EP3294302A1

EP3294302A1 - Ophthalmic composition

Info

Publication number: EP3294302A1
Application number: EP16726959.6A
Authority: EP
Inventors: Giovanni Ferrari
Original assignee: COC Farmaceutici Srl
Current assignee: COC Farmaceutici Srl
Priority date: 2015-05-12
Filing date: 2016-05-12
Publication date: 2018-03-21
Also published as: WO2016181342A1; ITMO20150103A1

Abstract

The ophthalmic composition comprises at least a pharmaceutically acceptable inert carrier agent and at least a pH adjuster, sodium hyaluronate present in the concentration by weight, evaluated compared to the total weight of the composition, between 0.2% and 0.6%.

Description

OPHTHALMIC COMPOSITION

Technical Field

The present invention relates to an ophthalmic composition.

Background Art

With particular reference to the field of medical devices the use is known of ophthalmic compositions for maintaining ocular hydration and/or relieving disorders and discomfort due to eye dryness, itching and burning.

In this regard it is pointed out that in the present context by the term ophthalmic compositions are meant collyria, ophthalmic solutions, solutions for ophthalmic use and eye drops.

From the anatomical point of view an eye has an outer surface visible to an observer without special equipment, and has a substantially spherical shape. The outer surface is composed of the sclera, a thin opaque tissue white in color, which covers about 95% of the outer surface of the eye itself and which is interrupted in the front, giving origin to a second spherical portion, the cornea. The cornea accounts for approximately the remaining 5% of the outer surface of the eye and is composed of a single biological multilayered tissue, transparent to light, without blood vessels and which is suitable for transmitting and focusing the light inside the eye itself and, furthermore, for acting as a barrier against the entry of bacteria or other pathogens.

Inside the sclera is a pigmented and vascularized layer, the choroid, which extends in front giving rise to the ciliary body and the iris.

The iris is a membranous disc with a central hole, the pupil, and, arranged at the rear, the crystalline lens, a transparent structure that acts as the human eye's natural lens.

The constituent parts of the outer surface of the eye, i.e., the cornea and the sclera, are hydrated in front by the tear film, a transparent fluid with lubricating action, and, nourished at the rear by the aqueous humor, a transparent liquid, produced by the ciliary body and contained in a chamber defined by the space between the cornea and the crystalline lens.

In detail, the tear film plays an essential role in the maintenance of the homeostasis of the eye's outer surface, carrying out several specialized functions aimed at nourishing, lubricating and protecting the outer surface itself against bacterial agents.

Today, numerous disorders are known related to qualitative and quantitative imbalances of the tear film which afflict a high percentage of the population. Among these disorders is the so-called "dry eye syndrome" caused by the combination of several factors that alter the secretion and/or the composition of the tear film, increasing evaporation and causing inflammation of the eye's outer surface.

People who suffer from this disorder are often affected by burning, itching, difficulty in opening the eyelids on awakening, photophobia and visual fogging; it is easy to appreciate, therefore, how such disturbances can affect the quality of a person's life, because if left untreated they can cause permanent eye damage.

Furthermore, among the many factors that determine the alteration of the secretion and/or composition of the tear film are environmental factors such as: air conditioning, heating, excessive exposure to sunlight, wind, salt air, smoke and pollution.

To the above factors must be added others related to ocular fatigue caused by the prolonged use of computers, contact lenses, or particular medical conditions due to the use of drugs or post-operative periods.

To date these disorders have been relieved by the use of ophthalmic compositions having a number of drawbacks among which the fact that they determine a partial hydration of the outer eye surface, relieving only temporarily the disorders described above and forcing the user to undergo various administrations close up to one another.

