueous vehicle.
Another aspect is an ophthalmiC~com~ositiQn _ _ __includi_~ an_ophthalmol -~-~ -1E;'NSAID~,a quaternary ammo~i~:-p~ré ~ lzLn~
amount o~ an ethoxylated octylphen'oi'`as~-a nonionic-surfactant. '~~
_ _ Another aspect is an o~t,h Im ~-' ~ ~ itio ~- .- .
~including~ an ophthalmologl,al~~éff'ec ~ in~
--'20 -NSAID-, benzalkonium chloride~as-a-p:r ~ ~d~a.',,~
, stabilizing amount ot an.ethoxylà'ted Qc~ylp~en.~.a-s,~a~
" non1 0n~1c'~ ~sur1'actant . ~~~
, Another aspect is an:ophthalmic co~mp~sition~
including:an ophthalmologica ~ ~e'~f.,~ectf~ amount o~ a, ' ` -' :
: 25 NSAID, benzalkonium chloride as a preservative and a _ _~st?bilizing amount o~ Oct, ~ ~l 40f,,as ~ -~
-surfactant. ."~,~
Another aspect is an o:phthalmic.comp~ it~on '`~
including an ophthalmologicall~~-ef'~ec'~ivé amo'unt of ,.-30 ketorolac or an isomer,:a~ ester~--or~a.ph=a-r`maceutically ,~
. ~ , acceptable salt thereo~, benzalkonium ch-lor~ ";'a's,':,a:,~ ,~, ,,, -,:. ~'. ~."
preserYative and a stabilizing-.am,ount of_OQto~nol..,40 as . .. . .,. -:
~' 'a nonionlc sur~actant.
*trade-mark ~ ' 35 - ~' 8408y ~ 2628C-FF
, , ~ 5 t~
In another aspect of the invention, methods tor Itreating ophthalmic diseases in mammals using the ophthal~ic pharmaceutical ~ormulations o~ the invention are also disclosed. These diseases are those that are ¦5 either caused by, associated with or accompanied by -in~lammatory processes, including, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy and conjunctivitis, or any -trauma caused by eye surgery or eye injury. ~-DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Detinitions _ As used herein, the term~"NSAiD" meàns: anaccepta~ non-steroi~a ~ ~
ant~-in~lammatory drug. Thé NSAID's include,-'-~r~~ ---'' ~'' example, rlurbipro~en, ketorolac, diclofenac, indomethacin, and the isomers, esters, and ~' -_ _ pharmaceutically acceptable--sa-lts-th -- ~ -As--used herein, the ~erm~-~q.s-."-~m ~
quantity su~icient to ac~iRve a- stated~nc'tio~ e7.~9-.'r ~ - ' -'~'`- '-- to bring a sol_tion t A~s used herein, the term~ntreatment-n--o~ ~rea*ing"~
means any treatment o~ a disease-in'~a~~mammal,~-lnclJcing~
- (i) preventing the disease, that is,'causing the clinlcal symptoms o~ the disease not to develop, -~~-~--~-'-' ~i~ lnhlbiting the ~ ea~se,~~~thf~ ~ ~ s æ ~ ~hë'~
_ development o~ clin ~ ~ ~ , -(iii) relieving the disease,- that ls, causing the regre~ssion o~ clinical symptoms. : n As used herein, the term-ne~ective~'~amount" means a -- ~ dosage su~icient to provide- treitment ~or the ~d-iséase~
~ state being treated. This~wlLL vary~d~p~ irng-on-~he~''' ~`''--- '''~ ~
; patient, the disease and the treatment being ef~ected. -'' ~ 35 - .
8408Y 26280-FF -' ' :~
~ -6- 1 32861 4 As used herein, the term "antimicrobially e~fective"
means ability to withstand the U.5. Phàrmacopia antimicrobial challenge. .
As used herein, the term "sur~actant"imeans a nonionic surfactant, preferably~ethoxyLated octylphenol compounds as described below.
As used herein, the term "quaternary ammonium preservative" means a quaternar~ ammonium c.ompound such.. ~ --as described below. .~
10As used herein, the~term nstab11iz-in'g"-means-keeping a formulation clear and ant~microbia~ly ef:fective for its :.:
minimum reasonable shel~ lirë.:, e-..g.~ at-le~ast~onë.;~-year..'~
is ~ ---- Thé:formulations of th~p~:~se~
- ' - NSAID active agent in an:effective amou~t~'-''f ~ halmic~
t;reatment, a quaternary~amm.o.ni'um'~~p`Ées;ervat'v"~-a'~~
stabil-i--zing amount of an'~
~ :nonionic-~surfactant, opti:~n'a-L-l~ -in~
:~ :' ... 20 é~x'cipient~ such as a chela~Ln ~ ~
fe- ~ system, a ~ .. ~ '-' - stabi~izing agents. Ophthalmic soiut on~ ~ e ~ -~
t'ypically,~,contain~an aqueous,,vè cle,rat`~ ~ p ~,a'n, ~ ~ ~ ',"~' ' vehic~e. r Ophthalmic rorm'u;liti'ons''m~st be sterilé, and i'f ~ ;', ~, 25 intended ~or multiple dosing-regimens, must be ~
., at le ~ ,~, - ~, ~ to three ~ears or more~ ~e ~ y j~ L~ a~
- formulations of the prèsent-~invéntion are'typically ~ 30 commercialiy available or~ca~-b~-m-adé---b~et~a~sv'~ea~ly-_k ~ known to-those skilled in the ar.~ '~' -'~"'-~~=~--~ ='~'---~' '''' '---- --Phar-maceutical ophthalmi'c:formulati~ ~ pl~a}l~
contain an efféctive amount,~e.g.,'O.bO,lX'~-t~o~10%''`wt~/vo'l~., ~
preferably 0.00'2%~to 5% wt/vol, most preferably 0.005X to -; ~ 3S 1% wt/vol of an active ingredient te.9., the NSAID of the :: :
D _7_ 1 3 2 8 6 1 4 present invention). The amount of active ingredient will vary with the particular formulation and the disease state for which it is intended. The total concentration o~ solutes should be such that, i~ possible, the 5 resulting solution is isotonic with the lacrimal fluid (though this is not absolutely necessary) and has a pH in the range of 6 to 8.
' The formulations-of the present invention are prepared as solutions incorporating the ibove-described ,:
10 ingredients within the following approximate ranges:
Ingredient Amount Active Agent - . 0.001% to lO.0% wt/vol.; :.
Preservative ~ , "O.OClX~,to ~ ,tt.vol~
5--~ac'~a-n~
Other Excipie.nts- .-,-0%-''t~ X wt:~o~ an~ ....... '}'~'`~
~ Purified Water ~ q.s. to 100%.
Optional~-other excipients, such a~s a~chelating agent and a tonic^ir-ier, are used ,i~~..e-fo~l,~o ~ ~ t1e,`-_,..'`"',~-''-",~~~-~.-,~'.-' ..proportions: , -,~,- ~ ,,c~
.20 ,, ~ Ingredient ''~ 's' `' 'A'mo~nt'~' = '`~'"' -' ~~''-`~~~'''~-,:~' .-. Chela.ting a ent- -~.... ; ~ ,'.,.
, ~ Tonicifier ~ q.s. tQ:r-ach e~e;~
.. - lsot.o ~ ty with~-' -~' '': - ':
~ ~ ~lacrimal.~luid; and ~
25 ' lN NaOH or lN HCl -q.s.... ta.adj,ust ~H.. :.-.ta-. ~ ' - - 6`0~
.
I ~
I , ~
'...... : 35 - : - :
8408Y 26280-FF ~.
, .:
. ~.
In a preferred ophthalmic NSAID solution, the ingredients are combined in the following proportions:
Ingredient Amount -NSAID 0.002% to 5.0% wt/vol.;
BAC 0.002% to l.OX wt/vol.; '~- , (50% aq. soln.) ' Octoxynol 40 0.001% to 1.0% wt/vol.; ' - ' (70% aq. soln.),, EDTA Na2 0.01% to 1.'0% wt/vol.; ~ -NaCl q.s. ~or isotonicity with ' lacrimal ~luid; ~"
lN NaOH or lN HCl q.s. to adjust pH to ,, ' P i~ie~ ~ t~ t i =
, - In another preferred,,o,~ thalmic'NSAID solution, the -ingredients are combined ihn 'the ~,o-llowi~ng proportian~s~
Ingredient ~ mou,n,t ,~
~ , NSAID ~ aQ~% -; t~ voI
; ~ 20,'~ AC ~ eQ
50% aq soln;~
Octoxynol 40 ,-~-0 ~ X to,l-OX; ~ ~ ~
(70X aq. soln.3- ', ' , ''`--~ ,';'~ ; '-~ ', E~TA Na2 0.01% to 1.0% wt/vol.;
;25 ~ , NaCl q.s.~or isotonlcity wlth"~
lN NaOH or lN-' ~ ~
,7.4,~.,4;-~aQd , ' Puri~ied Water '' q.s. to 100%.
: - n ~. r~ v ,::: - ~:
"j ~ ~ ":, ""~
~: ' ~'.; ' ' ' ' ;
:~
g . -:
In a more preferred ophthalmic NSAID solution, the ;.
ingredients are co~bined in the following proportions~
Ingredient Amount NSAID 0.50% wt/vol.; ~:
BAC 0.02% wt/vol.;
(50% aq. soln.) '~
Octoxynol 40 0.01% wt/vol.; .. '~.
~70% aq. soln.) , "' EDTA Na2 0.10% wtivol.;
, 10 NaCl ~ q.s. ~or isotonicity with ; , . lacrimal ~luid; ' lN NaOH or~:lN HCl q.s. to adjust pH to I :;
~ 4 ~.4,.:.and~
: Purified Wat ~, .. -~_s ;.t'~.l.O ~.
The invention r~ ~ t~
' , ~ ~ ~: -having a's the active~ageQt ophthalmologically acceptable '. ~ ' drugs (including the isome.rs, ,esters and;ph:a~maceutically:
.ac.eeptable salts:thereo.~, ~ a'~:~ r'.,~
'r ~ ,20 -,quater,nary ammonium compo ~ 'cu ~ ~ ~-~''`~;~''~'''`~`'''"
'drug;s with a carbo,xyl-group:'.--~"'..~,.''-~ ~ ~ ~ ~~ ~ ~ , ';,.
lnc}ude, tor example, keto ~ ~ a~d-the~'o~e-~,compàu~d5~ ` u;";
~ describéd as:belng oph,thal ~ic-alLy~et~'ectlve'`~in U'~,$.-~
; ~ 25 Patent'No,. 4,454,151 to Watérbury.J issued'June 12, 1984 G ~ dlolorenao, Including ' pharmacé~tical-ly-:~acoepta ~ ~ ~there~'.~---~~ 30~, ~ Preservatives use'~ul in the rormula.t,ions o~ the présent.lnvention incIu~e~uaternary~,am:monium,compounds, . : :,-such:as cetyltrimethylammonium b-~omid ~ L ~ ~ium~
- chlo de~and benzalkoni m hlo ~,- -re -~benzalkonium ~chloride.
:8408y ~ ;26280- *
t ~- :
-10- ~, The nonionic surfactants useful in the formulations of the present invention are preferably ethoxylated octylphenol compounds, such as octylphenoxypoly-(ethyleneoxy)ethanols, more preferably, a homologous series of surfactants sold under the trade name Igepal CA
with a numerical su~tix indicating the mole ratio ofethylene oxide to octylphenol, the ratio being 3 to 40.
Examples include Octoxynol 9, Octoxynol 12, Octoxynol 13, and Octoxynol 40, and most pre~erably Octoxynol 40, manu~actured and sold by GAF under the trade name Igepal CA897 (a 70X aqueous solution o~ Octo~ynol 40).
Among the optional excipients, the chelating agents usetul in the tormulations;o~ the present invention ... -include 8-hydroxyquinoline.sulfate,. c-itric acid, aad-~
pre~era~ly di50dium-edetate.-~und ~.~ ~ ans~`~ - .---;-`
the chelating agent may a}so-~ènhanTce:;thè ~ntl-microbial . e~fect due to its ability-t-o-rend:er essential metal ions unavailable to the microbes.
