A formulation for the treatment of interstitial cystitis disorder in particular

Abstract

The invention belongs to the field of medical device technology and relates to a formulation developed for the treatment of Interstitial Cystitis disorder in particular.

Description

[0001] A FORMULATION FOR THE TREATMENT OF INTERSTITIAL CYSTITIS DISORDER IN PARTICULAR

[0002] TECHNICAL FIELD

[0003] The invention belongs to the field of medical device technology and relates to a formulation developed for the treatment of Interstitial Cystitis disorder in particular.

[0004] PRIOR ART

[0005] Cystitis is one of the most common types of urinary tract infection (which can be abbreviated as UTI) and generally manifests itself as inflammation of the bladder and urinary tract. Said disorder is generally caused by bacterial infections and is a more common disorder especially among women. This condition is manifested by symptoms such as a burning sensation when urinating, frequent need to urinate, sudden urge to urinate, pain in the lower abdomen or back, and cloudy or foul-smelling urine.

[0006] Interstitial Cystitis, also known as painful bladder syndrome, is a debilitating, chronic condition characterized by chronic pelvic pain, urinary urgency and frequency as a result of inflammation and irritation of the bladder wall in the absence of other well- defined pathologies such as urinary tract infection or malignancy, with no generally accepted treatment. It is more common in women as the tube that carries urine out of the bladder, called the urethra, is shorter than in men. It is determined that the incidence of the disease in women is 9-10 times higher than in men. Although Interstitial Cystitis can occur in young people, it is most common between the ages of 30-40.

[0007] Interstitial Cystitis causes a decrease in the daily physical and social activities for the person and negative effects on the quality of life. Furthermore, it is well known to be associated with decreased work productivity, emotional changes, sleep, sexual dysfunction, and mobility.

[0008] Although the exact mechanism of occurrence of Interstitial Cystitis is not known, the most common mechanism is damage to the layer called glycosaminoglycan (GAG), which protects the inner surface of the bladder against urine in the bladder, such as the mucus layer that protects the stomach from its own acid. The surface of the damaged layer in the bladder is in direct contact with urine. This initiates an inflammatory and allergic process in the bladder. As a result of this inflammatory process, normally inactive pain fibers in the bladder become active and pain sensation begins. The process is perceived differently in the brain and the brain causes the pain in the bladder to feel severe. As the bladder heals, the process enters a vicious circle as a result of the formation of new vessels and new nerve fibers. Due to the so-called pain memory, even with the slightest stimulus, the pain resumes and makes itself felt in the bladder and perineum, the base of the buttocks, with varying intensity. Sometimes there is also pain in the groin.

[0009] Damage to the epithelium or bladder, penetration of irritants in the urine into the bladder due to a defect in the bladder epithelial layer, the presence of substances in the urine that damage the bladder, allergic reaction, hereditary causes, recurrent urinary tract infections, pain due to changes in the nerves that carry bladder sensation, the presence of inflammatory cells that release histamine and other chemicals are among the causes of Interstitial Cystitis disorder in the technique.

[0010] Known treatments of the disorder include drug treatment such as analgesics, antidepressants, antihistamines, corticosteroids, gabapentin, suplatast tosylate, quercetin, sodium pentosanpolysulfate, intravesical applications into the bladder, physical therapy, electrical nerve stimulation, alternative medicine, bladder training, bladder augmentation, smoking cessation, stress management, and surgical procedures.

[0011] Treatment is applied by sending an active substance containing high concentrations of glycosaminoglycan to the damaged target structure with intravesical applications, which is one of the above-mentioned treatment methods. Although fewer systemic side effects and more symptomatic relief have been reported, this method is associated with high cost, pain, risk of infection, and local side effects. Because of these possible effects, even intravesical applications, which are one of the most commonly used methods, cause high costs to the patient, the treatment process is long and a positive response cannot be obtained from the treatment. During the course of treatment, the patient usually has to visit the doctor every week, 4 times a month, and then once a month for 2 months, for a total of 6 times in total, and this period may be longer depending on the condition of the disorder. During this period, the patient continues to experience both high costs and difficulties in performing daily activities.