To this must be added the fact that, often, known ophthalmic compositions cannot be administered while wearing contact lenses; this means they can only be administered after the contact lens has been removed from the user's eye, thus greatly complicating the administration of the composition itself and increasing the risk of microbial contamination linked to the removal and subsequent reinsertion of the contact lens in the eye. Description of the Invention

The main aim of the present invention is to provide an ophthalmic composition with hydrating, lubricating and nourishing action to relieve and reduce the symptoms related to dry eye syndrome and ocular fatigue.

Another object of the present invention is to provide an ophthalmic composition with a protective and refreshing action and which allows to increase the stability of the ocular film for a prolonged period of time, due to adverse environmental conditions such as wind, salt air, smoke, pollution, excessive exposure to sunlight or particular medical conditions.

A further object of the present invention is to provide an ophthalmic composition which allows to overcome the mentioned drawbacks of the prior art within the framework of a simple, rational, easy, effective to use and affordable solution.

The above mentioned objects are achieved by the present ophthalmic composition having the characteristics of claim 1.

Brief Description

Other characteristics and advantages of the present invention will become better evident from the description of a preferred, but not exclusive, embodiment of an ophthalmic composition.

In the present description reference is made to an ophthalmic composition, usable e.g. by a person suffering from dry eye syndrome or disorders tied to the prolonged use of computers, of contact lenses, in particular medical conditions due to the use of drugs, post-operative periods or particular environmental conditions.

According to the invention, the ophthalmic composition comprises sodium hyaluronate present in the concentration by weight, evaluated compared to the total weight of the composition, between 0.2% and 0.6%.

Moreover the above composition comprises at least a pharmaceutically acceptable inert carrier agent and at least a pH adjuster for maintaining said composition at a pH between 6 and 8.

Sodium hyaluronate is a polymer the monomer of which is composed of two disaccharide units, D-glucuronic acid and N-acetyl-D-glucosamine, which give the molecule high polarity, and consequently, high solubility and the ability to retain a high volume of water.

Furthermore, sodium hyaluronate is a polymer physiologically present in ocular fluids and in the extracellular matrix; this means that its use in tear substitutes is well tolerated and does not cause cytotoxicity phenomena.

To this must be added that sodium hyaluronate provides muco-elastic and viscoelastic properties such as to ensure adequate lubrication of the ocular surface, protecting it from friction caused by the movements of the eyes.

In other words, said polymer is capable of retaining water and at the same time of interacting with the ocular epithelium.

For these reasons, sodium hyaluronate based ophthalmic formulations maintain the outer surface of the eye humidified, increase tear film stability and protect the surface itself from environmental agents.

In general, the properties of sodium hyaluronate can be identified in lubricating action (due to its viscoelastic behavior), humidifying action, and mucomimetic and bio-adhesive action.

Numerous studies show how the concentration of sodium hyaluronate in ocular fluids increases in response to damage of the ocular surface and during the reconstruction process of the ocular epithelium; it can be supposed, therefore, that the solutions containing sodium hyaluronate are able to establish a microenvironment favorable to the processes of tissue damage repair.

It is easy to appreciate how the lubricating action of the present composition is related to the presence of a viscoelastic polymer with thixotropic properties, such as sodium hyaluronate.

As part of the present discussion, by "thixotropic properties" is meant fluids having a time-dependent behavior, i.e., not fully reversible over time.

In the formulation of ophthalmic compositions, such behavior helps to obtain the degree of dispersion necessary to achieve the chemical-physical state intended for the end product.

In fact, during the blinking of the eyelids, when the tear film is preparing to be spread over the entire outer surface of the eye, the sodium hyaluronate fibers become extended, losing their spiral structure which favors their intertwining; this permits decreasing viscosity in favor of an elastic behavior.

The key feature which distinguishes sodium hyaluronate from other wetting agents such as hydroxypropyl methylcellulose (HPMC), carmellose, polyvinylpyrrolidone (PVP) and the like, concerns its water retention capacity which is independent of the state of humidity of the surrounding environment and ensures a high level of humidification.