Bu~ering systems op.~lonally useful in~-thè ~~
: ~ 20 ~ormulations ot the prese ~ invention are ba~sed-on-, for - -. example,~-citrate, borate,-~or phosphat~
0~14i~ rs-~t-i-~ ~ ns~
the present invention include-dèxtr~se~,~ potassl-~m chloride and/or sodium-.chlorid~,:-prefér.ably-sodium 25 Chloride, - - -Viscosity agents optiona-lly-:use~ul in:the:
c 11 1 s ot the pr - céllulose, sodium carboxymethylcelIuIose~ and : 30 hydroxye~hylcellulose.
: ~ : Other optional excipients--use~ul in the ~ormu}ations ~-o~ the present invention-~include~sta~iliz~ing-a~ents such as antioxidants, e.g.,- sod~m metabisuI~ate-and ascorbic -~ acid, depending on the NSAID used.
: ~ *tr ade -ma rk ~- ~ 8408y - - - ~ ~ 26280-FF
Il 1328614 These formulations are prepared by dissolving the solutes (e.g., the NSAID, the preservative, the sur~actant, the chelating agent, and the bu~fering agent) -in a suitable quantity o~ water, adjusting the pH to ~' about 6 to 8, preferably 6.8 to 8.0 and most preferably 7.4, making a final volume adjustment to 100% with ' additional water, and sterilizing the preparation using any suitable method known to those in the art. ~-It has been discovered that ophthalmic .40rmulations `'~''`
incorporating the preservative system o,4 the invention are physically stable (i.e., remain clear) and tunctionally ` , stable (1.e., remain antimicrobially e~.4ective) 40r at least the minimum reasonable-shelt li~e o, such~products.' 15 Pre~erred Formulations The pre erred preservative systém o. the invention includes a quaternary ammonium preservative and a -stabilizing amount o. a nonionic s~u-r actant~
The pre~erred ophthalmic rormulation o~ the ---, 2,0~1nvention,includes a NSAID~active~agént~ -~n ef'~ëctivë-~
amount tor ophthalmic treatment and,an antimicrob-ially , ' e~rectlve,-amount o~ the abo've-described~pre~erred , '-preservative system.~
, The~preferrod preservatlve o~ the invention is ~ ' 25 benzalkonium chloride.
" ~ - The prererred sur~actant--o-~ t,he''~=nve~t~on~
, Octoxynol~40, especially when~-combine~-wi,h--,~en ~ ~i'ùm'=-'~
chloride as the preservative. ~
The pre,4erred chelating agent o~ the invention is ' 0 disodium edetate, especially when combined with ~ ~-- benzalkon'ium chloride as the~pre,sérvati-,ve and '--Octoxynol~40 as the nonionic-~surr'actant.~
- The preferred ophthalmic solutions o~ the invéntion , 'include a NSAID, benzalkonium chloride,,Octoxynol 40 and -~ ~ 35 disodlum edetate.
2~280-FF ~ -~: ::~ - ' -:
..
A preferred ophthalmic NSAID solution, the ingredients are combined in the following proportions:
Ingredient Amount NSAID 0.002% to 5.0% wt/vol.;
BAC 0.002% to 1.0% wt/vol.;
(50% aq. soln.) Octoxynol 40 0.001% to 1.0% wt/vol.;
(70% aq. soln.) EDTA Na2 0.01% to 1.0% wt/vol.
NaCl q.s. for isotonicity with lacrimal fluid;
lN NaOH or lN HCl q.s. to adjust pH to ~ 7.4+0.4; and _ Purified Water - q.5. - ~o~
Another preferred ophthalmic NSAID solution, the ~ -ingredients are combined in the ~ollowing proportions:
Ingredient Amount NSAID ~ O.Q05%~to 1.0~ wt/vol BAC - 0.002% to~L.0% wt/vol., (50% aq. soln.) Octoxynol 40 -~ ~ o.ool%~~O~~l.a% wt~ivoI~
(70% aq. soln.) ~ ~ EDTA Na2 O.OlX to 1.0% wt/vol.;
NaCl q.s. ~or isotonicity - ~ with lacrimal--~lu~d,~
lN NaOH or lN HCl ~g.s~ to ad~Us*;p~---to~
7.4_0.4; and Puri~ied Water q.s. to 100%.
`-~ 35 ~ 8408Y 26280-FF
: : -.
~ : ' :
-13- 1 3286 1 4 : -~
A preferred ophthalmic NSAID solution has the following formulation: ~
Ingredient Amount .;-NSAID 0.50% wt/vol.
BAC 0.02% wt/vol. -(50X aq. soln.) --Octoxynol 40 0.01% wt/vol.
(70% aq. soln.) EDTA Na2 0.10% wt/vol.
NaCl q.s. for isotonicity with lacrimal fluid ;
lN NaOH or lN HCl q.s. to adjust pH to ~ -7.4+0.4 ~;
_ _ _ Purified Water --q.s. -to -~OOX --------- --~~ ~ -Most preferred is the ophthalmic solution according to the above formulation wherein the NSAIO is Ketorolac Tromethamine or an isomer thereof. ~ - ~ ` - - . -Utility an-d Administration Thls inventlon is directed_to NSAID ophthalmic -- -~ _ ~-~~rormuIations and a method useful for treating ophthalmic diseases ~n mammals. These diseases are either caused `
by~ associated wlth or accompanied by inflammatory processes, lncluding, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy and con~unctivitis, or any trauma caused~by eye-;-surge~ry-or~
eye injury.
The method of this invention is both curative and 30 preventat~ve. Where applied, for example, pre-surgically or immediately post-traumatically, i~e. before ~
inflamm tion develops, it prevents development of inflammation. When applied directly to the-eye~suffering ~ --from any of the named ophthalmic diseases, it supresses already developed inflammatory processes. -8408Y 26280-FF .
:: : ~ ' ' ',, ' Ophthalmic formulations are typically administered by topical application to the eyelids or for instillation into the space (cul-de-sac) between the eyeball and the eyelids, o~ topically applied ophthalmic solutions, suspensions or ointments, or by subconjunctival injection.
The dosage level will, of course, depend on the concentration of the drops, the condition of the subject and the individual magnitude of responses to treatment~
However, typical dosage ranges might be about 2 to lû
drops of 0.5X solution of active ingredient per day.
For a more detailed discussion o~ ophthalmic formulations, their preparation and administration, see Remington's Pharmaceutical Sciences, 15th Ed., pages 1489-1504, (197-5).
Testing Ophthalmic formulations such as the solutions o~ the present invention are typically tested ~or physical stability, chemical stability, and preservative efficacy, ~-20 both when they are first manu~actured and'-a~ter a fix~ed `' '-period of time (e.g., a~ter two years). They are -generally considered to be sate and clinlca`liy~ acce'ptacre`~
i~ proven to be well tolerated in the eye. "
Physical stability is determined by observation of a 25 solution after expiration of a fixed period of time. A
solution is considered to be physicall~-stable if- its ~
appearance (e.g., color and-clarity~ doés~not change'and if the pH remaihs constant, within acceptable limits.
Chemical stability involves a routine chemical analysis 30 of the solution, to be sure that its active ingredient "
and the excipients have not changed after a rixed period -of time.
Preservative efficacy is tested by the procedure ~-- described in the U.S. Pharmacopia Compendiary, whereby a 8408y 26280-FF :~
. ': -solution is challenged with a microbe and a determination is made as to whether the microbe survives in it. ~
EXAMPLES - -:
The following examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as a limitation on the scope or the invention, but merely as being illustrative and representative thereo~.
::
This example illustrate~s the preparation o~ a -- representative pharmaceutical ~ormulation for ophtha}mic administration containing the NSAID Ketorolac Tromethamine. - -- ; ~ -Ingredient Amount Ketorolac Tromethamine 0.50X wt~vo}
~ BA-C ~~~ ~ ~ 0.02X wt~vol.
(50% aq. soln.) Octoxynol 400.01% wt/vol.
(70% aq~ soln.) EDTA Na2 - - - -O.lOX wt~vol.--NaCl ~ `0.79% wt~ol.~
The above ingredients are mixed, adding purifled -30 water until they are dissolved, the pH is ad~usted to 7.4~0.4 and the balance o~ the ~ormulation is made up ~-with puri~ied water,-adding à quantity-su~icient to-make 100% volume. The solutlon is then sterilized.
Other NSAIDs or their isomers, salts or este~s, such 3S as those described above, can be used as the active -~ . ....... . .. .,, . - ,, ~ 8408y 26280-FF
.
- , ~ , ~ . . ,,- ~' " 'r`
compound in the preparation of the formulation of this example.
This example illustrates the preparation of a representative pharmaceutical ~ormulation for ophthalmic administration containing the NSAID Ketorolac Tromethamine.
' Ingredient Amount Ketorolac Tromethamine 0.50% wt/vol.
BAC 0.02X wt/vol.
(50X aq. soln.) Octoxynol 40 ~ ~ 0.02X-wt~-vol.~~
(70% aq. soln.) EDTA Na2 0.20X wt/vol.
NaCl 0.79% wt/vol. - ~ -The above ingredients are mLxed,~-ad~ing purified - - ~ ;
water until they are dissolved, the pH-is adjusted-to ---- 7.4 0.4 and the balance o~ the ~ormulation is made up ~~~~
with purified water, adding a quantity su~tlclent to make lOOX volume. The solution is then sterllized.
2fi Other NSAIDs or their isomers, salts or esters, such as those described above, can-be used~as the active compound in the preparation-~of the formulation of~this~
example.
- :.
This example illustrates the prepa-ration o~ a -representative pharmaceutical formulation ~or ophthalmic :~ : -, -17- 1 328614 ~-administration containing the NSAID Ketorolac ' Tromethamine.
. .
Ingredient Amount Ketorolac Tromethamine 0.10% wt/vol.
BAC 0.004% wt/vol.
(50X aq. soln.3 Octoxynol 40 0.004% wt/vol. '' (70% aq. soln.) '~
EDTA Na2 0.05% wt/vol. ' NaCl 0.88% wt/vol.
The above ingredients are mixed, adding puriried -water until they are dissolved, the pH is adjusted to 7.4~0.4 and the balance o-~-the-*orm~La-ti-on-is~made~up 15 with puriried water, adding a quantity sufficient'to make --lOOX volume. The solution is then sterilized. ~ ' Other NSAIDs their isomers, salts or esters, such as those described above, can be used as the active compound ~-in the preparation o~ the ~ormulation Or this example.
This example illustrates the preparation Or a representative pharmaceutical rormulation tor ophthalmic ~25 administration containing the NSAIO rlurbiprofen sodium. '~
Ingredient ' -~ 'Amount ''' - ;----~~- - ~- - ~~ ' ' Flurbipro~en Sodlum 0.03% ~t/vol. -BAC 0.02X wt/vol.
(50% aq. soln.~ ~-Octoxynol 40 0.01% wt/vol. '' (70% aq. soln.~
EDTA Na2 0.10% wt/vol. `-NaCl O.90X wt/vol.
`~ The above ingredients are mixed, adding purirled .
: 8 408Y 26280-FF
-18- 1328614 ~
water until they are dissolved, the pH is adjusted to 7.4+0.4 and the balance of the formulation is made up with purified water,.adding a quantity sufficient to make lOOX volume. The solution is then sterilized.
Other ophthalmic drugs and NSAIDs, such as those described above, can be used as the active compound in the preparation of the formulation of this example. ' EXAMPLE 5 ;
Physical stability o~ the formulations of the present invention is measured by preparing clear ~ormulations, in the concentrations shown in the table below, sealing them in sterilized containers, and observing the clarity o~ the solution after a period of one month and again after ~ive manths. ~ ons that =' remain clear are considered stabl-e in this'-procedure.
The ~ormulations o~ the present invention have proven to be stable when tested in accordance with the -~
20 above procedure. Formulations using~surfactants other than the nonionic sur~actants of the invention did-not ~ ~ ' r`emain clear and were not stable. '~
T~ree~sur~actants were--e~d'Iud ~ ~
to dissolve the ketorolac - benzalkonium chloride complex - - '' ' 25 and maintain a physically ciear solution over an~extended ;
period o~ time. The three sur~actants tested were: ' ~ Octoxynol 40; Polysorbate 80 (Tween 80~; and Myrl'52.
