CA2616531C - Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation - Google Patents

Abstract

The invention relates to a sterile, drop-forming, multi-phase, emulsifier-free ophthalmic product, in particular a gel product, comprising at least one liquid aqueous phase and at least one liquid hydrophobic phase, the product comprising at least one phosphate salt and having a viscosity in the range from > 200 mPa.s to < 2000 mPa.s.

Description

Sterile, Drop-forming, Multiphase, Emulsifier-free Ophthalmic Preparation The invention relates to a sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation, in particular a gel preparation. The ophthalmic preparation can be used, for example, as artificial tear liquid and for the treatment of "dry eye".

Use of aqueous preparations for the treatment of disorders related to irritated or inflamed eyes, in particular of dry eyes, keratoconjunctivitis sicca, is known in the state of the art. These preparations are usually present in the form of fluids, gels, creams, or ointments.

It is disadvantageous that ingredients are often added to solutions, which elicit hypersensitivity, lead to irritations, or cause sensitization to or incompatibility with the ingredients. It is also known that aqueous solutions often cause itching, burning, or other unpleasant side effects upon contact with the eye.

Furthermore, preparations, in particular in the form of gels, creams, or ointments, have the disadvantage that application by patients already suffering from a painful irritation of the eye is additionally unpleasant. Moreover, the distribution of these preparations in or on the eye must often be supported by rubbing, an event which causes additional sensations of pain in the patient.

Also, two-phase emulsions are known in the state of the art. However, their stability inter alia depends on their viscosity. Thus, emulsions become unstable, if, for example, a hydrophobic phase that is finely dispersed in a hydrophilic phase aggregates. This event limits the stability during storing of the emulsions and is slower the more viscous the hydrophilic phase of the emulsion is.

In order to provide sufficient stability of emulsions, emulsifiers are usually employed.
However, emulsifiers can also cause allergic reactions or reactions that are based on hypersensitivity of the patient.

An emulsifier-free preparation is for example disclosed in EP 0817610.
However, this preparation has the disadvantage that it exhibits a very high viscosity. Thus, the application of the preparation is unpleasant for the patient and supporting the distribution of the composition, for example, by rubbing on the eye causes an additional pain sensation.

It is an objective of the present invention to provide a preparation which overcomes at least one of the aforementioned disadvantages of the state of the art. In particular, it is an objective of the present invention to provide a preparation which is suitable for application on dry eye.

The objective is solved by a sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation, in particular a gel preparation, comprising at least one liquid aqueous phase and at least one liquid hydrophobic phase. This preparation comprises at least one phosphate salt and has a viscosity in the range of - 200 mPa=s to < 2000 mPa=s. Preferably, suitable phosphate salts are water -soluble, according to the present invention.
Advantageous embodiments of the sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to the present invention are mentioned in the dependent claims.

"Emulsifier-free," as referred to in the present invention, means that the preparation comprises only ingredients which are not emulsifiers within the meaning of the present invention. In particular, the preparation according to the present invention can comprise substances selected from the group comprising water-soluble phosphate salts, preferably sodium monohydrogen phosphate dodecahydrate, Na?HPO4 x 12 H20, polyacrylic acid, polymers of acrylic acid derivatives, preferably carbomer, triglycerides, preferably mid chain triglycerides, a vitamin A
component, preferably vitamin A palmitate, vitamin E, sorbitol, sodium hydroxide, preservatives such as cetrimide, benzododecinium chloride, benzalkonium chloride or thiomersal and/or water, whereby these substances are not emulsifiers in the sense of the present invention. In accordance with the present invention, the preparation can further comprise substances selected from the group comprising glycerol and/or alexidine, whereby these substances are not emulsifiers in the sense of the present invention.

"Emulsifiers" according to the present invention are interface-active substances which are able to decrease the interfacial tension between the oil phase and the aqueous phase by accumulating at the interface between these two phases. This is made possible by the amphiphilic molecular structure of the emulsifier, which possesses at least one polar (hydrophilic) group and at least one non-polar (lipophilic) group. Thus, they are soluble in the hydrophilic as well as in the lipophilic phase. The part which is more soluble in the corresponding phase extends into this phase and thereby lowers the interfacial tension between both phases.

A preferred embodiment is a preparation, in particular gel preparation, comprising at least one liquid aqueous phase and at least one liquid hydrophobic phase, wherein this preparation comprises at least one preferably water-soluble phosphate salt and has a viscosity in the range of _ 200 mPa=s to < 2000 mPa=s, wherein this preparation either does not contain any further emulsifiers or only in an amount such that the aforementioned substances do not exhibit emulsifying effects.

Another preferred embodiment is a preparation, in particular gel preparation, comprising at least one liquid aqueous phase and at least one liquid hydrophobic phase, wherein this preparation comprises at least a preferably water-soluble phosphate salt and has a viscosity in the range of _> 200 mPa=s to < 2000 mPa=s; it also comprises substances selected from the group comprising polyacrylic acid, preferably carbomer, mid-chain triglycerides, sodium monohydrogen phosphate dodecahydrate, Na2HPO4 x 12 H20, sorbitol, sodium hydroxide and water, wherein this preparation either does not contain any further emulsifiers or in an amount such that the aforementioned substances do not exhibit emulsifying effects.

A still more preferred embodiment is a preparation, in particular gel preparation, comprising at least one liquid aqueous phase and at least one liquid hydrophobic phase, wherein this preparation comprises at least a preferably water-soluble phosphate salt and has a viscosity in the range of _ 200 mPa=s to < 2000 mPa=s, wherein it also comprises substances selected from the group comprising polyacrylic acid, preferably carbomer, preferably mid-chain triglycerides, sodium monohydrogen phosphate dodecahydrate, Na2HPO4 x 12 H20, sorbitol, sodium hydroxide, water and, optionally, a vitamin A component, preferably vitamin A
palmitate, vitamin E and/or preservatives, preferably cetrimide, wherein this preparation either does not contain any further emulsifiers or in an amount such that the aforementioned substances do not exhibit emulsifying effects.

