Title of Invention	CATIONIC OPHTHALMIC OIL-IN WATER EMULSION CONTAINING PROSTAGLANDINS
Abstract	The present invention relates to cationic ophthalmic oil-in- water type emulsions, which comprise colloid particles having an oily core surrounded by an interfacial film, said emulsion comprising at least one cationic agent and at least one non ionic surfactant, said oily core comprising a prostaglandin selection from the group comprising in particular latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8- isoprostaglandinE2, or a mixture thereof, for treating ocular hypertension and/or glaucoma. These emulsions have the property to increase the chemical stability of prostaglandins.

Title of Invention

CATIONIC OPHTHALMIC OIL-IN WATER EMULSION CONTAINING PROSTAGLANDINS

Abstract

The present invention relates to cationic ophthalmic oil-in- water type emulsions, which comprise colloid particles having an oily core surrounded by an interfacial film, said emulsion comprising at least one cationic agent and at least one non ionic surfactant, said oily core comprising a prostaglandin selection from the group comprising in particular latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8- isoprostaglandinE2, or a mixture thereof, for treating ocular hypertension and/or glaucoma. These emulsions have the property to increase the chemical stability of prostaglandins.

Full Text	WO 2007/042262 PCT/EP2006/009783 OPHTHALMIC EMULSIONS CONTAINING PROSTAGLANDINS The present invention concerns ophthalmic cationic oil- in-water type emulsions containing prostaglandins. In the present invention, the term « prostaglandin » is indifferently used for prostaglandin, its precursors or analogs. The present invention is of particular interest for prostaglandin F2c analogs such as in particular latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandin E2 or a mixture of two or more thereof. By « ophthalmic it is meant an emulsion intended to be administered to the eye and which presents a pharmaceutical effect; preferably, it is topically applied. It is known to use prostaglandins in ophthalmic preparations in order to treat glaucoma. The problem encountered with prostaglandins, in particular with latanoprost, is that their concentration lowers in the formulation overtime. US6,011,062, US5,688,819, US5,849,792, US4,599,353 describe the use of several prostaglandin analogs for treating glaucoma and ocular hypertension. US5,849,792 discloses the use of a non ionic surfactant (polyethoxylated castor oil) to enhance the prostaglandin's chemical stability. However, the proposed solutions to enhance the stability of prostaglandins are not completely satisfactory. Furthermore, use of BAK or other quaternary ammonium as preservative agent for prostaglandins in ophthalmic preparations has been challenged, since C. Debbasch et al. in Investigative Ophthalmology & Visual Science, March 2001, Vol42 n°3, demonstrated important toxicity of long term use of BAK and/or other quaternary ammoniums. WO 2007/042262 PCT/EP2006/009783 - 2 - Latanoprost, Travoprost, Bimatoprost, unoprostone isopropyl, tafluprost, 8-isoprostaglandinE2, like most of the prostaglandin analogs, are almost insoluble in water. So, it is interesting to provide ophthalmic vehicles suitable for delivering hydrophobic drugs. In recent years, oil-in-water type emulsions, in particular emulsions having droplets of a submicron size (hereinafter "submicron emulsions") gained increasing importance. These emulsions are in general anionic emulsions. The major hurdle in developing topically applied ophthalmic drug delivery systems such as emulsions is the relatively low bioavailability of the drugs. To address this issue, cationic emulsions have been developed as topical ophthalmic vehicles; they have the advantage of increasing the bioavailability of the drugs by electrostatic attraction between the emulsions's positive charge and the negatives charges carried at the eye surface. However, stabilizing emulsions, including submicron emulsions, may be a concern for one skilled in the art. One known approach to stabilize an emulsion is to confer an electrostatic charge to the droplets surface which will result in droplet repulsion and less droplet coalescence. Colloidal particles dispersed in a solution are electrically charged due to their ionic characteristics and dipole attributes. This charge, which can be negative resulting in anionic emulsions or positive producing cationic emulsions (Klang et al., Pharm. Dev. Technology 2000, 5, 521-532) is known in the art as the "zeta potential". The zeta potential is a measure of the magnitude of the repulsion or attraction between particles (Washington, Adv. Drug Deliv. Reviews 1996, 20:131-145). Of particular interest are the following patents dealing with cationic emulsions for topical ocular administration: US Patent 6,007,826 discloses a cationic oil-in-water emulsion which comprises colloid particles with a positively WO 2007/042262 PCT/EP2006/009783 - 3 - charged interfacial film. The interfacial film is formed by cationic lipids (0.05-3% by weight) such as Cio-Cu primary alkylamines (disclosed are stearylamine or oleylamine), Ci0- C24 primary alkanolamine or a cholesterol betainate; phospholipids (0.5-3%) and non-ionic surfactants from the group consisting of poloxamers, tyloxapol, polysorbate, and polyoxyethylene fatty acid esters (0.05-3%). The concentration of the oily core is maintained within the 3-20% range. US Patent 6,007,826 emulsions zeta potential are not stable to thermal stress (see Tamilvanan et al., STP Pharma Sciences 2001, 11:421-426 and Example 12). Thus, there is still a need in ophthalmic prostaglandin products which are at least as efficient as the commercial products, which present an enhanced chemical stability of the prostaglandin, which are less toxic, which are more physically and chemically stable than conventional products, i.e. which are stable overtime and which present a good tolerability for the patient. By overtime in the meaning of this invention, it is meant a duration exceeding 1 year, preferably exceeding 2 years, more preferably exceeding 3 years. By "good tolerability" in the present the invention, it is understood that the ratio therapeutic benefit to ocular discomfort is acceptable by the patient, and preferably similar to a placebo or NaCl 0.9% solution. It is generally accepted that in order to show good ocular tolerability the cation content within the formulation should not exceed 0.1%, preferably not exceed 0.05% and even more preferably should not exceed 0.03%.. Quaternary amines such as benzalkonium chloride, benzododecinium bromide and benzethonium chloride are allowed by health authorities for ophthalmic administration up to concentration of WO 2007/042262 PCT/EP2006/009783 - A - approximately 0.03% (Furrer et al., Eur. J. Pharm. Biopharm. 2002, 53:263-280). This invention thus relates to a cationic ophthalmic oil- in-water type emulsion, which comprises colloid particles having an oily core surrounded by an interfacial film, said emulsion comprising at least one cationic agent and at least one non ionic surfactant selected from selected from the group consisting of poloxamers, tyloxapol, polysorbates, polyoxyethylene castor oil derivatives, sorbitan esters, polyoxyl stearates and a mixture of two or more thereof, said oily core comprising a drug selected from the group consisting of latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandin E2 or a mixture of two or more thereof, and said emulsion being free of water-soluble polymer selected from a polyvinyl compound, a water-soluble cellulose compound and a polysaccharide. In a prefered embodiment the emulsions of the invention includes latanoprost, as only drug or in combination with one or more prostaglandin selected from the group consisting of unoprostone isopropyl, travoprost, bimatoprost, tafluprost and 8-isoprostaglandin E2. According to a preferred embodiment, the emulsion of the invention is free of water-soluble polymer selected from (1) a polyvinyl compound such as polyvinylalcohol and polyvinylpyrrrolidone, (2) a water-soluble cellulose compound such as methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and/or sodium cellulose and (3) a polysaccharide selected from alginic acid, xanthan gum, carrageenan, and chitosan. According to an embodiment, the emulsion includes polyoxyethylene castor oil derivatives, especially polyethoxylated castor oil such as for example PEG PEG-30 PEG-35 PEG-50 castor oils. WO 2007/042262 PCT/EP2006/009783 - 5 - According to another embodiment, the emulsion is free of any polyoxyethylene castor oil derivatives. The term "free of" in combination with a compound or a list of compound, means that the emulsion does not contain any compound of that kind. According to a specific embodiment of the invention, the emulsion may further comprise an anti-inflammatory compound, preferably a non steroidal anti-inflammatory compound or a omega-3 fatty acid. Anti-inflammatory agents may be chosen in the group comprising COX-2 inhibitors, salicylates, 2- arylpropionic acids, N-arylanthranilic acids, oxicams, sulphonanilides, pyrazolidines derivatives, arylalkanoic acids, 3-benzolphenylacetic acids and derivatives; steroids such as cortisone, hydrocortisone, prednisone, prednisolone, methylprednisone, fluoromethalone, medrysone, betamethasone, loteprednol, flumethasone, mometasone, testosterone, methyltestosterone, danazol, beclomethasone, dexamethasone, dexamethasone palmitate, tramcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, difluprednate, rimexolone. In the emulsions of this invention, the chemical stability of prostaglandins is enhanced. Without being linked by any theory, it is believed that since the prostaglandin is solubilized in the oily core of the emulsion, it is less available to contact with agents enhancing its degradation. Said stability is defined as the extent to which a product retains, within specified limits and throughout its period of storage and use (i.e., its shelf life), the same properties and characteristics that it possessed at the time of manufacture. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies overtime under the influence of a variety of WO 2007/042262 PCT/EP2006/009783 - 6 - environmental factors such as temperature, humidity and light, and enables recommended storage conditions, re-test periods and shelf lives to be established. Although real-time stability studies include an evaluation of those factors that ultimately affect the expiration date of the drugs, they are time and cost- consuming. Conventionally, accelerated stability studies are used for predicting the shelf life of pharmaceutical products. Such accelerated studies subject the systems to a temperature of 40°C during 6 months. In order to understand the intrinsic stability mechanism of the molecule by establishing degradation pathways and identifying the likely degradation products, and thus to adjust the analytical procedures to be used, the Applicant has developed stress stability testing during which the emulsions are subjected to extreme conditions that is a temperature of 80°C during specified period of time. The amount of prostaglandins present in the oily core of the emulsion according to the invention depends on the nature of the prostaglandins and to the intended use. According to an embodiment, the amount of the drug(s) selected from the group comprising or consisting of latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8- isoprostaglandin E2 or a mixture of two or more thereof is of 0.001% to 1% w/w, preferably of 0.002% to 0.3% w/w and even more preferably of 0.004% to 0.15% w/w. In the present application, percentages are expressed in weight relative to the total weight of the emulsion (% w/w). The concentration of the cationic agent is comprised between 0.001 to 0.1% w/w, preferably between 0.002 to 0.05% w/w and even more preferably between 0.003 to 0.03%w/w. WO 2007/042262 PCT/EP2006/009783 - 7 - The concentration of the oily core is not higher than 7% w/w, preferably between 0.5 to 5% w/w and even more preferably between 1 to 3%w/w. The concentration of the non-ionic agent is less than 1% w/w, comprised preferably between 0.01 to 0.6% w/w. The cationic agent is selected in the group comprising or consisting of C10-C24 primary alkylamines, tertiary aliphatic amines, quaternary ammonium compounds selected from the group comprising benzalkonium halide, lauralkonium halide, cetrimide, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, behenalkonium halide, cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide, benzododecinium halide, chlorallyl methenamine halide, myristalkonium halide, stearalkonium halide or a mixture of two or more thereof, halide being preferably chloride or bromide, cationic lipids, amino alcohols, biguanide salts selected from the group comprising or consisting of chlorhexidine and salts thereof, polyaminopropyl biguanide, phenformin, alkylbiguanide or a mixture of two or more thereof, cationic compounds selected from 1, 2—dioleyl—3— trimethylammonium-propane, 1, 2—dioleoyl— sn-glycero— phosphatidylethanolamine, cationic glycosphingo- lipids or cationic cholesterol derivatives, or mixtures of two or more thereof. According to a specific embodiment of the invention, the emulsion does not contain chlorhexidine and salts thereof. According to a preferred embodiment, the cationic agent is selected from the group comprising benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzethenium chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide or a mixture of two or more thereof. According to a WO 2007/042262 PCT/EP2006/009783 - 8 - most preferred embodiment, the cationic agent included in the emulsion of the inventionis selected from at least one quaternary ammonium halide in which the nitrogen atom is substituted by at least one alkyl group