HK1259984A1 - Ophthalmological composition - Google Patents

Description

Ophthalmic composition

The present invention relates to an ophthalmic composition having high viscosity. The composition of the invention thus comprises or consists of hyaluronic acid or a hyaluronic acid derivative, such as an ophthalmically acceptable salt of hyaluronic acid and ectoin (ectoin) or an ophthalmically acceptable ectoin derivative. The composition is also characterized in that it is free of other pharmaceutically active ingredients.

Burning, itching and increased tear secretion with the feeling of sand entering the eye, or dry eye is a symptom of eye irritation. Typically, this is an indication that the eye has not been adequately supplied with moisture. However, another cause may also be an excessive sensitivity to certain substances (e.g. pollen, animal hair or house dust), so-called allergy. Since allergy is accompanied by the same symptoms, it is difficult to distinguish dry eye from eyes irritated by allergy.

Known solutions for counteracting irritation of the eye generally act only against one of the causes of said eye irritation or eye inflammation, namely against eye irritation and inflammation caused by dryness or by allergy.

Ectoine is a natural substance obtained from microorganisms living in extreme environments such as salt lakes. These microorganisms form the natural substance ectoin to protect themselves from the extreme environmental factors that are prevalent there.

From EP0671161B1, it is known that ectoin and its derivatives can be used as moisturizers in cosmetics to increase the moisture content of the skin. EP2214658B1 describes the use of ectoin in formulations containing penetrants for use in the case of dry nasal mucosa. The use of ectoin in solution to prevent and treat eye irritation and/or inflammation is not described in EP0671161B 1.

In contrast, DE102014007423a1 discloses a composition comprising ectoin for the treatment of ocular inflammation. In a random spot survey type examination of 59 patients, it was shown that the treatment of keratoconjunctivitis sicca with a composition comprising ectoin and/or hydroxyectoin and/or corresponding derivatives of these substances is somewhat more effective than the treatment with a hyaluronic acid solution.

It is now an object of the present invention to propose a solution for, or for use in, the prevention and treatment of eye irritation and/or inflammation, which is intended to be suitable for the prevention and treatment of eye irritation and/or inflammation caused by dryness and allergy, so that it is no longer necessary to distinguish between the various causes of the symptoms. In addition, the solution should not contain components that would normally cause eye irritation or impaired visual ability. Thus, the solution should have as high a viscosity as possible to ensure that the composition remains well adherent to the ocular surface for a long period of time. Furthermore, the solution should have as high a water binding capacity as possible to ensure continuous wetting of the eye.

Starting from the prior art, the object of the present invention is also to propose an ectoine-containing ophthalmic composition which has an improved effect in the treatment of eye irritation and/or inflammation and which can be produced more economically than conventional ophthalmic compositions containing hyaluronic acid.

This object is achieved by an ophthalmic composition according to the features of patent claim 1. The dependent patent claims therefore represent advantageous developments.

Accordingly, the present invention relates to an ophthalmic composition comprising or consisting of:

0.055 to 2.00% by weight of hyaluronic acid and/or an ophthalmically acceptable salt of hyaluronic acid,

-0.60% to 5.00% by weight of ectoin or an ophthalmologically acceptable ectoin derivative, and

-water to make up to 100% by weight,

the composition is free of other pharmaceutically active ingredients.

The solution according to the invention wets the cornea and conjunctiva and prevents excessive evaporation of tears. This stabilization of the tear film relieves ocular irritation associated with inflammatory symptoms, or ocular irritation caused by allergy. The burning and itching sensation of the eyes disappeared.

Sodium hyaluronate is a natural substance that can be found in the eye and other body parts. It ensures the formation of a uniform, stable and particularly long-term adherent wet film on the eye surface which cannot be rapidly rinsed off.

Ectoin increases the binding of water to cells on the surface of the eye and thus forms a physiological barrier in the conjunctiva, e.g., to mask substances that cause allergy. At the same time, ectoin stabilizes the lipid soluble portion of the tear film that prevents excessive tear evaporation.