- Two concentrations o~ each surfactant'werë i'nc~'rpa~ate~d~
~~ into the ophthalmic formulati'on',''~a'nd''these''~were'-'prace*'~at'~'' 30 various temperatures ~or ~uture visual'obse-rvations.
- - .. ~ . -:: 35 *trade-mark - '-:
-8408Y ~ - 262~0-~F - ~
.
: .
~':.
Octoxynol 40 Tween 80 Myrj 52 , 0.004% 0.02X0.00~5% O.OlX 0.0015X 0.01% ' 1 month 60C clear clear clear clear clear clear 40C clear clear very very turbid turbid turbid turbid RT clear clear turbid turbid clear clear ,, 4-40C clear clear turbid turbid clear clear '~
, 5 month ~ , 60C clear clear clear clear clear clear ~'' '~' 40C clear clear turbid turbid turbid turbid - ;
_ RI_ clear clear -turbid- tuEbid ''t-u~ t ~rbid~
- At the 5 month time period it was apparent that ,~ , the Octoxynol 40 surractant was superior to the other two , surractants. At 5 months, Tween 80 and Myr; 52 displayed turbidity when stored at RT. The presence o~ turbidity ' 20 suggested the inability to solubilize a~-p~recipitate , '-~ormation between the Ketorolac moiety ~anq---be~zal-,konlum -- :
chloride. -- ~'~ ~~~''' ,-'','~- ~~~''~~--~' - ~~-~~~~''''' : ,~ ' A rurther study has shown a 2 year shelr lire ~or the ophthalmic formulation. Precipitate rOrmation ~' 26 and turbidlty are not a problem with this formulation.
Preservative e~ricacy is maintained throughou~ t~e-2-year -' --,~
, -, :.
Preservative erricacy~of the ~ormula ffons~ the present invention is measured by preparing rormulations, e.g., according to the roregoing Examples, and subjecting them to the U.S. Pharmacopia antimicrobial,challenge.
8408y 26280-FF
~ 32861 4 :, The formulations of the present invention ' demonstrate preservative efficacy when tested in accordance with the above procedure.
EXAMPLE 7 '' The objective Or this clinical er~icacy study was to compare the errectiveness and sarety Or ketorolac with a control solution in reducing in~lammation following 10 cataract removal and intraocular lens implantation. All ;~
patients underwent an extracapsular cataract extraction ' with intraocular lens implantatio,n l day following ' ' initiation Or treatment.
~ -Ophthalmic examinations were perfarmed~
preoperatively (within 3 weeks ot surgery)-and-du'ri'ng=th~ ~
rirst week (postoperative days l to 3), second week -, (postoperative days 4 through 12), and third week (postoperative days 15 'hrough 27~ or;tr,eatq'en~t`.
Particular attention was given to slgns and 's~y,mptoms~
consistent with inrlammation. Among thé ocular ` m -charaeteristics assessed on a_scale,o~
moderate, or severe were: lid edema, corneal~edema,`' ~
con~unctival in~ections, ciliary tlush, and t'he presence or cells and tlare in the anterior chamber.
Fluorophotometry: Anterior segment intlammation - (i.e., iritis, cyclitis, iridocyclitis~ s~y~-qe~inlti a-dl sru,~ion~or the~blood-a'queous barr~
' inrlammation is present, a carerul slit lamp'~examination '- '' ' will reveal cells and rlare within the anterio'r chamber `~~
; 30~o~the ey~e. The clinical grading Or cells-and ~lare i5 a - measure o~ degree or anterior segment inr}ammation; b~t, ' -consistent grading o~ these observations--i~---di-~icuIt,~
even by~experts.
Ocular rluorophotometry is based on the ract that '' `~
35 the blood-aqueous barrier becomes permeable to ~ - - - . - -, . .
-21- 13286~4 .
intravascular cells and proteinaceous fluid (explaining the observed cells and flare) and also to intravascular ~luorescein. Furthermore, the appearance of fluorescein '' within the anterior chamber is a more sensitive indication of the breakdown o~ the blood-aqueous barrier than the gross observation of cells and flare~ and is ' consistently quanti~iable. For these reasons, a ~' Flurortron- Master (Coherent, Sunnyvale, Cali~ornia), ''' complete with sottware moditications designed ~or this study was used. Following oral administration o~
~luorescein, the ~luorophotometer was used to determine ~-the integrity o~ the a~ueous barrier by measuring the concentration o~ ~luorescein ln the anterior chamber.
- -- The ~luorophotometry data~were anaiyzed--usin~--th~ë-~Wilcoxon Rank Sum Test or ana~lysis o~ vàriance ('ANOVA)'~ot rank-transformed data by calculating the percentage ~ ~
di~erence in ~luorescein concentration between the ~' ' patient's two eyes, according to the ~ormula:
Percent dit~erence = ~luorescein concentration of operated eye - ~luorescein concentration o~
unoperated eye)/~luorescein concentration o~
unoperated eye] x 100. ' '''''' ~ ~ ' ThiC calculation allowed and corrected ~or any interpatient variation in the timing and concentration o~
25 ~luorescein administered.
129 patients began treatment ~or 21 days--with-either''~
ketorolac or vehicle. In this~study, the-ketorolac ~ormulation used was that illustrated in Example 1 above. During the ~irst week 118 patients and during the ' 30 second week 110 patients were evaluated ~or postoperative - in~lammation with ophthalmic examinations~and-~ 7 _ fl-uorophotometry. During the third week, 83~-patients~
- were evaluated with ophthalmic examinations alone. At 2 weeks ketorolac provide signi~icantly greater ' '' 35 ant~-in~lammatory activity than the vehicle as measured - .
. - .~ .
8408y 26280-FF
132861~ :
by fluorophotometry (p = O.Ol9). When patients were excluded who had greater than 40% difference in fluorescein concentration between eyes at basellne, the p-value during week 2 rose to 0.06. In addition, the vehicle-treated patients had more ocular inflammation seen on slit lamp examination, e.g., eyelid edena (p =
O.OOl), conjunctival injection (p = O.OOl), and Oescemet folds (p = 0.002) than did the ketorolac-treated patients. Finally, there were signiflcant}y more complaints (p = O.Ol) and more severe complaints consistent with ocular inrlammation (photophobia, iritis, '' '' con~unctival injection) in the vehicle-treated group than - ' in the ketorolac-treated g~roup.' In summary, ketorolac s~lutions prove~-sigRi-~-icant}y~
superior to vehicle in treating postope-r'ativ'e ~
inflammation as quantitated by fluorophotomëtry, by routine slit lamp examination, by patients having fewer and milder adverse events, and by inirequent need of additional corticosteroid therapy to contro'l in~Lammation. ' :. : ~ . - . -, - : :. : .
This was a double-blind, parallel comparlson with vehlcle to evaluate the erticacy Or ketorolac 0.5%
25 ophthalmlc solution in reduclng signs and symptoms o~ ' al}ergic conJunctivitis.~- ~etorolac 0~5%-~so}ution or a --vehlcle solution Or the~sa pH a g-to iclt v'-~
instilled four times daily'~into the éyes o~ patients with allergic con~unctivitis (ocular itching with and without ' -30-eosinophils~seen on conjunctival scrapings) ror 7 days.
Thirty patients with alEergic coniunctivitis- ' -~' participated in the study.~ Following admission o--the ~-study, patients reported to the investigator ~or baseline, mid-week~ and final one-week examinations. At each of these visits, patients received ophthalmic - .
8408Y 26280-FF ~
' ~ .
examinations (visual acuity, external eye exam using slit lamp biomicroscopy, measurement of intraocular pressure, and undilated ophthalmoscopic examination). Laboratory tests included a conjunctival scraping performed at ' baseline and the final exam.
All patients completed the study. There were no adverse events or toxicities in patients treated with vehicle while stinging on one occasion was.reported from : .
ketorolac 0.5% ophthalmic solution. K'etorolac treatment . :
was associated with a decrease in ~ree eosinophilic granules as compared to vehicle (p s 0.025 Fisher's Exact Test. two-tailed).
The results o~ this study show th~at--ketoEoLac 0.-5% - .-...~ ' -..
-ophthalmic solution applle.~.~cu~-times~ s~-en-:F~~
days produces a decrease-in.eo'slnop M L~c'~'gra'nules ~-s---'' ~` .~'~'~..
compared to vehicIe in the.-:t~eatm.en.t.of allergic :
conjunctivitis.
- . . ~ ~ .
EXAMPLE 9 :~
This study was a double-bLind.:,. eal ed~co ~ ison '`;~
design trial to evaluate the--t~olerance~a~ketorolac~0.5% -. ' ophthalmic solution and its véhicle in' 26 heaithy .
sub~ects. Solutions were instilled three times daily for 21 days. Complete ophthalmlc examinations wore done pretreatment and on days. 3~ 0~r^~-~7~-.-~ ¢2 days a~ter -~
: endlng treatment), and 45 -2-3 F~ays^i~te~-endlng -~
treatment). ~No statisticalLy'si ~ i-:~icant di~ference in ~ 3-~
~ symptoms (burning, stinging, itchiness, scratchiness, : '' 30 photophobla3 or signs (tearing, ocular discharge, ::' conjunctival~vasodilation, chen ~i's.~ keratitis,.~
~luorescein staining, Rose Bengal:s*aining)-was::found ~ '' -~ .
between ketorolac and vehicle.
., .
~ .
~ 8408Y 26280-FF '' . --':
An ocular formulation containing 5 mg/ml ketorolac .',', tromethamine was administered at a dose of 0.1 ml/eye . -S every one-hal~ hour ~or a total o~ 12 doses to both eyes ' :
o~ 6 New Zealand albino rabbits. The formulation contained benzalkonium chloride as the preservative :
system. Two additional groups o~ animals served as saline and vehicle controls, respectively.
Eyes were examined a~ter the last dose was administered and on days 1, 2, 3, and 6 ~ollowing ..... ' dosing. Results indicated that no eye irritation or '.
toxicity resulted ~rom.ketor-olac.trome.thamine.
- ' ' '''ad'ministration.
While the present invention has been described with re~erence to the speci~ic embodiments thereo~, it should ' ~ ' be.understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing ~rom the true spirit and scope~of the invention. In addit~onr=~3u~; m~di'~1c~s~4=R=s~3aR~b~-ma~e~
' to adapt a particular sit~ati;on-,. mate ~ ~ o'mp~osition o~' . '`.
:matter, process, process step or steps, ~o the obJectlve, .,.: :.
~ spirit and scope o~ the present invention. All such 25 modi~ications are intended to be within the scope o~ the ,claims appended hereto.' ~ , , ' ..... ..
- - . ., :
-::
30 - , .~. ', ~:
~ -- - - : - ; ~
-: - , ' .. -:
- . - - ' ~ .
....
- :., ,-
~.
...
~ 5 . .
.
PRESERVATIVE SYSTEM_FOR OPHTHALMIC FORMULATIONS
. ,.
BACKGROUND OF THE INVENTION .
The present invention: cela~es..t.o`.imp-rove~o'phthaim~c~-.
ormulat~ons, particularL~ t= ophth~aimié~r~r.mulàti-o~s-for ~-anti-in~lammatory drugs',-':an:d speci~ical ~ t~'''an'i-mpr~ve.d'~
preservative system ror-ophthalmic-~formulàtions''of~
carboxyl ( n-COOHn ) group-containing-~ru'g~s~,~'ëspecLa~ y~
~-~ .---= ...:._-~ _-~~non-s.te~f~3oC~anti-fn~la ~ drugs-t'~NS'A~
- ;~ The invention also r~lates t~o-methods ot usin~ thesé . ............... ~ ' ~20 :~ormulations ~or treating-'d~se'ases-that' are~-'either caused ~':'--~` ' _ _ _ . b.y,'~ssoc~i~ c-~th or ~ '~ ' ~processes,-including, among'otne.rs-,-'g~aucoma,-~cystoid ~
:` macular`edema, uveitis~ diabetic`:retinopathy,~and '~'-~~---=.~ ~~ .
conJunctivitis, or any trauma caused by eye surgery or eye inJury.
