Composition for the treatment of dry eye

Description

AREA OF INVENTION

[0001] The invention relates to a composition, as defined in the patent claims, for the prevention and treatment of dry eye or rewetting disorders of the cornea of ​​the eye. BACKGROUND OF THE INVENTION

[0002] Dry eye syndrome, also known as keratoconjunctivitis sicca, is a chronic and usually progressive disease caused by multiple factors and associated with a range of different symptoms. Recently, science has gained increasing insight into the precise pathogenesis of the disease, down to the molecular biological mechanisms of its development. According to current knowledge, there are several mechanisms that contribute to the development of the disease (Michael A. Lemp: The Definition and Classification of Dry Eye Disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Work Shop 2007. The Ocular Surface, April 2007, Vol. 5, no. 2).These include a decrease or complete cessation of tear film secretion, instability of the resulting tear film, hyperosmolarity of the tear film, deterioration of the tear film breakup time (TBUT), onset of inflammatory processes (expression of inflammatory-mediating cytokines such as interleukin-1, tumor necrosis factor alpha and matrix metalloproteinases), disturbance of the function of the meibomian glands and vitamin A deficiency in the corresponding regions.

[0003] The symptoms of affected patients, which are suitable as therapeutic targets, can include impaired visual function and vision (up to severe and highly restrictive manifestations), corneal staining in medical diagnostics (up to punctate erosions), deterioration of meibomian gland function (up to keratosis of the glands), deterioration of tear film breakup time (shortened to the immediate onset of tear film breakup), and deterioration of the Schirmer test (distance shortened to ≤ 2 mm / 5 min).

[0004] Current treatment for dry eye syndrome is stepwise, with the main focus, particularly in self-medication, on artificial tears. These contain gelling agents of varying strengths, ranging from hyaluronic acid (Hylo-Vision® range) to cellulose ethers and carbomer in varying concentrations.

[0005] Despite the undisputed effectiveness of this approach, there are weaknesses, including the following points. First, aqueous systems do not offer a satisfactory treatment option for vitamin A deficiency. Vitamin A is poorly water-soluble, and more water-soluble vitamin A derivatives exhibit increased toxicity (see also the publication by Myhre AM, Carlsen MH, Bøhn SK, Wold HL, Laake P, Blomhoff R. Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations. Am J Clin Nutr. 2003 Dec;78(6):1152-9).

[0006] The symptoms of dry eye syndrome in its hyperevaporative form, which is characterized by a disturbed or insufficient lipid layer on the tear film, can only be compensated for by very frequent use of purely aqueous eye drops, which almost inevitably leads to compliance problems.

[0007] Many other substances that occur physiologically in human tears cannot be adequately replaced by a gelling agent in aqueous formulations. This is particularly unsatisfactory because, based on positive observations with autologous serum eye drops prepared from patient material, significant positive effects in the treatment of dry eye syndrome could be expected if such substances were present in a suitable preparation.

[0008] In particular, other substances physiologically present in human tears are not substituted using state-of-the-art methods. Often, components of synthetic origin (e.g., polyvinylpyrrolidone or polyvinyl alcohol) or even bacterial origin are used instead of these naturally occurring substances. For example, the osmoprotective agent ectoine is isolated from the bacterium Halomonas elongata by fermentation (see, among others, the publication by Hansen et al. at TU Darmstadt). The disaccharide trehalose, which is also used, occurs in insects and yeasts, but not in mammals (cf. Baudouin et al., Role of Hyperosmolarity in the Pathogenesis and Management of Dry Eye Disease: Proceedings of the OCEAN Group Meeting. The Ocular Surface / October 2013, Vol. 11 No. 4).