The substances, which can be contained in the preparation according to the present invention, in particular water-soluble phosphate salts, polyacrylic acid, polymeric acrylic acid derivatives, preferably carbomer, triglycerides, a vitamin A component, vitamin E, sorbitol, sodium hydroxide, preservatives such as cetrimide, benzododecinium chloride, benzalkonium chloride or thiomersal or water, are preferably used in amounts, so that the aforementioned substances do not exhibit emulsifying effects. Furthermore, the composition according to the present invention can comprise the substances glycerol and/or alexidine, which are also used in amounts so that the aforementioned substances do not exhibit emulsifying effects.

Surprisingly, it turned out that the preparation according to the present invention, in particular a gel preparation, can be formulated such that it is stable in a viscosity range of < 2000 mPa=s.
This is surprising for a person skilled in the art, particularly for an emulsion of such low viscosity comprising a hydrophilic (for example, aqueous) phase and a hydrophobic phase, since they usually become rapidly unstable and separate from each other.

A particular advantage of these substances arises from the fact that the stability of the preparation can be achieved without the addition of emulsifiers. This provides an improvement in tolerance of the preparation according to the present invention.

Particularly, the use of phosphate salts allows the adjustment of low ranges of viscosity of the present invention. A specific advantage of the preparation of the present invention is achieved by using the phosphate salt, whereby an emulsifier-free preparation having low viscosity can be provided.

In particular it is advantageous that a preparation having low viscosity considerably improves the application for the patient. Preferably, a drop-forming preparation can be provided, which can be better distributed on the cornea of the eye, due to the low viscosity, and which irritates the eye less by an additional mechanical aid for distribution. It is of significant advantage that the preparation with low viscosity of the present invention only causes a low foreign body sensation on the eye and provides a more pleasant tolerance for the patient during application.
In preferred embodiments of the ophthalmic preparation, the composition has a viscosity in the range of _ 300 mPa=s to <_ 1800 mPa=s, preferably in the range of _ 400 mPa=s to _ 1500 mPa=s, preferably in the range of _ 500 mPa=s to <_ 1400 mPa=s, more preferably in the range of _ 600 mPa=s to <_ 1350 mPa=s, most preferably in the range of _ 650 mPa=s to _ 1300 mPa=s.

The sterile drop-forming ophthalmic preparation comprises preferably at least one water-soluble phosphate salt. Suitable water-soluble phosphate salts are preferably selected from the group comprising alkali phosphate salts, alkaline-earth phosphate salts, ammonium phosphate salts, mono- or dihydrogenphosphates thereof and/or mixtures thereof.
Preferably suitable are water-soluble phosphate salts, selected from the group comprising sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium dihydrogen phosphate, potassium monohydrogen phosphate and/or mixtures thereof. Most preferably sodium monohydrogen phosphate is used.

Preferably, the hydrate compounds can be water-soluble phosphate salts, preferably hydrate compounds selected from the group comprising hydrate compounds of alkali phosphate salts, alkaline-earth phosphate salts, ammonium phosphate salts, mono- or dihydrogenphosphates thereof and/or mixtures thereof, especially preferred are hydrate compounds selected from the group comprising hydrate compounds of sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium dihydrogen phosphate, potassium monohydrogen phosphate and/or mixtures thereof. Preferably, NaZHPO4 x n HZO with n = 2, 7 or 12 or NaH2PO4 x n H20 with n = 1 or 2 is used.

An especially preferred phosphate salt is sodium monohydrogen phosphate dodecahydrate, NaZHPO4 x 12 H20. The use of a possible designation such as sodium monohydrogen phosphate dodecahydrate in the sense of this invention also includes appropriate designations such as disodium hydrogen phosphate dodecahydrate or disodium phosphate dodecahydrate for the corresponding substance.

Preferably, a suitable proportion of water-soluble phosphate salt is in the range of _ 0.01 wt.-% to <_ 5.0 wt.-%, preferably in the range of _ 0.05 wt.-% to <_ 0.5 wt.-%, more preferably in the range of _ 0.08 wt.-% to <_ 0.2 wt.-%, based on the total weight of the preparation. In most preferred embodiments the preparation comprises about 0.1 wt.-% of the water-soluble phosphate salt, based on the total weight of the preparation. The amount as specified herein refers to the appropriate hydrate compound, unless indicated otherwise.

As a lower limit, a minimum proportion of 0.01 wt.-% of NaZHPO4 x 12 H20 based on the total weight of the preparation has been shown to be suitable. A proportion of Na2HPO4 x 12 H20 in the range of _ 0.01 wt.-% to <_ 5.0 wt.-%, based on the total weight of the preparation has been shown to be suitable. Preferably, a proportion of Na2HPO4 x 12 H20 in the range of _ 0.05 wt.-% to <_ 0.5 wt.-%, more preferably in the range of _ 0.08 wt.-% to <_ 0.2 wt.-%, based on the total weight of the preparation is used. In especially preferred embodiments, the preparation comprises about 0.1 wt.-% NaZHPO4 x 12 H20, based on the total weight of the preparation.

A further surprising effect of the preparation of the present invention is that the preparation is comparable to the three-phase composition of the natural tear film in the eye, mucin layer, aqueous phase and lipid layer, when applied to the eye and can replace the natural tear film. In particular, this is provided in favourable way independent from the phase of the natural tear film which is either present in amounts that are too small or is missing altogether.
Preferably, the multiphase preparation comprises the aqueous phase as continuous phase and the liquid hydrophobic phase, preferably a liquid oil phase, as droplets dispersed therein, preferably in the form of finely dispersed droplets. The preparation is preferably at least biphasic; in preferred embodiments it can also be triphasic. Furthermore, the preparation preferably comprises a polymeric gel-forming component in the aqueous phase.
Accordingly, the preparation of the present invention preferably comprises a biphasic, a liquid aqueous phase and a liquid hydrophobic phase comprising carrier liquid or a gel base.

The aqueous phase of the preparation is preferably formed so that the preparation has a significant water proportion. Preferably, the composition comprises a water proportion in the range of _ 60 wt.-% to <_ 98 wt.-%, based on the total weight of the preparation, preferably in the range of _ 90 wt.-% to <_ 96 wt.-%, especially preferred the preparation comprises about 94 wt.-% to <_ 95 wt.-% of water. Preferably, water for injection purposes is used.

In preferred embodiments, the aqueous phase of the preparation can reproduce the aqueous phase of the natural tear film, which moisturizes the cornea and provides a cleaning and protecting function.