.'`The topical use ~ot-~ AID~s,~-particu~àr y~
:'pyrrol-e~ ~ the treatme ~ phthatmic.d-~ e'asés-~was-'''~ -.'~
first~taught in U.S. Patent~No~--4~:454~15.1, where NSAID
compounds ~suc:h as those described in U.S. Patents :.
~: : 30 -4j-089-,969; 4,23290~8; 4,087,5~9 and; 4-~097:,519) weré ~~ '~~ ' :.' ': exempli~ied in ~ormuIation:with:NaH2~04-H20, ~:~ .-~'~'''~ ~- ~ .-.
' N-a2HP04~-H20, NaCl, benzalk~oni~um~chloride `(n~AC~ ~ ~~ ~` ~ ~ ` -. and sterilized water. While the formulations described~
-: : : - .
~: 35 ~ ~.
.
~ ~ 8408Y 26280-FF
~328614 --2-- ...
in the '151 patent were efficacious, an insoluble complex was ~ound to form between the NSAID and the BAC. The -formulations became cloudy or turbid and did not, therefore, have the stability desired for shelf life in ' 5 commercial applications. A reasonable m~nimum shelf li~e .~:
(that is, the time during which a solution remains clear ~ -and retains its pharmaceutical activity) is at least ~-about one year, representing su~ficient time to package, ,~
ship, and store a formulation~'without havLng-to replace 10 expired stock too frequently. The solutions of the .. ' present $nvention have shown a shelt life of at least one year. Thus, the present invention entails an improvement over the tormulations desc-~bed Ln the .'151~patent.
--In-g~ral, a-n op~nth~lm~ç--~ormuLa~i~a':'~.ontai-n-~.an. --~
~ -~~~ ~ 1s active compound and various-ophth-aI-moIogi:ca:l}y accept~ble excipients, in the form of.a soI'ution, an ointment, a suspension, etc. An excipient is:ophthalmologically a~eeptable--~f---i-t is non-iTrlt-r~o to~the e~e a~C=~f-Lts~
- - active ingredient penetr~e~ ~ ~roo~-~q~ùe'ous~'b'arrier '~
20 and!or di~uses through-~he-Ya~i-ous ocu=~ar substructures : -- ' . to the_site-where it i~
excipients can include a t-an~c~ifier,. a preservativeJ'i~
surfactant, a but~ering =s.ystem,~a chelatin.g:agent', à . .~ ' viscosity agent as well as other stabilizing agents.
25 Ophthalmic ~ormulations mus-t be-sterile, and.if intende~d .
: for multlple dosing regim ~ t-bé-pr'e:serve~d "wi'~h--an~~ ~~'~.~;-''~'.
_ - .etrective anti-microbia~3:e~b~
Organo-mercurials (e~ -thimerosal,~-phenylmercuric'' acetate and phenylmercuric nitrate) have been used 30 extensively as the preservative ln ophthalmic solutions.
- These co0pounds, however,.pos:e-'~-:dif~i'cu~ties due to~
potential mercury toxicit~~~as~-:well--as-poor ch'emical~~~
stability. Benzalkonium chloride, a quaternary ammonium compound, has been widely used in ophthalmic solutions, .:~
and is considered to be the preservative o~ choice.
- , ---- .......... - , ., .......... . . _. _,_ . .. . . _ . _ ,. . .
8408Y 26280-FF ~
However, BAC has typically been considered to be incompatible with anionic drugs ~e.g., salicylates or ..
nitrates, etc.), forming insoluble complexes which cause the solution to become cloudy or turbid. Such a complex between the anionic drug and benzalkonium chloride can cause a decrease in the pharmaceutical activity of the anionic drug.
Many NSAIDs (such as ketorolac, indomethacin, ~ `
~lurbipro~en and diclo~enac) are being devel'oped ~or ,.
10 ocular use because of their activity as anti-in~lammatory ,.
agents including their ability to prevent cystoid macular edema.
., = . .-. ~ , .: .......... ..
In the past, as in the case-with-:othër-o~hthalmic .-dr~s--~tnt-eonta~n-~ a~-gr~op~~ant51nf1~m~r~
~ f5 solutions o~ NSAIDs for occ~Ia~r ûse-hav~ ven t~
incompatible with quaternary~.ammonium compounds such as,. . ,, :~
BAC. This incompatibility"-is'due to--the ~act.~:that 'the - '--~
COOH group can torm a com~,~ th ~s~e~o~r~
' ,.,- ~ -ammonium-compounds, renderi-ng.,th~-,-pre~s~Fv3Ri~e~,les's ~'~
available to serve its function,_.and re.du~n~-the- ~ ,. .m . ~
activity o~ the active i ~ ~.
ophthalmic ~ormulations have he~ prepared~oweverr~
these are suspensions, not-solutions:.- O,cù~en Ophthalmic.
solution, an NSAID (rlurbipro~en) approved by the FDA ~or : 25 ophthalmic use, incorporates thimerosal (with EDTA) as ~--, -'- its preservative system. :,I,n.a~ ,p:a~èn~t=~-l4~4~ 51~thé'ré -,~r~- ~-,, -~= 'is a :disclosure o~ an oph ~ .~
ketorolac, benzalkonium chlo~ide-~as'th:e prese'rvative) ¦: and polysorbate 80, however~the solution became cloudy or ' :
:: 30 turbid a~ter a short period o~,ti-me. .: .
- : It has remained desiréd-~-to pro'vide~a st-able,-clear, antimicrobially e~fective ophtha~$~ ormu:iation-~ith-a prolonged shel~ e ~or -COOH group containing .:
:~:: ophthalmic drugs, especially NSAIDs, using BAO as the .:
preservative. ~ '. ' ~f R ¦ 1 3 2 8 6 1 4 r SUMMARY OF THE INVENTION
It has now been discovered that stable, clear and antimic.robially effective, NSAID-containing ophthalmic j formulations can be prepared which include a quaternary 5 ammonium preservative. These solutions have an improved shelf life, exhibiting no cloudiness or turbidity over - extended,periods.
In one aspect of the inv-ention, these compositions include an ophthalmologicaLIy effective:~,amount of a 10 NSAID, a quaternary ammonium preservative ànd a stabilizing amount o~ an ethoxylated octylphenol as a .
nonionic surfactant, all in an aqueous vehicle.
Another aspect is an ophthalmiC~com~ositiQn _ _ __includi_~ an_ophthalmol -~-~ -1E;'NSAID~,a quaternary ammo~i~:-p~ré ~ lzLn~
amount o~ an ethoxylated octylphen'oi'`as~-a nonionic-surfactant. '~~
_ _ Another aspect is an o~t,h Im ~-' ~ ~ itio ~- .- .
~including~ an ophthalmologl,al~~éff'ec ~ in~
--'20 -NSAID-, benzalkonium chloride~as-a-p:r ~ ~d~a.',,~
, stabilizing amount ot an.ethoxylà'ted Qc~ylp~en.~.a-s,~a~
" non1 0n~1c'~ ~sur1'actant . ~~~
, Another aspect is an:ophthalmic co~mp~sition~
including:an ophthalmologica ~ ~e'~f.,~ectf~ amount o~ a, ' ` -' :
: 25 NSAID, benzalkonium chloride as a preservative and a _ _~st?bilizing amount o~ Oct, ~ ~l 40f,,as ~ -~
-surfactant. ."~,~
Another aspect is an o:phthalmic.comp~ it~on '`~
including an ophthalmologicall~~-ef'~ec'~ivé amo'unt of ,.-30 ketorolac or an isomer,:a~ ester~--or~a.ph=a-r`maceutically ,~
. ~ , acceptable salt thereo~, benzalkonium ch-lor~ ";'a's,':,a:,~ ,~, ,,, -,:. ~'. ~."
preserYative and a stabilizing-.am,ount of_OQto~nol..,40 as . .. . .,. -:
~' 'a nonionlc sur~actant.
*trade-mark ~ ' 35 - ~' 8408y ~ 2628C-FF
, , ~ 5 t~
In another aspect of the invention, methods tor Itreating ophthalmic diseases in mammals using the ophthal~ic pharmaceutical ~ormulations o~ the invention are also disclosed. These diseases are those that are ¦5 either caused by, associated with or accompanied by -in~lammatory processes, including, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy and conjunctivitis, or any -trauma caused by eye surgery or eye injury. ~-DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Detinitions _ As used herein, the term~"NSAiD" meàns: anaccepta~ non-steroi~a ~ ~
ant~-in~lammatory drug. Thé NSAID's include,-'-~r~~ ---'' ~'' example, rlurbipro~en, ketorolac, diclofenac, indomethacin, and the isomers, esters, and ~' -_ _ pharmaceutically acceptable--sa-lts-th -- ~ -As--used herein, the ~erm~-~q.s-."-~m ~
quantity su~icient to ac~iRve a- stated~nc'tio~ e7.~9-.'r ~ - ' -'~'`- '-- to bring a sol_tion t A~s used herein, the term~ntreatment-n--o~ ~rea*ing"~
means any treatment o~ a disease-in'~a~~mammal,~-lnclJcing~
- (i) preventing the disease, that is,'causing the clinlcal symptoms o~ the disease not to develop, -~~-~--~-'-' ~i~ lnhlbiting the ~ ea~se,~~~thf~ ~ ~ s æ ~ ~hë'~
_ development o~ clin ~ ~ ~ , -(iii) relieving the disease,- that ls, causing the regre~ssion o~ clinical symptoms. : n As used herein, the term-ne~ective~'~amount" means a -- ~ dosage su~icient to provide- treitment ~or the ~d-iséase~
~ state being treated. This~wlLL vary~d~p~ irng-on-~he~''' ~`''--- '''~ ~
; patient, the disease and the treatment being ef~ected. -'' ~ 35 - .
8408Y 26280-FF -' ' :~
~ -6- 1 32861 4 As used herein, the term "antimicrobially e~fective"
means ability to withstand the U.5. Phàrmacopia antimicrobial challenge. .
As used herein, the term "sur~actant"imeans a nonionic surfactant, preferably~ethoxyLated octylphenol compounds as described below.
As used herein, the term "quaternary ammonium preservative" means a quaternar~ ammonium c.ompound such.. ~ --as described below. .~
10As used herein, the~term nstab11iz-in'g"-means-keeping a formulation clear and ant~microbia~ly ef:fective for its :.:
minimum reasonable shel~ lirë.:, e-..g.~ at-le~ast~onë.;~-year..'~
is ~ ---- Thé:formulations of th~p~:~se~
- ' - NSAID active agent in an:effective amou~t~'-''f ~ halmic~
t;reatment, a quaternary~amm.o.ni'um'~~p`Ées;ervat'v"~-a'~~
stabil-i--zing amount of an'~
~ :nonionic-~surfactant, opti:~n'a-L-l~ -in~
:~ :' ... 20 é~x'cipient~ such as a chela~Ln ~ ~
fe- ~ system, a ~ .. ~ '-' - stabi~izing agents. Ophthalmic soiut on~ ~ e ~ -~
t'ypically,~,contain~an aqueous,,vè cle,rat`~ ~ p ~,a'n, ~ ~ ~ ',"~' ' vehic~e. r Ophthalmic rorm'u;liti'ons''m~st be sterilé, and i'f ~ ;', ~, 25 intended ~or multiple dosing-regimens, must be ~
., at le ~ ,~, - ~, ~ to three ~ears or more~ ~e ~ y j~ L~ a~
- formulations of the prèsent-~invéntion are'typically ~ 30 commercialiy available or~ca~-b~-m-adé---b~et~a~sv'~ea~ly-_k ~ known to-those skilled in the ar.~ '~' -'~"'-~~=~--~ ='~'---~' '''' '---- --Phar-maceutical ophthalmi'c:formulati~ ~ pl~a}l~
contain an efféctive amount,~e.g.,'O.bO,lX'~-t~o~10%''`wt~/vo'l~., ~
preferably 0.00'2%~to 5% wt/vol, most preferably 0.005X to -; ~ 3S 1% wt/vol of an active ingredient te.9., the NSAID of the :: :
D _7_ 1 3 2 8 6 1 4 present invention). The amount of active ingredient will vary with the particular formulation and the disease state for which it is intended. The total concentration o~ solutes should be such that, i~ possible, the 5 resulting solution is isotonic with the lacrimal fluid (though this is not absolutely necessary) and has a pH in the range of 6 to 8.