Finally, sodium hyaluronate interacts with the precorneal mucin layer, forming a protective layer on the outer surface of the eye that prevents cell loss and increases the duration of the humidifying effect.

Usefully, the sodium hyaluronate used in the present composition is of biotechnological origin.

It is useful to point out that by "biotechnological origin" is meant sodium hyaluronate obtained from a microbial fermentation process and subsequently purified.

Advantageously, sodium hyaluronate is present in the concentration by weight, evaluated compared to the total weight of the composition, between 0.3% and 0.5%.

Preferably, sodium hyaluronate is present in the concentration by weight, evaluated compared to the total weight of the composition, substantially equal to 0.4%.

In the present embodiment, the carrier agent is water for injectable preparations and is present in the concentration by weight evaluated compared to the total weight of the composition, between 5% and 70%.

Nevertheless, alternative embodiments cannot be ruled out wherein the carrier agent is purified water, a glycol or an oil.

Furthermore, the pH adjuster is selected from the list: hydrochloric acid, boric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide, sodium tetraborate decahydrate, sodium phosphate, sodium citrate, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium citrate, potassium carbonate or a combination thereof. The aforementioned pH adjuster is present in the concentration by weight, evaluated compared to the total weight of the composition, between 0.03% and 6%.

In detail, the composition comprises at least a first pH adjuster and at least a second pH adjuster, wherein the first pH adjuster is boric acid and the second pH adjuster is sodium tetraborate decahydrate.

Moreover, the composition comprises at least one of a first hydrolat obtained from Ginkgo biloba, a second hydrolat obtained from Foeniculum vulgare, a third hydrolat obtained from Vaccinum myrtillus and a fourth hydrolat obtained from Centella asiatica.

It is useful to point out that in the present treatise by "hydrolat" is meant a plant extract the active ingredient of which is brought into aqueous solution by means of steam current distillation, also known to the technician in the field as "distilled water".

The first hydrolat comprises several polyphenols, the antioxidant action of which has been demonstrated thanks to the conveyance of electrons with respect to radical forms of oxygen.

In particular, the first hydrolat is able to act at mitochondrial level, unlike other compounds with antioxidant activity such as Vitamin E and Vitamin C.

More particularly, the extract obtained from Ginkgo biloba is usually used in clinical tests, in the form of standardized extract (EGg761 and LI 1370) by means of a multi-step procedure aimed at concentrating the active ingredients of the plant. The above standardized extract comprises about 24% of flavonoid glycosides, (mainly composed of quercetin, campherol and isorhamnetin), 6% of terpene lactones (2.8-3.4% of gmkgolides A, B and C and 2.6-3.2% of bilobalide).

Other components include proanthocyanidins, glucose, rhamnose, and organic acids (hydroxykynurenine acid, kynurenic acid, protocatechuic acid, vanillin acid and shikimic acid), D-glucaric acid, ginkgolic acid and other alkyl phenol compounds.

Finally, the first hydrolat has anti-inflammatory activities performed by interfering with the release of inflammatory cytokines by competitive inhibition of the platelet aggregating factor (PAF).

The second hydrolat obtained from Foeniculum vulgare, commonly called "fennel extract" has two commercially important forms, the so-called "bitter fennel" and the so-called "sweet fennel."

In Mediterranean areas fennel is used as an antispasmodic, diuretic, antiinflammatory, analgesic, secretomotor, secretolytic, galactagogue, antioxidant and as a dietary supplement.

In detail, the fennel is used for the treatment of gastrointestinal tract disorders, flatulence, intestinal cramping, indigestion and swelling.

The third hydrolat, obtained from Vaccinum myrtillus, so-called "blueberry extract" is used for the treatment of diarrhea, dysentery and for oropharyngeal inflammation.

The active ingredients of blueberry extract are obtained from the berries and leaves of Vaccinum myrtillus; in detail, the extract obtained from the former comprises anthocyanins, flavonoids, vitamins, sugars and pectins, while the extract obtained from the latter comprises quercetin, catechins, tannins, iridoids and acids.

