AU2014201978B2 - Compositions containing quaternary ammonium compounds - Google Patents

Abstract

Oil-in-water emulsion comprising an ammonium halide which is cetalkonium halide, an oil which is medium chain triglyceride, 5 at least one active principle, surfactants, additives selected in a group comprising antioxidants, tonicity, viscosifying, pI adjusting, buffering and/or preservative agents, and water.

Description

Compositions containing quaternary ammonium compounds The present application is a divisional application from Australian patent application number 2007278141, the entire disclosure of which is incorporated herein by reference. 5 This invention relates to pharmaceutical, ophthalmic or cosmetic compositions containing quaternary ammonium compounds, more preferably to ophthalmic emulsions being useful for eve care or for the treatment of eye conditions. This invention also relates to compositions including at least one quaternary 10 ammonium compound as cationic agent. Quaternarv ammonium compounds are organic compounds usually used as an antiseptic or antimicrobial agent. For example, benzalkonium chloride is a nitrogenous cationic surface-acting agent belonging to the quaternary ammonium group. Benzalkonium 15 chloride is generally defined as a mixtures of compounds of general formula CIiICHN(CH 2

)

2 RCl, wherein R is a 012-C24 alkyl group, Benzalkoniurn chloride, as usually provided by the manufacturers wanting to comply with the European and/or 20 American Pharmacopeia, is a mixture of n-alkyl dimethyl benzyl ammonium chlorides of various alkyl chain lengths. For example, FeF Chemicals A/S (Denmark) supplies, under reference 8100301U (BAK USP/NF), a mixture of three alkyl dimethyl benzyl ammonium chlorides including : (1) 60-70% of C 1 2 -alkyl dimethyl benzyl 25 ammonium chloride (2) 30-40% of CW alkyl dimethyl benzyl ammonium chloride, and less than 5% of C-alkyl dimethyl benzyl ammonium chloride. Benzalkonium chloride, as a mixture of alkyl dimethyl benzyl ammonium having various alkyl chain lengths is used as 30 preservative agent in topical ophthalmic products. Benzalkonium chloride also has cationic agent properties, and WO 2008/012367 PCEP077784 2 was used as oationic agents for emulsions, einptCially ophthalmic emlsions. When mixtures of henzalkonium chlorides having various alkyl 5 chain lengths are used in emulsions, they may act both as prescrvxrtive agents and cationic agents. The Applicant worked on long chain quaternary ammonium cmpounds, and noticed that the length of the aMyi chain was 10 important with regards to the function performed by the quaternarv amaniuam comnounds: acting on the length of the alyl chain resulted in enhancIng or reducing the cationic power of the quaternary ammonium ompounds. Without wantAng to be liked by any theory, the Applicant observed on working 15 on oI- inP-water emulsions, that long nhain quaternary ammonium compound are Preferentiallv localized at the oilwater interface of the emulsions, resulting in (w emulsions with higher zeta potential and (2) more stale emulisions. s quaternary ammonium may be considered as 20 undesirable or toxic, it is thus a goal ct tas invention to provide ationic composition flaving a reduced Content of uatern ary ammonium compoAd. The Appicant also observed that, in emuisions, waternaicy 25 ammonii m ompounds having long alkyl chains, for exam-pie . rn ammonium compnuds hanvin 014-34 alkyl chains, when compared to 012-alkyl chains, did not have a good bactericidal act ivity, whereas they conferred a greatest cationic power. 30 Moreover, the Appl acant observed that long chain guaternary ammonium compounds were present preferentially at tne WO 2008/012367 PCT/EP2007/057784 a oil/wer interface of the emulsion drplets, oo lodess in the aqueous phase. The fact that quaternary ammonium compounds may be present n the aqueous phase in a very small amonnnt only, or not prCsent, leads to a loss of preservative effect 5 or poor preservatiWe effect 1 as well as to less toxic emlsions. Thus, one of the goals of this invention iS o pr:de stable catlonic emulsions comprisin a reduced amount o 10 benralko"Ium corides, andI s-tl u-in sadbiahnu chlorides a a soume, or the onry soure or catonic agents 1 said emulsions being preserved or not. Another goal of the present intention is to provide emulsions that are not toxic, even if they comprise quaternery ammonium 15compounci Preferably, the emulons of the enuseul ophthalmic PurPOSES. In the meaning of this invention, 20 "Catownic emu sins are eMulSWK sios avfg a positive zeta potential, preferably a zeta on:lh et1 V "a hy" mans a saturaten or unsaturated hvdrocaroon o nn log tyl chain" aire aky moieties haing at least iS 25 "ccaen ammonium compourns refer to ammonium halides in WV nat1 ms ar least nd a hyl gron having at least 12 carbon atoms quaternary eonium compounds asbtntecuiey 5 include n-ethyl dimethyl- benvyl ammonlum chloride also called 30 benzalkonium chloride tere nafrer also reinerd to as BAK or ADBAC) ; n-ethyl dimtny benzyi emmonum brnmide; n-atyl 4 trimethyl ammonium bromide (also referred to as ATAB) , n-alkyl meaning an alkyl group of at least 12 carbon atoms; "C14alkyl ammonium halides " means ammonium halides in which the nitrogen atom of the ammonium group is substituted by at 5 least one alkyl group having at least 14 carbon atoms. BAK C12" refers to benzododecinium chloride (CAS 139-0>1); "BAK C14' refers to myristalkonium chloride (CAS 13908-2); "BAK C16" refers to cetalkonium chloride or CKC (CAS 122-18-9); ATAB C12" refers to lauryl trimethyl ammonium bromide (CAS 10 1119-94-4) ; "ATAB C14" refers to Myristil trimethyl ammonium bromide (CAS 1119-97-7); "ATAB C6" or "CTAB" refers to Cetyl trimethyl ammonium bromide CAS 57-09-0), "MCT" means Medium chain triglycerides; for the experimentation, Mygliol 812 (Sasol, Germany) was the MCT used; 15 "ND" means "not determined". The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these 20 matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application. Where the terms "comprise", "comprises", "comprised" or 25 "comprising" are used in this specification (including the claims) they are to be interpreted as specifying the presence of the stated features, integers, steps or components, but not precluding the presence of one or more other features, integers, steps or components, or group thereof.