' The formulations-of the present invention are prepared as solutions incorporating the ibove-described ,:
10 ingredients within the following approximate ranges:
Ingredient Amount Active Agent - . 0.001% to lO.0% wt/vol.; :.
Preservative ~ , "O.OClX~,to ~ ,tt.vol~
5--~ac'~a-n~
Other Excipie.nts- .-,-0%-''t~ X wt:~o~ an~ ....... '}'~'`~
~ Purified Water ~ q.s. to 100%.
Optional~-other excipients, such a~s a~chelating agent and a tonic^ir-ier, are used ,i~~..e-fo~l,~o ~ ~ t1e,`-_,..'`"',~-''-",~~~-~.-,~'.-' ..proportions: , -,~,- ~ ,,c~
.20 ,, ~ Ingredient ''~ 's' `' 'A'mo~nt'~' = '`~'"' -' ~~''-`~~~'''~-,:~' .-. Chela.ting a ent- -~.... ; ~ ,'.,.
, ~ Tonicifier ~ q.s. tQ:r-ach e~e;~
.. - lsot.o ~ ty with~-' -~' '': - ':
~ ~ ~lacrimal.~luid; and ~
25 ' lN NaOH or lN HCl -q.s.... ta.adj,ust ~H.. :.-.ta-. ~ ' - - 6`0~
.
I ~
I , ~
'...... : 35 - : - :
8408Y 26280-FF ~.
, .:
. ~.
In a preferred ophthalmic NSAID solution, the ingredients are combined in the following proportions:
Ingredient Amount -NSAID 0.002% to 5.0% wt/vol.;
BAC 0.002% to l.OX wt/vol.; '~- , (50% aq. soln.) ' Octoxynol 40 0.001% to 1.0% wt/vol.; ' - ' (70% aq. soln.),, EDTA Na2 0.01% to 1.'0% wt/vol.; ~ -NaCl q.s. ~or isotonicity with ' lacrimal ~luid; ~"
lN NaOH or lN HCl q.s. to adjust pH to ,, ' P i~ie~ ~ t~ t i =
, - In another preferred,,o,~ thalmic'NSAID solution, the -ingredients are combined ihn 'the ~,o-llowi~ng proportian~s~
Ingredient ~ mou,n,t ,~
~ , NSAID ~ aQ~% -; t~ voI
; ~ 20,'~ AC ~ eQ
50% aq soln;~
Octoxynol 40 ,-~-0 ~ X to,l-OX; ~ ~ ~
(70X aq. soln.3- ', ' , ''`--~ ,';'~ ; '-~ ', E~TA Na2 0.01% to 1.0% wt/vol.;
;25 ~ , NaCl q.s.~or isotonlcity wlth"~
lN NaOH or lN-' ~ ~
,7.4,~.,4;-~aQd , ' Puri~ied Water '' q.s. to 100%.
: - n ~. r~ v ,::: - ~:
"j ~ ~ ":, ""~
~: ' ~'.; ' ' ' ' ;
:~
g . -:
In a more preferred ophthalmic NSAID solution, the ;.
ingredients are co~bined in the following proportions~
Ingredient Amount NSAID 0.50% wt/vol.; ~:
BAC 0.02% wt/vol.;
(50% aq. soln.) '~
Octoxynol 40 0.01% wt/vol.; .. '~.
~70% aq. soln.) , "' EDTA Na2 0.10% wtivol.;
, 10 NaCl ~ q.s. ~or isotonicity with ; , . lacrimal ~luid; ' lN NaOH or~:lN HCl q.s. to adjust pH to I :;
~ 4 ~.4,.:.and~
: Purified Wat ~, .. -~_s ;.t'~.l.O ~.
The invention r~ ~ t~
' , ~ ~ ~: -having a's the active~ageQt ophthalmologically acceptable '. ~ ' drugs (including the isome.rs, ,esters and;ph:a~maceutically:
.ac.eeptable salts:thereo.~, ~ a'~:~ r'.,~
'r ~ ,20 -,quater,nary ammonium compo ~ 'cu ~ ~ ~-~''`~;~''~'''`~`'''"
'drug;s with a carbo,xyl-group:'.--~"'..~,.''-~ ~ ~ ~ ~~ ~ ~ , ';,.
lnc}ude, tor example, keto ~ ~ a~d-the~'o~e-~,compàu~d5~ ` u;";
~ describéd as:belng oph,thal ~ic-alLy~et~'ectlve'`~in U'~,$.-~
; ~ 25 Patent'No,. 4,454,151 to Watérbury.J issued'June 12, 1984 G ~ dlolorenao, Including ' pharmacé~tical-ly-:~acoepta ~ ~ ~there~'.~---~~ 30~, ~ Preservatives use'~ul in the rormula.t,ions o~ the présent.lnvention incIu~e~uaternary~,am:monium,compounds, . : :,-such:as cetyltrimethylammonium b-~omid ~ L ~ ~ium~
- chlo de~and benzalkoni m hlo ~,- -re -~benzalkonium ~chloride.
:8408y ~ ;26280- *
t ~- :
-10- ~, The nonionic surfactants useful in the formulations of the present invention are preferably ethoxylated octylphenol compounds, such as octylphenoxypoly-(ethyleneoxy)ethanols, more preferably, a homologous series of surfactants sold under the trade name Igepal CA
with a numerical su~tix indicating the mole ratio ofethylene oxide to octylphenol, the ratio being 3 to 40.
Examples include Octoxynol 9, Octoxynol 12, Octoxynol 13, and Octoxynol 40, and most pre~erably Octoxynol 40, manu~actured and sold by GAF under the trade name Igepal CA897 (a 70X aqueous solution o~ Octo~ynol 40).
Among the optional excipients, the chelating agents usetul in the tormulations;o~ the present invention ... -include 8-hydroxyquinoline.sulfate,. c-itric acid, aad-~
pre~era~ly di50dium-edetate.-~und ~.~ ~ ans~`~ - .---;-`
the chelating agent may a}so-~ènhanTce:;thè ~ntl-microbial . e~fect due to its ability-t-o-rend:er essential metal ions unavailable to the microbes.
Bu~ering systems op.~lonally useful in~-thè ~~
: ~ 20 ~ormulations ot the prese ~ invention are ba~sed-on-, for - -. example,~-citrate, borate,-~or phosphat~
0~14i~ rs-~t-i-~ ~ ns~
the present invention include-dèxtr~se~,~ potassl-~m chloride and/or sodium-.chlorid~,:-prefér.ably-sodium 25 Chloride, - - -Viscosity agents optiona-lly-:use~ul in:the:
c 11 1 s ot the pr - céllulose, sodium carboxymethylcelIuIose~ and : 30 hydroxye~hylcellulose.
: ~ : Other optional excipients--use~ul in the ~ormu}ations ~-o~ the present invention-~include~sta~iliz~ing-a~ents such as antioxidants, e.g.,- sod~m metabisuI~ate-and ascorbic -~ acid, depending on the NSAID used.
: ~ *tr ade -ma rk ~- ~ 8408y - - - ~ ~ 26280-FF
Il 1328614 These formulations are prepared by dissolving the solutes (e.g., the NSAID, the preservative, the sur~actant, the chelating agent, and the bu~fering agent) -in a suitable quantity o~ water, adjusting the pH to ~' about 6 to 8, preferably 6.8 to 8.0 and most preferably 7.4, making a final volume adjustment to 100% with ' additional water, and sterilizing the preparation using any suitable method known to those in the art. ~-It has been discovered that ophthalmic .40rmulations `'~''`
incorporating the preservative system o,4 the invention are physically stable (i.e., remain clear) and tunctionally ` , stable (1.e., remain antimicrobially e~.4ective) 40r at least the minimum reasonable-shelt li~e o, such~products.' 15 Pre~erred Formulations The pre erred preservative systém o. the invention includes a quaternary ammonium preservative and a -stabilizing amount o. a nonionic s~u-r actant~
The pre~erred ophthalmic rormulation o~ the ---, 2,0~1nvention,includes a NSAID~active~agént~ -~n ef'~ëctivë-~
amount tor ophthalmic treatment and,an antimicrob-ially , ' e~rectlve,-amount o~ the abo've-described~pre~erred , '-preservative system.~
, The~preferrod preservatlve o~ the invention is ~ ' 25 benzalkonium chloride.
" ~ - The prererred sur~actant--o-~ t,he''~=nve~t~on~
, Octoxynol~40, especially when~-combine~-wi,h--,~en ~ ~i'ùm'=-'~
chloride as the preservative. ~
The pre,4erred chelating agent o~ the invention is ' 0 disodium edetate, especially when combined with ~ ~-- benzalkon'ium chloride as the~pre,sérvati-,ve and '--Octoxynol~40 as the nonionic-~surr'actant.~
- The preferred ophthalmic solutions o~ the invéntion , 'include a NSAID, benzalkonium chloride,,Octoxynol 40 and -~ ~ 35 disodlum edetate.
2~280-FF ~ -~: ::~ - ' -:
..
A preferred ophthalmic NSAID solution, the ingredients are combined in the following proportions:
Ingredient Amount NSAID 0.002% to 5.0% wt/vol.;
BAC 0.002% to 1.0% wt/vol.;
(50% aq. soln.) Octoxynol 40 0.001% to 1.0% wt/vol.;
(70% aq. soln.) EDTA Na2 0.01% to 1.0% wt/vol.
NaCl q.s. for isotonicity with lacrimal fluid;
lN NaOH or lN HCl q.s. to adjust pH to ~ 7.4+0.4; and _ Purified Water - q.5. - ~o~
Another preferred ophthalmic NSAID solution, the ~ -ingredients are combined in the ~ollowing proportions:
Ingredient Amount NSAID ~ O.Q05%~to 1.0~ wt/vol BAC - 0.002% to~L.0% wt/vol., (50% aq. soln.) Octoxynol 40 -~ ~ o.ool%~~O~~l.a% wt~ivoI~
(70% aq. soln.) ~ ~ EDTA Na2 O.OlX to 1.0% wt/vol.;
NaCl q.s. ~or isotonicity - ~ with lacrimal--~lu~d,~
lN NaOH or lN HCl ~g.s~ to ad~Us*;p~---to~
7.4_0.4; and Puri~ied Water q.s. to 100%.
`-~ 35 ~ 8408Y 26280-FF
: : -.
~ : ' :
-13- 1 3286 1 4 : -~
A preferred ophthalmic NSAID solution has the following formulation: ~
Ingredient Amount .;-NSAID 0.50% wt/vol.
BAC 0.02% wt/vol. -(50X aq. soln.) --Octoxynol 40 0.01% wt/vol.
(70% aq. soln.) EDTA Na2 0.10% wt/vol.
NaCl q.s. for isotonicity with lacrimal fluid ;
lN NaOH or lN HCl q.s. to adjust pH to ~ -7.4+0.4 ~;
_ _ _ Purified Water --q.s. -to -~OOX --------- --~~ ~ -Most preferred is the ophthalmic solution according to the above formulation wherein the NSAIO is Ketorolac Tromethamine or an isomer thereof. ~ - ~ ` - - . -Utility an-d Administration Thls inventlon is directed_to NSAID ophthalmic -- -~ _ ~-~~rormuIations and a method useful for treating ophthalmic diseases ~n mammals. These diseases are either caused `
by~ associated wlth or accompanied by inflammatory processes, lncluding, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy and con~unctivitis, or any trauma caused~by eye-;-surge~ry-or~
eye injury.
The method of this invention is both curative and 30 preventat~ve. Where applied, for example, pre-surgically or immediately post-traumatically, i~e. before ~
inflamm tion develops, it prevents development of inflammation. When applied directly to the-eye~suffering ~ --from any of the named ophthalmic diseases, it supresses already developed inflammatory processes. -8408Y 26280-FF .