[0009] An overview of the stepwise treatment options, which include the evidence-based selection of appropriate over-the-counter (OTC) medications in pharmacies, is provided in the publication by Pfister et al. in the German Pharmacists' Journal, issue 03 / 2014 ("Decision aids for the treatment of dry eye"). These treatment options comprise the concepts presented in Table 1 below. Table 1 stage Active ingredient(s) Pharmaceutical classification I Hyaluronic acid + Eyebright Plant origin (eyebright from the family Orobanchaceae) I Polyvinylpyrrolidone Synthetic production from acetylene chemistry IIa Carbomer Synthetic; may contain residual solvents and monomers; incompatible with polyvalent cations that occur physiologically in tear fluid (e.g., calcium). IIa Hypromellose Synthetically produced by reacting cellulose with sodium hydroxide, propylene oxide and methyl chloride IIa Hyaluronic acid Natural component of human connective tissue (glycosaminoglycan) IIa Hyaluronic acid + Polyethylene glycol Synthetically produced by polymerization of ethylene oxide IIa Hyaluronic acid + Carbomer Carbomer is produced synthetically. IIa Hyaluronic acid + electrolytes Contains no physiologically occurring osmolyte; commercial preparations contain phosphate buffer, which is suspected of causing corneal precipitates. IIa Polyvinyl alcohol + polyvinylpyrrolidone Synthetically produced; hydrolysis of polyvinyl acetate IIa Tamarind seed polysaccharides Plant origin (tamarind tree from the Fabaceae family) IIb Polyethylene glycol + propylene glycol Propylene glycol is produced synthetically by hydrolysis of propylene oxide. III Cyclosporine Immunosuppressant; isolated from the ascomycetes Tolypocladium inflatum (W. Gams) and Cylindrocarpon lucidum (Booth) At night Carbomer + Dexpanthenol Carbomer is produced synthetically. At night Vitamin A in a lipid-containing base Lipid-containing base contains paraffins and olefins (residues from petroleum distillation) Lipid replacement Carmellose + Glycerol Cellulose treatment with chloroacetic acid Lipid replacement Paraffin + Propylene Glycol + Phospholipid Paraffin from petroleum distillation, propylene glycol Lipid replacement Phospholipids + Vitamin A + Vitamin E Contains no physiologically occurring osmolyte

[0010] As can be seen in the current decision-making guide from the German Pharmacists' Journal, the majority of preparations on the market are based on active principles that are either synthetically produced, do not occur naturally in tear fluid, or are isolated from plants, or even from fungi or bacteria. Due to the way these components are formulated, there is a fundamental risk that they will be recognized as foreign by the human immune system and may contain residues such as monomers or impurities like solvents, etc., from the synthesis process. There is also a need to improve the efficacy of state-of-the-art preparations.

[0011] EP2783695 A1 concerns a medication in the form of eye drops or gel for the treatment of dry eye. The medication may contain taurine.

[0012] It is an object of the present invention to overcome the above-mentioned shortcomings and to provide an improved composition for the prevention and / or treatment of dry eye syndrome and corneal lubrication disorders. SUMMARY OF THE INVENTION

[0013] To solve this problem, the present invention provides: A composition as defined in claim 1 for the prevention and / or treatment of dry eye or corneal dryness, wherein the composition contains one or more osmolytes. Preferred embodiments are defined in the further claims. DETAILED DESCRIPTION OF THE INVENTION

[0014] The invention provides a composition as defined in the claims for use in the treatment and prevention (preferably treatment) of dry eye or corneal dryness, wherein the composition contains one or more osmolytes. The composition of the invention comprises one or more lipophilic components and an aqueous solution containing one or more osmolytes.

[0015] The lipophilic components can be a lipophilic base, such as an ointment base. The composition as defined in the claims is a two-phase system with a lipophilic phase (such as a lipid phase) and an aqueous phase, wherein the osmolyte(s) are preferably contained in the aqueous phase. The composition can be an emulsion. The composition, such as the emulsion, can have a continuous aqueous phase and a dispersed lipophilic phase, e.g., an oil-in-water emulsion. Preferably, however, the composition, such as the emulsion, has a continuous lipophilic phase and a dispersed aqueous phase, as in a water-in-oil emulsion.