4a The invention relates to a cationic oil-in-water emulsion comprising an ammonium halide composition as cationic agent. The ammonium halide composition includes in a preferred embodiment only one ammonium halide, which is CI6 alkyl 5 quaternary ammonium halide. The oil-in-water emulsion of the invention presents the advantages to be very stable and non toxic, compared to emulsions comprising benzalkonium chlorides, By cationic oil-in-water emulsion is understood an oil-in-water 10 emulsion having a positive zeta potential. The emulsion of the invention has a positive zeta potential and is stable, which means that it keeps a positive zeta potential overtime.

WO 2008/012367 PCTEP2007/057784 Sa preferred embodiment, the oi-in-water emu sion accoroning to the invention includes droplets of size ±00 to. 500 nm, preferably 200 o OO m, 5 n a preferred emodiment, the ol-in-wate em siOn of the invention is useful for eye care or for the treatment of eye diseases or eye conditions. In a preferred embodiment of the present invention, eve disenases o eve condit ins means a1 dry eye condition, A0 A diminution of the quantity of tears produced and distributed through the lachrvmai ducts or a decrease in the stability of the tear fim p roduend, results in a coni on of the eye referred to as dry eye. Dry eye cdnions act t decrease -isal city, produce discomfort rangi from m intense and even ualy, if allowed to remain untreated and uncorrected, resutin permanent damage wit degradaniEon of the exposed ocular tissues, with a complete breakdown of Corneal tissue necess ating, in the ex reme, corneal transplants, 20 The symptoms assniated with dry eye are often exacerbated with sub eats using intact lens. A dry eve c ndition in this context therefore refers to Mry eve acmpanying racrimal fluid redoctionm tear deficiency, -eross n Tme eye, SlOgren s syndrome, keratocon i s 25 sicca JOCS), atopic keaoonbcavtsscca (AMi), vernal keratocnjunctiviis K teven oson sy e omphgoid of: the eye, maginal blepharii s , f a lure in eyelids closure, or sensory n1e numbness, dry eye accompanying alleri C COnjun not! dry eye arter vi 30 unctiitis dry eye after cornea surgery including laser in situ keratomieusis Q 2 ASIK) , dry eye after catara WO 2008/012367 PCTEP2007/057784 surgery dry eye associated with contact lens wearing, or dry eve associated withn VD tasks More preferably, the oil-in-water emulsion according to the > invention comprises: a) an oil phase, b) 0.0003% to 0.1 %ww preferably 0.001 to 0.02 % ww of the weight of the emulsion of a composition of amonium halides accoroIng to the invention, as do-scrbed hereabove, to the weight of the emulsion C) surfactants, d) optionally antioxidants tonaIt, viscsifying, pH adjusting 7 buffering, preservative, solubiltizers, chelating or thickener agents, iS a) water. In an emodiment of the present invention, said composition of ammonium halides comprises at least one ammonium gaternary ammonumt halide, in which the nitrogen atom of the is anmninm group is substituted bY only one or an |east one alkyl gronp having at least 12 caron atoms, said compose on inelding atlea.st 20% in weight by weight of the total composition of ammonium halides in which the nitrogen 25 atom is-ostituted by only one or at least one aMkyl group having at least 14 carbon atoms, preerably A or 16 carbon atoms and -more than 5, preferably more than 7% in weigh by weight of the total composition, of ammonIum nalides 30 in which the nitrogen atom iS substituted by only one or at least one alkyl group having at weast 16 carbon atoms W() 2008/0!2367 PCT/EP200707784 According toa rferd nodirnn of thiS invention, th comnpos rta fi ammonium nalides comprises only 016-,allvi. quaternary ammonium halider more preferably ammonium chloride 5 or bromide? in which the nitrogen sam of* UPh amonrumgru is substituted by only one or at least one alkyl group baying 16 Carton atoms Prerzeably, the composition of ammonium halides comprises C1F &lkvhhenal ammonium Panie, oreferab Cl 6 10 aikylbenzyldimethyl annium halide, preferably BAK 0.6 According to an embodiment of the oresenn invenon, tn5 compsition of ammonrum halides comprises a ClO-alky1 quate to ay ammonium halide, in which the nitrogen atom of the ammonum group is substituted by two or three wer alkyl 15 groups, pe0ferably by two or three methyl groups us, in a rrefered embodiment o the present invention, sain cr1-in-wnnate cwlision comprises 0. 