:: : ~ ' ' ',, ' Ophthalmic formulations are typically administered by topical application to the eyelids or for instillation into the space (cul-de-sac) between the eyeball and the eyelids, o~ topically applied ophthalmic solutions, suspensions or ointments, or by subconjunctival injection.
The dosage level will, of course, depend on the concentration of the drops, the condition of the subject and the individual magnitude of responses to treatment~
However, typical dosage ranges might be about 2 to lû
drops of 0.5X solution of active ingredient per day.
For a more detailed discussion o~ ophthalmic formulations, their preparation and administration, see Remington's Pharmaceutical Sciences, 15th Ed., pages 1489-1504, (197-5).
Testing Ophthalmic formulations such as the solutions o~ the present invention are typically tested ~or physical stability, chemical stability, and preservative efficacy, ~-20 both when they are first manu~actured and'-a~ter a fix~ed `' '-period of time (e.g., a~ter two years). They are -generally considered to be sate and clinlca`liy~ acce'ptacre`~
i~ proven to be well tolerated in the eye. "
Physical stability is determined by observation of a 25 solution after expiration of a fixed period of time. A
solution is considered to be physicall~-stable if- its ~
appearance (e.g., color and-clarity~ doés~not change'and if the pH remaihs constant, within acceptable limits.
Chemical stability involves a routine chemical analysis 30 of the solution, to be sure that its active ingredient "
and the excipients have not changed after a rixed period -of time.
Preservative efficacy is tested by the procedure ~-- described in the U.S. Pharmacopia Compendiary, whereby a 8408y 26280-FF :~
. ': -solution is challenged with a microbe and a determination is made as to whether the microbe survives in it. ~
EXAMPLES - -:
The following examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as a limitation on the scope or the invention, but merely as being illustrative and representative thereo~.
::
This example illustrate~s the preparation o~ a -- representative pharmaceutical ~ormulation for ophtha}mic administration containing the NSAID Ketorolac Tromethamine. - -- ; ~ -Ingredient Amount Ketorolac Tromethamine 0.50X wt~vo}
~ BA-C ~~~ ~ ~ 0.02X wt~vol.
(50% aq. soln.) Octoxynol 400.01% wt/vol.
(70% aq~ soln.) EDTA Na2 - - - -O.lOX wt~vol.--NaCl ~ `0.79% wt~ol.~
The above ingredients are mixed, adding purifled -30 water until they are dissolved, the pH is ad~usted to 7.4~0.4 and the balance o~ the ~ormulation is made up ~-with puri~ied water,-adding à quantity-su~icient to-make 100% volume. The solutlon is then sterilized.
Other NSAIDs or their isomers, salts or este~s, such 3S as those described above, can be used as the active -~ . ....... . .. .,, . - ,, ~ 8408y 26280-FF
.
- , ~ , ~ . . ,,- ~' " 'r`
compound in the preparation of the formulation of this example.
This example illustrates the preparation of a representative pharmaceutical ~ormulation for ophthalmic administration containing the NSAID Ketorolac Tromethamine.
' Ingredient Amount Ketorolac Tromethamine 0.50% wt/vol.
BAC 0.02X wt/vol.
(50X aq. soln.) Octoxynol 40 ~ ~ 0.02X-wt~-vol.~~
(70% aq. soln.) EDTA Na2 0.20X wt/vol.
NaCl 0.79% wt/vol. - ~ -The above ingredients are mLxed,~-ad~ing purified - - ~ ;
water until they are dissolved, the pH-is adjusted-to ---- 7.4 0.4 and the balance o~ the ~ormulation is made up ~~~~
with purified water, adding a quantity su~tlclent to make lOOX volume. The solution is then sterllized.
2fi Other NSAIDs or their isomers, salts or esters, such as those described above, can-be used~as the active compound in the preparation-~of the formulation of~this~
example.
- :.
This example illustrates the prepa-ration o~ a -representative pharmaceutical formulation ~or ophthalmic :~ : -, -17- 1 328614 ~-administration containing the NSAID Ketorolac ' Tromethamine.
. .
Ingredient Amount Ketorolac Tromethamine 0.10% wt/vol.
BAC 0.004% wt/vol.
(50X aq. soln.3 Octoxynol 40 0.004% wt/vol. '' (70% aq. soln.) '~
EDTA Na2 0.05% wt/vol. ' NaCl 0.88% wt/vol.
The above ingredients are mixed, adding puriried -water until they are dissolved, the pH is adjusted to 7.4~0.4 and the balance o-~-the-*orm~La-ti-on-is~made~up 15 with puriried water, adding a quantity sufficient'to make --lOOX volume. The solution is then sterilized. ~ ' Other NSAIDs their isomers, salts or esters, such as those described above, can be used as the active compound ~-in the preparation o~ the ~ormulation Or this example.
This example illustrates the preparation Or a representative pharmaceutical rormulation tor ophthalmic ~25 administration containing the NSAIO rlurbiprofen sodium. '~
Ingredient ' -~ 'Amount ''' - ;----~~- - ~- - ~~ ' ' Flurbipro~en Sodlum 0.03% ~t/vol. -BAC 0.02X wt/vol.
(50% aq. soln.~ ~-Octoxynol 40 0.01% wt/vol. '' (70% aq. soln.~
EDTA Na2 0.10% wt/vol. `-NaCl O.90X wt/vol.
`~ The above ingredients are mixed, adding purirled .
: 8 408Y 26280-FF
-18- 1328614 ~
water until they are dissolved, the pH is adjusted to 7.4+0.4 and the balance of the formulation is made up with purified water,.adding a quantity sufficient to make lOOX volume. The solution is then sterilized.
Other ophthalmic drugs and NSAIDs, such as those described above, can be used as the active compound in the preparation of the formulation of this example. ' EXAMPLE 5 ;
Physical stability o~ the formulations of the present invention is measured by preparing clear ~ormulations, in the concentrations shown in the table below, sealing them in sterilized containers, and observing the clarity o~ the solution after a period of one month and again after ~ive manths. ~ ons that =' remain clear are considered stabl-e in this'-procedure.
The ~ormulations o~ the present invention have proven to be stable when tested in accordance with the -~
20 above procedure. Formulations using~surfactants other than the nonionic sur~actants of the invention did-not ~ ~ ' r`emain clear and were not stable. '~
T~ree~sur~actants were--e~d'Iud ~ ~
to dissolve the ketorolac - benzalkonium chloride complex - - '' ' 25 and maintain a physically ciear solution over an~extended ;
period o~ time. The three sur~actants tested were: ' ~ Octoxynol 40; Polysorbate 80 (Tween 80~; and Myrl'52.
- Two concentrations o~ each surfactant'werë i'nc~'rpa~ate~d~
~~ into the ophthalmic formulati'on',''~a'nd''these''~were'-'prace*'~at'~'' 30 various temperatures ~or ~uture visual'obse-rvations.
- - .. ~ . -:: 35 *trade-mark - '-:
-8408Y ~ - 262~0-~F - ~
.
: .
~':.
Octoxynol 40 Tween 80 Myrj 52 , 0.004% 0.02X0.00~5% O.OlX 0.0015X 0.01% ' 1 month 60C clear clear clear clear clear clear 40C clear clear very very turbid turbid turbid turbid RT clear clear turbid turbid clear clear ,, 4-40C clear clear turbid turbid clear clear '~
, 5 month ~ , 60C clear clear clear clear clear clear ~'' '~' 40C clear clear turbid turbid turbid turbid - ;
_ RI_ clear clear -turbid- tuEbid ''t-u~ t ~rbid~
- At the 5 month time period it was apparent that ,~ , the Octoxynol 40 surractant was superior to the other two , surractants. At 5 months, Tween 80 and Myr; 52 displayed turbidity when stored at RT. The presence o~ turbidity ' 20 suggested the inability to solubilize a~-p~recipitate , '-~ormation between the Ketorolac moiety ~anq---be~zal-,konlum -- :
chloride. -- ~'~ ~~~''' ,-'','~- ~~~''~~--~' - ~~-~~~~''''' : ,~ ' A rurther study has shown a 2 year shelr lire ~or the ophthalmic formulation. Precipitate rOrmation ~' 26 and turbidlty are not a problem with this formulation.
Preservative e~ricacy is maintained throughou~ t~e-2-year -' --,~
, -, :.
Preservative erricacy~of the ~ormula ffons~ the present invention is measured by preparing rormulations, e.g., according to the roregoing Examples, and subjecting them to the U.S. Pharmacopia antimicrobial,challenge.
8408y 26280-FF
~ 32861 4 :, The formulations of the present invention ' demonstrate preservative efficacy when tested in accordance with the above procedure.
EXAMPLE 7 '' The objective Or this clinical er~icacy study was to compare the errectiveness and sarety Or ketorolac with a control solution in reducing in~lammation following 10 cataract removal and intraocular lens implantation. All ;~
patients underwent an extracapsular cataract extraction ' with intraocular lens implantatio,n l day following ' ' initiation Or treatment.
~ -Ophthalmic examinations were perfarmed~
preoperatively (within 3 weeks ot surgery)-and-du'ri'ng=th~ ~
rirst week (postoperative days l to 3), second week -, (postoperative days 4 through 12), and third week (postoperative days 15 'hrough 27~ or;tr,eatq'en~t`.
Particular attention was given to slgns and 's~y,mptoms~
consistent with inrlammation. Among thé ocular ` m -charaeteristics assessed on a_scale,o~
moderate, or severe were: lid edema, corneal~edema,`' ~
con~unctival in~ections, ciliary tlush, and t'he presence or cells and tlare in the anterior chamber.
Fluorophotometry: Anterior segment intlammation - (i.e., iritis, cyclitis, iridocyclitis~ s~y~-qe~inlti a-dl sru,~ion~or the~blood-a'queous barr~
' inrlammation is present, a carerul slit lamp'~examination '- '' ' will reveal cells and rlare within the anterio'r chamber `~~
; 30~o~the ey~e. The clinical grading Or cells-and ~lare i5 a - measure o~ degree or anterior segment inr}ammation; b~t, ' -consistent grading o~ these observations--i~---di-~icuIt,~
even by~experts.
Ocular rluorophotometry is based on the ract that '' `~
35 the blood-aqueous barrier becomes permeable to ~ - - - . - -, . .
-21- 13286~4 .
intravascular cells and proteinaceous fluid (explaining the observed cells and flare) and also to intravascular ~luorescein. Furthermore, the appearance of fluorescein '' within the anterior chamber is a more sensitive indication of the breakdown o~ the blood-aqueous barrier than the gross observation of cells and flare~ and is ' consistently quanti~iable. For these reasons, a ~' Flurortron- Master (Coherent, Sunnyvale, Cali~ornia), ''' complete with sottware moditications designed ~or this study was used. Following oral administration o~
~luorescein, the ~luorophotometer was used to determine ~-the integrity o~ the a~ueous barrier by measuring the concentration o~ ~luorescein ln the anterior chamber.
- -- The ~luorophotometry data~were anaiyzed--usin~--th~ë-~Wilcoxon Rank Sum Test or ana~lysis o~ vàriance ('ANOVA)'~ot rank-transformed data by calculating the percentage ~ ~
di~erence in ~luorescein concentration between the ~' ' patient's two eyes, according to the ~ormula:
Percent dit~erence = ~luorescein concentration of operated eye - ~luorescein concentration o~
unoperated eye)/~luorescein concentration o~
unoperated eye] x 100. ' '''''' ~ ~ ' ThiC calculation allowed and corrected ~or any interpatient variation in the timing and concentration o~
25 ~luorescein administered.
129 patients began treatment ~or 21 days--with-either''~
ketorolac or vehicle. In this~study, the-ketorolac ~ormulation used was that illustrated in Example 1 above. During the ~irst week 118 patients and during the ' 30 second week 110 patients were evaluated ~or postoperative - in~lammation with ophthalmic examinations~and-~ 7 _ fl-uorophotometry. During the third week, 83~-patients~
- were evaluated with ophthalmic examinations alone. At 2 weeks ketorolac provide signi~icantly greater ' '' 35 ant~-in~lammatory activity than the vehicle as measured - .