[0012] Drugs containing glycosaminoglycan (GAG) components are generally used in intravesical applications for the treatment of Interstitial Cystitis. Among its biggest advantages are that it is naturally synthesized in the body and has few side effects when taken externally. Hyaluronic acid (HA), heparin sulfate, heparin, chondroitin 4- sulfate, chondroitin 6-sulfate, dermatan sulfate, and keratan sulfate are known as GAG components. With intravesical applications, by healing the GAG layer in the damaged bladder, the pain can be eliminated. The main purpose of the GAG layer is to protect the cells in the bladder wall from irritants. The GAG layer retains water tightly without interacting with urine and therefore forms a waterproof barrier that protects bladder cells.

[0013] Urine is a solution of waste products and toxins ready to be excreted from the body. Damage to the GAG layer causes acids and toxins in the urine to reach the cells in the bladder wall directly. This can cause a feeling of urgency and pain, as well as inflammation. It can even cause bleeding. Damage to the GAG layer in the bladder wall also reduces the protective effect against infection caused by bacteria. The more concentrated the urine, the higher the potential for irritation and infection due to any compromise of the GAG layer.

[0014] Chemically, tannins are examined in two main groups: hydrolyzable tannins (pyrogallol type tannins) and condensed tannins. Tannins in the first group provide water-soluble compounds such as gallic acid, protocatechuic acid and sugar as a result of hydrolysis with an acid or enzyme. They are poorly soluble in water and well soluble in alcohol and acetone. Hydrolyzed tannins are divided into two groups: gallotannins (tannins derived from gallic acid) and ellagitannins (tannins derived from ellagic acid).

[0015] Tannins, also known as tannic acid, are polyphenolic compounds and are the name given to amorphous substances in the form of light yellow-brown powder, flakes or spongy masses obtained from plants such as rapeseed, broad beans, tea, and sorghum. Tannic acid is an important component in vegetable tanning of leather, iron gall ink, red wines, and as a traditional medicine in the treatment of various diseases. Tannic acid is known to reduce inflammation as an antioxidant, act as an antibiotic in common pathogenic bacteria, and induce apoptosis in various types of cancer. Tannic acid in certain concentrations is used for gastrointestinal disorders such as hemorrhoids and diarrhea, for the treatment of severe burns, and for protection against neurodegenerative diseases. Tannic acid is also used as a natural crosslinking agent to improve the mechanical properties of natural and synthetic hydrogels and polymers in biomaterials research, while also imparting anti-inflammatory, antibacterial, and anticancer activity to materials.

[0016] In the patent with the publication number US20210177771 A1 , it is applied to mice intravesically in combination with the CB2 receptor agonist beta-caryophyllene, which has a local anesthetic effect, in addition to the active substance DMSO for the treatment of Interstitial Cystitis. According to the data obtained in said patent, it shows that applying CB2 receptor agonist agents in combination form with DMSO is beneficial in reducing both inflammation and pain in the treatment of Interstitial Cystitis.

[0017] The patent with publication number W02004073584 A2 mentions that intravesical administration of high doses (400 mg / 20 mL) of chondroitin sulfate, a GAG (Glycosaminoglycan) component useful in the treatment of cystitis and bladder disorders, including Interstitial Cystitis, is an effective method of rapidly reducing symptoms in patients. In said patent, a solution comprising 20 mg / mL chondroitin sulfate in phosphate buffer comprising sodium chloride was prepared in a sterile Flint I type vial and the product was treated with intravesical administration once or twice a week.

[0018] As a result, all the above-mentioned problems have made it imperative to make an innovation in the relevant technical field.

[0019] SUMMARY OF THE INVENTION

[0020] The present invention aims to provide a formulation developed for use in the treatment of Interstitial Cystitis, also known as painful bladder, in order to eliminate the above- mentioned disadvantages and to bring new advantages to the relevant technical field. The primary object of the invention is to provide a formulation that provides treatment for Interstitial Cystitis disorder.

[0021] Another primary object of the invention is to provide a formulation that prevents the recurrence of the disorder in the damaged bladder area by creating a protective barrier in the bladder in direct contact with urine during the treatment and healing process of Interstitial Cystitis disorder.

[0022] An object of the invention is to provide a formulation that protects the GAG layer on the inner surface of the bladder against urine and reduces damage to the bladder surface.

[0023] Another object of the invention is to provide a formulation developed for reducing inflammation in the bladder.

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] In this detailed description, the subject of the invention relates to an effective formulation for the treatment of Interstitial Cystitis disorder in particular and is explained by way of example only for a better understanding of the subject, which shall not create any limiting effect.

[0026] In the invention, the term “Interstitial Cystitis in particular” is used as it has been determined that the formulation of the invention will be effective in the treatment of similar disorders or in the relief of symptoms arising from these disorders. The formulation in question is intended for the treatment of painful bladder syndrome, urethritis, which is another disease of the urethral tract, urethral wounds, and urethral postoperative care.

[0027] The first objective of the formulation of the invention for the patient is to provide rapid repair of damage to the bladder and urethra. Another objective is to protect the diseased area, which is still sensitive after repair.

[0028] The formulation of the invention contains components of therapeutic, antioxidant, antiinflammatory, and antimicrobial properties to ensure the repair of the diseased area. Another function desired to be provided by the formulation is to create a protective barrier at the diseased area, preventing the repaired damaged structure from being damaged again. During the healing process, the healing process is accelerated by preventing the recurrence of the disorder.

[0029] In this invention, “treatment” refers to all effects such as slowing the progression of Interstitial Cystitis and similar disorders, alleviating the occurring pain, protecting the bladder wall function, and increasing the general comfort of life.

[0030] The formulation of this invention contains at least one glycosaminoglycan (abbreviated as GAG) component.

[0031] In the invention, "glycosaminoglycan" refers to structures consisting of repeated disaccharide units, in which these units contain an amino sugar and a uronic acid.

[0032] In this present invention, the glycosaminoglycan component(s) is one of the main components for the formulation and enables the formulation to fulfill two essential functions. The glycosaminoglycan component(s) form a protective layer for the diseased area where it is applied. With this feature, it reduces inflammation in the bladder; prevents the recurrence of the damage and the direct access of irritating or infectious components such as toxins and acids in the urine to the damaged cells in the diseased area. This protective barrier accelerates the healing process of the damaged area. In addition, during the treatment of the diseased area, recurrence of the disorder or progression of the existing diseased state is prevented.

[0033] The formulation of the invention may contain hyaluronic acid, heparin, dermatan, chondroitin sulfate, keratin sulfate or at least one of the acceptable salts thereof as glycosaminoglycan.

[0034] In the most preferred embodiment, hyaluronic acid sodium salt is preferred as glycosaminoglycan compound.

[0035] It is aimed that the glycosaminoglycan component(s), which provides a protective barrier function for the diseased area with the properties mentioned in the invention, has therapeutic properties, in addition, it is aimed that its absorption and bioavailability properties also increase.

[0036] The glycosaminoglycan component(s) acting as the main component in the formulation of the invention is modified with at least one polyphenolic compound in order to have the targeted properties. The polyphenolic compound(s) used in its modification provide antioxidant, anti-inflammatory and antimicrobial properties within the formulation for the diseased area. Together with these properties, it provides a therapeutic effect for the damaged surface in the diseased area. In addition, it is possible to prevent inflammation by creating a protective barrier in the damaged area and to accelerate the healing process by reducing oxidative stress.

[0037] In this invention, "polyphenolic compound(s)" refers to compounds with structures containing one or more aromatic rings and hydroxyl (-OH) groups attached to these rings.

[0038] In this invention, modification refers to all compounds obtained by reacting at least one glycosaminoglycan component(s) with at least one polyphenolic compound(s).

[0039] In the invention, at least one compound from the tannin (tannic acid) group can be preferred as a modifying polyphenol compound.

[0040] From the tannin group, preferably gallotannins and / or ellagitannins can be included in the formulation as polyphenolic compounds.

[0041] In the most preferred embodiment, gallic acid is preferred as a modifying polyphenolic compound.

[0042] Accordingly, one of the innovative aspects of the formulation of the invention is that it contains at least one glycosaminoglycan modified with a polyphenolic compound.

[0043] In a preferred embodiment, the formulation may contain the glycosaminoglycan component in a modified form and also in an unmodified form. However, the inventors emphasize that the gallic acid-modified form of glycosaminoglycan component hyaluronic acid has more effective properties. In said formulation, the glycosaminoglycan component(s) modified with the polyphenolic compound will form a barrier on the surface of the damaged bladder in contact with the urine. With the formation of this barrier, the treatment of the Interstitial Cystitis disorder will be possible. This protective barrier will be provided by the absorption of the modified glycosaminoglycan component(s) contained in the formula by the cells in the damaged bladder wall. The absorption that takes place here is easy in some components and difficult in some components. Easily absorbed component(s) have a low residence time in the body and difficult to absorb component(s) cannot form a barrier in the damaged bladder wall. Here, the glycosaminoglycan component(s) is modified to create a new formulation that is both easily absorbed and forms a long- lasting barrier against the damaged bladder wall.

[0044] The most preferred embodiment is to modify the formulation with hyaluronic acid as a glycosaminoglycan component and gallic acid as a polyphenolic compound. It is known that the absorption of high molecular weight hyaluronic acids in the body is very slow compared to low molecular weight hyaluronic acids, and their residence time in the body is relatively longer. Gallic acid, on the other hand, is rapidly absorbed in the body due to its molecular structure. Here, especially by modifying high molecular weight hyaluronic acids, absorption of high molecular weight hyaluronic acids, which are not absorbed in the bladder wall and have a high residence time in the body, can be achieved. Thus, a protective barrier is formed on the bladder wall from hyaluronic acids, which have a high residence time in the body, and the disorder is completely eliminated. Furthermore, by modifying low molecular weight hyaluronic acids, which are rapidly absorbed in the bladder, the residence time of the barrier formed in the bladder wall is increased and the disorder is completely eliminated. In both applications, hyaluronic acid modified with gallic acid will be rapidly absorbed into the impaired bladder wall and form a long-lasting protective layer there. Thanks to this protective layer, the damaged bladder wall is repaired. This protective layer reduces inflammation in the bladder and protects the inner surface of the bladder, which is in direct contact with urine, from acids and toxins in the urine, preventing them from reaching the bladder cells directly. Thus, the symptoms of Interstitial Cystitis disorder are eliminated.

[0045] The formulation of the invention contains at least one hyaluronic acid salt, sodium hyaluronate, with a value in the range of 50 to 4,000 kDa. The formulation of the invention contains at least one modified glycosaminoglycan component at a value in the range of 0.005% to 3% by weight.

[0046] In a preferred embodiment, the formulation of the invention contains at least one buffer solution The buffer solution is included in the formulation to adjust the pH value and osmolality of the formulation. It ensures that the formulation adapts to the environment for the diseased area and remains stable.

[0047] In this invention, the formulation comprises at least one of the sodium chloride and / or phosphate buffer (PBS) solutions as a buffer solution.

[0048] If preferred, the formulation comprises at least one auxiliary component. Analgesic component(s) can be used as an auxiliary component. As analgesics, components such as lidocaine, prilocaine, bupivacaine, articaine, and mepivacaine may be used.

[0049] In a preferred embodiment, the pH value of the formulation is a value in the range of 6.8 to 7.6, and this value has been determined to be compatible with the pH value of the diseased area and especially the inner part of the bladder.

[0050] In a preferred embodiment, the osmolality value of the formulation is at a value in the range of 250 to 350 mOsmol / kg. Fluids with this osmolality value range maintain the osmotic balance of the human body and are important for the normal functioning of cells.

[0051] The formulation with these properties can preferably be stored in specified volumes by being filled into syringes or vials. When it is desired to be applied to the sick individual, the formulation is injected into the diseased area.

[0052] The physician can decide on the final catheter selection for all indications. In preferred embodiments, catheters of 8, 10 and 12 french diameter and 20 and 30 cm in length are used for injection in female patients. Catheters of 12, 14, 16 and 18 french diameter and 30 and 40 cm in length are used for injection in male patients. With the help of a catheter, the formulation is deposited into the diseased area. After the diseased area is completely emptied out, this product is injected by medical professionals trained in injection techniques into the bladder through formulation instillation. The aseptic technique is applied thoroughly to avoid infection. After injection, the catheter should be removed from the patient and the product should be left in the bladder for at least 30 minutes and up to 2 hours after injection and then emptied out of the bladder.

[0053] In another aspect, the invention describes a method for modifying hyaluronic acid, which is the main component in the formulation, with gallic acid, and includes the following process steps. However, the components provided here and the values specified depending on the use of the components may vary. For example, instead of acetic acid, other acids with similar effects may be used. The aim here is to provide technical teachings for the relevant technical field in showing what is meant by the modification process in the invention and which basic process steps are applied.

[0054] Obtaining gallic anhydride from gallic acid

[0055] Gallic acid (expressed as 1 in formula 1) at a value in the range of 10 to 20 mmol is dissolved in acetic acid in determined amounts. The obtained solution is boiled under a condenser for a period ranging from 1 to 5 hours and stirring process is carried out. Subsequently, the solvent is removed from the solution and the drying process is carried out. The obtained residue is distilled and a viscous liquid is obtained. The viscous liquid is collected and allowed to cool. When the liquid reaches room temperature, it solidifies. The obtained solid is purified by washing with diethyl ether.

[0056] Formula 1 .

[0057] Obtaining galloyl chloride from gallic acid

[0058] Gallic acid (expressed as 1 in formula 2) at a value in the range of 10 to 20 mmol is dissolved in thionyl chloride in determined amounts. The obtained solution is boiled under a condenser for a period ranging from 1 to 15 hours and stirring process is carried out. Subsequently, the solvent is removed from the solution and the drying process is carried out. The obtained residue is distilled and a viscous liquid is obtained. The viscous liquid is collected and allowed to cool.

[0059] Formula 2.

[0060] Reaction of sodium hyaluronate with p-toluene sulfonyl chloride

[0061] In argon gas medium, 0.1 to 1.5 g of sodium hyaluronate (expressed as 2 in formula 3) is dissolved with 20 to 50 mL of anhydrous pyridine. The ambient temperature of the solution is adjusted to -5 to 0 °C and p-toluene sulfonyl chloride (TsCI) (1.5 times the amount equivalent to the number of repetitive units of Sodium hyaluronate) is gradually added at this temperature. The solution is stirred with argon gas at a temperature of 0 to 5 °C overnight. After the reaction is completed, anhydrous ethyl alcohol at a temperature of 0 to 5 °C is added to the solution and tosylated hyaluronic acid (2a) is precipitated. The obtained solid is purified by washing with anhydrous ethyl alcohol.

[0062] Formula 3.

[0063] Halogenation of sodium hyaluronate (2b-c); 20 to 30 mL of anhydrous DMF is added to 0.1 to 1 g of sodium hyaluronate (expressed as 2 in formula 4) in argon gas medium and the suspension solution is stirred for at least 30 minutes. Methanesulfonyl chloride (for MsCI, 2b) or methanesulfonyl bromide (for MsBr, 2c) (10 times the amount equivalent to the number of repetitive units of sodium hyaluronate) is gradually added to the solution at a temperature of -10 to 0 °C. After the addition is finished, the mixture is stirred in an argon gas environment and at room temperature overnight. After the reaction time is over, the mixture is cooled to room temperature and the reaction is terminated by adding distilled water at a value in the range of 1 to 10 mL to the mixture. After the reaction is terminated, the mixture is preferably neutralized with 0.1 M NaOH. The solvent of the obtained mixture is removed with the help of an evaporator and halogenated sodium hyaluronate (2b-c) is obtained. The obtained solid is purified by washing with ethyl alcohol.

[0064] Formula 4.

[0065] Modification of sodium hyaluronate from gallic anhydride;

[0066] Distilled water at a value in the range of 1 to 20 mL is added to sodium hyaluronate (expressed as 2 in formula 5) at a value in the range of 0.1 to 1 g and the solution is stirred overnight at room temperature to dissolve. Preferably dimethyl sulfoxide (DMSO) at a value in the range of 1 to 20 mL is gradually added to the solution and stirred. Triethylamine (TEA) at a value in the range of 0.1 to 1 mL, 4- dimethylaminopyridine (DMAP) at a value in the range of 1 to 10 mg are added to this solution, respectively, and stirred until a homogeneous solution is obtained. This prepared solution is cooled to 0 to 5 °C and gallic anhydride (expressed as 1a in formula 5) dissolved in DMSO at a value in the range of 1 to 10 mL is gradually added. The solution is stirred overnight at room temperature. After the mixing process is finished, the solution is preferably adjusted to the pH range of 7.2-7.8 with 0.1 M HCI and saturated sodium chloride is added to precipitate the modified hyaluronic acid (expressed as 3 in formula 5). The obtained solid is purified by washing with ethyl alcohol and the solid substance is dried under vacuum. The obtained modified hyaluronic acid substance will be used in the formulation.

[0067] Formula 5.

[0068] Modification of sodium hyaluronate from galloyl chloride

[0069] Anhydrous DMF at a value in the range of 10 to 20 mL is added to sodium hyaluronate (expressed as 2 in formula 6) at a value in the range of 0.1 to 1 g and the suspended solution is stirred at room temperature. Anhydrous pyridine at a value in the range of 0.5 to 1.5 mL is added to this mixture. The mixture is stirred until it dissolves. Galloyl chloride (expressed as 1 b in formula 6) dissolved with anhydrous pyridine is gradually added to the solution and stirred overnight at room temperature. After the reaction is completed, the solution is preferably adjusted to the pH range of 7.2-7.8 with 0.1 M HCI and saturated sodium chloride (NaCI) is added to precipitate the modified hyaluronic acid (3). The obtained solid is purified by washing with ethyl alcohol and the solid substance is dried under vacuum. The obtained modified hyaluronic acid substance will be used in the formulation.

[0070]

[0071] Formula 6.

[0072] Modification of tosylated sodium hyaluronate or halogenated sodium hyaluronate with gallic acid

[0073] Gallic acid (equivalent to the number of repetitive units of Sodium hyaluronate) is weighed and anhydrous DMF at a value in the range of 20 to 50 mL is added. The solution is cooled in an ice bath and potassium carbonate (KCO3) (4 times the amount equivalent to gallic acid) is added. The solution is stirred until gas release is complete. Afterwards, the solution is cooled to 0 °C and halogenated sodium hyaluronate (expressed as 2b-c in formula 7) or tosylated sodium hyaluronate (expressed as 2a in formula 7) at a value in the range of 0.1 to 1 g is gradually added and the solution is brought to room temperature. The solution is stirred overnight at room temperature. After the reaction is completed, the solution is preferably adjusted to the pH range of 7.2-7.8 with 0.1 M HCI and saturated sodium chloride is added to precipitate the modified hyaluronic acid (expressed as 3 in formula 7). The obtained solid is purified by washing with ethyl alcohol and the solid substance is dried under vacuum. The obtained modified hyaluronic acid substance will be used in the formulation. Formula 7.

[0074] Modification of sodium hyaluronate with gallic acid

[0075] Gallic acid (3 times the amount equivalent to the number of repetitive units of sodium hyaluronate) is dissolved in anhydrous DMF at a value in the range of 1 to 15 mL. An amount of 1 -ethyl-3-(3'-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCI) equivalent to gallic acid is added to the solution and stirred for 1 hour at room temperature. Then, n-hydroxysuccinite (NHS) is added to the solution in an ice bath in an amount equivalent to gallic acid. The solution is stirred in an ice bath for 1 hour. 0.5 g of sodium hyaluronate (expressed as 2 in formula 8) dissolved with anhydrous DMF is added to the solution in the ice bath and the solution is stirred in the ice bath for 30 minutes and then taken to room temperature. The solution is stirred overnight at room temperature. After the reaction is completed, saturated sodium chloride (NaCI) is added to the solution and modified hyaluronic acid (3) is precipitated. The obtained solid is purified by washing with ethyl alcohol and the solid substance is dried under vacuum. The obtained modified hyaluronic acid substance will be used in the formulation.

[0076] Formula 8.

[0077] The scope of protection of the invention is specified in the appended claims and cannot be limited to what is described for illustrative purposes in this detailed description. It is clear that a person skilled in the art can produce similar embodiments in the light of what is explained above, without deviating from the main theme of the invention.

Claims

CLAIMS1 . A formulation suitable for use in the treatment of Interstitial Cystitis disorder in particular, characterized in that it contains at least one glycosaminoglycan component modified with at least one polyphenolic compound as an active ingredient.

2. A formulation according to claim 1 , characterized in that it comprises at least one of said group consisting of hyaluronic acid, heparin, dermatan, chondroitin sulfate, keratin sulfate or acceptable salts thereof.

3. A formulation according to claim 2, characterized in that the glycosaminoglycan is sodium hyaluronate in hyaluronic acid salts.

4. A formulation according to one of the preceding claims, characterized in that said polyphenolic compound is at least one of the group consisting of hydrolyzable tannins or condensed tannins.

5. A formulation according to claim 4, characterized in that the polyphenolic compound is gallic acid.

6. A formulation according to one of the preceding claims, characterized in that it comprises a glycosaminoglycan compound modified with a polyphenolic compound at a value in the range of 0.005% to 3% by weight.

7. A formulation according to one of the preceding claims, characterized in that the pH value is at a value in the range of 6.8 to 7.6.

8. A formulation according to claim 7, characterized in that it comprises at least one of sodium chloride and / or PBS solutions to be at said pH values.

9. A formulation according to one of the preceding claims, characterized in that it has an osmolality value at a value in the range from 250 to 350 mOsmol / kg.

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