having at least 14 carbon atoms. According to a specific embodiment of the invention, the emulsion contains benzalkonium halide as only cationic agent. The oily phase of the emulsion may comprise one or more components selected from the group comprising or consisting of vegetable oils (i.e. soybean oil, olive oil, sesame oil, cotton seed oil, castor oil, sweet almond oil), mineral oil (i.e. petrolatum and liquid paraffin), medium chain triglycerides (MCT) (i.e. a triglyceride oil in which the carbohydrate chain has about 8-12 carbon atoms), oily fatty acid, isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters, and in general any oily substance which is physiologically tolerated. According to an embodiment of the invention, the oil phase has a iodine value of less than 50, preferably equal or less than 15, more preferably equal or less than 5 and even more preferably equal or less than 1. In this embodiment;, the oil phase comprises one or more components selected from the group comprising or consisting of mineral oil such as for example petrolatum and liquid paraffin, and light mineral oil, medium chain triglycerides (MCT) which is generally defined as a triglyceride oil in which the carbohydrate chain has about 8-12 carbon atoms, coconut oil; hydrogenated oils comprising hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castor oil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oil derivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil or polyoxyl-100 hydrogenated castor WO 2007/042262 PCT/EP2006/009783 - 9 - oil. According to a preferred embodiment of the invention, the major component of the oily phase will be either vegetable oil, preferably with a iodine value of less than 50, and/or MCT. Fatty acids or fatty alcohols may be included in cases where the hydrophobic substance to be carried by the emulsion is not sufficiently soluble in the oily phase. Examples of MCT oil which may be used in emulsions of the present invention are TCM™ (Societe des Oleagineux, France), Miglyol 812™ (Dynamit Novel, Sweden). The non-ionic surfactant is selected from the group comprising or consisting of poloxamers, tyloxapol, polysorbates, polyoxyethylene castor oil derivatives, sorbitan esters, polyoxyl stearates and a mixture of two or more thereof. According to another preferred embodiment of the invention, rhe cationic ophthalmic emulsion comprises benzalkonium chloride as cationic agent and tyloxapol as non- ionic surfactant. According to still another preferred embodiment, the emulsion contains benzalkonium chloride as cationic agent and a combination of tyloxapol and poloxamer as non-ionic surfactants. The emulsion may also contain antioxidant such as Vitamin E, isotonic agent, buffering agent, preservative, etc. According to an embodiment of the invention, the emulsion includes at least one preservative. According to another embodiment of the invention, the emulsion does not contain any preservative. The colloidal particles of the emulsions according to the invention have an average particle size of equal or less than WO 2007/042262 PCT/EP2006/009783 - 10 - 1 um, advantageously equal or less than 300 nm, more advantageously in the range of 100 to 250 nm. The emulsion of the invention may be conditionned in monodosis containers or in multidosis containers. According to an embodiment, the containers for carrying the emulsion of the invention are made of glass, plastic materials, resins or the like. According to another embodiment of the invention, the cationic ophthalmic emulsion may comprise a further pharmaceutically active substance, either in the oily core or in the aqueous part of the emulsion. This pharmaceutically active substance may be an antiglaucomateous active substance, which may be selected from the group comprising beta-blockers such as levobunolol, befundol, metipranolol, forskolin, cartrolol, timolol; inhibitors of carbonic anhydrase such as brinzolamide, dorzolamide, acetazolamide, methazolamide, dichlorophenamide; sympathomimetics such as brimonidine, apraclonidine, dipivefrine, epinephrine; parasympathomimetics such as pilocarpine; cholinesterase inhibitors such as physostigmine, echothiophate and/or their derivatives; and/or optically acceptable salts thereof. The emulsions according to the invention are physically stable overtime as defined hereabove and keep a positive zeta potential in the specific measurement conditions as described in Tests A, B, C and/or D. According to the invention, the emulsions do not contain a sufficient amount of any substances susceptible of affecting the zeta potential overtime. Advantageously, the emulsions of the invention do not contain phospholipids. Substances susceptible of affecting the zeta potential may be phospholipids, and any substances which become negatively charged upon storage. The amount of substances affecting the zeta potential WO 2007/042262 PCT/EP2006/009783 - 11 - overtime must be such that at any time, the amount of positive charge is above the amount of negative charges. Zeta potential Zeta potential measures a physical property which is exhibited by any particle in suspension. Zeta potential can be used to predict behaviour of the suspension in different environments, to optimize the formulations of suspensions and emulsions as well as to predict overtime stability. In order to avoid the emulsion droplets to adhere to one another and form aggregates of successively increasing size, it is necessary to confer repulsive forces to the particles. One of the means to confer repulsive forces to a colloidal system is by electrostatic or charge stabilization. Electrostatic or charge stabilization has the benefits of stabilizing a system by simply altering the concentration of ions in the system. This is a reversible and inexpensive process. There might by many origins of this surface charge depending upon the nature of the particle and its surrounding medium but the most important mechanisms are the ionisation of surface groups or the adsorption of charged ions. The interaction of particles in polar liquids is not governed by the electrical potential at the surface of the particle, but by the effective potential of the particle and its associated ions. To utilize electrostatic control of dispersions, it is the zeta potential of the particle that must be measured rather than its surface charge. Charged particles will attract ions of opposite charge in the dispersant. Ions close to the surface are strongly bound; those further away form a more diffuse region. Within this region is a notional boundary, known as the slipping plane, within which the particle and ions act as a single entity. WO 2007/042262 PCT/EP2006/009783 - 12 - The potential at the slipping plane is known as the zeta potential. It has long been recognised that the zeta potential is a very good index of the magnitude of the interaction between colloidal particles and measurements of zeta potential are commonly used to assess the stability of colloidal systems. The zeta potential measured in a particular system is dependent on the chemistry of the surface, and also of the way it interacts with its surrounding environment. Therefore zeta potential must always be studied in a well defined environment (specifically pH and ionic strength). Electrophoretic mobility An important conseguence of the existence of electrical charges on the surface of particles is that they interact with an applied electric field. These effects are collectively defined as electrokinetic effects. If the motion is induced in a particle suspended in a liquid under the influence of an applied electric field, it is more specifically named electrophoresis. When an electric field is applied across an electrolyte, charged particles suspended in the electrolyte are attracted towards the electrode of opposite charge. Viscous forces acting on the particles tend to oppose this movement. When equilibrium is reached between these two opposing forces, the particles move with constant velocity. The velocity is dependent on the strength of electric field or voltage gradient, the dielectric constant of the medium, the viscosity of the medium and the zeta potential. The velocity of a particle in a unit electric field is referred to as its electrophoretic mobility. Zeta potential is related to the electrophoretic mobility by the Henry equation: WO 2007/042262 PCT/EP2006/009783 - 13 - where UE = electrophoretic mobility, z= zeta potential, e = dielectric constant, r\|= viscosity and f (xa) =Henry' s function. Electrophoretic determinations of zeta potential are most commonly made in aqueous media and moderate electrolyte concentration. f(Ka) in this case is 1.5, and this is referred to as the Smoluchowski approximation. Therefore calculation of zeta potential from the mobility is straightforward for systems that fit the Smoluchowski model, i.e. particles larger than about 0.2 microns dispersed in electrolytes containing more that 10-3 molar salt. For small particles in low dielectric constant media (eg non-aqueous media), f(Ka) becomes 1.0 and allows an equally simple calculation. This is referred to as the Huckel approximation. Tests A, B, C and D Test A consists in measuring the stability of the emulsion zeta potential under thermal stress conditions. Zeta potential of the emulsion is measured at T=0, i.e. as soon as the emulsion has been prepared, the obtained value being named Zo. Glass vials (Type I) of 10ml effective capacity containing between 5-10ml of emulsion and sealed under nitrogen atmosphere (without bubbling) are stored at 80°C. Then at T=15 hours the zeta potential Zi5h is measured. The value SA = Zi5h-Z0 is then calculated. For each measurement of the zeta potential, it is operated as follows: The zeta potential of the emulsion droplet surface is determined by electrophoretic mobility in an apparatus such WO 2007/042262 PCT/EP2006/009783 - 14 - as a Malvern Zetasizer 2000 (Malvern Instruments, UK) equipped with suitable software and calibrated with the supplied standard. The emulsion is diluted in double distilled water if needed in order to obtain the scattering intensity allowing optimal particle detection. The sample count rate should be between 100 to 1000 KCps, in homodyne detection (if heterodyne detection is used, the contribution of the reference beam should be deduced). Three consecutive measurements are performed at 25°C using a constant cell drive of 150mV. The electrophoretic mobility is converted into zeta potential values through the Smoluchowsky equation, using the dielectric constants and viscosity of water. The measured value corresponds to the average of the 3 obtained values. It is considered that the emulsion meets zeta potential stability Test A if 5A is less than the standard error of measurements, preferably less than lOmV, and even more preferably less than 5mV. According to an advantageous embodiment, the ophthalmic emulsion according to the invention meets zeta potential stability Test B. Test B is similar to Test A except that the emulsion is stored during 48 hours at 80°C, the zeta potential Z2 is measured on day 2 and 5B = Z2 -Zo is calculated. The emulsion is considered as meeting the requirements of zeta potential stability test B if 5B is less than the standard error of measurements, preferably less than lOmV, and even more preferably less than 5mV. According to a more advantageous embodiment of the invention, the ophthalmic emulsion according to the invention meets zeta potential stability Test C. WO 2007/042262 PCT/EP2006/009783 - 15 - Test C is similar to Test A except that the emulsion is stored during 7 days at 80°C, the zeta potential Z7 is measured on day 7 and 8C = Z7 -Zo is calculated. The emulsion is considered as meeting the requirements of zeta potential stability test C if 5C is less than the standard error of measurements, preferably less than lOmV, and even more preferably less than 5mV. According to a still more advantageous embodiment of the invention, the ophthalmic emulsion according to the invention meets zeta potential stability Test D. Test D is similar to Test A except that the emulsion is stored during 14 days at 80°C, the zeta potential Z14 is measured on day 14 and 8D = zi4 -z0 is calculated. The emulsion is considered as meeting the requirements of zeta potential stability test D if 5D is less than the standard error of measurements, preferably less than lOmV, and even more preferably less than 5mV. According to another aspect, the invention relates to a process for manufacturing the emulsions here-above described. The emulsions are prepared as follows: - the prostaglandin is dissolved into the oily phase, which is optionally added with another hydrophobic ophthalmologically active ingredient, - the aqueous phase , optionally added with another hydrophilic ophthalmologically active ingredient, is rapidly added to the oily phase, - the coarse emulsion obtained is rapidly heated, preferably at 75°C, - the emulsion droplet size is then decreased by any suitable means known by one skilled in the art, for example by shear mixing, WO 2007/042262 PCT/EP2006/009783 - 16 - - the emulsion temperature is cooled down to 20°C using an ice bath and then homogenized - pH is adjusted to 7-8, - the emulsion is sterilized. The inventions also relates to the use of a cationic ophthalmic oil-in-water emulsion as hereabove described for the preparation of an ophthalmic composition for treating ocular hypertension and/or for treating glaucoma. According to another aspect, the invention relates to ophthalmic formulation comprising an emulsion as previously described, optionally in combination with an ophthalmologically acceptable carrier, in the form of eye drops, eye ointment, ophthalmic gel. In said ophthalmic formulation there may be a pharmaceutically effective amount of an active ingredient in or within the ophthalmologically acceptable carrier. The invention is also