Advantageously, the ophthalmic preparation of the present invention is particularly well tolerated. It is of further advantage that the ophthalmic preparation of the present invention leads to no or only a very small irritation or unpleasantness during application to the eye. This provides a significant advantage since application to the eye often leads to a very unpleasant "burning" sensation in the eye.

Preferably, the preparation further comprises at least one polymeric gel-forming component, in particular a polyacrylic acid and/or a polymeric acrylic acid derivative.
Preferred polyacrylic acids have, for example, a molecular weight in the range of approximately 3 to 5 million Dalton. Especially preferred polyacrylic acids or polymeric acrylic acid derivatives are crosslinked polymers of acrylic acids that go by the name of carbomer under INCI
designation, preferably hydrophobic modified crosslinked polymers of acrylic acids. Preferred carbomers are available under the trade name Carbopol , for example, from the company Noveon Inc. Especially preferred carbomers are homopolymers of acrylic acid, for example, Carbopol -homopolymers, especially preferred Carbopol 980 NF is used, even more preferred is Carbopol 940 NF. The terms polyacrylic acid and polymeric acrylic acid are synonymously used in the sense of this application.

Preferably, the ophthalmic preparation comprises the polymeric gel-forming component, preferably polyacrylic acid and/or a polymeric acrylic acid derivative, in particular preferably a carbomer, in the range of _ 0.1 wt.-% to <_ 3 wt.-%, based on the total weight of the preparation, preferably in the range of _ 0.1 wt.-% to _ 1 wt.-%, especially preferred in the range of _ 0.15 wt.-% to <_ 0.5 wt.-%, most preferably at about 0.2 wt.-%.

In preferred embodiments, the preparation further comprises an ophthalmic and/or ophthalmologic acceptable, organic oil. In these embodiments the ophthalmic acceptable organic oil forms the liquid hydrophobic phase of the preparation of the present invention.
Suitable liquid hydrophobic oil components are, for example, fatty acid derivatives such as fatty acid esters, triglycerides and phthalic acid esters. Preferably the ophthalmic acceptable, organic oil of the preparation has as the ophthalmic acceptable organic oil mid-chain triglycerides, especially preferred triglycerides formed of at least 80 wt.-%, based on the total weight of the fatty acids, preferably at least 90 wt.-% and even more preferably at least 95 wt.-% of, preferably, Cg-C12-fatty acids, preferably Cg-Clo-fatty acids.

Especially preferred, the preparation has saturated mid-chain triglycerides.
Also preferred are triglycerides formed of at least 80 wt.-%, preferably at least 90 wt.-% more preferably at least 95 wt.-%, based on the total weight of the fatty acids of saturated C8- and C
i o-fatty acids.
Especially preferred are caprylic-capric acid-triglycerides, which are mixtures of esterified saturated C8 and Cio fatty acids.

Suitable triglycerides are available in the form of synthetic, half-synthetic or natural oils, like olive oil, palm oil, almond oil, coconut oil or mixtures thereof. Preferred triglycerides are available from coconut oil. Such mid-chain triglycerides are prepared, for example, from the oil of the endosperms of Cocos nucifera L., preferably from the solid dried part, or Elasis guineensis Jacq.. Additional preferred suitable triglycerides, preferably mid-chain triglycerides are neutral oils, for example, available under the trade name Myritol 318. In particular, mid-chain triglycerides are preferred, as described in the European Dispensatory, European Pharmacopoeia 5.0, 01/2005:0868, p. 2623, Triglycerida saturata media. Preferably, the acidic component comprises a mixture with a proportion of at least 90 wt.-%, preferably at least 94 wt.-%, more preferably at least 95 wt.-%, based on the total weight of the fatty acids of n-octanoic acid and n-decanoic acid.

An advantage of the preferred mid-chain triglycerides on the basis of a mixture formed from saturated C8 and CIO-fatty acids, preferably caprylic-capric acid triglycerides, is that the saturated fatty acids provide an improved stability of the lipid film and, thus, a surprisingly improved extended retention period of the preparation in the eye.

Advantageously, the mid-chain triglycerides can inhibit the evaporation of the aqueous component and prevent a too rapid running off of the tear film or the preparation.

Preferably, the sterile, drop-forming, ophthalmic preparation comprises an ophthalmic and/or ophthalmologic acceptable organic oil, preferably selected from the group of fatty acid derivatives, comprising fatty acid esters, triglycerides and/or phthalic acid esters, especially preferred mid-chain triglycerides in the range of ? 0.5 wt.-% to <_ 10 wt.-%, based on the total weight of the preparation, preferably in the range of _ 0.6 wt.-% to <_ 5wt.-%, especially preferred in the range of _ 0.8 wt.- % to _ 2 wt.-%, most preferably at about 1 wt.-%. In especially preferred embodiments, the sterile, drop-forming, ophthalmic preparation comprises caprylic-capric acid triglyceride or triglycerides formed of at least 80 wt.-%, preferably at least 90 wt.-%, more preferably at least 95 wt.-%, based on the total weight of the fatty acids of saturated C8 and CIo fatty acids in the range of >_ 0.5 wt.-% to <_ 10 wt.-%, based on the total weight of the preparation, preferably in the range of _>
0.6 wt.- % to <_ 5 wt.-%, more preferably in the range of _ 0.8 wt.-% to <_ 2 wt.-%, and especially preferred at about 1 wt.-%.

Preferred embodiments of the preparation of the present invention, in particular on the basis of gels, with amounts of gel-forming agents in the aqueous phase in the range of _ 0.1 wt.-% to 3 wt.-%, based on the total weight of the preparation, in particular about 0.2 wt.-%, comprise a mid-chain triglyceride in the range of ? 0.5 wt.-% to <_ 10 wt.-%, in particular about 1 wt.-%
mid-chain triglyceride.

A further specific advantage of the preparation is provided by the fact that the preparation can comprise a corresponding amount of triglycerides without using emulsifiers simultaneously.
This has the significant advantage that proportions of remaining natural tear liquid of the eye, which may still be present, are not destroyed by an emulsifier.

Preferably the triglycerides in the preparation of the present invention are present in the form of finely dispersed droplets. Without being bound to a certain theory, it is assumed that the presence of triglycerides in the preparation of the present invention in the form of finely dispersed droplets provides a surprising stability, even over extended storage times without adding emulsifiers.