. - .~ .
8408y 26280-FF
132861~ :
by fluorophotometry (p = O.Ol9). When patients were excluded who had greater than 40% difference in fluorescein concentration between eyes at basellne, the p-value during week 2 rose to 0.06. In addition, the vehicle-treated patients had more ocular inflammation seen on slit lamp examination, e.g., eyelid edena (p =
O.OOl), conjunctival injection (p = O.OOl), and Oescemet folds (p = 0.002) than did the ketorolac-treated patients. Finally, there were signiflcant}y more complaints (p = O.Ol) and more severe complaints consistent with ocular inrlammation (photophobia, iritis, '' '' con~unctival injection) in the vehicle-treated group than - ' in the ketorolac-treated g~roup.' In summary, ketorolac s~lutions prove~-sigRi-~-icant}y~
superior to vehicle in treating postope-r'ativ'e ~
inflammation as quantitated by fluorophotomëtry, by routine slit lamp examination, by patients having fewer and milder adverse events, and by inirequent need of additional corticosteroid therapy to contro'l in~Lammation. ' :. : ~ . - . -, - : :. : .
This was a double-blind, parallel comparlson with vehlcle to evaluate the erticacy Or ketorolac 0.5%
25 ophthalmlc solution in reduclng signs and symptoms o~ ' al}ergic conJunctivitis.~- ~etorolac 0~5%-~so}ution or a --vehlcle solution Or the~sa pH a g-to iclt v'-~
instilled four times daily'~into the éyes o~ patients with allergic con~unctivitis (ocular itching with and without ' -30-eosinophils~seen on conjunctival scrapings) ror 7 days.
Thirty patients with alEergic coniunctivitis- ' -~' participated in the study.~ Following admission o--the ~-study, patients reported to the investigator ~or baseline, mid-week~ and final one-week examinations. At each of these visits, patients received ophthalmic - .
8408Y 26280-FF ~
' ~ .
examinations (visual acuity, external eye exam using slit lamp biomicroscopy, measurement of intraocular pressure, and undilated ophthalmoscopic examination). Laboratory tests included a conjunctival scraping performed at ' baseline and the final exam.
All patients completed the study. There were no adverse events or toxicities in patients treated with vehicle while stinging on one occasion was.reported from : .
ketorolac 0.5% ophthalmic solution. K'etorolac treatment . :
was associated with a decrease in ~ree eosinophilic granules as compared to vehicle (p s 0.025 Fisher's Exact Test. two-tailed).
The results o~ this study show th~at--ketoEoLac 0.-5% - .-...~ ' -..
-ophthalmic solution applle.~.~cu~-times~ s~-en-:F~~
days produces a decrease-in.eo'slnop M L~c'~'gra'nules ~-s---'' ~` .~'~'~..
compared to vehicIe in the.-:t~eatm.en.t.of allergic :
conjunctivitis.
- . . ~ ~ .
EXAMPLE 9 :~
This study was a double-bLind.:,. eal ed~co ~ ison '`;~
design trial to evaluate the--t~olerance~a~ketorolac~0.5% -. ' ophthalmic solution and its véhicle in' 26 heaithy .
sub~ects. Solutions were instilled three times daily for 21 days. Complete ophthalmlc examinations wore done pretreatment and on days. 3~ 0~r^~-~7~-.-~ ¢2 days a~ter -~
: endlng treatment), and 45 -2-3 F~ays^i~te~-endlng -~
treatment). ~No statisticalLy'si ~ i-:~icant di~ference in ~ 3-~
~ symptoms (burning, stinging, itchiness, scratchiness, : '' 30 photophobla3 or signs (tearing, ocular discharge, ::' conjunctival~vasodilation, chen ~i's.~ keratitis,.~
~luorescein staining, Rose Bengal:s*aining)-was::found ~ '' -~ .
between ketorolac and vehicle.
., .
~ .
~ 8408Y 26280-FF '' . --':
An ocular formulation containing 5 mg/ml ketorolac .',', tromethamine was administered at a dose of 0.1 ml/eye . -S every one-hal~ hour ~or a total o~ 12 doses to both eyes ' :
o~ 6 New Zealand albino rabbits. The formulation contained benzalkonium chloride as the preservative :
system. Two additional groups o~ animals served as saline and vehicle controls, respectively.
Eyes were examined a~ter the last dose was administered and on days 1, 2, 3, and 6 ~ollowing ..... ' dosing. Results indicated that no eye irritation or '.
toxicity resulted ~rom.ketor-olac.trome.thamine.
- ' ' '''ad'ministration.
While the present invention has been described with re~erence to the speci~ic embodiments thereo~, it should ' ~ ' be.understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing ~rom the true spirit and scope~of the invention. In addit~onr=~3u~; m~di'~1c~s~4=R=s~3aR~b~-ma~e~
' to adapt a particular sit~ati;on-,. mate ~ ~ o'mp~osition o~' . '`.
:matter, process, process step or steps, ~o the obJectlve, .,.: :.
~ spirit and scope o~ the present invention. All such 25 modi~ications are intended to be within the scope o~ the ,claims appended hereto.' ~ , , ' ..... ..
- - . ., :
-::
30 - , .~. ', ~:
~ -- - - : - ; ~
-: - , ' .. -:
- . - - ' ~ .
....
- :., ,-
Claims (27)
1. An ophthalmic NSAID formulation comprising: a NSAID in an effective amount for ophthalmic treatment, a quaternary ammonium preservative, a stabilizing amount of a nonionic ethoxylated octylphenol surfactant, and an aqueous vehicle wherein said surfactant has a mole ratio of ethylene oxide to octylphenol of between 9:1 and 40:1.
2. The ophthalmic NSAID formulation of Claim 1 wherein said quaternary ammonium preservative is benzalkonium chloride.
3. The ophthalmic NSAID formulation of Claim 1 wherein said nonionic ethoxylated octylphenol surfactant is an octylphenoxypoly(ethyleneoxy)ethanol with a mole ratio of ethylene oxide to octylphenol of between 9:1 and 40:1.
4. The ophthalmic NSAID formulation of Claim 3 wherein said nonionic ethoxylated octylphenol surfactant is Octoxynol 40.
5. The ophthalmic NSAID formulation of Claim 4 including disodium edetate.
6. The ophthalmic NSAID formulation of Claim 1 wherein said NSAID is selected from the group: ketorolac, indomethacin, flurbiprofen, and diclofenac, or their isomers, pharmaceutically acceptable salts, or esters.
7. The ophthalmic NSAID formulation of Claim 6 wherein said NSAID is Ketorolac Tromethamine.
8. The ophthalmic NSAID formulation of Claim 6 wherein said NSAID is the (1)-isomer of ketorolac or one of its pharmaceutically acceptable salts.
9. The ophthalmic NSAID formulation of Claim 1 comprising:
NSAID 0.001% to 10.0% wt/vol.;
Preservative 0.001% to 1.0% wt/vol.;
Surfactant 0.001% to 1.0% wt/vol.;
and Purified Water q.s. to 100%.
NSAID 0.001% to 10.0% wt/vol.;
Preservative 0.001% to 1.0% wt/vol.;
Surfactant 0.001% to 1.0% wt/vol.;
and Purified Water q.s. to 100%.
10. The ophthalmic NSAID formulation of Claim 9 wherein said preservative is benzalkonium chloride.
11. The ophthalmic NSAID formulation of Claim 10 wherein said surfactant is Octoxynol 40.
12. The ophthalmic NSAID formulation of Claim 11 wherein said NSAID is Ketorolac Tromethamine.
13. The ophthalmic NSAID formulation of Claim 9 including:
Chelating agent 0.01% to 1.0%wt/vol.;
Tonicifier q.s. to achieve isotonicity with lacrimal fluid; and lN NaOH or lN HCl q.s. to adjust pH to 6.0 to 8.0
Chelating agent 0.01% to 1.0%wt/vol.;
Tonicifier q.s. to achieve isotonicity with lacrimal fluid; and lN NaOH or lN HCl q.s. to adjust pH to 6.0 to 8.0
14. The opthalmic NSAID formulation of Claim 13 comprising:
NSAID 0.50% wt/vol.;
BAC 0.02% wt/vol.;
(50% aq. soln.) Octoxynol 40 0.01% wt/vol.;
(70% aq. soln.) EDTA Na2 0.10% wt/vol.;
NaCl 0.79% wt/vol.;
lN NaOH or lN HCl q.s. to adjust pH to 7.4 ~
0.4; and Purified Water q.s. to 100%.
NSAID 0.50% wt/vol.;
BAC 0.02% wt/vol.;
(50% aq. soln.) Octoxynol 40 0.01% wt/vol.;
(70% aq. soln.) EDTA Na2 0.10% wt/vol.;
NaCl 0.79% wt/vol.;
lN NaOH or lN HCl q.s. to adjust pH to 7.4 ~
0.4; and Purified Water q.s. to 100%.
15. The opthalmic NSAID formulation of Claim 14 wherein said NSAID is Ketorolac Tromethamine.
16. The use of a formulation comprising an NSAID in an effective amount for opthalmic treatment, a quaternary ammonium preservative, a stabilizing amount of a nonionic surfactant, and an aqueous vehicle for treating ophthalmic diseases in a mammal suffering therewith wherein said surfactant is a nonionic ethoxylated octylphenol surfactant having a mole ratio of ethylene oxide to octylphenol of between 9:1 and 40:1.
17. The use of a formulation of Claim 16 for treating opthalmic diseases, wherein the preservative is benzalkonium chloride.
18. The use of a formulation of Claim 17 for treating opthalmic diseases, wherein the surfactant is Octoxynol 40.
19. The use of a formulation of Claim 16 for treating opthalmic diseases, wherein NSAID is selected from the group: ketorolac, indomethacin, flurbiprofen, and diclofenac, or their isomers, pharmaceutically acceptable salts, or esters.
20. The use of a formulation of Claim 19 for treating opthalmic diseases, wherein the NSAID is Ketorolac Tromethamine.
21. The use of an opthalmic NSAID formulation of Claim 20 for treating opthalmic diseases wherein said opthalmic NSAID formulation comprises:
Ketorolac Tromethamine 0.50% wt/vol.;
BAC 0.02% wt/vol.;
(50 % aq. soln.) Octoxynol 40 0.01% wt/vol.;
(70% aq. soln.) EDTA Na2 0.10% wt/vol.;
NaCl 0.79% wt/vol.;
lN NaOH or lN HCl to adjust pH to 7.4 ~
0.4; and Purified Water q.s. to 100%.
Ketorolac Tromethamine 0.50% wt/vol.;
BAC 0.02% wt/vol.;
(50 % aq. soln.) Octoxynol 40 0.01% wt/vol.;
(70% aq. soln.) EDTA Na2 0.10% wt/vol.;
NaCl 0.79% wt/vol.;
lN NaOH or lN HCl to adjust pH to 7.4 ~
0.4; and Purified Water q.s. to 100%.
22. An antimicrobially effective preservative system for opthalmologically acceptable, carboxyl group-containing drugs, said preservative system comprising a quaternary ammonium preservative and a stabilizing amount of a nonionic ethoxylated octylphenol surfactant wherein said surfactant has a mole ratio of ethylene oxide to octylphenol of between 9:1 and 40:1.
23. The preservative system of Claim 22 wherein said preservative is benzalkonium chloride and said surfactant is Octoxynol 40.
24. The use of a formulation of Claim 1 for the treatment or prevention of ocular inflammatory diseases.
25. The use of a preservative system of Claim 22 for the treatment or prevention of ocular inflammatory diseases.
26. A process for the preparation of an ophthalmic NSAID formulation which comprises mixing 0.001% to 10.0% wt/vol. of an NSAID, 0.001% to 1.0% wt/vol. of a preservative, 0.001% to 1.0% wt/vol. of a nonionic ethoxylated octylphenol surfactant wherein said surfactant has a mole ratio of ethylene oxide to octylphenol of between 9:1 and 40:1, and Purified Water q.s. to 100%.