[0016] Lipophilic components (compounds) that can be used in the composition are lipids and other lipophilic components. These components are known to those skilled in the art. Suitable lipophilic components include, for example, wool wax (Adeps Lanae) or wool wax substitutes, liquid paraffin, perliquid paraffin, petrolatum (e.g., white petrolatum), and lipids (e.g., natural vegetable oils) such as triglycerides (triacylglycerols, fats), phospholipids, steroids, castor oil, carotenoids, fatty acids, and waxes (alkyl fatty acid esters), which can be used individually or in combination with other components. The phospholipids can be phosphoglycerides (e.g., lecithins) and / or sphingomyelins. The acyl groups of the triglycerides, phospholipids, and waxes, and the fatty acids, can be saturated or unsaturated.The number of carbon atoms (chain lengths) of the acyl groups of the triglycerides, phospholipids, waxes, and fatty acids can range from 6 to 30, preferably from 14 to 24, and more preferably from 16 to 22. Generally, the acyl groups and fatty acids can be medium-chain (6 to 12 carbon atoms) or long-chain (14 to 30 carbon atoms), with the latter being preferred. Examples of suitable phosphoglycerides are 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG). A commercially available mixture of these is, for example, Softisan®.

[0017] The composition contains at least 60% by weight, preferably at least 70% by weight, and most preferably at least 80% by weight of lipophilic components. The high proportion of lipophilic components effectively compensates for disruption of the lipid layer in the tear film. This is particularly advantageous in the treatment of hyperevaporative dry eye syndrome.

[0018] The composition can be an ointment or a cream. Such formulations are known in principle to those skilled in the art, for example from dermatological preparations. Since the composition is an ointment or cream, the content of lipophilic components (compounds) is at least 60% by weight, preferably at least 70% by weight, and most preferably at least 80% by weight.

[0019] The composition, particularly for emulsions, may contain emulsifiers as needed to stabilize the composition or emulsion. Emulsifiers for pharmaceutical compositions are well known to those skilled in the art. For example, emulsifiers used in dermatological preparations may be employed. Some of the lipids mentioned above, such as phospholipids and fatty acids, can also act as emulsifiers. Other suitable emulsifiers include Kolliphor® EL (BASF), macrogol 15-hydroxystearate, and cetylstearyl alcohol. If emulsifiers are present, they are included in the calculation of the lipophilic component content.

[0020] The lipophilic base or phase may also contain other lipophilic components such as vitamin A, tocopherols, or tocotrienols. The vitamin A can be retinal, retinol, retinoic acid, retinyl palmitate, 3-dehydroretinol, and / or 3-dehydroretinal. A vitamin A content counteracts a mucin deficiency and defects in the mucin layer. This deficiency is caused by goblet cell dysfunction, which in turn is caused by a deficiency of this essential substance (see Karen Brian Fernandez, "A Stepwise Approach to Treatment of Dry Eyes," published in Primary Care Expert Opinion / Interview, May 23, 2013).

[0021] The composition of the invention comprises, in addition to the lipophilic components, an aqueous solution. The aqueous solution contains at least water and one or more osmolytes. The aqueous solution may contain further water-soluble pharmaceutical excipients. The osmolytes protect against disturbances of the aqueous phase of the tear film, which can lead to hyperosmolarity and subsequently trigger an inflammatory cascade. Since, on the other hand, the lipophilic components protect the lipid layer of the tear film, the composition of the invention exhibits an exceptional effect in protecting the tear film and in treating dry eye and tear film dysfunction.

[0022] The osmolyte(s) according to the invention is / are taurine and / or betaine (glycine betaine). Also disclosed are ectoine, sorbitol, trehalose, sarcosine, raffinose, trimethylamine N-oxide, glycerol, glycine, propylene glycol, butylene glycol, urea, lactic acid or salts thereof such as sodium lactate, dicycanamide, tremella extract, L-carnitine, erythritol, myo-inositol, dimethylsulfoniopropionate, and proline. It is also possible to combine the aforementioned osmolytes. A preferred combination is that of taurine and betaine; another combination is that of taurine, betaine, and glycine.