Another advantage of the preparation is achieved by the fact that the preparation, in particular in the form of single dose units, is very stable even without preservatives and not only under the conditions of moderate climate (21 C, 45% r. h., relative humidity) or Mediterranean subtropical climate (25 C, 40% r. h.), but also under very hot and moist climatic conditions, for example at 25 C, 60% r. h., at 30 C, 70% r. h. or at 40 C, 75% r. h., and shows small or only slight changes regarding pH value, osmolality, viscosity and appearance for at least three months, preferably six months, more preferably nine months, even more preferably twelve months, further preferred 18 months, most preferably 26 months.

The preparation of the present invention cannot preferably comprise drugs or pharmaceutically active agents such as antiviral agents, steroidal and nonsteroidal anti-inflammatory compounds or corticosteroids, antibiotics, antimycotics, anaesthetics, anti-inflammatory agents or anti-allergic agents. Pharmaceutically active agents in the sense of the invention do not include vitamin A and vitamin E, in particular.

In preferred embodiments, the preparation of the present invention can further comprise at least one ophthalmic active agent, for example a vitamin A component, preferably vitamin A-palmitate. Beyond the use of vitamins, such as vitamin A and/or vitamin E, there are preferably no pharmaceutically active components in the preparation of the present invention.
The particularly preferred content of vitamin A palmitate is about 1000 I.E.
vitamin A
palmitate per gram preparation, whereby preferably an additional 20% extra stability amount is used. Preferred suitable vitamin A palmitate has 1 million I.E. per gram vitamin A palmitate and comprises preferably butylated hydroxyanisole and/or butylated hydroxytoluene as stabilisers. Preferably, the content of a vitamin A component, in particular vitamin A
palmitate is in the range of _ 0.05 wt.-% to _ 0.5 wt.-%, preferably in the range of _ 0.08 wt.-% to 5 0.2 wt.-%, especially preferred at about 0.1 wt.-%, with consideration of the extra stability amount of about 0.12 wt.-%, based on the total weight of the preparation.

Particularly preferred, the vitamin A component is used in combination with an antioxidant such as vitamin E. The Vitamin A component is preferably stabilized with at least one antioxidant, preferably vitamin E, more preferably D,L-a-tocopherole.
Especially preferred, a small content of antioxidant is used for stabilization, preferably vitamin E, more preferably D,L-a-tocopherole, for example, in the range of _ 0.002 wt.-% to _< 0.01 wt.-%, preferably in the range of >_ 0.006 wt.- % to <_ 0.008 wt.-%, based on the total weight of the preparation.
Another advantage is that an active agent such as a vitamin A component, which is suspended or dissolved in the oil phase, can be dispersed more uniformly. The wettability of objects applied to the cornea, such as contact lenses or front lenses of ophthalmic devices, is thereby improved.

In preferred embodiments the preparation comprises one or more agents for adjusting the isotonicity, preferably multivalent alcohols such as dextrose, glycerol, propylene glycol, sorbitol or mannitol, preferably the preparation comprises sorbitol.

Preferably, the preparation has one or more agents for adjusting the isotonicity in an amount, which is sufficient to provide the preparation isotonically with natural tear liquid. In preferred embodiments, the preparation comprises isotonicity agents, preferably sorbitol in the range of _ 0.5 wt.-% to <_ 10 wt.-%, based on the total weight of the preparation, preferably in the range of _ I wt.-% to <_ 5 wt.-%, especially preferred at about 4 wt.-%. In further preferred embodiments the preparation comprises isotonicity agents, preferably sorbitol in the range of _ 3.5 wt.-% to <_ 4 wt.-%, preferably in the range of _ 3.6 wt.-% to <_ 3.7 wt.-%, based on the total weight of the preparation. In particular, the preparation can comprise sorbitol in the range of _ 3.6 wt.-% to <_ 3.7 wt.-%, more preferably at about 3.666 wt.-%, based on the total weight of the preparation, if the preparation comprises also glycerol.

In preferred embodiments the preparation has an osmolality in the range of _ 100 mosmol/kg to <_ 500 mosmol/kg, preferably in the range of _ 200 mosmol/kg to <_ 300 mosmol/kg, especially preferred in the range of ? 220 mosmol/kg to <_ 260 mosmol/kg.

Preferably the pH value of the ophthalmic preparation is adjusted with acids and/or bases, preferably with boric acid and/or sodium hydroxide solution, wherein the use of a 2 to 3 %
solution of sodium hydroxide in water is particularly preferred.

The sterile, drop-forming, ophthalmic preparation comprises preferably sodium hydroxide, preferably in the range of _ 0.02 wt.-% to <_ 1 wt.-%, based on the total weight of the preparation, further preferred in the range of _ 0.05 wt.-% to <_ 0.1 wt.-%, especially preferred in the range of _ 0.06 wt.-% to _ 0.07 wt.-%. These values refer to the solid sodium hydroxide, unless indicated otherwise. In especially preferred embodiments the preparation without preservatives comprises about 0.0665 wt.-% sodium hydroxide, based on the total weight of the preparation, and a preparation which comprises preservatives comprises preferably about 0.06333 wt.-% sodium hydroxide, based on the total weight of the preparation.

In preferred embodiments, the ophthalmic preparation comprises substances selected from the group comprising polyacrylic acid, polymeric acrylic acid derivatives, preferably carbomer, triglycerides, preferably mid-chain triglycerides, water-soluble phosphate salts, preferably Na2HPO4 x 12 H20, sorbitol, sodium hydroxide and/or water. In particularly preferred embodiments, the ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer, 4.0 wt.-% sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.0665 wt.-% sodium hydroxide and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-%
water, based on the total weight of the preparation.

In further preferred embodiments, the ophthalmic preparation comprises substances selected from the group comprising polyacrylic acid, polymeric acryl acid derivatives, in particular carbomers, triglycerides, in particular mid-chain triglycerides, water-soluble phosphate salts, in particular NazHPO4 x 12 H20, a vitamin A component, preferably vitamin A
palmitate, vitamin E, preferably D,L-a-tocopherole, sorbitol, sodium hydroxide and/or water. In further especially preferred embodiments the ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer, 4.0 wt.-% sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.0665 wt.-% sodium hydroxide, 0.12 wt.-% vitamin A palmitate, 0.006 wt.-% vitamin E, preferably D,L-a-tocopherole and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-% water, based on the total weight of the preparation.