0005 to 0.1 A of WO6 alky! quaternary aenvonium halide, in weight by weight of the MAcrding to a prenrd embodiment, the emulsion of the invention conmpAises ci phase, comprising mineral oil, castor oi MC, corn u olive oil, soybean oil or any 25 suitable vegetable o il .cr nabl said oil phase comprises mineral oil, castor oll or AC. According to a preferred emboament, te emulsion of te ivention f urther nompri ses tyloXapora According toc a preferred embAodmnt, teeuso f h 30 invent on futaner comprises a toniclty agent such as rot example glycerol, mannitol, sorbitol, sodium chloride; others surfactants such as poloxamer; and optionally at least one WO 2008/012367 PCT/EP2007057784 8 suffering agent uan as far example citrate, phosphate, tris, borate, acetate, car onate, hoate-polyo1 complexes histidine, gluconate and lactate. wn one preferred embodiment of the present invention, said emualsion cOmpses Manntol as toicity agent, rin another prefer red e~mbodiment OA tha present invention 7 said emu son comprises yel as o i agent Preferably, the emuli<on inldes 1 t 5 % of oil phase. preferably of HCT castor oil or mineral oil, in weigh by Pref erably, the mineral oil phase Is a mixure of heavy and ligh mineral oil The main droplet core is composed by 50% light mineral Oi and 50% heavy mineral oil. 15 Mineral oil is a mixture of refined lquid saturate a] inha tic (014-Cl) and cyclic hydrocarbons obtained from petoleum. Light miners oil is less viscous and has a lower spenific arayity than heay mineral aI. Heavy and lgh. mineral o are well known excipients, used in a variety of 20 pharoaeutical formlations including oral, and topical (up to 95%) preparations. i ophthalmic ointments, mineral oil can be found as An excpient at concentrations of up to GO% A nominationn of ligh aMnd heavy neral oil in ophthalmooy has been recognized by the US atories as ueanng 25 emollient properties particular adapted to dry eye treatment (21A CER 549) Preferably, te emulsion includes 0.1 to 1 % of surfactants, SUo as tylOxapol and optionally poOXamer M and/or 30 polvsorbate sO and/or tacopherol polyethylene drool succinte and/or sorbitan molaurate, in weight by weigt of the emulsion.

WO 20081012367 PCTEP207/057784 pre fe rablv, the emls ion ompise's ti,3, of tyloxapiol and ptional 0,1, of pa ... m 188, in weight by weight of the Ereferahl, the Caulsion comprises 0,1% to 51 of tonicity 5 agent (s) , mar preferably 0.5% to and even more preferably 0, 9% to 3%4, in weight by weight of the emulsion. n one eodiment the cm si compose 0 of mannitol, more preferaly 0 .5% to 4% and even more 0.% to .3%, in weAht by weight of the emulsion. 10 in another embodiment, the emulsion aomorises 0. 1 to 2.5' of qlyceroln more Dreferablv 0.19% to 1 6% in weight by weights o the emulsions in one preferred embodiment o the present inventian? the 15 emlsion comprises lighr and heavy mineral; N 1, tyloxpol . aoloxamer U8, mannitol and cetalkonium chloride. Preferably? said emulsion comprises 05% of light mineral oil, 0,5% of henany mineral oil, 0. 3% of tQoxapol, 0.1% of poioxamen 188, 3.3% of mannitol, and 0,002% of cetalkonium cloride, in 20 weight by weight of the emulion In another preferred embodiment of the present Anventi , the emulsion comprises light and heavy mineral oil, tyloxapol, poioxamer 188, glycerol and cetalkonium chlride. Preerably, 2b said emulion comprises 0. 5 of light mineral oil, 0.5% of heavy mineral oil, 0.3% of tylozapol, 0.1% of pooxamer 103 1.% of glycerol, and 0.002% of cetalkomm chloride, in weight by wegbr of the emuisin 30 Acrding to a preferred embodiment of the invention, the emulsion is hypotonic with regards to the normal. tears tonicity.