[0023] The osmolytes can generally be present in the composition in a total amount of 0.1 to 10 wt.%, preferably 0.2 to 5 wt.%, and more preferably 0.4 to 3 wt.% of the total mass of the composition. Depending on the desired mixing ratio of all the lipophilic components, the lipophilic base, or the lipophilic phase to the water content or aqueous solution in the composition, the osmolyte content in the aqueous solution can be chosen to be correspondingly higher in order to obtain the desired osmolyte content in the composition after mixing with the lipophilic components.

[0024] It may be provided that hyaluronic acid is included in the composition at a concentration of 0.05 to 0.5% wt.%, preferably 0.1 to 0.3% wt.%, as is the case in known, purely aqueous systems, for example the preparations Hylo-Vision ®< HD, Hylo-Vision ®< HD plus, Hylo-Vision ®< SafeDrop ®< and Hylo-Vision ®< SafeDrop ®< Gel. A suitable concentration of butylene glycol and propylene glycol in the composition, derived from purely aqueous systems, is between 0.1 and 0.5 wt%, preferably around 0.3 wt% (Stephen Cohen, Anna Martin, and Kenneth Sall, Evaluation of clinical outcomes in patients with dry eye disease using lubricant eye drops containing polyethylene glycol or carboxymethylcellulose. Clin Ophthalmol. 2014; 8: 157-164). A suitable concentration of sorbitol in the composition, derived from purely aqueous systems, is in the range of 1.5 to 4 wt%.-%, as is the case, for example, in the commercial preparations Vidisic®, Vidisic® Gel, Viscotears®, and Viscotears Gel® (summarized, for example, in: David A. Sullivan, Darlene A. Dartt, Michele A. Meneray. Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2. 1998, page 750). A suitable concentration of taurine in the composition, derived from purely aqueous systems, ranges from 0.05 wt% (Fuchs, SA, Berger, R., Klomp, LWJ, deKoning, TJ, 2005. D-aminoacids in the central nervous system in health and disease. Mol. Genet. Metab. 85, 168-180) up to 1 or even 4 wt%, as, for example, in commercially available eye drops such as Bestoxol®. A suitable concentration of betaine in the composition, derived from purely aqueous systems, lies between 0.1 wt% and 0.2 wt% (Wei Chen; Xin Zhang; Jinyang Li; Yu Wang; Qi Chen; Chao Hou; Qian Garrett Efficacy of Osmoprotectants on Prevention and Treatment of Murine Dry Eye.Investigative Ophthalmology & Visual Science September 2013, Vol. 54, 6287-6297). A suitable concentration of urea in the composition, derived from purely aqueous systems, is less than or equal to 0.5 wt%, preferably between 0.1 and 0.4 wt%, as specified, for example, in topical applications as specified in the 'Inactive ingredients list' available on the website of the US Food and Drug Administration (FDA).

[0025] In a preferred embodiment, the osmolyte(s) is / are selected from the group consisting of taurine and betaine, and the composition contains a total amount of these osmolytes of 0.1 to 10 wt.%, preferably 0.2 to 5 wt.%, more preferably 0.4 to 3 wt.% of the total mass of the composition.

[0026] The aqueous solution and composition may further contain excipients consisting of buffer substances, inorganic salts, organic salts, antioxidants, preservatives, stabilizers (e.g., EDTA), osmolarity regulators, and mixtures thereof. The aqueous solution may contain dissolved electrolytes, preferably one or more ions selected from the group consisting of sodium ions, potassium ions, calcium ions, magnesium ions, and chloride ions, and / or proteins, preferably one or more proteins selected from the group consisting of lacritin, lactoferrin, and serum albumin, preferably bovine serum albumin, and / or sugars, preferably glucose, and / or allantoin and / or dexpanthenol. Furthermore, the composition may also contain vitamins such as vitamin B12, vitamin A, or vitamin E.