Surprisingly, a synergistic effect of hyaluronic acid or a derivative thereof and ectoin on viscosity can be established using the composition of the invention. If these components are used at the concentrations of the present invention, it can be observed that the composition has a higher viscosity than a single solution containing only one of the components (hyaluronic acid or ectoin). The viscosity of the composition of the invention is even higher than the sum of the viscosities of the individual solutions.

The same applies to the water binding force: surprisingly, it has been found that in addition to a synergistic increase in viscosity, the water binding capacity is synergistically increased by the combination of the two substances. The compositions of the present invention are able to better and more strongly moisturize the eye and stabilize the tear film relative to comparable eye drop formulations. The best results are achieved by synergy with the minimum use of raw materials.

These findings also have a positive impact on the production costs of the composition. Hyaluronic acid and ectoin are both expensive raw materials. Thus, a synergistic increase in viscosity and water binding power proves to be very advantageous for saving raw materials and costs. Due to the synergistic effect, a selected viscosity and water binding capacity can be produced at lower raw material usage compared to prior art ophthalmic compositions, thus providing cost savings.

The composition of the invention comprising both ectoin and/or ectoin derivatives and hyaluronic acid and/or hyaluronic acid salts at said concentrations adheres better to the cornea and to the surface of the eye during application than conventional ophthalmic solutions. Thus ensuring that the protective film is retained on the surface of the eye, more effectively protecting the eye from external influences.

In cooperation with sodium hyaluronate and ectoin, it also provides a strong long-term adherent moist membrane to the eye and prevents tear evaporation. Thus, the irritation caused by the environment and dryness leading to the inflammatory symptoms is relieved as is typical of itching and burning that occurs during allergic reactions.

The compositions of the present invention are particularly suitable for use in the treatment or prevention of dry eye (sjogren's syndrome), for the treatment or prevention of conjunctival inflammation (conjunctivitis) and/or for the treatment or prevention of allergic reactions of the eye, such as hay fever.

In addition, the compositions of the present invention protect the eye from premature cellular damage. It is known from the literature that under hypertonic conditions, i.e. osmotic stress, very rapid formation of Reactive Oxygen Species (ROS) is caused. This is shown, for example, in Primary Human Corneal Epithelial Cells (Ruzhi Deng, Xia Hua, Jin Li, Wei Chi, Zongduan Zhang, Fan Lu, Lili Zhang, Stephen C.Pflugfelder and De-Quan Li, Oxidative Stress Markers Induced by hyper homogeneity in Primary Human Corneal Epithelial Cells, PLoS one.2015; 10(5): e 0126561). These reactive molecules form in response to osmotic stress, leading to cell damage (lipid peroxidation, oxidative changes in proteins and oxidative DNA damage) up to apoptosis, whether or not inflammation is present.

The combination of hyaluronic acid and ectoin in the form of viscous eye drops serves to different levels, counteracting the production of this reactive molecule and limiting damage if ROS are produced.

On the other hand, ectoin has a function of stabilizing a protein. Therefore, ectoin also stabilizes antioxidants in the tear film, such as Cu-Zn-SOD. On the other hand, ectoin is a substance having a high association-promoting ability (kosmotropic) which exhibits a strong interaction with water. It promotes the formation of clusters of water molecules and increases the surface tension of the water, which counteracts evaporation and correspondingly reduces or prevents osmotic stresses. However, since ectoin itself has osmotic activity, the osmotic stress to the eye should be reduced anyway, and therefore, the minimum amount of ectoin is desired. The beneficial properties of water binding power and viscosity of ectoin at low ectoin concentrations are ensured to achieve maximum effect by synergistic effect in combination with hyaluronic acid. Finally, by combining ectoin and the hyaluronic acid component, the synergistic increase in viscosity imparts longer residence time and hence extended protection, as long term wetting of the eye surface reduces osmotic stress and hence ROS generation.

It is further preferred according to this that the content of hyaluronic acid and/or ophthalmologically acceptable salts of hyaluronic acid is from 0.10% to 1.00% by weight, further preferably from 0.10% to 0.45% by weight, further preferably from 0.125% to 0.45% by weight, particularly preferably from 0.15% to 0.25% by weight, in particular from 0.15% to 0.20% by weight.