directed to a delivery device selected from the group comprising lenses, ocular patch, implant, insert, said device containing an emulsion as previously described. The invention is further illustrated by the examples below. EXAMPLES In the following examples, the following abbreviations are used: Medium Chain Triglycerides MCT: TCM™ (Societe des Oleagineux) BAK: benzalkonium chloride (FeF Chemicals , Denmark) Lutrol: Lutrol F68™ (BASF) Tyloxapol : Triton WR1339 (Ruger Chemicals , USA) WO 2007/042262 PCT/EP2006/009783 - 17 - Z29 : latanoprost Example 1 Emulsion Composition Z29EM002 1%MCT 0.1 % Lipoid 0.05% OA 0.005% vit E 0.25% Lutrol 2.25% Glycerin Water to 100% Z29 0.005% Z29EM003 1%MCT 0.1%Tyloxapol 0.05% OA 0.005% vit E 0.25% Lutrol 2.25% Glycerin Water to 100% Z29 0.005% Z29EM005 0.02% BAK 1 % MCT 0.16%Tyloxapol 0.01% vit E 0.25% Lutrol 2.25% Glycerin Water to 100% Z29 0.005% Z29EM007 0.02% BAK 1%MCT 0.3% Tyloxapol 0.01% vit E 0.1% Lutrol 2.25% Glycerin Water to 100% Z29 0.005% Zeta potential stress test TO: 22.4 T7:24.1 T15: 19.8 TO: 21.8 T7: 18.8 T15: 18.9 Droplet size (nm) stress test TO: 160 T7: 173 T15:185 TO: 212 T7: 225 T15:236 Emulsion Composition Z29EM008 0.02% BAK 1%MCT 0.3% Tyloxapol 0.1% Lutrol 2.25% Glycerin Water to 100% Z29 0.005% Z29EM011 0.01% BAK 1%MCT 0.3% Tyloxapol 0.1 % Lutrol 2.25% Glycerin Water to 100% Z29 0.005% Zeta potential stress test TO: 20.6 T7: 18.5 T15: 16.2 Droplet size stress test TO: 201 T7: 212 T15:216 The oily phase components including 0.005% latanoprost (named Z29 in the Tables) were successively weighed in the same beaker and then magnetically stirred under a slight heating (40°C) until a slightly viscous phase is obtained. Aqueous WO 2007/042262 PCT/EP2006/009783 - 18 - phase components were successively weighed in the same beaker and then magnetically stirred under a slight heating (40°C) until a transparent, limpid and fluid phase is obtained. Both phases were heated to 65°C. The coarse emulsion was formed by rapid addition of the aqueous phase in the oily phase and was then rapidly heated to 75°C. The aqueous phase and coarse emulsion beakers were protected by a film to avoid any water evaporation. The emulsion was white and slightly transparent. The emulsion droplet size was then decreased by a 5 minutes high shear mixing with a POLYTRON PT 6100. The emulsion became milky. The emulsion temperature was cooled down to 20°C using an ice bath. The final emulsion was obtained by homogenization in a microfluidizer (C5, Avestin) using continuous cycles for 5 min at a pressure of 10,000 psi. The emulsion was milky, very fluid and did not adhere on the glass. The emulsion temperature was decreased to 25°C. Its pH was measured and then adjusted to 7.0 using a 0.1 M HC1 or 0.1 M NaOH solution. Emulsion was conditioned in glass vials with nitrogen bubbling and then sterilized in an autoclave 20 minutes at 121°C. The mean particle size of the emulsions droplets was determined by quasi-elastic light scattering after dilution in water using a High Performance Particle Sizer (Malvern Instruments, UK). The electrophoretic mobility was measured at 25°C in a Malvern Zetasizer 2000 (Malvern Instruments, UK) following a 1:200 dilution in double distilled water as detailed above and converted into zeta potential through the Smoluchowski equation. WO 2007/042262 PCT/EP2006/009783 - 19 - Example 2 Latanoprost stability improvement in emulsion compared to commercial product (Xalatan®) The chemical stability of latanoprost within the emulsion was compared to the commercial product Xalatan® at 80°C for 14 days (figure 1). Prostaglandin contents were analysed by an HPLC-UV method. In emulsions according to the invention, latanoprost is chemically stabilized. Example 3: In vivo studies demonstrating that latanoprost emulsion is as efficient as the commercial product (Xalatan®) in reducing IOP (intraocular pressure) Methods: Eight adult female cynomolgus monkeys, each weighing 3-6 kg, in which glaucoma had been induced by diode laser photocoagulation of the mid-trabecular meshwork, were used in SUBSTITUTE SHEET (RULE 26) WO 2007/042262 PCT/EP2006/009783 - 20 - this study. Intraocular pressure (IOP) was measured at 0 hr (before drug administration) and then hourly until 6 hrs after drug administration for one baseline day, one vehicle - treated day, and treatment days 1,3, and 5 with 30/zl of Z29EM007 (similar to the emulsion described in Example 1) or 0.005% Latanoprost (Xalatan; Pharmarcia & Upjohn, Kalamazoo, MI) . The products were topically applied to the glaucomatous eye once daily for 5 consecutive days in a crossover design with a washout period at least 2 weeks between the two drugs. Results: Once daily administration of both Z2 9EM007 and Xalatan for 5 days significantly (p hr to 5 hrs after the first dose compared to the vehicle treatment day (figure 2). The ocular hypotensive effect was enhanced by repeated dosing for both Z29EM007 and Xalatan. No statistical difference of IOP reduction (p> 0.80) was observed during the 5 days treatment when comparing Z2 9EM007 and Xalatan. IOP on the baseline day and vehicle-treated day was not statistically different between the two drugs (p>0.90). Latanoprost in the emulsions according to the invention is as efficient as commercially available Xalatan™' SUBSTITUTE SHEET (RULE 26) WO 2007/042262 PCT/EP2006/009783 - 21 - CLAIMS l.A cationic ophthalmic oil-in-water type emulsion, which comprises colloid particles having an oily core surrounded by an interfacial film, said emulsion comprising at least one cationic agent and at least one non ionic surfactant selected from the group consisting of poloxamers, tyloxapol, polysorbates, polyoxyethylene castor oil derivatives, s.orbitan esters, polyoxyl stearates and a mixture of two or more thereof, said oily core comprising a drug selected from the group consisting of latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandin E2 or a mixture of two or more thereof said emulsion being free of water-soluble polymer selected from a polyvinyl compound, a water-soluble cellulose compound and a polysaccharide. 2.A cationic ophthalmic oil-in-water type emulsion according to claim 1, wherein the drug is latanoprost. 3.A cationic ophthalmic oil-in-water type emulsion according to any of claims 1 or 2, said emulsion being free of water-soluble polymer selected from (1) a polyvinyl compound such as polyvinylalcohol and polyvinylpyrrrolidone, (2) a water-soluble cellulose compound such as methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and/or sodium cellulose and (3) a polysaccharide selected from alginic acid, xanthan gum, carrageenan, and chitosan. 4. A cationic ophthalmic emulsion according to anyone of claims 1 to 3, comprising at least one further pharmaceutically active substance, either in the oily core or in the agueous part of the emulsion. WO 2007/042262 PCT/EP2006/009783 - 22 - 5. A cationic ophtalmic oil-in-water type emulsion according to any of claims 1 to 4, further comprising an anti-inflanunatory compound, preferably a non steroidal anti-inflammatory compound or a omega-3 fatty acid. 6. A cationic ophtalmic oil-in-water type emulsion according to any of claims 1 to 4, wherein the emulsion further comprise at least one further antiglaucomateous pharmaceutically active substance selected from the group comprising beta-blockers such as levobunolol, befundol,forskolin, metipranolol, cartrolol, timolol; inhibitors of carbonic anhydrase such as brinzolamide, dorzolamide, acetazolamide, methazolamide, dichlorophenamide; sympathomimetics such as brimonidine, apraclonidine, dipivefrine, epinephrine; parasympathomimetics such as pilocarpine; cholinesterase inhibitors such as physostigmine, echothiophate and/or their derivatives; and/or optically acceptable salts thereof. 7. A cationic ophthalmic oil-in-water type emulsion according to anyone of claims 1 to 6, wherein the amount of the drug selected from the group consisting of latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandin E2 or a mixture of two or more thereof in the oily core is 0.001 to 1% w/w, preferably 0.002 to 0.3% w/w and even more preferably 0.004 to 0.15% w/w. 8.A cationic ophthalmic oil-in-water type emulsion according to anyone of claims 1 to 7, wherein the concentration of the cationic agent is comprised between 0.001 to 0.1% w/w, preferably between 0.002 to 0.05% w/w and even more preferably between 0.003 to 0.03%w/w. 9.A cationic ophthalmic oil-in-water type emulsion according to anyone of claims 1 to 8, wherein the WO 2007/042262 PCT/EP2006/009783 - 23 - concentration of the oily core is not higher than 7% w/w, preferably between 0.5 to 5% w/w and even more preferably between 1 to 3%w/w. 10. A cationic ophthalmic emulsion according to anyone of claims 1 to 9, wherein the concentration of the non-ionic agent is less than 1% w/w, comprised preferably from 0.01 to 0.6% w/w. 11. A cationic ophthalmic oil-in-water emulsion according to anyone of claims 1 to 10, wherein the cationic agent is selected in the group consisting of C10-C24 primary alkylamines, tertiary aliphatic amines, quaternary ammonium compounds, cationic lipids, amino alcohols, biguanide salts, cationic compounds and a mixture of two or more thereof. 12. A cationic ophthalmic oil-in-water emulsion according to claim 11, wherein the biguanide salt is selected from the group comprising chlorhexidine and salts thereof, polyaminopropyl biguanide, phenformin, alkylbiguanide or a mixture of two or more thereof. 13. A cationic ophthalmic oil-in-water emulsion according to claim 11, wherein the quaternary ammonium compound is selected from the group comprising benzalkonium halide, lauralkonium halide, cetrimide, hexadecyltrimethy1ammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, behenalkonium halide, cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide, benzododecinium halide, chlorallyl methenamine halide, myristylalkonium halide, stearalkonium halide or a mixture of two or more thereof, halide being preferably chloride or bromide. WO 2007/042262 PCT/EP2006/009783 - 24 - 14. A cationic ophthalmic emulsion according to anyone of claims 1 to 10, wherein said cationic agent is selected from the group comprising benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzethenium chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide or a mixture of two or more thereof. 15. A cationic ophthalmic emulsion according to anyone of claims 1 to 10, wherein the cationic agent is selected from at least one quaternary ammonium halide in which the nitrogen atom is substituted by at least one alkyl group having at least 14 carbon atoms. 16. A cationic ophthalmic emulsion according to anyone of claims 1 to 15, wherein the oil phase has a iodine value of less than 50, preferably equal or less than 15, more preferably equal or less than 5 and even more preferably equal or less than 1. 17. A cationic ophthalmic emulsion according to claim 16, wherein the oil phase comprises one or more components selected from the group consisting of mineral oil and light mineral oil, medium chain triglycerides (MCT), coconut oil; hydrogenated oils comprising hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castor oil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oil derivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl- 60 hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil. 18. A cationic ophthalmic emulsion according to anyone of claims 1 to 17, wherein the oil is MCT. 19. A cationic ophthalmic emulsion according to anyone of claims 1 to 18, comprising benzalkonium WO 2007/042262 PCT/EP2006/009783 - 25 - chloride as cationic agent and tyloxapol as non-ionic surfactant. 20. A cationic ophthalmic emulsion according to anyone of claims 1 to 19, wherein the emulsion contains benzalkonium chloride as cationic agent and a combination of tyloxapol and poloxamer. 21. A cationic ophthalmic emulsion according to anyone of claims 1 to 20, wherein said colloidal particles have an average particle size of equal or less than 1 um, advantageously equal or less than 300 nm, more advantageously in the range of 100 to 250 nm. 22. A cationic ophthalmic oil-in-water type emulsion according to anyone of claims 1 to 21, wherein the emulsion meets zeta potential stability Test A requirements. 23. An ophthalmic emulsion according to anyone of claims 1 to 21, which meets zeta potential stability Test B requirements. 24. An ophthalmic emulsion according to anyone of claims 1 to 21, which meets zeta potential stability Test C requirements. 25. An ophthalmic emulsion according to anyone of claims 1 to 21, which meets zeta potential stability Test D requirements. 26. Use of a cationic ophthalmic oil-in-water emulsion according to any one of claims 1 to 25, for the preparation of an ophthalmic composition for treating ocular hypertension and/or for treating glaucoma. 27. Ophthalmic formulation comprising an emulsion according to any of claims 1 to 25, optionally in combination with an ophthalmologically acceptable carrier, said formulation being in the form of eye drops, eye ointment, ophthalmic gel. WO 2007/042262 PCT/EP2006/009783 - 26 - 28. Delivery device selected from the group comprising lenses, ocular patch, implant, insert, said device containing an emulsion according to anyone of claims 1 to 25. The present invention relates to cationic ophthalmic oil-in- water type emulsions, which comprise colloid particles having an oily core surrounded by an interfacial film, said emulsion comprising at least one cationic agent and at least one non ionic surfactant, said oily core comprising a prostaglandin selection from the group comprising in particular latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8- isoprostaglandinE2, or a mixture thereof, for treating ocular hypertension and/or glaucoma. These emulsions have the property to increase the chemical stability of prostaglandins.