[0027] In a preferred embodiment, the composition does not contain any antimicrobial preservatives, in particular no cationic surfactants as preservatives such as benzalkonium chloride, since these can damage the cornea.

[0028] Possible buffers for the aqueous solution include borate buffer, citrate buffer, phosphate buffer, Tris buffer, bicarbonate buffer, and mixtures or combinations thereof. Preferred buffers are citrate and Tris buffers, also in combination with other buffer salts. In one embodiment, the aqueous solution contains no buffer. The pH of the composition can range between 7.0 and 7.4.

[0029] The osmolality of the aqueous solution can be adjusted to 100-1000 mOsm / kg, preferably 200-500 mOsm / kg, particularly preferably 220-350 mOsm / kg, especially in the presence of a buffer system.

[0030] The composition of the invention can be prepared by mixing the components using methods known to those skilled in the art. For example, it is possible to first prepare separate mixtures of the lipophilic components on the one hand and the hydrophilic components on the other. If the composition contains two or more lipophilic components, these can be mixed, for example, by melting them together or by mixing solutions of them in an alcohol with a boiling point below 100°C, such as ethanol (the alcohol is subsequently removed). The aqueous solution can be prepared by dissolving all water-soluble components in water and adjusting the pH if necessary. The lipophilic components can then be mixed with the aqueous solution. Methods for preparing ointments, creams, water-in-oil, and oil-in-water emulsions are known to those skilled in the art. Liposome compositions and their preparation are also known.For example, the liposomes described in WO2017074475 and WO2018073720 (without the active ingredients mentioned therein) can be used. The composition can be sterilely filled into suitable single-dose or multi-dose containers. The preparations are tested for various specification parameters. The compositions can have a viscosity in the range of 5,000 to 300,000 mPa·s at 25°C, preferably a viscosity in the range of 10,000 to 200,000 mPa·s at 25°C.

[0031] The composition of the invention is used for the prevention or treatment of dry eye or corneal dryness, in particular hyperevaporative dry eye. Prevention or treatment can be performed on humans or animals, preferably on humans. Liquid or flowable formulations can be administered by instilling drops into the eyes. Ointments and creams can be applied to the eyelids and surrounding areas. Due to the preferably high content of lipophilic components, the composition can temporarily impair the refractive properties of the cornea and thus visual acuity. Therefore, the composition is preferably applied to the eyes, especially the eyelids and surrounding areas, before a break during which no particular demands are placed on visual acuity or before going to bed.Due to the high proportion of lipophilic components, frequent repetition of the treatment is not necessary. In one application variant, it may even be sufficient to apply the formula only before bedtime, i.e., once daily. The treatment can be continued as long as symptoms of dry eye or impaired lubrication persist.

[0032] In one embodiment, the composition is intended for use in the long-term treatment of dry eye syndrome, wherein the composition is administered at least once daily for a period of more than two and preferably more than six months. In another embodiment, the composition is intended for use in the treatment of dry eye syndrome by application to the eye before bedtime. The approach underlying the invention is extremely efficient in overcoming even severe symptoms of dry eye syndrome in long-term therapy.

[0033] Due to its content of both lipophilic components and osmolytes, this composition is particularly effective against ocular dryness and wetting disorders, and can be used for the treatment and / or prevention of hyperevaporative dry eye. Simultaneously, the composition provides moisture due to the water-binding properties of the osmolytes, thereby stabilizing both the middle aqueous layer of the tear film and the inner layer of the tear film facing the cornea. This significantly prolongs the tear film breakup time of the patient.

[0034] The composition according to the invention closely mimics the composition of tears with their physiological components. This approach is advantageous because it allows missing physiological components to be replaced without having to accept potential side effects such as allergic reactions to synthetic or bacterial substances.