27. The process of Claim 26 which further comprises mixing 0.01% to 1.0%wt/vol. of a chelating agent, q.s. of a tonicifier to achieve isotonicity with lacrimal fluid, and q.s. of lN NaOH or lN HCl to adjust pH to 6.0 to 8Ø
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9617387A | 1987-09-11 | 1987-09-11 | |
| US096,173 | 1987-09-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1328614C true CA1328614C (en) | 1994-04-19 |
Family
ID=22256043
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000576880A Expired - Lifetime CA1328614C (en) | 1987-09-11 | 1988-09-09 | Preservative system for ophthalmics formulations |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0306984B1 (en) |
| JP (1) | JPH0696542B2 (en) |
| KR (1) | KR950013754B1 (en) |
| AT (1) | ATE74750T1 (en) |
| AU (1) | AU626798B2 (en) |
| CA (1) | CA1328614C (en) |
| DE (1) | DE3870111D1 (en) |
| DK (1) | DK174702B1 (en) |
| FI (1) | FI94924C (en) |
| HK (1) | HK27894A (en) |
| HU (2) | HU199072B (en) |
| IE (1) | IE60717B1 (en) |
| IL (1) | IL87724A (en) |
| NO (1) | NO175404C (en) |
| NZ (1) | NZ226100A (en) |
| PH (1) | PH25422A (en) |
| ZA (1) | ZA886757B (en) |
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|---|---|---|---|---|
| US5414011A (en) * | 1987-09-11 | 1995-05-09 | Syntex (U.S.A.) Inc. | Preservative system for ophthalmic formulations |
| DE59005084D1 (en) * | 1989-09-21 | 1994-04-28 | Ciba Vision Ag | Antimicrobial compositions. |
| IL95942A0 (en) * | 1989-10-13 | 1991-07-18 | Syntex Inc | Collagen-containing ophthalmic formulation |
| AU661818B2 (en) * | 1990-03-16 | 1995-08-10 | Procter & Gamble Company, The | Use of ketorolac for treatment of periodontal disease |
| US5464609A (en) * | 1990-03-16 | 1995-11-07 | The Procter & Gamble Company | Use of ketorolac for treatment of oral diseases and conditions |
| UA26334A (en) * | 1990-12-27 | 1999-08-30 | Еллергаh Іhк. | METHOD OF DISACTIFICATION OF COATS AND LOSS AND COMPOSITION FOR DISINFECTION OF COATS |
| US5227152A (en) * | 1991-04-09 | 1993-07-13 | Merck Frosst Canada, Inc. | Radiopharmaceutical bacteriostats |
| US5093105A (en) * | 1991-04-09 | 1992-03-03 | Merck Frosst Canada, Inc. | Radiopharmaceutical bacteriostats |
| US5306482A (en) * | 1991-04-09 | 1994-04-26 | Merck Frosst Canada, Inc. | Radiopharmaceutical bacteriostats |
| CA2179147A1 (en) * | 1993-12-17 | 1995-06-22 | Gerald D. Cagle | Improved intraocular irrigating solution containing non-steroidal antiinflammatory agent |
| US5474985A (en) * | 1993-12-22 | 1995-12-12 | The Regents Of The University Of California | Preventing and treating elevated intraocular pressure associated with administered or endogenous steroids using non-steroidal cyclooxygenase inhibitors |
| ES2079320B1 (en) * | 1994-05-17 | 1996-10-16 | Cusi Lab | OPHTHALMIC DISSOLUTION BASED ON A DICLOFENACO AND TOBRAMYCIN AND ITS APPLICATIONS. |
| WO1995033456A2 (en) * | 1994-06-07 | 1995-12-14 | Telor Ophthalmic Pharmaceuticals, Inc. | Reducing intraocular pressure using aryloxy- and aryl-acetic acids |
| CA2201134A1 (en) * | 1994-10-10 | 1996-04-18 | Alfred Sallmann | Ophthalmic and aural compositions containing diclofenac potassium |
| US5603929A (en) * | 1994-11-16 | 1997-02-18 | Alcon Laboratories, Inc. | Preserved ophthalmic drug compositions containing polymeric quaternary ammonium compounds |
| DE69526369T2 (en) * | 1995-01-20 | 2002-11-07 | Wakamoto Pharma Co Ltd | ANTI-INFLAMMATORY EYE DROPS |
| US5599535A (en) * | 1995-06-07 | 1997-02-04 | Regents Of The University Of California | Methods for the cyto-protection of the trabecular meshwork |
| US5674888A (en) * | 1995-06-07 | 1997-10-07 | University Of California | Method for the treatment of a trabecular meshwork whose cells are subject to inhibition of cell division |
| TW434023B (en) * | 1995-09-18 | 2001-05-16 | Novartis Ag | Preserved ophthalmic composition |
| JPH09278653A (en) * | 1996-04-05 | 1997-10-28 | Santen Pharmaceut Co Ltd | Retinal disease-treating preparation |
| MX9701946A (en) * | 1997-03-14 | 1998-04-30 | Arturo Jimenez Bayardo | Transporting ophthalmic solution. |
| DE19729879C2 (en) | 1997-07-11 | 1999-07-08 | Mann Gerhard Chem Pharm Fab | Storage stable ophthalmic compositions comprising diclofenac and ofloxacin |
| JP2006111636A (en) * | 1997-12-26 | 2006-04-27 | Astellas Pharma Inc | Sustained release pharmaceutical composition |
| ES2307498T3 (en) * | 1999-03-02 | 2008-12-01 | Vitreo-Retinal Technologies, Inc. | PHARMACOS TO TREAT OR PREVENT OCULAR DISORDERS, ADMINISTERED BY INTRAVITREA VIA. |
| DE19918324A1 (en) * | 1999-04-22 | 2000-10-26 | Mann Gerhard Chem Pharm Fab | Bactericidal, virucidal, fungicidal and antiprotozoal pharmaceutical composition, especially for ophthalmological use, contains benzalkonium salt |
| US20020035107A1 (en) | 2000-06-20 | 2002-03-21 | Stefan Henke | Highly concentrated stable meloxicam solutions |
| DE10161077A1 (en) | 2001-12-12 | 2003-06-18 | Boehringer Ingelheim Vetmed | Highly concentrated stable meloxicam solutions for needleless injection |
| US8992980B2 (en) | 2002-10-25 | 2015-03-31 | Boehringer Ingelheim Vetmedica Gmbh | Water-soluble meloxicam granules |
| PT1586316E (en) | 2003-01-21 | 2008-05-28 | Senju Pharma Co | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| CA2468664C (en) | 2003-06-03 | 2012-03-06 | Allergan, Inc. | Ketorolac tromethamine compositions for treating or preventing ocular pain |
| DK1654002T4 (en) | 2003-08-07 | 2014-02-17 | Allergan Inc | Compositions for applying therapeutic agents to the eyes |
| EP1568369A1 (en) | 2004-02-23 | 2005-08-31 | Boehringer Ingelheim Vetmedica Gmbh | Use of meloxicam for the treatment of respiratory diseases in pigs |
| WO2005102303A2 (en) * | 2004-04-21 | 2005-11-03 | Advanced Ocular Systems Limited | Antiprostaglandins for the treatment of ocular pathologies |
| US9161905B2 (en) * | 2005-01-12 | 2015-10-20 | Ocular Research Of Boston, Inc. | Dry eye treatment |
| US9192571B2 (en) | 2008-03-03 | 2015-11-24 | Allergan, Inc. | Ketorolac tromethamine compositions for treating or preventing ocular pain |
| WO2011046853A1 (en) | 2009-10-12 | 2011-04-21 | Boehringer Ingelheim Vetmedica Gmbh | Containers for compositions comprising meloxicam |
| AU2010347598B2 (en) | 2010-03-03 | 2014-11-27 | Boehringer Ingelheim Vetmedica Gmbh | Use of meloxicam for the long-term treatment of musculoskeletal disorders in cats |
| US9795568B2 (en) | 2010-05-05 | 2017-10-24 | Boehringer Ingelheim Vetmedica Gmbh | Low concentration meloxicam tablets |
| JP2013082682A (en) * | 2011-09-29 | 2013-05-09 | Senju Pharmaceut Co Ltd | Aqueous formulation containing chlorite |
| CN110448530A (en) * | 2018-05-07 | 2019-11-15 | 北京蓝丹医药科技有限公司 | A kind of florfenicol residues |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4087538A (en) * | 1976-09-09 | 1978-05-02 | Merck & Co., Inc. | Ophthalmic suspensions |
| DE3026402A1 (en) * | 1980-07-11 | 1982-02-04 | Syntex Corp., Palo Alto, Calif. | Non-steroidal antiinflammatory agents - for treatment of micro:vascular disease, e.g. diabetic retinopathy or diabetic nephropathy |
| HU195918B (en) * | 1984-03-14 | 1988-08-29 | Jerome Corbiere | Process for producing pharmaceutical compositions containing non-steroide antiflogistic active components |
-
1988
- 1988-09-09 NO NO884020A patent/NO175404C/en not_active IP Right Cessation
- 1988-09-09 IE IE274088A patent/IE60717B1/en not_active IP Right Cessation
- 1988-09-09 EP EP88114804A patent/EP0306984B1/en not_active Expired - Lifetime
- 1988-09-09 JP JP63227343A patent/JPH0696542B2/en not_active Expired - Lifetime
- 1988-09-09 CA CA000576880A patent/CA1328614C/en not_active Expired - Lifetime
- 1988-09-09 FI FI884160A patent/FI94924C/en not_active IP Right Cessation
- 1988-09-09 DE DE8888114804T patent/DE3870111D1/en not_active Expired - Lifetime
- 1988-09-09 IL IL87724A patent/IL87724A/en not_active IP Right Cessation
- 1988-09-09 ZA ZA886757A patent/ZA886757B/en unknown
- 1988-09-09 KR KR1019880011664A patent/KR950013754B1/en not_active IP Right Cessation
- 1988-09-09 NZ NZ226100A patent/NZ226100A/en unknown
- 1988-09-09 HU HU884648A patent/HU199072B/en unknown
- 1988-09-09 AT AT88114804T patent/ATE74750T1/en not_active IP Right Cessation
- 1988-09-09 DK DK198805056A patent/DK174702B1/en not_active IP Right Cessation
- 1988-09-09 AU AU22042/88A patent/AU626798B2/en not_active Expired
- 1988-09-09 PH PH37525A patent/PH25422A/en unknown
-
1994
- 1994-03-24 HK HK278/94A patent/HK27894A/en not_active IP Right Cessation
- 1994-07-01 HU HU94P/P00006P patent/HU210610A9/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU2204288A (en) | 1989-03-16 |
| NO175404C (en) | 1994-10-12 |
| ZA886757B (en) | 1990-05-30 |
| FI884160A (en) | 1989-03-12 |
| HUT47839A (en) | 1989-04-28 |
| ATE74750T1 (en) | 1992-05-15 |
| DK505688A (en) | 1989-03-12 |
| NO175404B (en) | 1994-07-04 |
| HK27894A (en) | 1994-03-31 |
| JPH0696542B2 (en) | 1994-11-30 |
| HU199072B (en) | 1990-01-29 |
| EP0306984B1 (en) | 1992-04-15 |
| EP0306984A1 (en) | 1989-03-15 |
| IL87724A0 (en) | 1989-02-28 |
| NZ226100A (en) | 1990-12-21 |
| JPH01104023A (en) | 1989-04-21 |
| KR950013754B1 (en) | 1995-11-15 |
| FI94924C (en) | 1995-11-27 |
| KR890004691A (en) | 1989-05-09 |
| IE882740L (en) | 1989-03-11 |
| AU626798B2 (en) | 1992-08-13 |
| IL87724A (en) | 1992-01-15 |
| IE60717B1 (en) | 1994-08-10 |
| FI884160A0 (en) | 1988-09-09 |
| DE3870111D1 (en) | 1992-05-21 |
| FI94924B (en) | 1995-08-15 |
| HU210610A9 (en) | 1995-05-29 |
| NO884020L (en) | 1989-03-13 |
| DK505688D0 (en) | 1988-09-09 |
| PH25422A (en) | 1991-07-01 |
| NO884020D0 (en) | 1988-09-09 |
| DK174702B1 (en) | 2003-09-29 |
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