EA045563B1 - OPHTHALMOLOGICAL COMPOSITION - Google Patents

Description

Application area

The present invention relates to the field of compositions for the prevention and/or treatment of ophthalmic pathologies, in particular dry eye syndrome.

Prerequisites for creation

Dry eye syndrome, also known as dry eye or keratoconjunctivitis sicca (KCS), is a condition in which the amount of tears produced by the tear glands is insufficient or the tear film evaporates too much. Decreased tear production can result in insufficient or no tear film production on the surface of the eye. The tear film is essential for lubrication between the eyelid and the surface of the eye. As a result of the absence or insufficient amount of tear film, the epithelial layers can be seriously injured. This leads to unpleasant sensations in the eyes, which are accompanied by itching, tingling and/or burning.

Dry eyes can be the result of abnormal tear glands, eyelid inflammation, eye inflammation due to allergies, refractive surgery (including laser), deficiencies of certain lipids in the eye, an unbalanced diet, prolonged contact lens wear, hormonal changes, autoimmune diseases, or side effects from certain medications.

When treating dry eyes, saline or artificial tears, also called lubricating or moisturizing eye drops, are sometimes recommended. Artificial tears of low and medium viscosity are usually made from polyvinyl alcohols or cellulose derivatives. These remedies provide only some local relief for a short time. In addition, they have one drawback - they change the surface of the cornea, reducing its density (A.R. Wegener, L.M. Mayer and K.L. Schonfield. The effect of viscous substances on the density of the cornea in dry eye syndrome. Journal of Ocular Pharmacology and Therapy 31, 504-508 (2015)).

Eye drops containing hyaluronic acid, a natural biopolymer with excellent viscoelasticity, high water-holding capacity and hygroscopicity, are widely used in the context of dry eye treatment. Hyaluronic acid is used in eye drops to moisturize the cornea. It forms a transparent film on the surface of the eye, which moisturizes the cornea and protects it from drying out. These properties make it possible to effectively relieve clinical manifestations. However, eye drops of previous generations containing hyaluronic acid are limited in duration and force the patient to apply eye drops more often. Moreover, hyaluronic acid in the eyes is known to cause mild discomfort that lasts from a few seconds to a few minutes after instillation and is often accompanied by slight blurred vision.

Finally, it should be mentioned that hyaluronic acid eye drops are more effective for mild to moderate dry eyes than saline or artificial tears based on polyvinyl alcohols or cellulose derivatives. Patients with severe dry eyes may also experience some relief, but usually must use other products that contain additional active ingredients, such as immunosuppressants (eg, cyclosporine) or anti-inflammatory drugs (eg, lifitegrast). However, the use of such additional active ingredients may have undesirable side effects, especially when used for a long time.

The previous generation of drops introduced formulations that combined hyaluronic acid with additional ingredients to improve the treatment of dry eye syndrome. However, it has so far been difficult to develop a user-friendly solution without the aforementioned disadvantages.

Thus, there is a need for solutions with improved composition for the treatment of dry eye syndrome and related pathologies.

Purpose of the invention and brief description

The inventors have developed an ophthalmic composition for the treatment of ocular pathologies, in particular dry eye syndrome, without the above-mentioned disadvantages. This composition contains a combination of hyaluronate with ectoine and panthenol, which provides many benefits.

The inventors discovered that the triple compound of hyaluronate with ectoine and panthenol exhibits a surprisingly high water binding capacity, thereby improving eye hydration. The water-binding capacity of the ternary compound is substantially greater than would be expected based on the ability of the individual components to retain water or the combination of components taken two at a time, thus demonstrating a synergistic effect.

Thus, the first object of the invention is an ophthalmic composition containing, relative to the total weight of the composition: from 0.001 to 2% by weight of hyaluronic acid or its ophthalmologically acceptable salt, from 0.5 to 5.00% by weight of ectoine or its ophthalmologically acceptable salt or derivative, from 0.5 to 5% by weight of a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid and a compound thereof, and adding an amount of water up to 100% of the total weight of the composition.

In addition to its enhanced water-binding capacity, this formula also has a surprisingly high dynamic viscosity, which ensures that the formulation adheres to the ocular surface and remains there for a long time. However, the viscosity is not so high as to cause discomfort to the user or block the tear duct when instilled into the eye (or after). Advantageously, the viscosity of the proposed formulation is rapidly reduced by the application of shear stress, avoiding damage to the corneal surface. The triple compound of the proposed composition successfully balances effectiveness with residue and comfort. Generally, the persistence or persistence of a formulation is defined as the time during which the specified formulation continues to operate without reapplication. In the context of the invention, the residual composition can be assessed by measuring the thickness of the tear film. Tear film thickness can be measured using high-resolution optical coherence tomography.

Moreover, the inventors discovered that the presence of dexpanthenol in the composition unexpectedly leads to a decrease in surface tension. This is very important because tear film thickness increases exponentially with decreasing surface tension (Crich JL, Du LT, Fatt I, Radke KJ. In vivo determination of tear film thickness and its effect on tear film stability Current Research in Eye Medicine 1998;17:1058-1066). In addition, clinical studies have shown that tear surface tension increases in patients with dry eye syndrome (Tiffany, J.M., Winter, N., and Bliss, G. (1989) Tear film stability and tear surface tension, Current Research in Ophthalmic Medicine, 8:5, 507-515).

The above-mentioned positive effects are indicated for the proposed composition in the examples disclosed in this application. Specifically, the synergistic binding capacity of water is shown in FIG. 1, the synergistic viscosity is shown in FIG. 9, the reduced surface tension is shown in FIG. 7, the increased dynamic viscosity is shown in FIG. 8, and the decrease in dynamic viscosity is shown in FIG. 6.

Finally, the present formulation is a highly effective treatment for dry eye syndrome and related conditions, preferably without the need for additional active ingredients or additional excipients or carrier media, and does not require preservatives. The absence of preservatives and additional active ingredients, fillers or carrier media guarantees the absence of unwanted side effects such as allergic reactions, secondary dry eye syndrome, trabecular meshwork degeneration, mitochondrial dysfunction and ocular inflammation.

Overall, the proposed ophthalmic formulation is superior to previous generation formulations due to the proper balance between hydration and residue, and the absence of discomfort and unwanted side effects. Based on this, the created ophthalmic composition is effective for the prevention and/or treatment of ophthalmic pathologies, such as dry eye syndrome, Sjogren's syndrome, inflammation of the conjunctiva, irritation, itching, burning and allergic reactions in the eyes, and related conditions, while it is very user friendly. The expression associated conditions in this application is understood as conditions that are associated with insufficient hydration of the ocular surface.

Thus, the second object of the invention is an ophthalmic composition, according to the definition of the first object of the invention, for use in the prevention and/or treatment of ophthalmic pathology selected from the group consisting of dry eye syndrome, Sjögren's syndrome, conjunctival inflammation, irritation, itching, burning and allergic eye reactions and related conditions. It may also be formulated as an ophthalmic composition, as defined in the first aspect of the invention, for use in the prevention and/or treatment of ophthalmic pathologies selected from the group consisting of dry eye syndrome, Sjögren's syndrome, conjunctival inflammation, irritation, itching, burning and allergic eye reactions and related conditions. The invention also relates to a method for the prevention and/or treatment of dry eye syndrome, Sjogren's syndrome, inflammation of the conjunctiva, irritation, itching, burning and allergic reactions of the eye, as well as related conditions, including the administration of a therapeutically effective amount of an ophthalmic composition, according to the definition of the first object of the invention, in subject in need, including people.

Brief description of images

Fig. 1: Synergistic effect of sodium hyaluronate (HA) and ectoine compounds with or without dexpanthenol on water binding capacity. The ectoine content can be calculated as 100% sodium hyaluronate% dexpanthenol%.

Fig. 2: Dynamic viscosity change as a function of shear factor for formulations containing sodium hyaluronate with an intrinsic viscosity of 0.51 m ³ /kg, which refers to a weight average molecular weight (Mw) of approximately 196 kDa.

Fig. 3: Dynamic viscosity change as a function of shear factor for formulations containing sodium hyaluronate with an intrinsic viscosity of 0.95 m ³ /kg, which refers to a weight average molecular weight (Mw) of approximately 410 kDa.

Fig. 4: Dynamic viscosity change as a function of shear factor for formulations containing sodium hyaluronate with an intrinsic viscosity of 1.00 m ³ /kg, which refers to a weight average molecular weight (Mw) of approximately 410-450 kDa.

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Fig. 5: Change in dynamic viscosity depending on the shear coefficient for formulations containing different concentrations of D-panthenol.

Fig. 6: Dynamic viscosity reduction measured between maximum and minimum viscosity value.

Fig. 7: Effect of D-panthenol on surface tension.

Fig. 8: Dynamic viscosity for formulations containing dexpanthenol, sodium hyaluronate and ectoine (series 67-71HED0919 do not contain dexpanthenol).

Fig. 9: Synergistic effect on viscosity after adding dexpanthenol.

Detailed Description of the Invention

The present application provides an aqueous ophthalmic composition containing a synergistic compound of hyaluronic acid or an ophthalmologically acceptable salt, ectoine or an ophthalmologically acceptable salt or a derivative thereof, and a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid and a compound thereof.

Hyaluronic acid (American Chemical Society registration number: 9004-61-9) is a naturally occurring substance found in the eyes and other parts of the body. It is a long-chain polymer consisting of disaccharide units of glucuronic acid and N-acetylglucosamine linked through alternating β-(1^4) and β-(1^3) glycosidic bonds. Hyaluronic acid can have a length of 25,000 disaccharide repeats. Hyaluronic acid polymers can range in size from 5,000 to 20,000,000 Da in vivo. It ensures the formation of a homogeneous, stable, and most importantly, long-lasting film of moisture on the surface of the eye, which cannot be quickly washed off.

There are several ophthalmologically acceptable salts of hyaluronic acid that can be used in the present formulation, the most common of which is sodium hyaluronate (herein also referred to as HA, PubChem CID: 23663392). The term ophthalmologically acceptable salts covers any salt formed from ophthalmologically acceptable non-toxic acids, including inorganic or organic acids. There are no restrictions on salts, except that if they are used for therapeutic purposes, they must be acceptable from an ophthalmological point of view.

The concentration of hyaluronic acid or its ophthalmologically acceptable salt in the proposed composition ranges from 0.001 to 2% by weight. In this application, % mass fraction means % w/v, that is, the percentage of the mass of the ingredient relative to the total volume of the composition. In other words, x to y% by weight of ingredient A represents x to y grams of ingredient A per 100 ml of formulation. In some embodiments, the composition contains from 0.1 to 0.5% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof. In other embodiments, the composition contains from 0.15 to 0.4% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof. In other embodiments, the composition contains from 0.3 to 0.4% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof. In some embodiments, the composition contains 0.3% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof.

Hyaluronic acid and its ophthalmologically acceptable salt may be in the form of a cross-linked polymer. It is desirable that the polymer is not cross-linked. In addition, the weight average molecular weight (Mw) of hyaluronic acid or an ophthalmologically acceptable salt thereof is preferably 5 to 2500 kDa, preferably 100 to 800 kDa. In some embodiments, the molecular weight of hyaluronic acid or an ophthalmologically acceptable salt thereof is between 150 and 500 kDa. In other embodiments, the molecular weight of hyaluronic acid or an ophthalmologically acceptable salt thereof is between 200 and 450 kDa. The weight average molecular weight of hyaluronic acid or its ophthalmologically acceptable salt can be determined using size extrusion chromatography-multiangle laser scattering (SEC MALS).

In a specific embodiment, the ophthalmologically acceptable hyaluronic acid salt is selected from the group consisting of sodium hyaluronate, potassium hyaluronate, and compounds thereof. In a specific embodiment, the ophthalmologically acceptable salt of hyaluronic acid is sodium hyaluronate.

In some embodiments, the composition contains from 1 to 3% by weight of ectoine or an ophthalmologically acceptable salt or derivative thereof. In some embodiments, the composition contains from 1.5 to 2.5% by weight of ectoine or an ophthalmologically acceptable salt or derivative thereof. In some embodiments, the composition contains 2% by weight of ectoine or an ophthalmologically acceptable salt or derivative thereof.

Ectoines are low molecular weight cyclic amino acids that act as cell protectors and are naturally found in extremophilic microorganisms. According to the preamble, ectoine increases the binding of water to cells, protects cells from dehydration and stabilizes proteins in the tear film through an exclusion mechanism. Moreover, ectoine, forming clusters with water, has a strong effect on the stability of cell membranes. In one embodiment, the ectoine present in the proposed composition is L-3045563 ectoine ((S)-2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid, CAS number: 96702-03-3; PubChem CID: 126041). In a specific embodiment, the ophthalmologically acceptable ectoine derivative is selected from the group consisting of an ophthalmologically acceptable ectoine ester, hydroxyectoine (CAS number: 165542-15-4; PubChem CID: 12011795) or an ophthalmologically acceptable salt thereof, an ophthalmologically acceptable hydroxyectoine ester, and a compound thereof . Suitable ophthalmologically acceptable salts are, for example, sodium salts, potassium salts and salts with organic amines, for example trometamol or triethylamine. Suitable esters are those which can be prepared by converting the 4-carboxyl group with alcohols, in particular straight or branched chain mono- or divalent alcohols with 1-18 carbon atoms, and/or the 5-hydroxy group with carboxylic acids, in particular mono- or divalent straight or branched chain alkyl carboxylic acids with 2 to 20 carbon atoms, for example alkyl monocarboxylic acids, amides as a reaction product with an alkylamine where the alkyl chain contains up to 18 carbon atoms in linear or branched form, and acid addition salts with inorganic or organic acids. In specific embodiments, the present formulation contains an ophthalmologically acceptable salt of L-ectoine, such as a sodium salt, a potassium salt, or an organic amine salt, such as trometamol or triethylamine. In another embodiment, the proposed composition contains an ophthalmologically acceptable salt of hydroxyectoine, such as a sodium salt, a potassium salt, or an organic amine salt, such as trometamol or triethylamine.

In some embodiments, the composition contains from 1 to 3% by weight, or from 1.5 to 2.5% by weight, or from 1.5 to 2.5% by weight, such as 2% by weight of a compound selected from the group , consisting of panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid and a compound thereof.

Panthenol (also called pantothenol) (CAS number: 16485-10-2, PubChem CID: 4678) is an alcohol analogue of pantothenic acid (vitamin B5, CAS number: 599-54-2) and is thus a provitamin B5. In organisms it is quickly oxidized to pantothenic acid. In specific embodiments, the compound is D-panthenol (also referred to herein as dexpanthenol or DEX, CAS number: 81-13-0; PubChem CID: 131204). In other specific embodiments, the compound is an ophthalmologically acceptable salt of pantothenic acid, which may be selected from sodium pantothenate and calcium pantothenate.

The proposed ophthalmic composition may have a weight ratio of hyaluronic acid or an ophthalmologically acceptable salt thereof to ectoine or an ophthalmologically acceptable salt or derivative thereof to a compound selected from panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid, and a compound thereof of 1:1.5:1 .5 to 1:100:100. In specific embodiments, the weight ratio is from 1:1.5:1.5 to 1:30:30. In other embodiments, the weight ratio is from 1:2:2 to 1:10:10. In other embodiments, the weight ratio is from 1:4:4 to 1:8:8, such as 1:6.7:6.7.

The proposed composition may additionally contain an additive selected from the group of non-ionic isotonic substances, antioxidants and/or buffer systems. In another specific embodiment, the proposed formulation is an isotonic or hypotonic formulation with an osmolality preferably between 170 and 350 mOsmol/kg. This characteristic can be obtained, for example, by adding an osmolarity adjusting agent such as sodium chloride (NaCl). Thus, in certain embodiments, the proposed composition further comprises sodium chloride. Sodium chloride may be present in the composition from 0.01 to 0.1% of the total mass. In some embodiments, the composition contains from 0.03 to 0.06% or from 0.04 to 0.05% by weight sodium chloride.

In addition, the ophthalmic composition may be improved by the addition of at least one buffer system, for example, a buffer selected from the group consisting of borate buffer, citrate buffer, phosphate buffer, Tris buffer, trometamol/maleic acid. In specific embodiments, the composition contains a citrate buffer. However, in some embodiments, the composition lacks a buffer system.

The pH of the proposed composition may be from 5 to 9. In certain embodiments, the pH is from 5.5 to 7.5 or from 6 to 7. For example, the pH of the proposed composition may be 6.2 or 6.3. The pH of the composition can be determined using a pH meter or pH strip. In particular, the above pH ranges can be determined using the WTWpH 1970i pH meter. The preferred pH value can be achieved by adding a pH adjusting agent such as hydrochloric acid (HCl) and/or sodium hydroxide (NaOH).

According to the most preferred embodiment, the proposed composition does not contain preservatives. By preservative is meant any substance that can be used as an ophthalmic preservative, such as the following preservatives. Preservatives can damage the precorneal tear film and lead to a decrease in the number of microvilli and microvilli on the surface of corneal epithelial cells, leading to irritation and/or inflammation

- 4 045563 eyes. Thus, by eliminating preservatives from the proposed composition, such irritation and/or inflammation can be avoided. In particular, the proposed composition does not contain benzalkonium chloride, which is the most commonly used preservative in eye drops. The proposed composition also does not contain phosphates. According to the literature, phosphates increase the risk of calcification of corneal tissue, which leads to burning of the eye and clouding of the cornea.

It is also desirable that the proposed ophthalmic composition does not contain additional pharmaceutically active ingredients. In particular, the proposed composition does not contain anti-inflammatory substances and/or immunosuppressants. In specific embodiments, the composition does not contain additional excipients and carrier media. Thus, specific embodiments refer to a composition comprising hyaluronic acid or an ophthalmologically acceptable salt thereof, ectoine or an ophthalmologically acceptable derivative thereof, a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid, and compounds thereof as active ingredients only and may further comprise an osmolarity adjusting agent such as NaCl, a pH adjusting agent such as HCl and/or NaOH, and water. These formulations may also contain a buffer, such as a citrate buffer. Thus, in preferred embodiments, the proposed composition does not contain preservatives, additional active ingredients, excipients and carrier media.

In one embodiment, the ophthalmic composition desirably contains sodium hyaluronate, L-ectoine and D-panthenol as the sole active ingredients, water and, optionally, an osmolarity adjusting agent such as NaCl and/or a pH adjusting agent such as as HCl and/or NaOH. It is desirable that the specified composition does not contain preservatives, additional active ingredients, excipients and carrier media. In one embodiment, the proposed composition actually consists of sodium hyaluronate, L-ectoine and D-panthenol as the only active ingredients, water and, optionally, an osmolarity adjusting agent such as NaCl and/or a pH adjusting agent such as HCI and/or NaOH. The weight average molecular weight (Mw) of sodium hyaluronate is from 5 to 2500 kDa, preferably from 100 to 800 kDa, more preferably from 150 to 500 kDa, most preferably from 200 to 450 kDa.

Advantageously, the proposed composition has a dynamic viscosity suitable for targeted topical ophthalmic use. It has been determined that easy and safe removal through the lacrimal duct is better when the dynamic viscosity of the ophthalmic composition/tear mixture is less than 50 mPa.s, and this is achieved with the proposed composition. Thus, in some embodiments, the proposed composition has a dynamic viscosity at 20°C from 1 to 50 mPa.s. In specific embodiments, the viscosity is from 4 to 40 mPa.s, preferably from 8 to 20 mPa.s. These values correspond to those measured using a BROOKFIELD DV3T rotational viscometer at 20°C.

Surprisingly, a ternary combination of hyaluronic acid or an ophthalmologically acceptable salt thereof, ectoine or an ophthalmologically acceptable salt or derivative thereof, and a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid, and the compounds thereof exhibits a synergistic effect. on the viscosity of the composition (see Fig. 9).

The synergistic effect achieved by the ternary compound in the proposed formulation also has a positive effect on the production costs of the formulation. These ingredients are expensive raw materials. The synergistic increase in viscosity and water binding capacity is very beneficial in saving raw materials and costs. As a result of the synergistic effect, the selected viscosity and water binding capacity can be achieved using fewer raw materials than the latest generation ophthalmic formulations, resulting in cost savings. In addition, the advantage of having fewer active ingredients is that such a formulation will cause fewer unwanted side effects.

As already mentioned, this is quite convenient if the proposed composition does not contain additional active ingredients. However, in other embodiments, the proposed composition may also contain one or more active ingredients in therapeutically effective amounts. Said active substances can be selected, for example, from antibiotics, antibacterial, antifungal, antiviral, immunosuppressive, anti-inflammatory or antilaucomatous substances, such as prostaglandins, beta-blockers, carbonic anhydrase inhibitors or alpha-adrenergic agonists. Such an active substance, in particular, can be selected from the following group: aceclidine, acetazolamide, acyclovir, anecortav, apraclonidine, atropine, azapentacene, azelastine, bacitracin, befunolol, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, carbachol, cardolol, celecoxib, chloramphenicol, chlortetracycline, ciprofloxacin, cromoglycate, cyclopentolate, cyclosporine, dapiprazole, demecarium, dexamethasone, diclofenac, dichlorphenamide, dipivefrin, dorzolamide, echothiophal, emedastine, epinastine, epinephrine, erythromycin, ethoxzolamide, eucatropine, fludrocortisone , fluorometholone, flurbiprofen, fomivirsen, framycetin, ganciclovir, gatifloxacin,

- 5 045563 gentamicin, homatropine, hydrocortisone, idoxuridine, indomethacin, isoflurofat, ketorolac, ketotifen, latanoprost, levobetaxolol, levobunolol, levocabastine, levofloxacin, lodoxamide, loteprednol, medrisone, methazolamide, metypranolol, moxifloc sacin, naphazoline, natamycin, nedocromil, neomycin, norfloxacin , ofloxacin, olopatadine, oxymetazoline, pemirolast, pegaptanib, phenylephrine, physostigmine, pilocarpine, pindolol, pyrenoxine, polymyxin B, prednisolone, proparacaine, ranibizumab, rimexolone, scopolamine, seasonamide, squalamine, sulfacetamide, suprofen, tetracaine, tetracycline in, tetrahydrozoline, tetrizoline, timolol, tobramycin, travoprost, triamcinulone, trifluorometazolarnide, trifluridine, trimethoprim, tropicamide, unoprostone, vidarbine, xylometazoline, pharmaceutically acceptable salts or compounds thereof.

Quaternary ammonium compounds, especially benzalkonium chloride or polyquad, optionally in combination with EDTA, are commonly used as preservatives. Other preservatives include, for example: guanidine-based preservatives (PHMB, chlorhexidine), benzyl alcohol; parabens (methyl, ethyl, propyl, ...); mercury-based preservatives such as thimerosal; chlorobutanol; benzethonium chloride; oxidative preservatives (Purite®, ...).

The proposed ophthalmic composition can be formulated in a convenient form of eye drops. The composition can be placed in a single-dose (single-dose) or reusable bottle, made, for example, of low-density polyethylene (LDPE), predominantly of additive-free PE quality. Non-limiting examples of disposable vials (single dose) or refillable vials for administering preservative-free eye drops over several days include Abak®, Comod®, OSD® or Novelia®. In addition to eye drops, other non-limiting dosage forms for the proposed formulation include cream, gel, hydrogel, lotion, ointment and spray, all of which are intended for use on the eyes. When used, excipients and carrier media included in the proposed composition must be ophthalmologically acceptable. Ophthalmically acceptable excipients or carrier media refer to ophthalmologically acceptable raw materials, formulations or carrier media. Each component must be ophthalmically acceptable in the sense of compatibility with the other ingredients of the ophthalmic formulation. It must also be suitable for use on the eye and not be excessively toxic, cause irritation, allergic reaction, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.

The second object of the invention is an ophthalmic composition, as described above, for use in the prevention and/or treatment of ophthalmic (or ocular) pathology. In specific embodiments, the ophthalmic pathology is selected from the group consisting of dry eye syndrome, Sjögren's syndrome, conjunctival inflammation, irritation, itching, burning and allergic ocular reactions and related conditions. In a specific embodiment, the ophthalmic pathology is dry eye syndrome.

Hyaluronic acid or an ophthalmologically acceptable salt thereof may also be considered as a second moiety for use in the prevention and/or treatment of ophthalmic (or ocular) pathology when used in combination with ectoine or an ophthalmologically acceptable salt or derivative thereof and a compound selected from the group consisting of panthenol, pantothenic acid, ophthalmologically acceptable salt of pantothenic acid and their compounds. It may also be formulated as a compound of hyaluronic acid or an ophthalmologically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of an ophthalmic (or ocular) pathology when used in combination with ectoine or an ophthalmologically acceptable salt or a derivative thereof and a compound selected from the group consisting of from panthenol, pantothenic acid, ophthalmologically acceptable salt of pantothenic acid and compounds thereof.

As a second component, ectoine or an ophthalmologically acceptable salt or derivative thereof may also be considered for the prevention and/or treatment of ophthalmic (or ocular) pathology when used in combination with hyaluronic acid or an ophthalmologically acceptable salt thereof and a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid and compounds thereof. It may also be formulated as a compound of ectoine or an ophthalmologically acceptable salt or derivative thereof for the preparation of a medicament for the prevention and/or treatment of an ophthalmic (or ocular) pathology when used in combination with hyaluronic acid or an ophthalmologically acceptable salt thereof and a compound selected from the group consisting of from panthenol, pantothenic acid, ophthalmologically acceptable salt of pantothenic acid and compounds thereof.

The second subject may also include a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmically acceptable salt of pantothenic acid, and compounds thereof for use in the prevention and/or treatment of ophthalmic (or ocular) pathology, when used in conjunction with hyaluronic acid or an ophthalmologically acceptable salt thereof and ectoine or an ophthalmologically acceptable salt or derivative thereof.

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It may also be formulated as a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmically acceptable salt of pantothenic acid and compounds thereof for the preparation of a medicament for the prevention and/or treatment of ophthalmic (or ocular) pathology when used in combination with hyaluronic acid or an ophthalmologically acceptable salt thereof and ectoine or an ophthalmologically acceptable salt or derivative thereof.

The components of this compound can be administered simultaneously, sequentially or separately. It is preferable to administer them simultaneously, as part of the same formulation.

The proposed composition can be used for both humans and animals. According to a preferred embodiment, the composition is for topical application, preferably by eye drops.

The dose is adapted to the severity of the pathology, but usually consists of one to several drops of the proposed composition per day administered to the affected area. The proposed composition makes it possible to increase the intervals between administrations in comparison, in particular, with a composition that does not contain a triple compound of ingredients. So the dose is less than 5 drops per day per eye or even less than 4, 3, 2 or even 1 drop per day and such a dose can also be considered.

The present application also contemplates that the ternary compound of the proposed composition, as defined above, provides the basis for sustained release formulations (drug delivery system) to improve the bioavailability, residual and therefore the effectiveness of the formulation, particularly as described above. Thus, another embodiment relates to a sustained release ophthalmic formulation comprising the present formulation as defined above, as well as its use for the prevention and/or treatment of an ophthalmic pathology, in particular dry eye syndrome.

For completeness, the various components of the proposed composition are set forth in the following numbered embodiments:

Option 1.

An ophthalmic composition containing from 0.001 to 2% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof, from 0.5 to 5% by weight of ectoine or an ophthalmologically acceptable salt or derivative thereof, from 0.5 to 5% by weight of a compound of the selected from the group consisting of panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid and compounds thereof, and adding an amount of water to 100% of the total weight of the composition.

Embodiment 2.

The ophthalmic composition according to embodiment 1, containing from 0.1 to 0.5% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof.

Embodiment 3.

The ophthalmic composition according to embodiment 2, containing from 0.15 to 0.4% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof.

Embodiment 4.

The ophthalmic composition according to embodiment 3, containing from 0.3 to 0.4% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof.

Embodiment 5.

The ophthalmic composition according to embodiment 4, containing 0.3% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof.

Embodiment 6.

The ophthalmic composition according to embodiment 1-5, containing from 1 to 3% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof.

Embodiment 7.

The ophthalmic composition according to embodiment 6, containing from 1.5 to 2.5% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof.

Embodiment 8.

The ophthalmic composition according to embodiment 7, containing 2% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof.

Embodiment 9.

The ophthalmic composition according to any one of embodiments 1-8, containing from 1 to 3% by weight of a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid, and combinations thereof.

Embodiment 10.

The ophthalmic composition of Embodiment 9, comprising 1.5 to 2.5% by weight of a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmically acceptable salt of pantothenic acid, and combinations thereof.

Embodiment 11.

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The ophthalmic composition according to any one of embodiments 9, containing from 2% by weight of a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid, and compounds thereof.

Embodiment 12.

The ophthalmic composition according to any one of embodiments 1 to 11, wherein the weight average molecular weight (Mw) of the hyaluronic acid or an ophthalmologically acceptable salt thereof is from 5 to 2500 kDa, preferably 100 to 800 kDa.

Embodiment 13.

The ophthalmic composition according to embodiment 12, wherein the weight average molecular weight (Mw) of the hyaluronic acid or an ophthalmologically acceptable salt thereof is from 150 to 500 kDa.

Embodiment 14.

The ophthalmic composition according to embodiment 13, wherein the weight average molecular weight (Mw) of the hyaluronic acid or an ophthalmologically acceptable salt thereof is from 200 to 450 kDa.

Embodiment 15.

The ophthalmic composition according to any of embodiments 1-14, comprising sodium hyaluronate.

Embodiment 16.

The ophthalmic composition according to any one of embodiments 1-15, comprising ectoine or an ophthalmologically acceptable salt thereof, optionally selected from sodium salt, potassium salt and organic amine salts, optionally selected from trometamol and triethylamine.

Embodiment 17.

The ophthalmic composition according to any one of embodiments 1-16, comprising Lectoine.

Embodiment 18.

The ophthalmic composition according to any one of embodiments 1-17, comprising an ophthalmologically acceptable ectoine derivative selected from the group consisting of an ophthalmologically acceptable ectoine ester, hydroxyectoine or an ophthalmologically acceptable hydroxyectoine salt, an ophthalmologically acceptable hydroxyectoine ester, and a combination thereof.

Embodiment 19.

The ophthalmic composition according to any one of embodiments 1-18, containing Dpanthenol.

Embodiment 20. The ophthalmic composition according to any one of embodiments 1-18, comprising an ophthalmologically acceptable salt of pantothenic acid selected from sodium pantothenate and calcium pantothenate.

Embodiment 21.

The ophthalmic composition according to any one of embodiments 1 to 20, wherein the weight ratio of hyaluronic acid or an ophthalmologically acceptable salt thereof, ectoine or an ophthalmologically acceptable derivative thereof to a compound selected from panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid and compounds thereof is from 1 :1.5:1.5 to 1:100:100.

Embodiment 22.

The ophthalmic composition according to the previous embodiment, in which the mass ratio is from 1:1.5:1.5 to 1:30:30.

Embodiment 23.

The ophthalmic composition according to the previous embodiment, in which the mass ratio is from 1:2:2 to 1:10:10.

Embodiment 24.

The ophthalmic composition according to the previous embodiment, in which the mass ratio is from 1:4:4 to 1:8:8.

Embodiment 25.

The ophthalmic composition according to the previous embodiment, in which the mass ratio is from 1:6.7:6.7.

Embodiment 26.

The ophthalmic composition according to any of the previous embodiments, further comprising an osmolarity adjusting agent.

Embodiment 27.

The ophthalmic composition according to the previous embodiment, wherein the osmolarity adjusting agent is sodium chloride.

Embodiment 28.

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The ophthalmic composition according to any of the previous embodiments, further comprising a buffer.

Embodiment 29.

The ophthalmic composition according to the previous embodiment, wherein the buffer is selected from the group consisting of borate buffer, citrate buffer, phosphate buffer, Tris buffer, trometamol/maleic acid

Embodiment 30.

An ophthalmic composition according to any of the previous embodiments, the pH of which is from 6 to 7.

Embodiment 31.

The ophthalmic composition according to the previous embodiment, the pH of which is 6.3.

Embodiment 32.

The ophthalmic composition according to any of the previous embodiments 27-31, containing a citrate buffer.

Embodiment 33. An ophthalmic composition according to any of the previous embodiments, comprising a pH adjusting agent selected from HCl and/or NaOH.

Embodiment 34.

The ophthalmic composition according to any of the previous embodiments, which does not contain preservatives and/or any other pharmaceutically active ingredients.

Embodiment 35.

The ophthalmic composition according to any of the previous embodiments, further comprising a buffer.

Embodiment 36.

The ophthalmic composition according to any of the previous embodiments, which does not contain preservatives.

Embodiment 37.

An ophthalmic composition according to any of the previous embodiments, having a dynamic viscosity, measured by the Brookfield method at 20° C., from 1 to 50 mPa-s.

Embodiment 38.

The ophthalmic composition according to the previous embodiment, having a dynamic viscosity, measured by the Brookfield method at 20° C., from 4 to 40 mPa-s.

Embodiment 39.

The ophthalmic composition according to the previous embodiment, having a dynamic viscosity, measured by the Brookfield method at 20°C, from 8 to 20 mPa-s.

Embodiment 40.

The ophthalmic composition according to any of the previous embodiments, provided in the form of eye drops.

Embodiment 41.

The composition defined in any of the previous embodiments for use in the prevention and/or treatment of ophthalmic pathology.

Embodiment 42.

The composition for use in accordance with the previous embodiment, wherein the ophthalmic pathology is selected from the group consisting of dry eye syndrome, Sjögren's syndrome, conjunctival inflammation, irritation, itching, burning and allergic reactions of the eye and related conditions.

Embodiment 43.

Composition for use according to the previous embodiment, wherein the ophthalmic pathology is dry eye syndrome.

Throughout the description and claims of the proposed composition, the word contain and its variations are not intended to exclude other technical characteristics, additives, components or steps. In addition, the word contain covers the phrases actually consisting of and/or consisting of. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration and are not intended to limit the present invention. Moreover, the present invention covers all possible combinations of the specific and preferred embodiments described herein.

Examples

Substances

Experiments were carried out with L-ectoine, dexpanthenol and sodium hyaluronate. Sodium hyaluronate was used with the following weight average molecular weight (Mw):

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Table 1. Mw for a given range of intrinsic viscosity of HA Internal viscosity Average [m3/kg] molecular weight

[kDa]

0.51 196 0.95 410 1.00 485

Compositions

A total of aqueous formulations were prepared with different concentrations of sodium hyaluronate and ectoine (comparative formulations) and sodium hyaluronate, ectoine and dexpanthenol. Some formulations also contain 0.44 NaCl and adjust the pH to 6.3 with HCl or NaOH if necessary. By way of non-limiting examples, the preparation of these two formulations is described in detail below.

A composition containing 0.1% or 0.2% or 0.3% or 0.4% or 0.5% sodium hyaluronate, 2% ectoine and 2% dexpanthenol was prepared as follows: first dissolved in a beaker 44 mg sodium chloride in approximately 70 ml deionized water. After complete dissolution, add 2007.0 mg of ectoine and stir until a clear solution is obtained. Then slowly add 102 mg, or 204 mg, or 306 mg, or 408 mg, or 510 mg of sodium hyaluronate and stir at elevated temperature (50°C) until a clear solution is obtained. In the second beaker, 2013 mg of dexpanthenol is added to approximately 10 ml of deionized water and stirred until a clear solution is obtained. At the next stage, a solution with dexpanthenol is added to the first glass. After this, the solution is added to 300 ml with deionized water and the pH is adjusted to 6.3 with 0.1 M HCl.

Composition containing 0.1% or 0.2% or 0.3% or 0.4% or 0.5% sodium hyaluronate, 2% ectoine and 2% dexpanthenol: first dissolve 501 mg of sodium citrate in a beaker and 52 mg citric acid in approximately 200 ml deionized water. After complete dissolution, add 6000.0 mg of ectoine and stir until a clear solution is obtained. Then slowly add 919 mg of sodium hyaluronate and mix at elevated temperature (35 ° C) until a clear solution is obtained. In the second beaker, 6041 mg of dexpanthenol is added to approximately 30 ml of deionized water and stirred until a clear solution is obtained. At the next stage, a solution with dexpanthenol is added to the first glass. The mixture is stirred, after which the solution is added with deionized water to 300 ml.

Water binding ability

Water binding capacity was defined as the maximum amount of water absorbed by the sample and retained during low-speed centrifugation (Heraeus Sepatech centrifuge, model Labofuge Ae). This effect was measured gravimetrically using a microbalance with d (smallest division) = 0.001 mg (Sartorius balance, model MSA66P), as described below.

Sodium hyaluronate, L-ectoine and dexpanthenol were weighed into pre-weighed Eppendorf flasks in various proportions as shown for the compounds in Fig. 1 (the total weight of the mixtures was 50 mg in all cases). The initial total mass of the mixture (w0) was noted. Distilled water was then added in small drops, stirring with a needle after each addition until the mixture was completely wetted without any spreading effect. Water was then added to the sample without stirring until a slight excess of water appeared at the top of the mixture. The sample was then centrifuged at 4000 rpm for 5 min at ambient temperature. After centrifugation, a small amount of supernatant was discarded. Then, after removing the supernatant (w1), the total weight of the mixture was determined.

The measured water binding capacity (WBC) was determined using the following formula:

(wi- Wo) 100% TDS (gravimetrically) in % =------------Wo where wo' is the weight of the initial total mass of the mixture;

w ₁ = weight of the total mass of the mixture after centrifugation and without supernatant.

In addition, the %MRV was measured for each pure ingredient described above (pure sodium hyaluronate, pure ectoine, pure dexpanthenol, each weighed at 50 mg).

The theoretical TER of the compounds was then calculated as the sum of the TER% of the pure ingredients in the proportions of the ingredients present in the mixture, or as the sum of the TER% of pure dexpanthenol and the TER% of the compounds sodium hyaluronate and L-ectoine. This theoretical SER represents the water binding capacity that would be expected in the case of a fully additive effect.

The deviation of the measured TER from the calculated theoretical TER reflects the synergistic effect, which can be calculated using the following equation:

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Synergy = measured TER * 100% theoretical TER

- 100

In other words, the synergistic effect shows how much the concentration of sodium hyaluronate in the composition can be reduced to maintain the same level of TDS. The synergistic effect can be seen in FIG. 1.

In fig. Figure 1 shows the synergistic effect of SSV with increasing concentrations of dexpanthenol for 5, 10 and 20% concentrations of sodium hyaluronate and various concentrations of ectoine. The ectoine content can be calculated as 100% minus % sodium hyaluronate minus % dexpanthenol (1OO-HA%-DEX%). It was observed that the addition of dexpanthenol increased the amount of bound water compared to a formulation containing only sodium hyaluronate and ectoine (Figure 1). The effect became more significant when the concentration of sodium hyaluronate was reduced below 20% w/v.

Viscosity reduction depending on shear ratio

Dynamic viscosity was determined using a Brookfield LV DV3T viscometer. Samples were taken directly for viscosity measurements without any dissolution. An exact sample volume of 6.7 mL was poured into the chamber tube surrounded by a water cooling jacket, an SC4-18 spindle was placed into the sample, and analysis began when the sample reached a temperature of 20.0 ± 0.2 °C. Data were collected over a spindle rotation range of 2–250 rpm.

The proposed composition is characterized by increased dynamic viscosity. If the dynamic viscosity of the eye drops used is within the range of physiological tears, they are removed after a few minutes. The advantage of increasing the viscosity of the eye drops used is that the time it takes to remove the drops from the surface of the eye increases, as shown in FIG. Figure 8 shows the effect of adding dexpanthenol on increasing the dynamic viscosity of the proposed compositions.