In advantageous embodiments, the preparation has a pH value in the range of >_ 6 to <_ 8, preferably in the range of _ 6,5 to <_ 7,5. In particularly advantageous embodiments, the preparation has a pH value in the range of _ 6.8 to <_ 7.2.

The preparation of the present invention can further comprise components, for example, preservatives, preferably selected from the group comprising cetrimide, benzododecinium chloride, benzalkonium chloride and/or thiomersal. Preferably the preservatives are selected from the group comprising cetrimide and/or alexidine. Preferably the preparation comprises preservatives, preferably selected from the group comprising cetrimide, benzododecinium chloride, benzalkonium chloride and/or thiomersal in the range of _ 0.001 wt.-% to <_ 0.05 wt.-%, based on the total weight of the preparation, more preferably in the range of _ 0.005 wt.-%
to <_ 0.01 wt.-%.

"Cetrimide" is the common name for N-cetyl-N,N,N-trimethyl-ammonium bromide, "benzododecinium chloride" for N-benzyl-N-dodecyl-N,N-dimethyl-ammonium chloride, "benzalkonium chloride" for benzyllauryldimethylammonium chloride, and "thiomersal" for the sodium salt of 2-(ethylmercurythio)-benzoate.

In preferred embodiments, the preparation comprises 0.01 wt.-% cetrimide and/or benzododecinium chloride, based on the total weight of the preparation. In further preferred embodiments, the preparation comprises 0.01 wt.-% benzalkonium chloride, based on the total weight of the preparation. In particularly preferred embodiments, the preparation is free of preservatives.

The preparation of the present invention can comprise alexidine as further substance, preferably alexidine hydrochloride, preferably the preparation of the present invention can comprise about 3 ppm of alexidine=2HCI, based on the total weight of the preparation.
Alexidine is not an emulsifier in the sense of the present invention, or alexidine is comprised in amounts such that the substance does not exhibit an emulsifying effect.

As a further substance the preparation of the present invention can comprise glycerol, also designated as glycerine, for example, in an amount of about 0.2 wt.-%, based on the total weight of the preparation. Glycerine is not an emulsifier in the sense of the present invention, or glycerine is comprised in amounts such that the substance does not exhibit an emulsifying effect.

Preferably, the preparation can comprise glycerol in the range of _ 0.01 wt.-%
to _ 1.0 wt.-%, based on the total weight of the preparation, preferably in the range of >_ 0.lwt.-% to <_ 0.5 wt.-%, especially preferred in the range of >_ 0.2 wt.-% to S 0.3 wt.-%. The preparation can comprise glycerol in the form of 100 % glycerol or 85 % glycerol, which is preferably a mixture with water. In preferred embodiments, the preparation can comprise 0.2 wt.-%
glycerol (100 %) or 0.23 5 wt.-% glycerol (85 %).

In preferred embodiments, the ophthalmic preparation comprises substances selected from the group comprising polyacrylic acid, polymeric acrylic acid derivatives, preferably carbomers, triglycerides, preferably mid-chain triglycerides, water-soluble phosphate salts, preferably NaZHPO4 x 12 H20, a vitamin A component, preferably vitamin A palmitate, vitamin E, preferably D,L-a-tocopherol, sorbitol, sodium hydroxide, preservatives, preferably cetrimide, benzododecinium chloride, benzalkonium chloride or alexidine, glycerol and/or water.

In still more preferred embodiments, the ophthalmic preparation comprises substances selected from the group comprising polyacrylic acid, polymeric acrylic acid derivatives, in particular carbomers, triglycerides, in particular mid-chain triglycerides, water-soluble phosphate salts, in particular Na2HPO4 x 12 H20, sorbitol, sodium hydroxide, glycerol and/or water. In further especially preferred embodiments, the ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer, 3.666 wt.-% sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.063 wt.-% sodium hydroxide, 0.235 wt.-% glycerol (85 %) or 0.2 wt.-% of glycerol (100%) and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-% water, based on the total weight of the preparation.

In still further preferred embodiments, the ophthalmic preparation comprises substances selected from the group comprising polyacrylic acid, polymeric acrylic acid derivatives, in particular carbomers, triglycerides, in particular mid-chain triglycerides, water-soluble phosphate salts, in particular Na2HPO4 x 12 H20, a vitamin A component, preferably vitamin A palmitate, vitamin E, in particular D,L-a-tocopherol, sorbitol, sodium hydroxide, glycerol and/or water. In further especially preferred embodiments, the ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer, 3.666 wt.-%
sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.063 wt.-% sodium hydroxide, 0.12 wt.-% vitamin A
palmitate, 0.006 wt.-% vitamin E, preferably D,L-a-tocopherol, 0.235 wt.-% glycerol (85 %) or 0.2 wt.-% glycerol (100 %) and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-% water, based on the total weight of the preparation.

In further preferred embodiments, the ophthalmic preparation comprises substances selected from the group comprising polyacrylic acid, polymeric acrylic acid derivatives, preferably carbomer, triglycerides, preferably mid-chain triglycerides, water-soluble phosphate salts, preferably Na2HPO4 x 12 H20, a preservative, preferably cetrimide, sorbitol, sodium hydroxide and/or water. In further particularly preferred embodiments, the ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer, 4.0 wt.-%
sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.06333 wt.-% sodium hydroxide, 0.1 wt.-%

cetrimide and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-%
water, based on the total weight of the preparation. In especially preferred embodiments, the ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer, 4.0 wt.-%
sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.06333 wt.-% sodium hydroxide, 0.01 wt.-%
cetrimide and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-%
water, based on the total weight of the preparation.