Full Text

WO 2007/042262 PCT/EP2006/009783
OPHTHALMIC EMULSIONS CONTAINING PROSTAGLANDINS
The present invention concerns ophthalmic cationic oil-
in-water type emulsions containing prostaglandins.
In the present invention, the term « prostaglandin » is
indifferently used for prostaglandin, its precursors or
analogs.
The present invention is of particular interest for
prostaglandin F2c analogs such as in particular latanoprost,
unoprostone isopropyl, travoprost, bimatoprost, tafluprost,
8-isoprostaglandin E2 or a mixture of two or more thereof.
By « ophthalmic it is meant an emulsion intended to be
administered to the eye and which presents a pharmaceutical
effect; preferably, it is topically applied.
It is known to use prostaglandins in ophthalmic
preparations in order to treat glaucoma. The problem
encountered with prostaglandins, in particular with
latanoprost, is that their concentration lowers in the
formulation overtime.
US6,011,062, US5,688,819, US5,849,792, US4,599,353
describe the use of several prostaglandin analogs for
treating glaucoma and ocular hypertension. US5,849,792
discloses the use of a non ionic surfactant (polyethoxylated
castor oil) to enhance the prostaglandin's chemical
stability.
However, the proposed solutions to enhance the stability
of prostaglandins are not completely satisfactory.
Furthermore, use of BAK or other quaternary ammonium as
preservative agent for prostaglandins in ophthalmic
preparations has been challenged, since C. Debbasch et al. in
Investigative Ophthalmology & Visual Science, March 2001,
Vol42 n°3, demonstrated important toxicity of long term use
of BAK and/or other quaternary ammoniums.

WO 2007/042262 PCT/EP2006/009783
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Latanoprost, Travoprost, Bimatoprost, unoprostone
isopropyl, tafluprost, 8-isoprostaglandinE2, like most of the
prostaglandin analogs, are almost insoluble in water. So, it
is interesting to provide ophthalmic vehicles suitable for
delivering hydrophobic drugs. In recent years, oil-in-water
type emulsions, in particular emulsions having droplets of a
submicron size (hereinafter "submicron emulsions") gained
increasing importance. These emulsions are in general anionic
emulsions. The major hurdle in developing topically applied
ophthalmic drug delivery systems such as emulsions is the
relatively low bioavailability of the drugs. To address this
issue, cationic emulsions have been developed as topical
ophthalmic vehicles; they have the advantage of increasing
the bioavailability of the drugs by electrostatic attraction
between the emulsions's positive charge and the negatives
charges carried at the eye surface. However, stabilizing
emulsions, including submicron emulsions, may be a concern
for one skilled in the art. One known approach to stabilize
an emulsion is to confer an electrostatic charge to the
droplets surface which will result in droplet repulsion and
less droplet coalescence. Colloidal particles dispersed in a
solution are electrically charged due to their ionic
characteristics and dipole attributes. This charge, which can
be negative resulting in anionic emulsions or positive
producing cationic emulsions (Klang et al., Pharm. Dev.
Technology 2000, 5, 521-532) is known in the art as the "zeta
potential". The zeta potential is a measure of the magnitude
of the repulsion or attraction between particles (Washington,
Adv. Drug Deliv. Reviews 1996, 20:131-145).
Of particular interest are the following patents dealing
with cationic emulsions for topical ocular administration:
US Patent 6,007,826 discloses a cationic oil-in-water
emulsion which comprises colloid particles with a positively