Furthermore, although the action mechanism of the blueberry extract has not yet been fully understood, recent studies have shown its positive implications in increased eye oxygenation, in the transmission of blood to the eyes and in the elimination of radical forms of oxygen that can lead to the breakage of collagen structures and contribute to the onset of pathogenic conditions such as cataracts and macular degeneration.

To this must be added the fact that anthocyanins have high affinity with the pigment epithelium of the retina.

The beneficial properties of blueberry extract can be summarized in improvement of eyesight, glaucoma, cataracts and diabetic retinopathy.

Finally the fourth hydrolat, obtained from Centella asiatica, has many active components of which the most important are triterpene saponins (asiaticosides, centellosides, madecassoside and Asiatic acid) to which must be added the presence of other components such as volatile oils, flavonoids, tannins, phytosterols, amino acids and sugars. The above triterpene saponins and their respective sapogenins (obtainable from saponins by hydrolysis of same) have a fundamental role in the wound healing process, having positive effects on the vascular level within the wound site itself

Advantageously, the composition comprises the first hydrolat, the second hydrolat, the third hydrolat and the fourth hydrolat present in the following concentrations by weight, evaluated compared to the total weight of the composition:

- first hydrolat 5% - 30%

- second hydrolat 5% - 30%

- third hydrolat 5% - 30%

- fourth hydrolat 5% - 30%.

Preferably, the composition comprises at least an isotonizing agent selected from the list: sodium chloride, sodium bicarbonate, sodium citrate, disodium sodium phosphate, sodium sulfite, calcium chloride, calcium lactate, glucose, sucrose, mannitol or a combination thereof.

Conveniently, the isotonizing agent is present in the concentration by weight, evaluated compared to the total weight of the composition, between 0.2% and 10%.

Embodiments of the Invention

With particular reference to the present embodiment, the isotonizing agent is sodium chloride.

Alternative embodiments cannot be ruled out wherein the isotonizing agent is different, e.g., calcium lactate, or sodium bicarbonate, etc.

Furthermore, the ophthalmic composition is free of preservatives.

Alternative embodiments cannot however be ruled out wherein preservatives are present chosen from the list: benzalkonium chloride, chlorhexidine, chlorobutanol, thimerosal, sodium hydroxymethylglycinate, also known as sodium N-(hydroxymethyl)glycinate.

It is underlined that this preparation, thanks to the additive action of the various components, has a hydrating, lubricating and nourishing action suitable for relieving and reducing the symptoms related to dry eye syndrome and ocular fatigue.

EXAMPLE 1

An opthalmic composition has been made comprising sodium hyaluronate, the first hydrolat, the second hydrolat, the third hydrolat, the fourth hydrolat, boric acid, sodium tetraborate decahydrate, sodium chloride, water for injectable preparations in the following concentrations by weight, evaluated compared to the total weight of the composition:

- sodium hyaluronate 0.4%

- first hydrolat 10%

- second hydrolat 10%

- third hydrolat 10%

- fourth hydrolat 10%

- boric acid 0.6%

- sodium tetraborate decahydrate 0.05%

- sodium chloride 0.58%

- water for injectable preparations 58.37%

Furthermore, studies have been accomplished to assess the cytotoxicity (in vitro and in vivo) of the above composition.

In the study for the assessment of the cytotoxicity in vitro, a cell line of fibroblasts of murine origin was used (BALB 3T3 line - A31 clone) having a high proliferation capacity.

In the present case, the cell cultures were grown in a multi-well plate until the formation of a cell single layer confluent and occupying the entire surface of the plate.

Subsequently, the cell cultures were diluted to different concentrations in DMEM medium to which was added an aliquot of the composition.

Each sample was incubated at 37°C ± 1°C for 24 hours in an atmosphere enriched with 10% carbon dioxide.