In further preferred embodiments, the ophthalmic preparation comprises substances selected from the group comprising polyacrylic acid, polymeric acrylic acid derivatives, preferably carbomers, triglycerides, preferably mid-chain triglycerides, water-soluble phosphate salts, preferably Na2HPO4 x 12 H20, a vitamin A component, preferably vitamin A
palmitate, vitamin E, preferably D,L-a-tocopherol, sorbitol, sodium hydroxide, preservatives, preferably cetrimide or benzododecinium chloride and/or water. In further preferred embodiments, the ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer, 4.0 wt.-% sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.06333 wt.-% sodium hydroxide, 0.1 wt.-%
cetrimide, 0.12 wt.-% vitamin A palmitate, 0.006 wt.-% vitamin E, preferably D,L-a-tocopherol and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-%
water, based on the total weight of the preparation. In still further preferred embodiments, the ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer, 4.0 wt.-%
sorbitol, 0.1 wt.-% NaZHPO4 x 12 H20, 0.06333 wt.-% sodium hydroxide, 0.01 wt.-%
cetrimide, 0.12 wt.-% vitamin A palmitate, 0.006 wt.-% vitamin E, preferably D,L-a-tocopherol and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-%
water, based on the total weight of the preparation.

In still more preferred embodiments, the ophthalmic preparation comprises substances selected from the group comprising polyacrylic acid, polymeric acrylic acid derivatives, preferably carbomers, triglycerides, preferably mid-chain triglycerides, water-soluble phosphate salts, preferably Na2HPO4 x 12 H20, glycerol, sorbitol, sodium hydroxide, preservatives, preferably cetrimide or benzalkonium chloride and/or water. In still further preferred embodiments, the ophthalmic preparation comprises 0.2 wt.-%
polymeric acrylic acid, preferably carbomer, 3.666 wt.-% sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.063 wt.-%
sodium hydroxide, 0.01 wt.-% cetrimide or 0.01 wt.-% benzalkonium chloride, 0.2 wt.-%
glycerol (100 %) or 0.235 wt.-% glycerol (85 %) and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-% water, based on the total weight of the preparation.

In yet further preferred embodiments, the ophthalmic preparation comprises substances selected from the group comprising polyacrylic acid, polymeric acrylic acid derivatives, preferably carbomers, triglycerides, preferably mid-chain triglycerides, water-soluble phosphate salts, preferably Na2HPO4 x 12 H20, glycerol, sorbitol, sodium hydroxide, preservatives, preferably alexidine and/or water. In other preferred embodiments, the ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer, 3.666 wt.-% sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.063 wt.-% sodium hydroxide, 0.0003 wt.-% alexidine HC1, 0.2 wt.- % glycerol (100%) or 0.235 wt.-% glycerol (85 %) and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-% water, based on the total weight of the preparation.

In particularly preferred embodiments, the ophthalmic preparation comprises the following substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 4.0 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.0665 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f ad 100 wt.-% water.

Unless indicated otherwise, the amount of the respective substances contained in the preparation are selected such that the total amount of the respective substances does not exceed 100 wt.-%, based on the total weight of the preparation.

Within the meaning of this invention the term "substance" describes substances which are in the preparation, in particular those selected from the group comprising polymeric acrylic acid, polymeric acrylic acid derivatives, carbomer, sorbitol, water-soluble phosphate salt, preferably Na2HPO4 x 12 H20, sodium hydroxide, mid-chain triglycerides, preservatives, preferably cetrimide, vitamin A component, preferably vitamin A palmitate, vitamin E, preferably D,L-a-tocopherol, glycerol and/or water.

In further preferred embodiments the ophthalmic preparation comprises the following substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 4.0 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.06333 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.1 wt.-% cetrimide;
g. ad 100 wt.-% water.

In still further preferred embodiments, the ophthalmic preparation comprises the following substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 4.0 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.06333 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.1 wt.-% cetrimide;
g. 0.12 wt.-% vitamin A palmitate;
h. 0.006 wt.-% D,L-a-tocopherol;
i. ad 100 wt.-% water.

In other preferred embodiments, the ophthalmic preparation comprises the following substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 4.0 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.06333 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.01 wt.-% cetrimide;
g. ad 100 wt.-% water.
In still further preferred embodiments, the ophthalmic preparation comprises the following substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 4.0 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.06333 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.01 wt.-% cetrimide;
g. 0.12 wt.-% vitamin A palmitate;
h. 0.006 wt.-% D,L-a-tocopherol;
i. ad 100 wt.-% water In yet preferred embodiments, the ophthalmic preparation comprises the following substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 3.666 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.063 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;

f. 0.01 wt.-% benzalkonium chloride;
g. 0.2 wt.-% glycerol (100 %), or 0.235 wt.-% glycerol (85 %);
h. ad 100 wt.-% water.

In other preferred embodiments, the ophthalmic preparation comprises the following substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 3.666 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H-)O;
d. 0.063 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.0003 wt.-% alexidine HCI;
g. 0.2 wt.-% glycerol (100 %), or 0.235 wt.-% glycerol (85 %);
h. ad 100 wt.-% water.

In yet further preferred embodiments, the ophthalmic preparation comprises the following substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 3.666 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H?O;
d. 0.063 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.2 wt.-% glycerol (100 %), or 0.235 wt.-% glycerol (85 %);
g. ad 100 wt% water.

The preparation of the present invention is advantageously prepared aseptic without any problems and is well tolerated. The preparation of the sterile composition of the present invention, in particular gel composition, is preferably carried out in a multi-step method. In particular, at least one water-soluble phosphate salt is added to the aqueous phase of the composition of the present invention.

It is apparent that the ophthalmic preparation is preferably sterile for use.
Sterile substances are, therefore, either used under sterile conditions or the preparation is sterilized after the incorporation of these substances.

In a preferred method of production of a preparation of the present invention, a suspension of the polymeric acrylic acid or the polymeric acrylic acid derivative, in particular a carbomer, is prepared, preferably under aseptic conditions. To this suspension, a sterile-filtered solution of the isotonicity agent, preferably sorbitol, also comprising sodium monohydrogen phosphate dodecahydrate or other phosphate salts, and if necessary a preservative, is then added. Here, preferably sterile-filtered nitrogen or compressed air as pressure gas is used. After thoroughly mixing, the carboxyl groups of the polyacrylic acid component are neutralized by adding a suitable base (preferably sterile 2% to 3% sodium hydroxide solution), the gel-forming of the polyacrylic acid component is then induced and the mixture is stirred preferably until homogeneity of the gel is achieved.

To the prepared sterile hydrogel, the hydrophobe liquid phase, preferably the mid-chain triglyceride component is then added under aseptic conditions. Preferably, the mid-chain triglyceride is dispersed homogeneously into the continuous aqueous phase, in particular the sterile hydrogel.