Alternatively or additionally, it is also preferred that the content of ectoin or an ophthalmologically acceptable ectoin derivative is from 0.75% to 3.00% by weight, preferably from 1.00% to 3.00% by weight.

Thus, the ophthalmically acceptable salt of hyaluronic acid is preferably selected from sodium hyaluronate, potassium hyaluronate and mixtures or combinations thereof.

In particular, the ectoin is L-ectoin ((S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid). Thus, preferred ectoin derivatives are selected from hydroxyectoin ((4S,5S) -5-hydroxy-2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid); salts, such as the sodium or potassium salt of ectoin; esters obtained by conversion of a 4-carboxyl group with an alcohol, in particular a linear or branched mono-or diol having from 1 to 20 carbon atoms, and/or of a 5-hydroxyl group with a carboxylic acid, in particular a linear or branched mono-or di-alkyl carboxylic acid having from 2 to 20 carbon atoms, for example an alkyl monocarboxylic acid; and acid addition salts of inorganic or organic acids.

Particular preference is given here to the alkyl groups of the alcohols or carboxylic acids each having up to 10 carbon atoms, in particular up to 5 carbon atoms.

According to a particularly preferred embodiment, the composition of the invention is free of preservatives. According to the invention, a preservative is thus understood to be any substance which can be used as an ophthalmic preservative, such as the further listed preservatives.

Preservatives can disrupt the pre-corneal tear film and cause a reduction in the number of microvilli and microfoldings on the surface of the corneal epithelial cells, which leads to eye irritation and/or inflammation. By omitting preservatives in the solutions of the present invention, such irritation and/or inflammation can thus be avoided.

In an alternative preferred embodiment, the composition of the invention may also comprise one or more than one preservative, in particular an ophthalmically acceptable or approved preservative. These preservatives are preferably selected from quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide or polyquaternium 1; mercury compounds such as thimerosal or phenylmercuric acetate; alcohols such as chlorobutanol; carboxylic acids, such as sorbic acid; phenols, such as parabens; amidines, such as chlorohexidine; EDTA, particularly the disodium salt of EDTA; sodium hydroxymethylgluconate; sodium perborate; a phosphonic acid; (ii) a porinium chloride; sodium chlorite and mixtures or combinations thereof. Preferably, however, the composition does not contain a preservative, in particular does not contain the aforementioned preservatives.

It is also advantageous that the ophthalmic composition comprises at least one buffer system, preferably a buffer system selected from borate buffers, citrate buffers, phosphate buffers, tris buffers, tromethamine/maleic acid, and mixtures or combinations thereof.

In particular, it is advantageous here for the ophthalmic composition to consist of ectoin or an ectoin derivative, hyaluronic acid or a hyaluronic acid derivative, a buffer system and water.

However, the ophthalmic composition may be free of a buffer system.

A particularly preferred embodiment provides an ophthalmic composition that is phosphate-free. In the sense of the present invention, phosphate-free means that if phosphate ions are included, they are only below the detection limit of the current analytical method.

According to the invention, phosphate is understood to be any type of phosphate, i.e. for example mono-, di-, tri-, polyphosphate and cyclic phosphate. Also included within the scope of this preferred embodiment are results where the solution must be free of phosphate buffer.

In the case of extended use of phosphate-containing solutions in the eye, corneal haze can result from binding and/or deposition of poorly soluble phosphate, such as calcium phosphate bound or deposited into or onto the cornea and conjunctiva of the eye. Degeneration of the cornea of the eye is also known as corneal zonal degeneration or zonal keratopathy. Indeed, small amounts of incorporation and/or deposition of insoluble phosphate in or on the cornea of the eye can lead to a substantial increase in glare sensitivity, which can be due to the light scattering effect of the deposited or incorporated insoluble phosphate. In particular, night vision ability is thus greatly impaired. As a result of the complete absence of phosphate in the preferred solutions according to the invention, the formation of sparingly soluble phosphate and the consequent impairment of visual performance due to corneal opacification can be avoided.