WO 2008/012367 PCTJEP2007/057784 10 According to a preferred embodiment, the oiln-water emulsran of the invention is less toxic than a solution comprising the same smonnot Of the same Ci-aiyl u 5 aPMmo rum hao i de, 20 Weight by weight of the SMolun Fox: example, the toxicity can be evaluated by a redness test or a Praise test. as sn in the examoes, According to a preferred embodimen the oil in -water 10 emssion of the invention is l ess tOi thKan aNI emulsio _n rompsriing 0. 01 to 0.1% of BAK in weight by weight of the emlsion, said PAK being a mixture of C12 014 and Cl6alkyl qiaternar ammorTm halide comply vng or European .harmacopera specificarioHn. According to a preferred embodiment, the oil-in-water emulsion of the invention does not induce redness in albino iabit conjunctia before administration of 9 drops of 50pi said drops oein adminisrated each 5 mwtes P rbiy 20 before administration of 11 drops, and more pOrfrably before anmn ist ration of- 13 tons, Acording to a first embodiment, the emuslWon does not contain any active principn in thIS embodiment 1 the 25 emulsion is nartioux1arty useful as artificial tears? or f or the treatment of dy eye condition soon as for example eDry Eve 5yndroe or Chronic cy EYE Dis ase (CDED, both clinicaly known as keratoco cti rtis sicca. According to a second cmtcximent the compoitin of the 30 invention con ains a active principle In one emnodiment, said actie principle s selected rom sec acggues sucn as piloc arpine or celameline, wo 2008m12367 PCTEP20071057784 .mmunsppessive agents such as natural or synthetic cyclosporins 1 tcrnliinus or sirolimus, muein secretagocues such as 15 (S HETE, ecabet or diquafosol, androgen mimetics, flaxseed oil supplements, steroids, agonists of adenosine AS 5 receptor, squalene, vitamin A; said active principle being preferably cclosporine. In another embodiment, said active principle is chosen among the active substances capalf of having additional o syneristic theraeutic effects r treating KS. 0 Preferably, sCH acil principle can be selened in tne group comprising astringents such as zin sUMate, demulcents including ellulose derines oarboxymethylen aulose sodium 1 hydroxvethyzl celalose; nvrmeilse, methvleulose dextran 70, g elation, polyethylene glyc I 5 300, polethylene glycol 400, polysorbate 0, propylene glycol, polyvinyl alchol and povidone such as polyethylene glycol 6000, emollients such as lanolin preparatiOns or oleaginouns ingredientsI vasconstrictors such as naphazoline ephe6rIne, tetraydrozine and phenylephnine sans. 2 0 in an embodiment of the invention, the oil-in-water emulsion is pressed. in another esnodiment or the invention, the oil-in-water emulsion is inneseed; i an embodiment, the emulsion is 25 packaged in unitary doses; in another embodiment, the emulsion is packaged in S4itable mitidose containers. The present invention also relates to the cr1-in-water emulsion as described here above, havinAg a hign viscsi 30 and being dispensed to the patient in the form of a gel suitable for ophthalmic use.

12 Another aspect of the present invention is also a medicament comprising the oil-in-water emulsion as described here above. The present invention also relates to a kit for dry eye treatment comprising a first emulsion as described here above, 5 which does not comprise an active principle, and a second emulsion which contains an active principle, preferably cyclosporine. According to an embodiment said second emulsion comprising an active principle is an emulsion according to the present 10 invention. According to another embodiment, said second emulsion comprising an active principle is any emulsion suitable for ophthalmic use. Another aspect of this invention is a pre-concentrate of the 15 therapeutic oil-in-water emulsion of the invention and a process for manufacturing said pre-concentrate. Another aspect of this invention is a-n oil-in-water emulsion comprising an ammonium halide which is cetalkonium halide, an oil which is medium chain triglyceride, at least one active 20 principle, surfactants, additives selected in a group comprising antioxidants, tonicity, viscosifying, pH adjusting, buffering and/or preservative agents, and water. According to this invention, a pre-concentrate is defined as an emulsion having an amount of oil higher than the amount of oil 25 of the therapeutic emulsion administered to a patient. in a first embodiment, the amount of oil in the pre-concentrate is of at least 4% v/v. in a second embodiment, the amount of oil in the pre-concentrate is of at least 8% v/, In a third embodiment, the amount of oil in the pre-concentrate is of at 30 least 10% v/v., preferably of at least 20% v/v more preferably of at least 30% v/.