Preferably, it is stirred until complete homogenization is achieved. The dimension of the so prepared droplets of the hydrophobic liquid phase, or oil drops, in the dispersion has a maximum size of about 100 m. Afterwards, the sterile preparation can be converted in the usual manner.

In the production method of a preparation of the present invention an active agent such as vitamin A palmitate can also be added to the so prepared sterile gel.
Preferably, the active agent is added under aseptic conditions and mixed homogeneously. Preferably, the vitamin A
component and the very small amount of antioxidant, which is preferably present, are dissolved in the hydrophobic phase and then filtered sterilely. The sterile, hydrophobic, active agent-containing phase is then incorporated into the gel under agitation.

It is especially advantageous that the ophthalmic preparation of the present invention is useful for preparing a cosmetic and/or pharmaceutical preparation for the treatment of diseases or conditions of the eye or of the organs or tissue surrounding the eye or connected therewith, in particular of dry eye.

Due to the advantageous substances of the preparation, it can be used for the treatment of diseases or conditions of the eye or the organs or tissues surrounding the eye or connected therewith, in particular in the form of a gel preparation. In particular, the preparation is suitable for relieving discomfort related to dry eye and/or for the symptomatic treatment of dry eye.

In particular, the preservative-free ophthalmic preparation of the present invention is advantageously suitable for the long-term application of dry eye. Due to the advantageous substances of the ophthalmic preparation, the preservative-free ophthalmic preparation can especially be safely reapplied and used, for example, as a tear replacement agent.
Surprisingly, it was found that within a few minutes after application of the preparation, significant improvement of disorders, such as feeling of dryness in the eye as well as burning, itching, redness, or swelling can be achieved. It is of particular advantage that these disorders are continuously relieved by the preparation of the present invention.

For application, the preparation of the present invention is preferably filled up in suitable containers, which are preferably formed such that the content can be applied onto the eye, for example in dropping bottles, in particular in containers well known under the designation Ophtiole , advantageously based on polyethylene, preferably HDPE (polyethylene of high density, high density polyethylene) or LDPE (polyethylene of low density, low density polyethylene).

In preferred embodiments of the ophthalmic preparation, the preparation is contained in a single-dose unit, preferably in a single-dose container, for example, known under the designation single-dose-Ophtiole , preferably based on LDPE. In particularly preferred embodiments of the ophthalmic preparation, the preparation is present in the form of a gel preparation in a single-dose container free of preservatives.

In further preferred embodiments of the sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation, the preparation is contained in a multi-dose unit, for example a multi-dose container. In especially preferred embodiments of the ophthalmic preparation, the preparation is preferably present in the form of a gel preparation in a multi-dose container free of preservatives.

A multi-dose unit contains a larger quantity of the sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation, for example several doses. Thus, it is advantageously possible that, for example, a multiple dose can be contained in one container.

The viscosity was determined by the cone/plate-method ("Platte-Kegel-Verfahren") with a rheometer of the type DV-III+ by the company Brookfield using a CP51-spindle at 5 U/rpm at 20 C. Viscosity data refers to the viscosity of the composition prior to application on the eye, unless indicated otherwise.

The following embodiment example serves to explain the invention and does not represent any restriction.

Example 1 Eye gel comprising, based on 100 kg:
- 0.2 kg polymeric acrylic acid* ~;
- 4.0 kg sorbitol;

- 0.1 kg Na2HPO4 x 12 H20;
- 0.0665 kg sodium hydroxide;
- 1 kg mid-chain triglycerides*2;
- ad 100 kg water.

For example available under the trade name Carbopol 980 NF from the company Noveon Inc.
*2 For example available under the trade name Myritol 318 .

The preparation has a viscosity of 781 mPa=s, determined by the cone/plate-method ("Platte-Kegel-Verfahren") with a rheometer of the type DV-III+ by the company Brookfield using a CP51-spindle at 5 U/min, at 20 C, a pH value of 7,0 and an osmolality of 261 mosmol/kg.

Claims (62)

1. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation, comprising at least one liquid aqueous phase and at least one liquid hydrophobic phase, characterised in that the preparation comprises at least one phosphate salt and has a viscosity in the range of >= 200 mPa.cndot.s to <= 2000 mPa.cndot.s, determined by the cone/plate-method ("Platte-Kegel-Verfahren") at 20°C.

2. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation as claimed in claim 1, wherein said ophthalmic preparation is a gel preparation.

3. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation as claimed in claims 1 or 2, characterised in that the viscosity is in the range of >= 300 mPa.cndot.s to <= 1800 mPa.cndot.s.

4. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation as claimed in claim 3, wherein the viscosity is in the range of >= 400 mPa.cndot.s to <= 1500 mPa.cndot.s.

5. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation as claimed in claim 4, wherein the viscosity is in the range of >= 500 mPa.cndot.s to <= 1400 mPa.cndot.s.

6. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation as claimed in claim 5, wherein the viscosity is in the range >= 600 mPa.cndot.s to <= 1350 mPa.cndot.s.

7. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation as claimed in claim 6, wherein the viscosity is in the range of >= 650 mPa.cndot.s to <= 1300 mPa.cndot.s.

8. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1 - 7, characterised in that the at least one phosphate salt is water soluble and is selected from the group of phosphate salts consisting of alkali phosphate salts, alkaline-earth phosphate salts, ammonium phosphate salts, mono- or dihydrogen phosphates thereof and/or mixtures thereof.

9. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation as claimed in claim 8, wherein the at least one phosphate salt is selected from the group consisting of sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium dihydrogen phosphate, potassium monohydrogen phosphate and/or mixtures thereof.

10. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-9, characterised in that the preparation comprises Na2HPO4 x 12 H2O in the range of >= 0.01 wt.-% to <= 5.0 wt.-%, based on the total weight of the composition.

11. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation as claimed in claim 10, wherein the preparation comprises Na2HPO4 x 12 H2O in the range of >= 0.05 wt.-%
to <= 0.5 wt.-% based on the total weight of the composition.

12. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation as claimed in claim 11, wherein the preparation comprises Na2HPO4 x 12 H2O in the range of >= 0.08 wt.-%
to <= 0.2 wt.-%.

13. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation as claimed in claim 12, wherein the preparation comprises about 0.1 wt.-% of Na2HPO4 x 12 H2O.

14. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-13, characterised in that the preparation comprises the aqueous phase as continuous phase and the hydrophobic phase as droplets dispersed therein.

15. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-14, characterised in that the preparation comprises at least one polymeric gel-forming component.

16 The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 15, wherein the preparation comprises a polyacrylic acid and/or a polymeric acrylic acid derivative.

17. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 16, wherein the polyacrylic acid and/or a polymeric acrylic acid derivative is a carbomer.

18. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-17, characterised in that the preparation comprises an ophthalmic acceptable organic oil.

19. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 18, wherein the ophthalmic acceptable organic oil is a triglyceride.

20. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 19, wherein the triglyceride is a mid-chain triglyceride.

21. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-20, characterised in that the preparation comprises at least one ophthalmic active agent.

22. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 21, wherein the ophthalmic active agent has a vitamin A component.

23. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 22, wherein the vitamin A component is vitamin A palmitate.

24. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 23, wherein the vitamin A palmitate is in combination with an antioxidant.

25. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 24, wherein the antioxidant is vitamin E.

26. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-25, characterised in that the preparation comprises sorbitol.

27. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-26, characterised in that the preparation comprises sodium hydroxide.

28. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-27, characterised in that the preparation comprises preservatives, selected from the group of preservatives consisting of cetrimide, benzododecinium chloride, benzalkonium chloride, alexidine and/or thiomersal.

29. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 28, wherein the preservatives are selected from the group of preservatives consisting of cetrimide, alexidine, or mixtures thereof.

30. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-29, characterised in that the preparation comprises glycerol, in the range of 0.01 wt.-% to <= 1.0 wt.-%, based on the total weight of the preparation.

31. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 30, wherein the preparation comprises glycerol in the range of >= 0.1 wt.-% to <= 0.5 wt.-%, based on the total weight of the preparation.

32. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 31, wherein the preparation comprises glycerol in the range of >=
0.2 wt.-% to <= 0.3 wt.-%, based on the total weight of the preparation.

33. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-32, characterised in that the preparation has an osmolality in the range of 100 mosmol/kg to <= 500 mosmol/kg.

34. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 33, wherein the osmolality is in the range of >= 200 mosmol/kg to <= 300 mosmol/kg.

35. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 33, wherein the osmolality is in the range of >= 220 mosmol/kg to <= 260 mosmol/kg.

36. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-35, characterised in that the preparation has a pH value in the range of >= 6 to <= 8.

37. The sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 36, wherein the pH value is in the range of >= 6.8 to <=
7.2.

38. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-37, characterised in that the preparation comprises one or more substances selected from the group of substances consisting of polyacrylic acid, polymeric acrylic acid derivatives, triglycerides, water-soluble phosphate salts, vitamin A, vitamin E, sorbitol, sodium hydroxide, a preservative, glycerol and water.

39. The ophthalmic preparation as claimed in claim 38, wherein said polymeric acrylic acid derivative is a carbomer.

40. The ophthalmic preparation as claimed in claim 38, wherein said triglycerides are mid-chain triglycerides.

41. The ophthalmic preparation as claimed in claim 38, wherein said phosphate salt is Na2HPO4 x 12 H2O.

42. The ophthalmic preparation as claimed in claim 38, wherein said vitamin A
component is vitamin A palmitate.

43. The ophthalmic preparation as claimed in claim 38, wherein said vitamin E
component is D,L-.alpha.-tocopherol.

44. The ophthalmic preparation as claimed in claim 38, wherein said preservative is selected from the group of preservatives consisting of cetrimide, benzododecinium chloride, benzalkonium chloride, and alexidine.

45. Sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-44, characterised in that the preparation comprises the following substances, based on the total weight of the preparation:

a. 0.2 wt.-% polymeric acrylic acid;
b. 4.0 wt.-% sorbitol;

c. 0.1 wt.-% Na2HPO4 x 12 H2O;
d. 0.0665 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. ad 100 wt.-% water.

46. Method of preparing a sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1 to 45, characterised in that a liquid hydrophobic phase is homogeneously dispersed into a continuous aqueous phase.

47. Method of preparing a sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 46, wherein the liquid hydrophobic phase is a mid-chain triglyceride.

48. Method of preparing a sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 46 or 47, wherein the aqueous phase is a sterile hydrogel previously prepared.

49. Method of preparing a preparation according to claims 46-48, characterised in that a polyacrylic acid and/or a polymeric acrylic acid derivative is used, which is converted for gel-forming by neutralisation of the carboxyl groups with a suitable base.

50. Method of preparing a preparation according to claim 49, wherein the polyacrylic acid and/or a polymeric acrylic acid derivative used is a carbomer.

51. Method of preparing a preparation according to claim 49 or 50, wherein said suitable base is sodium hydroxide solution.

52. Method of preparing a preparation according to claims 46-51, characterised in that at least one water-soluble phosphate salt is added to the aqueous phase.

53. Method of preparing a preparation according to any one of claims 1-52, characterised in that an active agent is added under aseptic conditions and homogeneously mixed into the sterile preparation.

54. Method of preparing a preparation according to claim 53, wherein the active agent is vitamin A.

55. Use of a sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-54 for the preparation of a cosmetic and/or pharmaceutical preparation for the treatment of diseases or conditions of the eye or the organs or tissues surrounding the eye or being connected therewith.

56. Use of a sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to claim 55, wherein it is for the treatment of dry eye.

57. Preparation for the treatment of diseases or conditions of the eye or organs or tissues surrounding the eye or being connected therewith, comprising substances in accordance with any one of claims 1-56.

58. The preparation for the treatment of diseases or conditions of the eye or organs or tissues surrounding the eye or being connected therewith of claim 57, wherein such preparation is in the form of a gel preparation.

59. Single-dose container comprising a sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-58.

60. Single-dose container according to claim 59, characterised in that the ophthalmic preparation is free of preservatives.

61. Multiple-dose container comprising a sterile, drop-forming, multiphase, emulsifier-free ophthalmic preparation according to any one of claims 1-60.

62. Multiple-dose container according to claim 61, characterised in that the ophthalmic preparation is free of preservatives.