In a preferred embodiment, in particular in the presence of a buffer system, the osmolality (or tonicity) of the solution is adjusted to from 100 to 1000mOsm/kg, preferably from 200 to 500mOsm/kg, particularly preferably from 220 to 350 mOsm/kg.

In a particularly preferred embodiment, the buffer is a borate buffer.

It is therefore particularly preferred that the solution according to the invention comprises or consists of ectoin, sodium hyaluronate, borate buffer and water. Or it is also preferred that the solution of the invention comprises or consists of ectoin, sodium hyaluronate, borate buffer, preservative and water.

Furthermore, it is preferred that the borate buffer comprises or consists of boric acid and borax.

In a further preferred embodiment of the solution according to the invention, the proportion of boric acid in the solution is from 2.5mg/ml to 10mg/ml, preferably from 7.2mg/ml to 8.8mg/ml, particularly preferably from 7.7mg/ml to 7.9mg/ml, in particular from 7.80mg/ml to 7.82 mg/ml.

In a further preferred embodiment of the solution according to the invention, the proportion of borax in the solution is from 0.1mg/ml to 1mg/ml, preferably from 0.3mg/ml to 0.7mg/ml, particularly preferably from 0.4mg/ml to 0.5mg/ml, in particular from 0.41mg/ml to 0.43 mg/ml.

The ophthalmic compositions therefore preferably have a pH of from 5 to 9, preferably from 6 to 8, in particular from 6.8 to 7.8.

Preferably, the kinematic viscosity of the ophthalmic composition according to the invention is 10mm as measured by capillary viscometry as described in PhEur 7.2 general method 2.2.8²S to 500mm²S, preferably 30mm²S to 300mm²S, particularly preferably 50mm²S to 250mm²/s。

In particular, the composition according to the invention is sterile.

Preferably, the ophthalmic composition according to the present invention is configured in the form of eye drops or ophthalmic gel.

The ophthalmic composition may be administered to the eye from 1 to 10 times per day, preferably from 2 to 6 times per day. In particular, the ophthalmic composition is administered by instillation into the eye.

In a particularly preferred embodiment, the ophthalmic composition is formulated as follows:

0.55mg to 5mg of sodium hyaluronate

0.50mg to 3mg of ectoin

Boric acid 2.5mg to 10mg

0.1mg to 1mg of borax

Make up to 1ml with water

The density of the composition according to the invention with this formulation was about 1.0068g/cm³. The solution wets the cornea and conjunctiva and prevents the excess of tearsAnd (4) evaporating. It can be used for preventing or treating eye irritation and/or inflammation caused by eye not being adequately wetted by tear film and/or being hypersensitive and/or allergic. The burning and itching sensation of the eyes caused by irritation and/or inflammation disappears.

Furthermore, preferably, the ocular irritation and/or inflammation is caused by the eye not being adequately wetted by the tear film and/or being hypersensitive and/or allergic.

The invention is described in more detail with reference to the following embodiments, but without limiting the invention to the tests specifically shown.

Description of the test

A total of 12 solutions with varying concentrations of hyaluronic acid and ectoin were produced with the following basic formulation:

0. the production basic formula does not contain hyaluronic acid and ectoin:

first, 781mg of boric acid and 42mg of borax were dissolved in about 80ml of distilled water in this order. After the starting material was completely dissolved, the solution was added to 100ml with distilled water.

1. The production basic formula does not contain hyaluronic acid and contains 1 percent of ectoin:

1g of ectoin, 781mg of boric acid and 42mg of borax were dissolved in about 965ml of distilled water. After the starting material was completely dissolved, the solution was added to 100ml with distilled water.

2. The production basic formula does not contain hyaluronic acid and contains 2 percent of ectoin:

2g of ectoin, 781mg of boric acid and 42mg of borax are dissolved in succession in about 95ml of distilled water. After the starting material was completely dissolved, the solution was added to 100ml with distilled water.