12a The ore-concentrate may be in a liquid form or in a gel form, or in any form suitable in view of its further dilution with water.

WO 2008/012367 PCT/EP20W757784 According to an embodiment, the pre-concentrate of ophtaamic oil-in-wate: emulsion according to the present invention may be sterilized, for example, by heat, such as by autolaving, or by filtering or filtration, or by irradiation or by gas 5 sterilization. in another embodimentte concentrate of the ophthald e fusion is prepared in an aseptic manner. This intention also relates to a process for manufacturing a ore-cn entra toerpeutic oil-in- ate emulsion 10 Comprsing the steps o emulsIfing/mixng the cii Phase w.n an aqueos ph ase and with urfce-active component (s)e wherein the optionally active pAnciple is dissolved in the "t pose, The process for manufacturing said fr-concetrOa comrises emulsing an amount of oil with an acuecus pase 1 and with suitable surfactnts in order to obtain an emlsion having an amount in oil higher than te amount in oil of the corresponding emulsion to he administered for therapeutic purposes. 20 Before beginning the manufacturing press h the rapeutic oi- n-atr mulsion is dsign, wit A wished concentration A oil, the type of il (suitable for ophthnlminc ue, such as oy example mineral oil, castor oi, or NOT) the type oi elements needed for emlsificaton such 25 as sufatants or example, and optionally an active principle. The concentration a1 the concentrate iS then decided, depending on the idndstrial volmes needed, This invention also relates to a prices for manufacturing a i therapeutic oil-in-water emulsion comprising (1 manufacturing a pre-concentrate of an ophthalmic oil in water emulsion, said ore-concentrate having a content in oil of at WO 2008/012367 P C TJEPZ1007/105778 4 least 4 % v/v, preferably of % v/v or more, more preferably of 20% v or more, even more preferably of 30% v/v or more by emusifying/mixing an oil suitable for ophthamic use selected in the group comprising mineral oil, castor oil and 5 M, said oil phase Containing optionally one or more active principle and a CIG-alkyl caternarv ammonium halide and with suic-cze compon ent (S , with a~n aqueous phase and then (2) diaing one volume of the resulting p once with 2 to 50 volumes of- 4aer Accrdngtoan emodiment, thEeusfcto is such that' the droplet size or the distribution of the doplet size in the preconcentate is about the same as the droplet size or the distribuion of the droplet size of the therapeutic oil 15 in-water emusion. According to an embodiment, the diluting water may compise additives selected from the group camprising tonicity agents? sucK as for example NaVI, glycero or Mannita, viscosifying agents buf fering agents, preservatives, antioindants or zu colorants, According to an embodiment, the diluting water may alsO comprise a C6-asl jquaternary ammonium halide 25 Then according to the inventin a pre-concenate Of lh desi ed emulsnon is produced by mXing the oal suitable for oSnhhami use, with an aqueous phase and wth surface actve component (s; the average hydrophimic-lpophilic balance (FIB) of the -s rraco-actrv component (s) mayadntgolt 30 be about equal to the HLB or average HLB emulsion requirement of the ol Or oils used in the present compositions.

WO 2008/01267 PCTIEP200Wf05774 15 An advantage of this invention is to produce large volumes or emulsions without having to saaie-up the emujifyinq process This invention relates to a process for manufacturing a therapeutic ola.Vn-water emnulsion accoxrdinc to the inentin comprisino manufacturing a concentrate according to the anove -mentioned nr ocess and then Jult Inc said concentrate, oy mixing 1 volume of concentrate with 2 to 50 volumes of water, to obtain a final tnerapeutrc emulsion having an oil 10 content of 5% v/v of less, preferably of 3 v/v or less, more preferably of 2% v/ or, lesr y or less, This invention also relates to a method for the treatonent of 15 olar diseases or conditions consisting in the administration to a patient of an ophthalmic emulsion prepared from a pre-concentrate, according to the above described prorcess 20 Te invention also relates to oil-in-water emulsaons obtainable by the prices of the invent on, i a. by manf acturing a concentrate including optionally an active principle, and then diluting said concentrate wit 2 to 50 O umes f wate said water optionaly comprising additives 25 such as ror example toniolty agents, viscosirying agents buffering agents, preservatives, antioxidants or colorants One advantage of- the invention is that the oil-n-water emufsions obtained by dilution of the concentrates are f orm-ed - with redued energy input.