WO 2007/042262 PCT/EP2006/009783
- 3 -
charged interfacial film. The interfacial film is formed by
cationic lipids (0.05-3% by weight) such as Cio-Cu primary
alkylamines (disclosed are stearylamine or oleylamine), Ci0-
C24 primary alkanolamine or a cholesterol betainate;
phospholipids (0.5-3%) and non-ionic surfactants from the
group consisting of poloxamers, tyloxapol, polysorbate, and
polyoxyethylene fatty acid esters (0.05-3%). The
concentration of the oily core is maintained within the 3-20%
range.
US Patent 6,007,826 emulsions zeta potential are not
stable to thermal stress (see Tamilvanan et al., STP Pharma
Sciences 2001, 11:421-426 and Example 12).
Thus, there is still a need in ophthalmic prostaglandin
products which are at least as efficient as the commercial
products, which present an enhanced chemical stability of the
prostaglandin, which are less toxic, which are more
physically and chemically stable than conventional products,
i.e. which are stable overtime and which present a good
tolerability for the patient.
By overtime in the meaning of this invention, it is
meant a duration exceeding 1 year, preferably exceeding 2
years, more preferably exceeding 3 years.
By "good tolerability" in the present the invention, it
is understood that the ratio therapeutic benefit to ocular
discomfort is acceptable by the patient, and preferably
similar to a placebo or NaCl 0.9% solution.
It is generally accepted that in order to show good ocular
tolerability the cation content within the formulation should
not exceed 0.1%, preferably not exceed 0.05% and even more
preferably should not exceed 0.03%.. Quaternary amines such
as benzalkonium chloride, benzododecinium bromide and
benzethonium chloride are allowed by health authorities for
ophthalmic administration up to concentration of

WO 2007/042262 PCT/EP2006/009783
- A -
approximately 0.03% (Furrer et al., Eur. J. Pharm. Biopharm.
2002, 53:263-280).
This invention thus relates to a cationic ophthalmic oil-
in-water type emulsion, which comprises colloid particles
having an oily core surrounded by an interfacial film,
said emulsion comprising at least one cationic agent and
at least one non ionic surfactant selected from selected from
the group consisting of poloxamers, tyloxapol, polysorbates,
polyoxyethylene castor oil derivatives, sorbitan esters,
polyoxyl stearates and a mixture of two or more thereof, said
oily core comprising a drug selected from the group
consisting of latanoprost, unoprostone isopropyl, travoprost,
bimatoprost, tafluprost, 8-isoprostaglandin E2 or a mixture
of two or more thereof, and said emulsion being free of
water-soluble polymer selected from a polyvinyl compound, a
water-soluble cellulose compound and a polysaccharide.
In a prefered embodiment the emulsions of the invention
includes latanoprost, as only drug or in combination with one
or more prostaglandin selected from the group consisting of
unoprostone isopropyl, travoprost, bimatoprost, tafluprost
and 8-isoprostaglandin E2.
According to a preferred embodiment, the emulsion of the
invention is free of water-soluble polymer selected from (1)
a polyvinyl compound such as polyvinylalcohol and
polyvinylpyrrrolidone, (2) a water-soluble cellulose compound
such as methylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose, and/or sodium cellulose and (3)
a polysaccharide selected from alginic acid, xanthan gum,
carrageenan, and chitosan.
According to an embodiment, the emulsion includes
polyoxyethylene castor oil derivatives, especially
polyethoxylated castor oil such as for example PEG PEG-30
PEG-35 PEG-50 castor oils.

WO 2007/042262 PCT/EP2006/009783
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According to another embodiment, the emulsion is free of
any polyoxyethylene castor oil derivatives.
The term "free of" in combination with a compound or a
list of compound, means that the emulsion does not contain
any compound of that kind.
According to a specific embodiment of the invention, the
emulsion may further comprise an anti-inflammatory compound,
preferably a non steroidal anti-inflammatory compound or a
omega-3 fatty acid. Anti-inflammatory agents may be chosen in
the group comprising COX-2 inhibitors, salicylates, 2-
arylpropionic acids, N-arylanthranilic acids, oxicams,
sulphonanilides, pyrazolidines derivatives, arylalkanoic
acids, 3-benzolphenylacetic acids and derivatives; steroids
such as cortisone, hydrocortisone, prednisone, prednisolone,
methylprednisone, fluoromethalone, medrysone, betamethasone,
loteprednol, flumethasone, mometasone, testosterone,
methyltestosterone, danazol, beclomethasone, dexamethasone,
dexamethasone palmitate, tramcinolone, triamcinolone
acetonide, fluocinolone, fluocinolone acetonide,
difluprednate, rimexolone.
In the emulsions of this invention, the chemical
stability of prostaglandins is enhanced. Without being linked
by any theory, it is believed that since the prostaglandin is
solubilized in the oily core of the emulsion, it is less
available to contact with agents enhancing its degradation.
Said stability is defined as the extent to which a product
retains, within specified limits and throughout its period of
storage and use (i.e., its shelf life), the same properties
and characteristics that it possessed at the time of
manufacture. The purpose of stability testing is to provide
evidence on how the quality of a drug substance or drug
product varies overtime under the influence of a variety of

WO 2007/042262 PCT/EP2006/009783
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environmental factors such as temperature, humidity and
light, and enables recommended storage conditions, re-test
periods and shelf lives to be established.
Although real-time stability studies include an
evaluation of those factors that ultimately affect the
expiration date of the drugs, they are time and cost-
consuming. Conventionally, accelerated stability studies are
used for predicting the shelf life of pharmaceutical
products. Such accelerated studies subject the systems to a
temperature of 40°C during 6 months.
In order to understand the intrinsic stability mechanism
of the molecule by establishing degradation pathways and
identifying the likely degradation products, and thus to
adjust the analytical procedures to be used, the Applicant
has developed stress stability testing during which the
emulsions are subjected to extreme conditions that is a
temperature of 80°C during specified period of time.
The amount of prostaglandins present in the oily core of the
emulsion according to the invention depends on the nature of
the prostaglandins and to the intended use. According to an
embodiment, the amount of the drug(s) selected from the group
comprising or consisting of latanoprost, unoprostone
isopropyl, travoprost, bimatoprost, tafluprost, 8-
isoprostaglandin E2 or a mixture of two or more thereof is of
0.001% to 1% w/w, preferably of 0.002% to 0.3% w/w and even
more preferably of 0.004% to 0.15% w/w.
In the present application, percentages are expressed in
weight relative to the total weight of the emulsion (% w/w).
The concentration of the cationic agent is comprised
between 0.001 to 0.1% w/w, preferably between 0.002 to 0.05%
w/w and even more preferably between 0.003 to 0.03%w/w.

WO 2007/042262 PCT/EP2006/009783
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The concentration of the oily core is not higher than 7%
w/w, preferably between 0.5 to 5% w/w and even more
preferably between 1 to 3%w/w.
The concentration of the non-ionic agent is less than 1%
w/w, comprised preferably between 0.01 to 0.6% w/w.
The cationic agent is selected in the group comprising or
consisting of C10-C24 primary alkylamines, tertiary aliphatic
amines, quaternary ammonium compounds selected from the group
comprising benzalkonium halide, lauralkonium halide,
cetrimide, hexadecyltrimethylammonium halide,
tetradecyltrimethylammonium halide, dodecyltrimethylammonium
halide, cetrimonium halide, benzethonium halide,
behenalkonium halide, cetalkonium halide, cetethyldimonium
halide, cetylpyridinium halide, benzododecinium halide,
chlorallyl methenamine halide, myristalkonium halide,
stearalkonium halide or a mixture of two or more thereof,
halide being preferably chloride or bromide, cationic lipids,
amino alcohols, biguanide salts selected from the group
comprising or consisting of chlorhexidine and salts thereof,
polyaminopropyl biguanide, phenformin, alkylbiguanide or a
mixture of two or more thereof, cationic compounds selected
from 1, 2—dioleyl—3— trimethylammonium-propane, 1, 2—dioleoyl—
sn-glycero— phosphatidylethanolamine, cationic glycosphingo-
lipids or cationic cholesterol derivatives, or mixtures of
two or more thereof.
According to a specific embodiment of the invention, the
emulsion does not contain chlorhexidine and salts thereof.
According to a preferred embodiment, the cationic agent is
selected from the group comprising benzalkonium chloride,
lauralkonium chloride, benzododecinium bromide, benzethenium
chloride, hexadecyltrimethylammonium bromide,
tetradecyltrimethylammonium bromide, dodecyltrimethylammonium
bromide or a mixture of two or more thereof. According to a

WO 2007/042262 PCT/EP2006/009783
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most preferred embodiment, the cationic agent included in the
emulsion of the inventionis selected from at least one
quaternary ammonium halide in which the nitrogen atom is
substituted by at least one alkyl group having at least 14
carbon atoms. According to a specific embodiment of the
invention, the emulsion contains benzalkonium halide as only
cationic agent.
The oily phase of the emulsion may comprise one or more
components selected from the group comprising or consisting
of vegetable oils (i.e. soybean oil, olive oil, sesame oil,
cotton seed oil, castor oil, sweet almond oil), mineral oil
(i.e. petrolatum and liquid paraffin), medium chain
triglycerides (MCT) (i.e. a triglyceride oil in which the
carbohydrate chain has about 8-12 carbon atoms), oily fatty
acid, isopropyl myristate, oily fatty alcohols, esters of
sorbitol and fatty acids, oily sucrose esters, and in general
any oily substance which is physiologically tolerated.
According to an embodiment of the invention, the oil
phase has a iodine value of less than 50, preferably equal or
less than 15, more preferably equal or less than 5 and even
more preferably equal or less than 1. In this embodiment;, the
oil phase comprises one or more components selected from the
group comprising or consisting of mineral oil such as for
example petrolatum and liquid paraffin, and light mineral
oil, medium chain triglycerides (MCT) which is generally
defined as a triglyceride oil in which the carbohydrate chain
has about 8-12 carbon atoms, coconut oil; hydrogenated oils
comprising hydrogenated cottonseed oil, hydrogenated palm
oil, hydrogenate castor oil or hydrogenated soybean oil;
polyoxyethylene hydrogenated castor oil derivatives
comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60
hydrogenated castor oil or polyoxyl-100 hydrogenated castor

WO 2007/042262 PCT/EP2006/009783
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oil.
According to a preferred embodiment of the invention,
the major component of the oily phase will be either
vegetable oil, preferably with a iodine value of less than
50, and/or MCT. Fatty acids or fatty alcohols may be included
in cases where the hydrophobic substance to be carried by the
emulsion is not sufficiently soluble in the oily phase.
Examples of MCT oil which may be used in emulsions of
the present invention are TCM™ (Societe des Oleagineux,
France), Miglyol 812™ (Dynamit Novel, Sweden).
The non-ionic surfactant is selected from the group
comprising or consisting of poloxamers, tyloxapol,
polysorbates, polyoxyethylene castor oil derivatives,
sorbitan esters, polyoxyl stearates and a mixture of two or
more thereof.
According to another preferred embodiment of the
invention, rhe cationic ophthalmic emulsion comprises
benzalkonium chloride as cationic agent and tyloxapol as non-
ionic surfactant.
According to still another preferred embodiment, the
emulsion contains benzalkonium chloride as cationic agent and
a combination of tyloxapol and poloxamer as non-ionic
surfactants.
The emulsion may also contain antioxidant such as
Vitamin E, isotonic agent, buffering agent, preservative,
etc.
According to an embodiment of the invention, the emulsion
includes at least one preservative.
According to another embodiment of the invention, the
emulsion does not contain any preservative.
The colloidal particles of the emulsions according to the
invention have an average particle size of equal or less than

WO 2007/042262 PCT/EP2006/009783
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1 um, advantageously equal or less than 300 nm, more
advantageously in the range of 100 to 250 nm.
The emulsion of the invention may be conditionned in
monodosis containers or in multidosis containers.
According to an embodiment, the containers for carrying the
emulsion of the invention are made of glass, plastic
materials, resins or the like.
According to another embodiment of the invention, the
cationic ophthalmic emulsion may comprise a further
pharmaceutically active substance, either in the oily core or
in the aqueous part of the emulsion. This pharmaceutically
active substance may be an antiglaucomateous active
substance, which may be selected from the group comprising
beta-blockers such as levobunolol, befundol, metipranolol,
forskolin, cartrolol, timolol; inhibitors of carbonic
anhydrase such as brinzolamide, dorzolamide, acetazolamide,
methazolamide, dichlorophenamide; sympathomimetics such as
brimonidine, apraclonidine, dipivefrine, epinephrine;
parasympathomimetics such as pilocarpine; cholinesterase
inhibitors such as physostigmine, echothiophate and/or their
derivatives; and/or optically acceptable salts thereof.
The emulsions according to the invention are physically
stable overtime as defined hereabove and keep a positive zeta
potential in the specific measurement conditions as described
in Tests A, B, C and/or D.
According to the invention, the emulsions do not contain a
sufficient amount of any substances susceptible of affecting
the zeta potential overtime. Advantageously, the emulsions of
the invention do not contain phospholipids.
Substances susceptible of affecting the zeta potential
may be phospholipids, and any substances which become
negatively charged upon storage.
The amount of substances affecting the zeta potential

WO 2007/042262 PCT/EP2006/009783
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overtime must be such that at any time, the amount of
positive charge is above the amount of negative charges.
Zeta potential
Zeta potential measures a physical property which is
exhibited by any particle in suspension. Zeta potential can
be used to predict behaviour of the suspension in different
environments, to optimize the formulations of suspensions and
emulsions as well as to predict overtime stability.
In order to avoid the emulsion droplets to adhere to one
another and form aggregates of successively increasing size,
it is necessary to confer repulsive forces to the particles.
One of the means to confer repulsive forces to a colloidal
system is by electrostatic or charge stabilization.
Electrostatic or charge stabilization has the benefits of
stabilizing a system by simply altering the concentration of
ions in the system. This is a reversible and inexpensive
process.
There might by many origins of this surface charge
depending upon the nature of the particle and its surrounding
medium but the most important mechanisms are the ionisation
of surface groups or the adsorption of charged ions.
The interaction of particles in polar liquids is not
governed by the electrical potential at the surface of the
particle, but by the effective potential of the particle and
its associated ions. To utilize electrostatic control of
dispersions, it is the zeta potential of the particle that
must be measured rather than its surface charge. Charged
particles will attract ions of opposite charge in the
dispersant. Ions close to the surface are strongly bound;
those further away form a more diffuse region. Within this
region is a notional boundary, known as the slipping plane,
within which the particle and ions act as a single entity.

WO 2007/042262 PCT/EP2006/009783
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The potential at the slipping plane is known as the zeta
potential. It has long been recognised that the zeta
potential is a very good index of the magnitude of the
interaction between colloidal particles and measurements of
zeta potential are commonly used to assess the stability of
colloidal systems. The zeta potential measured in a
particular system is dependent on the chemistry of the
surface, and also of the way it interacts with its
surrounding environment. Therefore zeta potential must always
be studied in a well defined environment (specifically pH and
ionic strength).
Electrophoretic mobility
An important conseguence of the existence of electrical
charges on the surface of particles is that they interact
with an applied electric field. These effects are
collectively defined as electrokinetic effects. If the motion
is induced in a particle suspended in a liquid under the
influence of an applied electric field, it is more
specifically named electrophoresis. When an electric field is
applied across an electrolyte, charged particles suspended in
the electrolyte are attracted towards the electrode of
opposite charge. Viscous forces acting on the particles tend
to oppose this movement. When equilibrium is reached between
these two opposing forces, the particles move with constant
velocity. The velocity is dependent on the strength of
electric field or voltage gradient, the dielectric constant
of the medium, the viscosity of the medium and the zeta
potential. The velocity of a particle in a unit electric
field is referred to as its electrophoretic mobility. Zeta
potential is related to the electrophoretic mobility by the
Henry equation:

WO 2007/042262 PCT/EP2006/009783
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where UE = electrophoretic mobility, z= zeta potential,
e = dielectric constant, r|= viscosity and f (xa) =Henry' s
function.
Electrophoretic determinations of zeta potential are
most commonly made in aqueous media and moderate electrolyte
concentration. f(Ka) in this case is 1.5, and this is
referred to as the Smoluchowski approximation. Therefore
calculation of zeta potential from the mobility is
straightforward for systems that fit the Smoluchowski model,
i.e. particles larger than about 0.2 microns dispersed in
electrolytes containing more that 10-3 molar salt. For small
particles in low dielectric constant media (eg non-aqueous
media), f(Ka) becomes 1.0 and allows an equally simple
calculation. This is referred to as the Huckel approximation.
Tests A, B, C and D
Test A consists in measuring the stability of the
emulsion zeta potential under thermal stress conditions.
Zeta potential of the emulsion is measured at T=0, i.e.
as soon as the emulsion has been prepared, the obtained value
being named Zo. Glass vials (Type I) of 10ml effective
capacity containing between 5-10ml of emulsion and sealed
under nitrogen atmosphere (without bubbling) are stored at
80°C.
Then at T=15 hours the zeta potential Zi5h is measured.
The value SA = Zi5h-Z0 is then calculated.
For each measurement of the zeta potential, it is
operated as follows:
The zeta potential of the emulsion droplet surface is
determined by electrophoretic mobility in an apparatus such

WO 2007/042262 PCT/EP2006/009783
- 14 -
as a Malvern Zetasizer 2000 (Malvern Instruments, UK)
equipped with suitable software and calibrated with the
supplied standard.
The emulsion is diluted in double distilled water if
needed in order to obtain the scattering intensity allowing
optimal particle detection. The sample count rate should be
between 100 to 1000 KCps, in homodyne detection (if
heterodyne detection is used, the contribution of the
reference beam should be deduced). Three consecutive
measurements are performed at 25°C using a constant cell
drive of 150mV. The electrophoretic mobility is converted
into zeta potential values through the Smoluchowsky equation,
using the dielectric constants and viscosity of water. The
measured value corresponds to the average of the 3 obtained
values.
It is considered that the emulsion meets zeta potential
stability Test A if 5A is less than the standard error of
measurements, preferably less than lOmV, and even more
preferably less than 5mV.
According to an advantageous embodiment, the ophthalmic
emulsion according to the invention meets zeta potential
stability Test B.
Test B is similar to Test A except that the emulsion is
stored during 48 hours at 80°C, the zeta potential Z2 is
measured on day 2 and 5B = Z2 -Zo is calculated. The emulsion
is considered as meeting the requirements of zeta potential
stability test B if 5B is less than the standard error of
measurements, preferably less than lOmV, and even more
preferably less than 5mV.
According to a more advantageous embodiment of the
invention, the ophthalmic emulsion according to the invention
meets zeta potential stability Test C.

WO 2007/042262 PCT/EP2006/009783
- 15 -
Test C is similar to Test A except that the emulsion is
stored during 7 days at 80°C, the zeta potential Z7 is
measured on day 7 and 8C = Z7 -Zo is calculated. The emulsion
is considered as meeting the requirements of zeta potential
stability test C if 5C is less than the standard error of
measurements, preferably less than lOmV, and even more
preferably less than 5mV.
According to a still more advantageous embodiment of the
invention, the ophthalmic emulsion according to the invention
meets zeta potential stability Test D.
Test D is similar to Test A except that the emulsion is
stored during 14 days at 80°C, the zeta potential Z14 is
measured on day 14 and 8D = zi4 -z0 is calculated. The
emulsion is considered as meeting the requirements of zeta
potential stability test D if 5D is less than the standard
error of measurements, preferably less than lOmV, and even
more preferably less than 5mV.
According to another aspect, the invention relates to a
process for manufacturing the emulsions here-above described.
The emulsions are prepared as follows:
- the prostaglandin is dissolved into the oily phase,
which is optionally added with another hydrophobic
ophthalmologically active ingredient,
- the aqueous phase , optionally added with another
hydrophilic ophthalmologically active ingredient, is
rapidly added to the oily phase,
- the coarse emulsion obtained is rapidly heated,
preferably at 75°C,
- the emulsion droplet size is then decreased by any
suitable means known by one skilled in the art, for
example by shear mixing,

WO 2007/042262 PCT/EP2006/009783
- 16 -
- the emulsion temperature is cooled down to 20°C using an
ice bath and then homogenized
- pH is adjusted to 7-8,
- the emulsion is sterilized.
The inventions also relates to the use of a cationic
ophthalmic oil-in-water emulsion as hereabove described for
the preparation of an ophthalmic composition for treating
ocular hypertension and/or for treating glaucoma.
According to another aspect, the invention relates to
ophthalmic formulation comprising an emulsion as previously
described, optionally in combination with an
ophthalmologically acceptable carrier, in the form of eye
drops, eye ointment, ophthalmic gel. In said ophthalmic
formulation there may be a pharmaceutically effective amount
of an active ingredient in or within the ophthalmologically
acceptable carrier.
The invention is also directed to a delivery device
selected from the group comprising lenses, ocular patch,
implant, insert, said device containing an emulsion as
previously described.
The invention is further illustrated by the examples
below.
EXAMPLES
In the following examples, the following abbreviations are
used:
Medium Chain Triglycerides MCT: TCM™ (Societe des
Oleagineux)
BAK: benzalkonium chloride (FeF Chemicals , Denmark)
Lutrol: Lutrol F68™ (BASF)
Tyloxapol : Triton WR1339 (Ruger Chemicals , USA)

WO 2007/042262 PCT/EP2006/009783
- 17 -
Z29 : latanoprost
Example 1
Emulsion
Composition Z29EM002
1%MCT
0.1 % Lipoid
0.05% OA
0.005% vit E
0.25% Lutrol
2.25% Glycerin
Water to 100%
Z29 0.005% Z29EM003
1%MCT
0.1%Tyloxapol
0.05% OA
0.005% vit E
0.25% Lutrol
2.25% Glycerin
Water to 100%
Z29 0.005% Z29EM005
0.02% BAK
1 % MCT
0.16%Tyloxapol
0.01% vit E
0.25% Lutrol
2.25% Glycerin
Water to 100%
Z29 0.005% Z29EM007
0.02% BAK
1%MCT
0.3% Tyloxapol
0.01% vit E
0.1% Lutrol
2.25% Glycerin
Water to 100%
Z29 0.005%
Zeta potential
stress test TO: 22.4
T7:24.1
T15: 19.8 TO: 21.8
T7: 18.8
T15: 18.9
Droplet size
(nm)
stress test TO: 160
T7: 173
T15:185 TO: 212
T7: 225
T15:236

Emulsion
Composition Z29EM008
0.02% BAK
1%MCT
0.3% Tyloxapol
0.1% Lutrol
2.25% Glycerin
Water to 100%
Z29 0.005% Z29EM011
0.01% BAK
1%MCT
0.3% Tyloxapol
0.1 % Lutrol
2.25% Glycerin
Water to 100%
Z29 0.005%
Zeta
potential
stress test TO: 20.6
T7: 18.5
T15: 16.2
Droplet size
stress test TO: 201
T7: 212
T15:216
The oily phase components including 0.005% latanoprost (named
Z29 in the Tables) were successively weighed in the same
beaker and then magnetically stirred under a slight heating
(40°C) until a slightly viscous phase is obtained. Aqueous

WO 2007/042262 PCT/EP2006/009783
- 18 -
phase components were successively weighed in the same beaker
and then magnetically stirred under a slight heating (40°C)
until a transparent, limpid and fluid phase is obtained. Both
phases were heated to 65°C. The coarse emulsion was formed by
rapid addition of the aqueous phase in the oily phase and was
then rapidly heated to 75°C. The aqueous phase and coarse
emulsion beakers were protected by a film to avoid any water
evaporation. The emulsion was white and slightly transparent.
The emulsion droplet size was then decreased by a 5 minutes
high shear mixing with a POLYTRON PT 6100. The emulsion
became milky. The emulsion temperature was cooled down to
20°C using an ice bath.
The final emulsion was obtained by homogenization in a
microfluidizer (C5, Avestin) using continuous cycles for 5
min at a pressure of 10,000 psi. The emulsion was milky, very
fluid and did not adhere on the glass. The emulsion
temperature was decreased to 25°C. Its pH was measured and
then adjusted to 7.0 using a 0.1 M HC1 or 0.1 M NaOH
solution. Emulsion was conditioned in glass vials with
nitrogen bubbling and then sterilized in an autoclave 20
minutes at 121°C.
The mean particle size of the emulsions droplets was
determined by quasi-elastic light scattering after dilution
in water using a High Performance Particle Sizer (Malvern
Instruments, UK).
The electrophoretic mobility was measured at 25°C in a
Malvern Zetasizer 2000 (Malvern Instruments, UK) following a
1:200 dilution in double distilled water as detailed above
and converted into zeta potential through the Smoluchowski
equation.

WO 2007/042262 PCT/EP2006/009783
- 19 -
Example 2
Latanoprost stability improvement in emulsion compared to
commercial product (Xalatan®)
The chemical stability of latanoprost within the emulsion was
compared to the commercial product Xalatan® at 80°C for 14
days (figure 1).
Prostaglandin contents were analysed by an HPLC-UV method.
In emulsions according to the invention, latanoprost is
chemically stabilized.
Example 3:
In vivo studies demonstrating that latanoprost emulsion is
as efficient as the commercial product (Xalatan®) in
reducing IOP (intraocular pressure)
Methods: Eight adult female cynomolgus monkeys, each weighing
3-6 kg, in which glaucoma had been induced by diode laser
photocoagulation of the mid-trabecular meshwork, were used in
SUBSTITUTE SHEET (RULE 26)

WO 2007/042262 PCT/EP2006/009783
- 20 -
this study. Intraocular pressure (IOP) was measured at 0 hr
(before drug administration) and then hourly until 6 hrs
after drug administration for one baseline day, one vehicle -
treated day, and treatment days 1,3, and 5 with 30/zl of
Z29EM007 (similar to the emulsion described in Example 1) or
0.005% Latanoprost (Xalatan; Pharmarcia & Upjohn, Kalamazoo,
MI) .
The products were topically applied to the glaucomatous eye
once daily for 5 consecutive days in a crossover design with
a washout period at least 2 weeks between the two drugs.
Results: Once daily administration of both Z2 9EM007 and
Xalatan for 5 days significantly (p hr to 5 hrs after the first dose compared to the vehicle
treatment day (figure 2).
The ocular hypotensive effect was enhanced by repeated dosing
for both Z29EM007 and Xalatan. No statistical difference of
IOP reduction (p> 0.80) was observed during the 5 days
treatment when comparing Z2 9EM007 and Xalatan. IOP on the
baseline day and vehicle-treated day was not statistically
different between the two drugs (p>0.90).
Latanoprost in the emulsions according to the invention is as
efficient as commercially available Xalatan™'
SUBSTITUTE SHEET (RULE 26)

WO 2007/042262 PCT/EP2006/009783
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CLAIMS
l.A cationic ophthalmic oil-in-water type emulsion,
which comprises colloid particles having an oily core
surrounded by an interfacial film,
said emulsion comprising at least one cationic agent
and at least one non ionic surfactant selected from the
group consisting of poloxamers, tyloxapol, polysorbates,
polyoxyethylene castor oil derivatives, s.orbitan esters,
polyoxyl stearates and a mixture of two or more thereof,
said oily core comprising a drug selected from the
group consisting of latanoprost, unoprostone isopropyl,
travoprost, bimatoprost, tafluprost, 8-isoprostaglandin
E2 or a mixture of two or more thereof
said emulsion being free of water-soluble polymer
selected from a polyvinyl compound, a water-soluble
cellulose compound and a polysaccharide.
2.A cationic ophthalmic oil-in-water type emulsion
according to claim 1, wherein the drug is latanoprost.
3.A cationic ophthalmic oil-in-water type emulsion
according to any of claims 1 or 2, said emulsion being
free of water-soluble polymer selected from (1) a
polyvinyl compound such as polyvinylalcohol and
polyvinylpyrrrolidone, (2) a water-soluble cellulose
compound such as methylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose, and/or sodium cellulose and
(3) a polysaccharide selected from alginic acid, xanthan
gum, carrageenan, and chitosan.
4. A cationic ophthalmic emulsion according to anyone
of claims 1 to 3, comprising at least one further
pharmaceutically active substance, either in the oily
core or in the agueous part of the emulsion.

WO 2007/042262 PCT/EP2006/009783
- 22 -
5. A cationic ophtalmic oil-in-water type emulsion
according to any of claims 1 to 4, further comprising an
anti-inflanunatory compound, preferably a non steroidal
anti-inflammatory compound or a omega-3 fatty acid.
6. A cationic ophtalmic oil-in-water type emulsion
according to any of claims 1 to 4, wherein the emulsion
further comprise at least one further antiglaucomateous
pharmaceutically active substance selected from the group
comprising beta-blockers such as levobunolol,
befundol,forskolin, metipranolol, cartrolol, timolol;
inhibitors of carbonic anhydrase such as brinzolamide,
dorzolamide, acetazolamide, methazolamide,
dichlorophenamide; sympathomimetics such as brimonidine,
apraclonidine, dipivefrine, epinephrine;
parasympathomimetics such as pilocarpine; cholinesterase
inhibitors such as physostigmine, echothiophate and/or
their derivatives; and/or optically acceptable salts
thereof.
7. A cationic ophthalmic oil-in-water type emulsion
according to anyone of claims 1 to 6, wherein the amount
of the drug selected from the group consisting of
latanoprost, unoprostone isopropyl, travoprost,
bimatoprost, tafluprost, 8-isoprostaglandin E2 or a
mixture of two or more thereof in the oily core is 0.001
to 1% w/w, preferably 0.002 to 0.3% w/w and even more
preferably 0.004 to 0.15% w/w.
8.A cationic ophthalmic oil-in-water type emulsion
according to anyone of claims 1 to 7, wherein the
concentration of the cationic agent is comprised between
0.001 to 0.1% w/w, preferably between 0.002 to 0.05% w/w
and even more preferably between 0.003 to 0.03%w/w.
9.A cationic ophthalmic oil-in-water type emulsion
according to anyone of claims 1 to 8, wherein the

WO 2007/042262 PCT/EP2006/009783
- 23 -
concentration of the oily core is not higher than 7% w/w,
preferably between 0.5 to 5% w/w and even more preferably
between 1 to 3%w/w.
10. A cationic ophthalmic emulsion according to
anyone of claims 1 to 9, wherein the concentration of the
non-ionic agent is less than 1% w/w, comprised preferably
from 0.01 to 0.6% w/w.
11. A cationic ophthalmic oil-in-water emulsion
according to anyone of claims 1 to 10, wherein the
cationic agent is selected in the group consisting of
C10-C24 primary alkylamines, tertiary aliphatic amines,
quaternary ammonium compounds, cationic lipids, amino
alcohols, biguanide salts, cationic compounds and a
mixture of two or more thereof.
12. A cationic ophthalmic oil-in-water emulsion
according to claim 11, wherein the biguanide salt is
selected from the group comprising chlorhexidine and
salts thereof, polyaminopropyl biguanide, phenformin,
alkylbiguanide or a mixture of two or more thereof.
13. A cationic ophthalmic oil-in-water emulsion
according to claim 11, wherein the quaternary ammonium
compound is selected from the group comprising
benzalkonium halide, lauralkonium halide, cetrimide,
hexadecyltrimethy1ammonium halide,
tetradecyltrimethylammonium halide,
dodecyltrimethylammonium halide, cetrimonium halide,
benzethonium halide, behenalkonium halide, cetalkonium
halide, cetethyldimonium halide, cetylpyridinium halide,
benzododecinium halide, chlorallyl methenamine halide,
myristylalkonium halide, stearalkonium halide or a
mixture of two or more thereof, halide being preferably
chloride or bromide.

WO 2007/042262 PCT/EP2006/009783
- 24 -
14. A cationic ophthalmic emulsion according to
anyone of claims 1 to 10, wherein said cationic agent is
selected from the group comprising benzalkonium chloride,
lauralkonium chloride, benzododecinium bromide,
benzethenium chloride, hexadecyltrimethylammonium
bromide, tetradecyltrimethylammonium bromide,
dodecyltrimethylammonium bromide or a mixture of two or
more thereof.
15. A cationic ophthalmic emulsion according to
anyone of claims 1 to 10, wherein the cationic agent is
selected from at least one quaternary ammonium halide in
which the nitrogen atom is substituted by at least one
alkyl group having at least 14 carbon atoms.
16. A cationic ophthalmic emulsion according to
anyone of claims 1 to 15, wherein the oil phase has a
iodine value of less than 50, preferably equal or less
than 15, more preferably equal or less than 5 and even
more preferably equal or less than 1.
17. A cationic ophthalmic emulsion according to
claim 16, wherein the oil phase comprises one or more
components selected from the group consisting of mineral
oil and light mineral oil, medium chain triglycerides
(MCT), coconut oil; hydrogenated oils comprising
hydrogenated cottonseed oil, hydrogenated palm oil,
hydrogenate castor oil or hydrogenated soybean oil;
polyoxyethylene hydrogenated castor oil derivatives
comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-
60 hydrogenated castor oil or polyoxyl-100 hydrogenated
castor oil.
18. A cationic ophthalmic emulsion according to
anyone of claims 1 to 17, wherein the oil is MCT.
19. A cationic ophthalmic emulsion according to
anyone of claims 1 to 18, comprising benzalkonium

WO 2007/042262 PCT/EP2006/009783
- 25 -
chloride as cationic agent and tyloxapol as non-ionic
surfactant.
20. A cationic ophthalmic emulsion according to
anyone of claims 1 to 19, wherein the emulsion contains
benzalkonium chloride as cationic agent and a combination
of tyloxapol and poloxamer.
21. A cationic ophthalmic emulsion according to
anyone of claims 1 to 20, wherein said colloidal
particles have an average particle size of equal or less
than 1 um, advantageously equal or less than 300 nm, more
advantageously in the range of 100 to 250 nm.
22. A cationic ophthalmic oil-in-water type
emulsion according to anyone of claims 1 to 21, wherein
the emulsion meets zeta potential stability Test A
requirements.

23. An ophthalmic emulsion according to anyone of
claims 1 to 21, which meets zeta potential stability Test
B requirements.
24. An ophthalmic emulsion according to anyone of
claims 1 to 21, which meets zeta potential stability Test
C requirements.
25. An ophthalmic emulsion according to anyone of
claims 1 to 21, which meets zeta potential stability Test
D requirements.

26. Use of a cationic ophthalmic oil-in-water
emulsion according to any one of claims 1 to 25, for the
preparation of an ophthalmic composition for treating
ocular hypertension and/or for treating glaucoma.
27. Ophthalmic formulation comprising an emulsion
according to any of claims 1 to 25, optionally in
combination with an ophthalmologically acceptable
carrier, said formulation being in the form of eye drops,
eye ointment, ophthalmic gel.

WO 2007/042262 PCT/EP2006/009783
- 26 -
28. Delivery device selected from the group
comprising lenses, ocular patch, implant, insert, said
device containing an emulsion according to anyone of
claims 1 to 25.

The present invention relates to cationic ophthalmic oil-in-
water type emulsions, which comprise colloid particles having an
oily core surrounded by an interfacial film, said emulsion
comprising at least one cationic agent and at least one non
ionic surfactant, said oily core comprising a prostaglandin
selection from the group comprising in particular latanoprost,
unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-
isoprostaglandinE2, or a mixture thereof, for treating ocular
hypertension and/or glaucoma. These emulsions have the property
to increase the chemical stability of prostaglandins.

Documents:

01290-kolnp-2008-abstract.pdf

01290-kolnp-2008-claims.pdf

01290-kolnp-2008-correspondence others.pdf

01290-kolnp-2008-description complete.pdf

01290-kolnp-2008-drawings.pdf

01290-kolnp-2008-form 1.pdf

01290-kolnp-2008-form 2.pdf

01290-kolnp-2008-form 3.pdf

01290-kolnp-2008-form 5.pdf

01290-kolnp-2008-international publication.pdf

01290-kolnp-2008-international search report.pdf

01290-kolnp-2008-others.pdf

01290-kolnp-2008-pct request form.pdf

1290-KOLNP-2008-(09-07-2013)-CORRESPONDENCE.pdf

1290-KOLNP-2008-(09-07-2013)-FORM-3.pdf

1290-KOLNP-2008-(09-07-2013)-OTHERS.pdf

1290-KOLNP-2008-(15-07-2013)-PETITION UNDER SECTION 8 (1).1.pdf

1290-KOLNP-2008-(15-07-2013)-PETITION UNDER SECTION 8 (1).pdf

1290-kolnp-2008-CANCELLED PAGES.pdf

1290-KOLNP-2008-CORRESPONDENCE OTHERS 1.1.pdf

1290-KOLNP-2008-CORRESPONDENCE-1.2.pdf

1290-kolnp-2008-CORRESPONDENCE.pdf

1290-kolnp-2008-DECISION.pdf

1290-kolnp-2008-EXAMINATION REPORT.pdf

1290-kolnp-2008-form 18.pdf

1290-kolnp-2008-FORM 26 1.1.pdf

1290-KOLNP-2008-FORM 26.pdf

1290-kolnp-2008-GRANTED-ABSTRACT.pdf

1290-kolnp-2008-GRANTED-CLAIMS.pdf

1290-kolnp-2008-GRANTED-DESCRIPTION (COMPLETE).pdf

1290-kolnp-2008-GRANTED-DRAWINGS.pdf

1290-kolnp-2008-GRANTED-FORM 1.pdf

1290-kolnp-2008-GRANTED-FORM 2.pdf

1290-kolnp-2008-GRANTED-FORM 3.pdf

1290-kolnp-2008-GRANTED-FORM 5.pdf

1290-kolnp-2008-GRANTED-LETTER PATENT.pdf

1290-kolnp-2008-GRANTED-SPECIFICATION-COMPLETE.pdf

1290-kolnp-2008-INTERNATIONAL PUBLICATION.pdf

1290-kolnp-2008-INTERNATIONAL SEARCH REPORT & OTHERS.pdf

1290-KOLNP-2008-PCT REQUEST-1.1.pdf

1290-kolnp-2008-PETITION UNDER RULE 137.pdf

1290-kolnp-2008-REPLY TO EXAMINATION REPORT.pdf

1290-kolnp-2008-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf

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Patent Number

262698

Indian Patent Application Number

1290/KOLNP/2008

PG Journal Number

37/2014

Publication Date

12-Sep-2014

Grant Date

05-Sep-2014

Date of Filing

31-Mar-2008

Name of Patentee

NOVAGALI PHARMA SA

Applicant Address

1 RUE PIERRE FONTAINE 91000 EVRY

Inventors:

#	Inventor's Name	Inventor's Address
1	PHILIPS, BETTY	193 RUE ADOLPHE PAJEAUD 92160 ANTONY
2	RABINOVICH-GUILATT, LAURA	C/O YOEL GUILATT POB 3641 KADIMA 60920
3	LAMBERT, GRÉGORY	LES MURS BLANCS 19 RUE HENRI MARROU 92290 CHATENAY MALABRY
4	BAGUE, SÉVERINE	RÉSIDENCE LE MURAT 20 RUE DES ROSSAYS 91360 EPINAY-SUR-ORGE

PCT International Classification Number

A61K 9/00,A61K 9/107

PCT International Application Number

PCT/EP2006/009783

PCT International Filing date

2006-10-10

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	PCT/EP2005/011648	2005-10-10	EPO