3. The production basic formula does not contain hyaluronic acid and contains 3 percent of ectoin:

3g of ectoin, 781mg of boric acid and 42mg of borax are dissolved in succession in about 95ml of distilled water. After the starting material was completely dissolved, the solution was added to 100ml with distilled water.

4. Production base formula containing 0.1% hyaluronic acid and no ectoin:

first, about 45ml of distilled water was added to a beaker and 100mg of hyaluronic acid was dissolved therein (solution 1). In a second beaker 781mg boric acid and 42mg borax are dissolved in about 45ml distilled water (solution 2) in sequence. After all the starting materials were completely dissolved, solution 2 was slowly added to solution 1 with stirring. The solution was then brought to 100ml with distilled water.

5. Production base formula containing 0.2% hyaluronic acid and no ectoin:

first, about 45ml of distilled water was added to a beaker and 200mg of hyaluronic acid was dissolved therein (solution 1). In a second beaker 781mg boric acid and 42mg borax are dissolved in about 45ml distilled water (solution 2) in sequence. After all the starting materials were completely dissolved, solution 2 was slowly added to solution 1 with stirring. The solution was then brought to 100ml with distilled water.

6. Production base formula containing 0.1% hyaluronic acid and 1% ectoin:

first, about 45ml of distilled water was added to a beaker and 100mg of hyaluronic acid was dissolved therein (solution 1). In a second beaker, 1g of ectoin, 781mg of boric acid and 42mg of borax are dissolved in succession in about 45ml of distilled water (solution 2). After all the starting materials were completely dissolved, solution 2 was slowly added to solution 1 with stirring. The solution was then brought to 100ml with distilled water.

7. Production base formula containing 0.1% hyaluronic acid and 2% ectoin:

first, about 45ml of distilled water was added to a beaker and 100mg of hyaluronic acid was dissolved therein (solution 1). In a second beaker, 2g of ectoin, 781mg of boric acid and 42mg of borax are dissolved in succession in about 45ml of distilled water (solution 2). After all the starting materials were completely dissolved, solution 2 was slowly added to solution 1 with stirring. The solution was then brought to 100ml with distilled water.

8. Production base formula containing 0.1% hyaluronic acid and 3% ectoin:

first, about 45ml of distilled water was added to a beaker and 100mg of hyaluronic acid was dissolved therein (solution 1). In a second beaker, 3g of ectoin, 781mg of boric acid and 42mg of borax are dissolved in succession in about 45ml of distilled water (solution 2). After all the starting materials were completely dissolved, solution 2 was slowly added to solution 1 with stirring. The solution was then brought to 100ml with distilled water.

9. Production base formula containing 0.2% hyaluronic acid and 1% ectoin:

first, about 45ml of distilled water was added to a beaker and 200mg of hyaluronic acid was dissolved therein (solution 1). In a second beaker, 1g of ectoin, 781mg of boric acid and 42mg of borax are dissolved in succession in about 45ml of distilled water (solution 2). After all the starting materials were completely dissolved, solution 2 was slowly added to solution 1 with stirring. The solution was then brought to 100ml with distilled water.

10. Production base formula containing 0.2% hyaluronic acid and 2% ectoin:

first, about 45ml of distilled water was added to a beaker and 200mg of hyaluronic acid was dissolved therein (solution 1). In a second beaker, 2g of ectoin, 781mg of boric acid and 42mg of borax are dissolved in succession in about 45ml of distilled water (solution 2). After all the starting materials were completely dissolved, solution 2 was slowly added to solution 1 with stirring. The solution was then brought to 100ml with distilled water.

11. Production base formula containing 0.2% hyaluronic acid and 3% ectoin:

first, about 45ml of distilled water was added to a beaker and 200mg of hyaluronic acid was dissolved therein (solution 1). In a second beaker, 3g of ectoin, 781mg of boric acid and 42mg of borax are dissolved in succession in about 45ml of distilled water (solution 2). After all the starting materials were completely dissolved, solution 2 was slowly added to solution 1 with stirring. The solution was then brought to 100ml with distilled water.

And detecting the viscosity of the prepared solution.

The viscosity was measured using an Ubbelohde viscometer 50120/II as described in PhEur 7.2 general method 2.2.8.