Second, the dynamic viscosity of tears decreases during blinking due to the very high shear stress generated by the eyelids, which prevents damage to the eye. From an eye safety point of view, the rate at which dynamic viscosity decreases is an important parameter. The faster the dynamic viscosity decreases during blinking, the safer the eye drops and their effect on the corneal surface. In fig. Figures 2, 3 and 4 show the effect of hyaluronic acid chain length on dynamic viscosity as a function of shear factor. It is noteworthy that all formulations with a hyaluronic acid concentration equal to or lower than 0.2%, regardless of the molecular weight tested, behave as Newtonian fluids within the analyzed shear ratio range (0-250 rpm), in Fig. 8 it can be seen that all formulations containing 2% D-panthenol showed higher viscosity than the same formulations without dexpanthenol.

The synergistic effect of adding dexpanthenol to formulations containing sodium hyaluronate and L-ectoine was also studied (formulations and results are shown in Fig. 9). The dexpanthenol formulation was observed to have a higher viscosity than expected, consistent with the theoretical coupling of the viscosity of formulations containing dexpanthenol (without sodium hyaluronate or ectoine) and formulations containing sodium hyaluronate and ectoine (without dexpanthenol). The greatest synergistic effect is observed for 2% dexpanthenol (390.5%, Fig. 9).

In addition, the rate of viscosity decrease with increasing shear coefficient depends on the concentration of dexpanthenol. It is important to note that the largest reduction in viscosity, measured as the difference between the maximum and minimum viscosity value (within the shear factor range), can be observed for 2% dexpanthenol (Δμ=8.66 mPa*s, Fig. 6).

Surface tension

Surface tension is a very important parameter in terms of moisturizing the corneal surface. Surface tension must be greater than gravitational forces in order to adhere to and spread across the corneal surface. Patients suffering from dry eye syndrome usually have a higher surface tension than tears from healthy people.

The purpose of these experiments was to determine the effect of the addition of D-panthenol on the change in surface tension. Surface tension was measured in the sessile drop using the Wilhelmy method, and solutions were taken directly for analysis without dissolution. It was observed that the addition of dexpanthenol did reduce the surface tension of the proposed compositions (this can be seen in Fig. 7). Surface tension was measured for a dexpanthenol concentration range of 0–3% using a Kruss K20 tensiometer.

Documents mentioned in the application

A.R. Wegener, L.M. Mayer and K.L. Schonfield. Effect of viscous substances on corneal density in dry eye syndrome. Journal of Ocular Pharmacology and Therapeutics 31, 504-508(2015).

Creech JL, Du LT, Fatt I, Radke KJ. In vivo determination of tear film thickness and its effect on tear film stability. Current Research in Ophthalmic Medicine, 1998; 17: 1058-1066.

Tiffany J.M., Winter N. and Bliss G. (1989) Tear film stability and tear surface tension, Current Research in Ophthalmic Medicine, 8:5, 507-515.

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Claims (14)

CLAIM 1. An ophthalmic composition comprising from 0.001 to 2% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof, from 0.5 to 5% by weight of ectoine or an ophthalmologically acceptable salt thereof, or an ophthalmologically acceptable ester of ectoine, or hydroxyectoine or an ophthalmologically acceptable salt hydroxyectoine, an ophthalmically acceptable hydroxyectoine ester, or a combination thereof, from 0.5 to 5% by weight of a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid, and combinations thereof, and water in an amount up to 100% of the total weight composition. 2. The ophthalmic composition according to claim 1, where the composition contains from 0.15 to 0.4% by weight of hyaluronic acid or an ophthalmologically acceptable salt thereof, from 1 to 3% by weight of ectoine or an ophthalmologically acceptable salt thereof, or an ophthalmologically acceptable ester ectoine, or hydroxyectoine or an ophthalmologically acceptable salt of hydroxyectoine, or an ophthalmologically acceptable ester of hydroxyectoine, or a combination thereof, from 1 to 3% by weight of a compound selected from the group consisting of panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid, and combinations thereof, and water in amounts up to 100% of the total mass of the composition. 3. Ophthalmic composition according to claims 1, 2, where the weight average molecular weight (Mw) of hyaluronic acid or its ophthalmologically acceptable salt is from 100 to 800 kDa. 4. The ophthalmic composition according to claim 3, wherein the weight average molecular weight (Mw) of hyaluronic acid or an ophthalmologically acceptable salt thereof is from 150 to 500 kDa. 5. Ophthalmic composition according to any one of claims 1 to 4, according to which the composition contains sodium hyaluronate, L-ectoine and D-panthenol. 6. An ophthalmic composition according to any one of claims 1 to 5, wherein the weight ratio of hyaluronic acid or an ophthalmologically acceptable salt thereof to ectoine or an ophthalmologically acceptable salt thereof, or an ophthalmologically acceptable ectoine ester, or hydroxyectoine or an ophthalmologically acceptable salt of hydroxyectoine, an ophthalmologically acceptable hydroxyectoine ester , or a combination thereof and to a compound selected from panthenol, pantothenic acid, an ophthalmologically acceptable salt of pantothenic acid, or a combination thereof, is from 1:1.5:1.5 to 1:30:30. 7. Ophthalmic composition according to claim 6, where the mass ratio is from 1:2:2 to 1:10:10. 8. Ophthalmic composition according to claims 1-7, additionally containing sodium chloride. 9. An ophthalmic composition according to any one of claims 1 to 8 without containing preservatives and/or any additional pharmaceutically active ingredient. 10. Ophthalmic composition according to any one of claims 1 to 9, having a pH from 5 to 7.5. 11. An ophthalmic composition according to any one of claims 1 to 10, wherein the dynamic viscosity of the composition, measured by the Brookfield method at 20°C, is from 1 to 50 mPa-s. 12. Ophthalmic composition according to any one of claims 1 to 11, where the composition is in the form of eye drops. 13. Use of a composition according to any one of claims 1-12 for the prevention and/or treatment of ophthalmological pathology selected from the group consisting of dry eye syndrome, Sjögren's syndrome, inflammation of the conjunctiva, irritation, itching, burning and allergic reactions of the eyes and associated with them states. 14. Use according to claim 13, where the ophthalmic pathology is dry eye syndrome. -