At the same time, positive and negative controls were prepared which underwent the same procedure as the samples described above.

After incubation the cells were stained with neutral red; this allows the assessment of cell viability, based on the ability of same to retain such dye within the lysosomes, and thus provide a specific light intensity, measured by a photometer.

In the case in question, the intensity of staining of each sample is proportional to the viability of the cells contained in the sample itself and inversely proportional to the cytotoxicity of the composition.

The calculation of the cytotoxicity of each sample was based on predetermined assessment parameters of cell viability (Table 1), and interpretation of the results (Table 2).

Table 2

In detail, two samples were analyzed with different concentrations of the composition being examined: SAMPLE 1 (500 mg/ml) and SAMPLE 2 (250 mg/ml).

The table below (Table 3) shows the values thus obtained extrapolated after 6 tests in a row. Number of tests

% viability performed

Sample 1 6 73.7 ± 4.6%

Sample 2 6 89.4 ± 13.6%

Negative control 6 100%

Positive control 6 22.2 ± 2.2%

Table 3

In conclusion, the sample 2 is considered non-cytotoxic by virtue of the assessment interpretation parameters of the cell viability and the interpretation of the previously-described results.

Subsequently, an assessment was made of the delayed hyper- sensitivity skin reaction.

The above assessment was performed by means of the so-called "Guinea Pig Maximization test", in conformity with the ISO 10993-10:2010 and ISO 10993- 02:2006 standards.

Such test was performed on guinea pigs, proceeding according to the following three distinct stages, subsequent to one another:

preliminary stage;

induction stage;

stimulation stage.

The preliminary stage aims at identifying the specific concentration of composition to be used in the subsequent stages of the test. In the case in question, during the induction stage, the maximum concentration is selected able to cause a slight or moderate erythema without seriously jeopardizing the health of the animal, and during the stimulation stage, the maximum concentration is selected which does not cause erythema.

To select the above concentrations, three occlusive bandages were used, one of which soaked in 0.5 ml of the composition (BANDAGE I), and the remaining two soaked in 0.5 ml of composition diluted at 75% (BANDAGE II) and 50% (BANDAGE III) respectively with sodium chloride for injections.

All three bandages were applied to the back of three different animals and kept in position for 24 hours. The table below (Table 4) shows the data gathered after 24 hours from the positioning of the occlusive bandages.

It is useful to point out that by the numerical index 0 is indicated the total absence of erythema.

Table 4

In the light of these results, the bandage I, soaked with the composition as is, i.e. not diluted, was used for the subsequent stages of the test.

The procedure was continued according to the following experimental design which involves the use of a first experimental group (GROUP 1) comprising 10 animals and a second control group (GROUP 2) comprising 5 animals.

During the induction stage, each animal belonging to the two groups was treated with three pairs of intradermal injections, each of 0.1 ml and comprising:

1) stable emulsion of Freund, also known as complete Freund's adjuvant and indicated with the acronym CFA, diluted in a sodium chloride solution for inj ections in a 50 : 50 v/v ratio ;

2) undiluted composition for the first experimental group (GROUP 1) and a sodium chloride solution for the second control group (GROUP 2);

3) diluted composition with the stable emulsion of CFA and sodium chloride for injections concentrated at 50% for the first experimental group (GROUP 1) and sodium chloride for injections diluted in 50:50 v/v ratio with the stable emulsion of CFA and sodium chloride for injections at 50% for the second control group (GROUP 2).

After six days from the intradermal injections of all the animals belonging to both the first experimental group (GROUP 1) and the second control group (GROUP 2), a local application was made of 1 ml of sodium lauryl sulfate at 10%, by means of a skin massage.

After seven days from the intradermal injections, 1 ml of the composition was administered by the dermal route to each animal belonging to the first experimental group (GROUP 1), and the latter left in place for 48 hours.

The same treatment was carried out for the animals belonging to the second control group (GROUP 2).