The following viscosity values were thus obtained for the various compositions, these values being listed in the table below:

comparative test

As shown in tests 6 to 8 or 9 to 11 according to the invention, the presence of hyaluronic acid and ectoin produces a clear synergistic effect on the viscosity, demonstrating that the viscosity in these combined tests is higher than the sum of the individual measurements in the individual tests (tests 1 to 3 or tests 4 to 5).

In addition, assays with different HA: water binding power of 7 different hyaluronic acids and ectoin mixtures (nos. 12 to 18) in ectoin weight ratio. For this purpose, two different methods are applied.

In one aspect, the water binding capacity is determined gravimetrically. Hyaluronic acid and ectoin are expressed as m in the following table_HAAnd m_EcIs added to an Eppendorf vessel, said ratio being the ratio relative to the total weight of 100mg (hyaluronic acid + ectoine). The total mass of the Eppendorf container after addition was recorded. Subsequently, water was added dropwise until a slight excess of water and a clear solution was obtained. The solution was centrifuged at 200 rpm. The supernatant was then removed and the total weight of the Eppendorf vessel was determined again. The water binding force was calculated as the difference between the total weight after centrifugation and the initially recorded total weight.

The following table shows the results of gravimetric determination of percent water binding force (WBK). In addition, the table shows the values of the expected water binding capacity in case of purely additive effect based on WBK for pure hyaluronic acid (test 12) and WBK for pure ectoin (test 18). The deviation of the measured WKB from the calculated theoretical WBK reflects the synergistic effect.

On the other hand, the water binding force was measured by indirect karl fischer titration using oven technique. For this purpose, after centrifugation in the gravimetric method and removal of the supernatant, 5 to 7mg of sample are taken from the Eppendorf vessel. The sample was heated to an initial temperature of 50 ℃ and then heated to 200 ℃ in a closed vessel at a heating rate of 2 ℃/minute. The water evaporated in this way is introduced into the titration cell via the hollow needle by means of a gas flushing. The water collected here was reacted with karl fischer solution and the content of the sample and the water binding capacity were calculated by the end point of the titration curve. FIGS. 1 to 4 show the thermograms of mixtures 13, 14, 16 and 17 plotted in the Karl Fischer analysis described above: fig. 1 shows the measurement curves obtained during the analysis of the mixture 13. Fig. 2 shows a thermogram of the analyzed mixture 14. Fig. 3 shows a thermogram obtained during analysis of the mixture 16, and fig. 4 is an analysis result of the mixture 17.

From these figures, the weight of the sample at 200 ℃ and the mass of water detected can be obtained. In order to correct the measured water quality, a time shift of the measuring instrument must also be included.

The results of the percentage of water binding force (WBK) determined using oven technology according to the indirect karl fischer method are contained in the table below. In addition, the table shows the values of the expected water binding capacity based on the purely additive effect of WBK for pure hyaluronic acid (test 12) and WBK for pure ectoin (test 18). The deviation of the measured WKB from the theoretically calculated WBK also forms a measure of the synergistic effect here.

WBK (regardless of the method of measurement), hyaluronic acid and ectoin have a synergistic effect on water binding. In the case of purely additive effects, for example in mixture 15, according to karl fischer titration the value of the water binding capacity is expected to be 62.8% (═ 0.5 · 32.00+0.5 · 87.00), whereas the value measured is 80.2%. The same applies to gravimetric determination: purely additive effects, the water binding capacity of mixture 15 is expected to be 59.5% (═ 0.5 · 31.80+0.5 · 93.80), whereas WBK was measured to be 74.0%.

Claims (15)

1. An ophthalmic composition comprising or consisting of:

0.055 to 2.00% by weight of hyaluronic acid and/or an ophthalmically acceptable salt of hyaluronic acid,

0.60 to 5.00% by weight of ectoin or an ophthalmologically acceptable ectoin derivative, and

water to make up to 100% by weight,

the composition is free of other pharmaceutically active ingredients.

2. The ophthalmic composition according to claim 1, for use in the treatment or prevention of dry eye (sjogren's syndrome), for use in the treatment or prevention of conjunctival inflammation (conjunctivitis), and/or for use in the treatment or prevention of allergic reactions of the eye, such as hay fever.

3. An ophthalmic composition according to any of the preceding claims, characterized in that,

the hyaluronic acid and/or the ophthalmologically acceptable salt of hyaluronic acid is present in an amount of 0.10% to 1.00% by weight, preferably 0.10% to 0.45% by weight, further preferably 0.125% to 0.45% by weight, particularly preferably 0.15% to 0.25% by weight, in particular 0.15% to 0.20% by weight, and/or

The content of ectoin or an ophthalmologically acceptable ectoin derivative is 0.75 to 3.00% by weight, preferably 1.00 to 3.00% by weight.

4. An ophthalmic composition according to any one of the preceding claims, characterized in that the ophthalmologically acceptable salt of hyaluronic acid is selected from sodium hyaluronate, potassium hyaluronate and mixtures or combinations thereof.

5. An ophthalmic composition according to any one of the preceding claims, characterized in that ectoin is L-ectoin ((S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid), and/or that an ectoin derivative is selected from hydroxyectoin ((4S,5S) -5-hydroxy-2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid); salts, such as the sodium or potassium salt of ectoin; esters obtainable by conversion of a 4-carboxyl group with an alcohol, in particular a linear or branched mono-or diol having from 1 to 20 carbon atoms, and/or by conversion of a 5-hydroxyl group with a carboxylic acid, in particular a linear or branched mono-or dicarboxylic alkyl acid having from 2 to 20 carbon atoms, for example a monoalkylcarboxylic acid; and acid addition salts of inorganic or organic acids.

6. Ophthalmic composition according to the preceding claims, characterized in that the alkyl group of the alcohol or carboxylic acid, respectively, has at most 10 carbon atoms, in particular at most 5 carbon atoms.

7. An ophthalmic composition according to any of the preceding claims, characterized in that the ophthalmic composition is free of preservatives,

or

Comprising at least one preservative, in particular selected from quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide or polyquaternium 1; mercury compounds such as thimerosal or phenylmercuric acetate; alcohols such as chlorobutanol; carboxylic acids, such as sorbic acid; phenols, such as parabens; amidines, such as chlorohexidine; EDTA, particularly the disodium salt of EDTA; sodium hydroxymethylgluconate; sodium perborate; a phosphonic acid; (ii) a porinium chloride; sodium chlorite and mixtures or combinations thereof.

8. An ophthalmic composition according to any preceding claim, characterized in that it comprises at least one buffer system, preferably selected from borate buffers, citrate buffers, phosphate buffers, tris buffer, tromethamine/maleic acid and mixtures or combinations thereof,

or no buffer system.

9. An ophthalmic composition according to any preceding claim, characterized in that the ophthalmic composition is free of phosphate ions.

10. Ophthalmic composition according to any one of the preceding claims, characterized in that the osmolality of the solution is between 100 and 1000mOsm/kg, preferably between 200 and 500mOsm/kg, particularly preferably between 220 and 350 mOsm/kg.

11. An ophthalmic composition according to any one of the preceding claims, characterized in that the pH of the ophthalmic composition is from 5 to 9, preferably from 6 to 8, in particular from 6.8 to 7.8.

12. The ophthalmic composition according to any one of the preceding claims, characterized in that the kinematic viscosity of the ophthalmic composition measured by capillary viscometry according to PhEur 7.2 general method 2.2.8 is 10mm²S to 500mm²S, preferably 30mm²S to 300mm²S, particularly preferably 50mm²S to 250mm²/s。

13. Ophthalmic composition according to any one of the preceding claims, characterized in that the composition is sterile.

14. Ophthalmic composition according to any one of the preceding claims, characterized in that it is configured in the form of eye drops or ophthalmic gel.

15. Ophthalmic composition according to any one of the preceding claims, characterized in that it is administered in the eye from 1 to 10 times a day, preferably from 2 to 6 times a day, preferably by instillation into the eye.