WO 2008/012367 PCT/EP2007/057784 16 The following examples and figures illustrate the invennto and should not me interpreted in any way as reducing the scope of this Anvention. 5 Figure 1 refers to the timing of appearance of redness in culaa surface. Figure 2 refers to Draize Test evauation. ExaPes: 10 All onentations iO the sinlsion formulae are expressed in weigt 'weiahr of the entire simulation, unless stated nlrverently. Example 1: Reduced toxicity of quaternary amines when is incorporated into emulsions Materials: 1. Sounion at 0.02% BO (BAS 5A Ezoipients Z015OL472 BAK US 0 .02 Na~l 0.,612 0,069% Tris 1-1l Tris Buffer Sm PH 7.1 Tis Bs Water -Ad 100 2. Emulsion at 0.02%BAK (BAK Em) Excip ents Z 0 1EM4 71 Miner'al oii neavy 0.500 Mineral oil lighL 0,700 TylQ/apol 0.300 0,069%TTris 02 Pcis 5ufe . 1:C,006% Iris ase P .lox.a. 188 .100 Wae (up to 100)A10 WO 20081012367 PCT/EP2007/057784 12-200-7 /U / /84 17 EPO DG1 3. Solution at 0.002% CKC (CKC Sol) 2Z01S0L473 cNaCl o .626 Tris Buttffer 5&M pH 7. -0,069% Tris Cl r 0.006% Tris base Water jAd 100 ______ 5 4. Emulsion at 0.002%CKC (CKC Em) Excipients Z01EM264 Mineral oil heavy 0.500 Mineral oil light 10.500 TyIoxapol 0 .300 CKC 0.002 0.069% Tris HCl Tris Buffer 5mM pH 7.1 0.006% Tris Base Poloxamer 188 0.100 Glycerol 1.6 Water (u to-- 10)A-o 5. PBS Methods: 10 Albino rabbits were administrated with 1 drop (50i) each 5 minutes, for 15 times. 1/ Evaluation of toxicity bo t f redness and DRAIZE test items analyzed at H4 and D1. 15 The time of the beginning of the redness in conjunctiva following the 15 times of instillations was evaluated (Figure 1) . PBS did not induce any redness during all instillation period (data not shown) . BAK Sol induced conjunctival redness 20 very fast about 10 to 15 minutes after the first instillation (after 2-3 drops) . BAK Em, CKC Sol-instilled WO 2008/012367 PCT/EP2007/05 784 groups showed redness at about 25-35 minutes after the first instillation of eye drops (after 5-- drops) ,0KG Em presented a vire redness at almost the end of the experimentation: 60 to minutes after the rUrst instillation (after 12=13 :drops.) Draize Test clearly showed that at four hours (H-1) after the last instillation the ocular irritation was the moss important in BAY SoS-instilled group, which was higher than 1s BAK Enm and 0KG Sal grouos (wth no diffe~nre between these two grOUps) . BAK Shl, BAK Em, 0KG Sol all showed higher cular irritation than 0G am, whlch presented no difference with PBS-istilled ground (Figure 2). One day after the administrations (Di) , PBS BAK Em, 0KG SoT n and 0KG Em all returned to normal aspect witnou difference among them. But BAK Sol stil nuced more important cular irritton t -an all other groups (P0 000)) Example 2: Stability of the emulsions of the invention J I 1. Emulsions composition Some emulsions are desotd below: _______ ZO1EM2O6 ZOlEM2O9 M n 1tm-- OAK 01 0G) 002 0.025mM water c: cclO gpl P D %'%