Finally, after 21 days from the start of treatment on both animal groups (GROUP 1 and GROUP 2), the stimulation stage was terminated by the administration of 1 ml of composition on the right part of the back of each animal and of 1 ml of sodium chloride by injections on the left side. The back of each animal was then bandaged for 24 hours.

After 24 and 72 hours from the start of the stimulation stage, the skin reactions of both groups of animals (GROUP 1 and GROUP 2) were assessed.

In this regard, it is useful to point out that no skin anomalies were observed in either animal group (GROUP 1 and GROUP 2).

On the basis of these results, interpreted in accordance with the ISO 10993-10: 2010 standard, the composition is not considered sensitizing.

Afterwards, toxicology studies were performed to evaluate eye irritation.

The above studies were performed in accordance with ISO 10993-10: 2010 and ISO 10993-02: 2006 standards.

The eye irritation test was carried out by administering 0.1 ml of the composition in the conjunctival sac of three male albino rabbits of New Zealand origin.

The left eye of each rabbit was not treated, but used as a control.

The eyes of each rabbit were examined, by means of a binocular magnifying lens, after 1, 24, 48 and 72 hours from the start of the stimulation stage.

In detail, no anomalies were found relating to the conjunctiva eye area, especially the iris; to this must be added the absence of conjunctival redness, conjunctival edema (chemosis) and secretions.

In the light of these results, the composition is considered non-irritating to the eye.

The next step was the evaluation of the compatibility of the composition with the use of contact lenses.

The test was conducted on daily (disposable) contact lenses and biweekly contact lenses readily available on the market. It is useful to point out that the test was conducted on this type of contact lenses since, consisting of highly hydrophilic materials, they are the most critical and the most sensitive to chemical-physical changes of the lacrimal fluid, compared to rigid and semi-rigid contact lenses.

Furthermore, the test was performed in accordance with ISO 1 1981 : 2009 and ISO 18369-2: 2012 standards, operating according to the following steps:

- visual inspection carried out by means of a stereo microscope, in order to assess any imperfections, opacity and indefinite edges;

- dimensional analysis carried out by means of a profile projector; and

- determination of the transmittance of the UV and visible spectrum (between 280 and 800 nm).

A contact lens for each of the different types was soaked in the composition for 2 and 4 hours at a temperature of 32.5 °C ± 2.5 °C (SAMPLE UNDER EXAMINATION).

In this regard, it is useful to point out that the above temperature conditions are considered extreme, i.e., not easily found in normal conditions of contact lens use.

At the same time, one lens for each type of contact lens was kept soaked in physiological liquid, contained in the package on the market, under the same experimental conditions described above (CONTROL SAMPLE).

The different types of analyzed lenses are shown below:

- purha giornaliere Acqua⁺ (Acqua daily⁺) - Salmoiraghi & Vigano (composition: 31% Nelfilcon A, 69% water);

- fresh look - one day color contact lenses - Ciba Vision (composition: 31% Nelfilcon A, 69% water);

- one day acuvue - Johnson & Johnson (composition: 42% Etafilcon A, 58% water); and

- purha bisettimanali (biweekly) - VistaSi (composition: 55% Metafilcon A, 45% water).

Finally, the values examined for the sample under examination and for the control sample were considered acceptable, inasmuch as the differences measured with respect to the control sample are not significant and therefore the composition was deemed compatible with the use of soft contact lenses.

According to the same procedure, an evaluation test of the compatibility of the composition was performed with the use of semi-rigid and rigid contact lenses. The examined contact lenses are made up of the following transparent plastic materials:

- polymethylmethacrylate (PMMA);

- cellulose acetate butyrate (CAB);

- polysiloxane resins;

- polyacrylate;

- butylstyrene;

- fluorinated polymers;

- fluorosilane.

The above materials are to be deemed compatible with the use of the composition, since the latter maintains intact the transparency, physical- mechanical and chemical-physical integrity characteristics of the contact lenses even under extreme conditions.