[0035] In summary, the composition according to the invention for use in the treatment of dry eye syndrome consists of a lipophilic base and a dispersed aqueous phase containing one or more osmolytes, wherein the osmolytes are preferably detectable in natural tear fluid, such as the ingredients taurine or betaine. The preparation may be preservative-free. The preparation is an ointment or a cream. It may additionally contain the osmolytes ectoine, sorbitol, trehalose, sarcosine, raffinose, trimethylamine N-oxide, glycerol, glycine, propylene glycol, butylene glycol, lactic acid, or lactates such as sodium lactate, dicyanamide, tremella extract, L-carnitine, erythritol, myo-inositol, dimethylsulfoniopropionate, urea, or proline, individually or in combination and in an appropriate concentration.It may contain other, comparable, particularly physiological, osmolytes found in human tear fluid that have not been mentioned above. It may contain physiological components in the aqueous phase that also occur in human tear fluid, either modified or unchanged, or that can be replaced by analogous components, for example, from animals or synthetically, such as certain electrolytes (e.g., sodium chloride, potassium chloride, calcium chloride, and magnesium chloride), proteins (e.g., lactoferrin, serum albumin), vitamins, or glucose. It may contain a combination of the aforementioned components in a therapeutically applicable concentration.

[0036] Some preferred embodiments of the composition, which are disclosed but not claimed, are as follows: a composition comprising one or more lipophilic components or a lipophilic base and an aqueous solution, the aqueous solution containing one or more osmolytes selected from the group consisting of taurine, betaine, ectoine, trimethylamine N-oxide, glycine, urea and proline in a total concentration of these osmolytes of 0.1 to 10 wt.%, preferably 0.2 to 5 wt.%, more preferably 0.4 to 3 wt.% of the total mass of the composition.

[0037] A composition comprising one or more lipophilic components or a lipophilic base and an aqueous solution, the aqueous solution containing one or more osmolytes selected from the group consisting of taurine, betaine, trimethylamine N-oxide, glycine, and proline in a total concentration of these osmolytes of 0.1 to 10 wt.%, preferably 0.2 to 5 wt.%, more preferably 0.4 to 3 wt.% of the total mass of the composition.

[0038] A composition comprising one or more lipophilic components or a lipophilic base and an aqueous solution, the aqueous solution containing one or more osmolytes selected from the group consisting of taurine, betaine, trimethylamine N-oxide, glycine, urea and proline in a total concentration of these osmolytes of 0.1 to 10 wt.%, preferably 0.2 to 5 wt.%, more preferably 0.4 to 3 wt.% in the total mass of the composition, and the composition containing at least 50 wt.% of lipophilic components (compounds).

[0039] A composition comprising one or more lipophilic components or a lipophilic base and an aqueous solution, the aqueous solution containing one or more osmolytes selected from the group consisting of taurine, betaine, trimethylamine N-oxide, glycine, urea and proline in a total concentration of these osmolytes of 0.1 to 10 wt.%, preferably 0.2 to 5 wt.%, more preferably 0.4 to 3 wt.% in the total mass of the composition, and the composition containing at least 60 wt.%, preferably at least 70 wt.% of lipophilic components (compounds).

[0040] These preferred embodiments can be combined with other preferred features described above, including the use for the prevention and preferably the treatment of dry eye or eye wetting disorders.

[0041] Further details and advantages of the invention will become apparent from the exemplary embodiments presented below. EXAMPLES

[0042] Further details and advantages of the invention will become apparent from the exemplary embodiments presented below. All percentages refer to weight percent of the total composition. Examples 1 to 7 relate to the first aspect of the invention. Examples 8 to 13 relate to the second aspect of the invention. Example 1

[0043] Vitamin A-containing ointment in combination with betaine and propylene glycol for the prophylaxis or treatment of dry eye syndrome against disturbances of the lipid, mucin and aqueous phases of the tear film: ingredient Portion function White petroleum jelly 42,00% Lipid phase, antievaporative paraffin 30,00% Lipid phase, antievaporative Adeps Lanae 12,47% Lipid phase, antievaporative Vitamin A palmitate 0,03% Vitamin substitute Dexpanthenol 2,00% Tear film stabilizer α-Tocopherol acetate 0,10% Antioxidant, free radical scavenger Cetylstearyl alcohol 2,30% Emulsifier Betaine 0,20% Physiological osmolyte Propylene glycol 1,00% Humectant Water for injection purposes 9,90% solvent

[0044] The preparation is manufactured according to recognized pharmaceutical technology standards and Sterilia's Good Manufacturing Practice (GMP). The ingredients of the lipid phase (petroleum jelly, liquid paraffin, wool wax or wool wax substitute, and the appropriate emulsifier) ​​are heated and melted together. Vitamin A is added, the mixture is homogenized, and then the resulting mixture is sterile filtered (0.22 µm pore size). Simultaneously, the components of the aqueous phase (dexpanthenol, α-tocopherol acetate, betaine, and propylene glycol) are dissolved in the provided water for injection and passed through a suitable sterile filter. After performing the appropriate in-process controls, the mixtures are homogenized and aseptically filled into sterile tubes, which are then labeled. Example 2

[0045] Vitamin A-containing ointment in combination with taurine and sorbitol for overnight treatment of dry eye syndrome against disorders of the lipid, mucin and aqueous layers of the tear film and in combination with electrolytes as natural components of the aqueous phase of human tears: ingredient Portion function White petroleum jelly 50,0% Lipid phase, antievaporative paraffin 18,25% Lipid phase, antievaporative Softisan ®< 16,6% Lipid phase, antievaporative Vitamin A palmitate 0,03% Vitamin substitute Dexpanthenol 2,0% Tear film stabilizer α-Tocopherol acetate 0,1% Antioxidant, free radical scavenger Cetylstearyl alcohol 2,3% Emulsifier Sorbitol 1,5 % Humectant / Osmolyte Taurine 1,0 % Humectant / physiological osmolyte Sodium chloride 0,2 % electrolyte Potassium chloride 0,1 % electrolyte Calcium chloride 0,02 % electrolyte Water for injection purposes 7,9% solvent

[0046] The manufacturing process is analogous to example 1. Examples 3 to 6

[0047] Analogous to Example 1, compositions are prepared in which the betaine is replaced by myo-inositol, dimethylsulfoniopropionate and proline or trimethylamine N-oxide (Examples 3-5). In Example 6, the betaine from Example 1 is replaced by 0.1% betaine plus 0.1% taurine. Example 7 (not according to the invention)

[0048] Emulsion based on natural raw materials for the lipid phase. For example, sunflower seed, coconut, or castor oil can be used as the vegetable oil. ingredient Portion function Vegetable oil 2,0 % Lipid content Glycerol 1,0 % Humectant Tylaxapol 0,15 % Emulsifier Poloxamer 188 0,05 % Co-emulsifier Tris 0,05 % buffer Taurine 0,5% Osmolyte Water Ad 100.0% Solvent

[0049] The emulsion is prepared according to pharmaceutical standards. The fat-soluble components are dispersed in the aqueous phase by vigorous stirring. Subsequently, the pH value and zeta potential of the emulsion, as well as other quality parameters, are determined, and the pH is adjusted as needed. Example 8 (not according to the invention)

[0050] Low-concentration hyaluronic acid gel in combination with betaine for the prophylaxis of dry eye syndrome, especially against disturbances of the mucin and aqueous phases of the tear film, with the ingredients listed in the following table: ingredient Portion function Sodium hyaluronate 0,10 g Physiological gelling agent Sodium chloride 0,10 g electrolyte Sodium citrate 0,10 g buffer salt Betaine 0,20 g Physiological osmolyte Sorbitol qs Physiological tonic agent for adjusting tonicity Citric acid pH=7.0 to 7.4 pH adjustment Water for injection purposes Ad 100 ml solvent

[0051] The preparation is manufactured according to recognized pharmaceutical technology standards and Sterilia's Good Manufacturing Practice (GMP). A solution of the salts, sorbitol, and betaine in water for injection is homogenized and mixed with the gelling agent. After dissolving this component and stirring for a sufficient duration, sterilization is achieved by filtration with a pore size of 0.22 µm. The sterile filter is made of a suitable, non-particle-releasing material that is itself sterilizable by an appropriate method and does not adsorb the contained components. After performing the appropriate in-process controls, the resulting gel is aseptically filled into sterile dropper bottles for ophthalmic use or subjected to a blow-fill process to produce single-dose vials, and then labeled. Example 9 (not according to the invention)

[0052] Highly viscous eye gel with taurine and physiological electrolytes for the treatment of particularly severe forms of dry eye syndrome, containing the ingredients listed in the following table: ingredient Portion function Sodium hyaluronate 0,30 g Physiological gelling agent Sodium citrate 0,10 g buffer salt Taurine 0,20 g Physiological osmolyte Sodium chloride 0,10 g electrolyte Potassium chloride 0,10 % electrolyte Calcium chloride 0,02 % electrolyte Magnesium chloride 0,20 % electrolyte Sorbitol qs Physiological tonic Citric acid pH=7.0 to 7.4 pH adjustment Water for injection purposes ad 100 mL solvent The manufacturing process is analogous to example 7. Examples 10 to 13 (not according to the invention)

[0053] Analogous to Example 8, compositions are prepared in which the betaine is replaced by urea, choline, or trimethylamine N-oxide (Examples 10-12). In Example 13, the betaine from Example 8 is replaced by 0.1% betaine plus 0.1% taurine.

Claims

1. Composition for use in the treatment or prevention of dry eye or of corneal wetting disorders, wherein the composition contains one or more osmolytes, wherein the composition is an ointment or a cream and contains a lipophilic phase and an aqueous phase, and the aqueous phase contains the one or more osmolytes, wherein the composition contains at least 60% by weight of lipophilic components and wherein the composition contains taurine and / or betaine as osmolytes.

2. The composition for the use according to claim 1, wherein the composition contains one or more lipophilic components or a lipophilic base and an aqueous solution, and the aqueous solution contains the one or more osmolytes.

3. The composition for the use according to any one of claims 1 or 2, wherein the composition has an aqueous continuous phase and a dispersed lipophilic phase (oil-in-water emulsion); or wherein the composition has a continuous lipophilic phase and a dispersed aqueous phase (water-in-oil emulsion).

4. The composition for the use according to claim 2 or 3, wherein the composition contains at least 70% by weight and preferably at least 80% by weight of lipophilic components (compounds).

5. The composition for the use according to any one of claims 2 to 4, wherein the lipophilic components or the lipophilic base or the lipophilic phase contains lipophilic substances selected from the group consisting of lanolin, white petrolatum, paraffinum subliquidum, paraffinum perliquidum, and lipids such as triglycerides (such as medium-chain triglycerides), castor oil, phospholipids, steroids, carotenoids, fatty acids, and waxes.

6. The composition for the use according to any one of claims 2 to 5, wherein the lipophilic base or lipophilic phase comprises vitamin A, which is preferably one or more compounds selected from the group consisting of retinal, retinol, retinoic acid, retinyl palmitate, 3-dehydroretinol and 3-dehydroretinal.

7. The composition for the use according to any one of the preceding claims for use in the treatment of hyperevaporative dry eye.

8. The composition for the use according to any one of the preceding claims, wherein the composition contains from 0.1 to 10% by weight, preferably from 0.2 to 5% by weight, more preferably from 0.4 to 3% by weight of osmolytes measured relative to the total mass of the composition.

9. Single-dose container or multi-dose container containing the composition for the use according to any one of the preceding claims.