&J

WO 2008/012367 PCT/EP2007/057784 psin ZO1EM419 z01EM264 Z01EM387 ZO1EM418 Z01EM418 Light mineral 0.5% 0.5% 0,5% 0. 5 0.51 Heavy mineral 3.5%' .5% 0,5% 0.5 05 oil ____ Tyloxapol 0.3% .3% 0,3% 0.3- 03 Pooaer 188 0.1% 0,1% -- - 0 .19 PEG 300 0.19% PEG 400 - 19% .... Mannitol 3.3% .- 2% 4.5U to9 Glycerol - 1,Z% 0,19% 0.9% Getalkonium 0.002% 0.,002 % 0,002% 0.002% 0,002% ohA A cr Vhe Tromethamine 0.006% 0.006% . Tis 111 0,071% 0,071% Water ip to Up to Up to to U n to ____________ 100% 100% 100% 10% 100% Compnosi tion Z01EM393-4 Z0EM39n-6 W" 1 -2% 1-2% Tyloxapol 0.3% 0,3% PG 0.4% _ _ _ _ __ _ _ Manitol ________0,.9% G lycerol1.' Getalkonlum chloride 0.01% 0.01% Wate ________ Up to 100% Up to 100% 2. Emulsions preparation he di y and the water phases of the emulsion whic miht contain or not an active principle, may be separately heated to an appropriare temperatures This temperature inay be te 1. same in both oases, Surfactants might be dissolved in the oil, water phase or in both. A first coarse emulsion is generated by manecicsrrrrrng, and. tae droplet size s WO 2008/01237 PCT/EP2007/057784 20 reduced by high shear mixng, high pressure homogenization 1 or both. The oil-inaser emlsions of the present invention can be serialized after preparation using heat, for example, S autoclave steam sterilizatioc. 3. Impact of chain length on emulsions characteristics Emulsion droplet size 10 The mean diameter of the ol drnlets i determined by dynamic light scattering using a High Performance Particze Sizer tune HEPS 501 (Malvern Instruments, Worstershire, UK), Measurements are perrored at 25"C following dilution of the emulsion in double distile water. 1j Table 1; Emulsions droplet size values (nm) Emulsions of Table 1 and Table 2 contain 2% |MtT, 0.3% Tuloxapol and 0 ,1%: Poloxamer 188 and 2.25% glycerol and compositiocs of BAiK; concentrations of BAK range from 0.001 20 to 0 .% ir eightt to tne wght of the. mu.sion. 0ji% 0.0025% 0.005 0,010.21.04 01% C , 0 8 18: b) Emulsion zeta potential Zeta potential can ne measured by a zetameter su cn as Zetasizer 2000 Malvern Instruments Ltd, UK. The zeta potential of the eusion droplet surfaces is determined by electrophoretic mobility Measureme.nts are performed at 25 0 30 following daipt ion at 1:250 of the emulsion in double WO 200012367 CMEP20057784 21 ditile wte.The elcrpoei obt 1 itv is converted into zeta otenial values through the Smoluchows a The folowing table and raph show the evolution of the zeta notential (indicative of the suxrace charge) at icesn 5 concentratnsofe o sr ved that ipophilic anger) chain lengths, positive charges are attained more rapidly and a lower concentratons suggesting a deferential paritin within the oil droplet sufac. Table 2' Emi nne zata potential values BAKCIk 114 196 +22.9 ±2, +9. 45 c) Emulsion stability over time The sta lfty of the ema Isions n a be evaluated by he evolution of their aspect wit a visual score wth a visual score going from 13 - bent as t L I tal hase separation. 20 it cap be observed from the 1 n' ge tha eguimrarcocetraio, Onmer (mor li 1pophili) Chai length QA results in more stable emulsion. Type an oo fAtrpeaato olwn otsa M AK C1 5 at A 12 1A 0 It AK '1 11 _ _ _ _

Claims (22)

1. Oil-in-water emulsion comprising an ammonium halide which is cetalkonium halide, an oil which is medium chain triglyceride, at least one active principle, surfactants, additives selected in a group comprising antioxidants, tonicity, viscosifying, pH 5 adjusting, buffering and/or preservative agents, and water.

2. Oil-in-water emulsion according to claim 1, comprising cetalkonium chloride, medium chain triglyceride, cyclosporine A, tyloxapol, poloxamer 188, and water.

3. Oil-in-water emulsion according to claim 1 or 2, comprising cetalkonium chloride, medium chain triglyceride, sirolimus, tyloxapol, poloxamer 188, and water. 10

4. Oil-in-water emulsion according to any one of claims 1 to 3, wherein the surfactants are selected in a group comprising tyloxapol, poloxamer 188, polysorbate 80, tocopherol polyethylene glycol succinate, and/or sorbitan monolaurate.

5. Oil-in-water emulsion according to any one of claims 1 to 4, wherein the tonicity agent is selected in a group comprising glycerol, mannitol, sorbitol, sodium chloride. 15

6. Oil-in-water emulsion according to any one of claims 1 to 5, wherein the buffering agent is selected in a group comprising citrate, phosphate, tris, borate, acetate, carbonate, borate-polyol complexes, histidine, gluconate and lactate.

7. Oil-in-water emulsion according to any one of claims 1 to 6, wherein the active principle is selected in a group comprising secretagogues selected in a group comprising 20 pilocarpine and celameline; immunosuppressive agents selected in a group comprising natural or synthetic cyclosporine, tacrolimus and sirolimus; mucin secretagogues selected in a group comprising 15(S)-HETE, ecabet and diquafosol; androgen mimetics; flaxseed oil supplements; steroids; agonists of adenosine A3 receptor; squalene; vitamin A. 25

8. Oil-in-water emulsion according to any one of claims 1 to 7, wherein the active principle is cyclosporine.

9. Oil-in-water emulsion according to any one of claims 1 to 8, comprising an active substance selected in a group comprising astringents; demulcents selected in a group 23 comprising cellulose derivatives, carboxymethylcellulose sodium and hydroxyethylcellulose; hypromellose; methylcellulose; dextran 70; gelatin; polyethylene glycol 300; polyethylene glycol 400; polysorbate 80; propylene glycol; polyvinyl alcohol; povidone; emollients selected in a group comprising lanolin preparations and 5 oleaginous ingredients; vasoconstrictors selected in a group comprising naphazoline, ephedrine, tetrahydrozoline and phenylephedrine salts.

10. Oil-in-water emulsion according to any one of claims 1 to 9, wherein the active substance is an astringent, said astringent being zinc sulfate.

11. Oil-in-water emulsion according to any one of claims 1 to 10, comprising 0.0005 to 10 0.1% in weight relative to the total weight of the emulsion of only one ammonium halide wherein said ammonium halide is cetalkonium halide, 1 to 5% (w/w) of an oil selected in a group comprising medium chain triglyceride, at least one active principle, 0.1 to 1% (w/w) of surfactants, additives selected in a group comprising antioxidants, tonicity, viscosifying, pH adjusting, buffering, solubilizing, preservative, and/or chelating or 15 thickener agents, and water.

12. Oil-in-water emulsion according to any one of claims 1 to 11, comprising 0.3 % of tyloxapol and optionally 0.1% of poloxamer 188.

13. Oil-in-water emulsion according to any one of claims 1 to 12, comprising 0.1 to 5% of mannitol. 20

14. Oil-in-water emulsion according to any one of claims 1 to 13, comprising 0.1 to 2.5% of glycerol.

15. Oil-in-water emulsion according to any one of claims 1 to 14, comprising 0.005% in weight relative to the total weight of the emulsion of cetalkonium chloride, 2% (w/w) of medium chain triglyceride, 0.05 to 0.1% (w/w) of cyclosporine A, 0.3% (w/w) of 25 tyloxapol, 2.25% (w/w) of glycerol, 0.1% (w/w) of poloxamer 188, and water qsp 100%.

16. Oil-in-water emulsion according to any one of claims 1 to 15, wherein said emulsion is dispensed to the patient in the form of a gel suitable for ophthalmic use.

17. Medicament for eye care or for the treatment of eye diseases or eye conditions comprising the oil-in-water emulsion according to any one of claims 1 to 16. 24

18. Use of an emulsion according to any one of claims 1 to 16, for the preparation of an ophthalmic composition for eye care or for the treatment of eye diseases or eye conditions, preferably dry eye conditions.

19. Use of an emulsion according to any one of claims 1 to 16, for the preparation of an 5 ophthalmic composition for dry eye accompanying lacrimal fluid reduction, tear deficiency, xerosis of the eye, Sjogren's syndrome, keratoconjunctivitis sicca (KCS), atopic keratoconjunctivitis sicca (AKC), vernal keratoconjunctivitis (VKC), Stevens Johnson syndrome, pemphigoid of the eye, marginal blepharitis, failure in eyelids closure, or sensory nerve numbness, dry eye accompanying allergic conjunctivitis, dry 10 eye after viral conjunctivitis, dry eye after cornea surgery including laser in situ keratomileusis (LASIK), dry eye after cataract surgery, dry eye associated with contact lens wearing, or dry eye associated with VDT tasks.

20. Oil-in-water emulsion according to any one of claims 1 to 16, packaged in unitary dose or in suitable multidose containers. 15

21. A method of treating eye diseases or eye conditions, preferably dry eye conditions comprising the step of administering to a subject in need thereof a therapeutically effective amount of an oil-in-water emulsion according to any one of claims 1 to 16.

22. A method of treating eye diseases or eye conditions selected from the group consisting of dry eye accompanying lacrimal fluid reduction, tear deficiency, xerosis of the eye, 20 Sjogren's syndrome, keratoconjunctivitis sicca (KCS), atopic keratoconjunctivitis sicca (AKC), vernal keratoconjunctivitis (VKC), Stevens-Johnson syndrome, pemphigoid of the eye, marginal blepharitis, failure in eyelids closure, or sensory nerve numbness, dry eye accompanying allergic conjunctivitis, dry eye after viral conjunctivitis, dry eye after cornea surgery including laser in situ keratomileusis (LASIK), dry eye after cataract 25 surgery, dry eye associated with contact lens wearing and dry eye associated with VDT tasks, comprising the step of administering to a subject in need thereof a therapeutically effective amount of an oil-in-water emulsion according to any one of claims 1 to 16. 30