Finally, the above composition proved to be stable over time; this means that its stability was assessed by determining chemical-physical parameters such as appearance, pH, osmolality, viscosity, the percentage of weight loss, and their possible alterations after 1, 3 and 6 months from the production of the composition itself, evaluating such chemical-physical parameters at a temperature of 40°C ± 2°C/75% RH ± 5% RH, 30°C ± 2°C/65% RH ± 5% RH and 25 °C ± 2°C/60% RH ± 5% RH.

It has in practice been ascertained that the described invention achieves the intended objects.

Furthermore, it is stressed that the particular solution of providing the use of sodium hyaluronate combined with the presence of numerous hydrolats containing plant components permits providing an ophthalmic composition with hydrating, lubricating and nourishing actions suitable for relieving and reducing the symptoms associated with the dry eye syndrome, ocular fatigue, and adverse environmental conditions such as wind, salt air, smoke, pollution, excessive exposure to sunlight or particular medical conditions.

Claims

1) An ophthalmic composition, comprising at least a pharmaceutically acceptable inert carrier agent and at least a pH adjuster, characterized by the fact that it comprises sodium hyaluronate present in the concentration by weight, evaluated compared to the total weight of the composition, between 0.2% and 0.6%.

2) Composition according to claim 1, characterized by the fact that said sodium hyaluronate is present in the concentration by weight, evaluated compared to the total weight of the composition, substantially equal to 0.4%.

3) Composition according to one or more of the preceding claims, characterized by the fact that it comprises at least one of a first hydrolat obtained from Ginkgo biloba, a second hydrolat obtained from Foeniculum vulgare, a third hydrolat obtained from Vaccinum myrtillus and a fourth hydrolat obtained from Centella asiatica.

4) Composition according to one or more of the preceding claims, characterized by the fact that it comprises said first hydrolat, said second hydrolat, said third hydrolat and said fourth hydrolat present in the following concentrations by weight, evaluated compared to the total weight of the composition:

- first hydrolat 5% - 30%

- second hydrolat 5% - 30%

- third hydrolat 5% - 30%

- fourth hydrolat 5% - 30%.

5) Composition according to one or more of the preceding claims, characterized by the fact that said carrier agent is water for injectable preparations and is present in the concentration by weight, evaluated compared to the total weight of the composition, between 5% and 70%.

6) Composition according to one or more of the preceding claims, characterized by the fact that said pH adjuster is selected from the list: hydrochloric acid, boric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide, sodium tetraborate decahydrate, sodium phosphate, sodium citrate, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium citrate, potassium carbonate or a combination thereof, said pH adjuster being present in the concentration by weight, evaluated compared to the total weight of the composition, between 0.03% and 6%.

7) Composition according to one or more of the preceding claims, characterized by the fact that it comprises at least a first pH adjuster and at least a second pH adjuster, said first pH adjuster being said boric acid and said second pH adjuster being said sodium tetraborate decahydrate.

8) Composition according to one or more of the preceding claims, characterized by the fact that it comprises at least an isotonizing agent selected from the list: sodium chloride, sodium bicarbonate, sodium citrate, disodium sodium phosphate, sodium sulfite, calcium chloride, calcium lactate, glucose, sucrose, mannitol or a combination thereof, said isotonizing agent being present in the concentration by weight, evaluated compared to the total weight of the composition, between 0.2% and 10%.

9) Composition according to one or more of the preceding claims, characterized by the fact that said isotonizing agent is said sodium chloride.

10) Composition according to one or more of the preceding claims, characterized by the fact that it comprises said sodium hyaluronate, said first hydrolat, said second hydrolat, said third hydrolat, said fourth hydrolat, said boric acid, said sodium tetraborate decahydrate, said sodium chloride, said water for injectable preparations in the following concentrations by weight, evaluated compared to the total weight of the composition: