Reparaxin liquid suspension

Abstract

The present invention relates to a stable and ready-to-use liquid suspension of reparixin and its use.

Description

Technical Field

[0001] The present invention relates to a liquid suspension containing repalixine.

Background Art

[0002] Repalixine, also known as R-(-)-2-(4-isobutylphenyl)propionylmethanesulfonamide and reperatixin, is a non-competitive allosteric inhibitor of interleukin 8 (IL-8) receptors, CXCR1 and CXCR2 (Bertini R et al., Proc Natl Acad Sci., 2004; 101(32): 11791-6). Repalixine has therapeutic potential in preventing or treating pathological conditions where activation of this pathway is harmful.

[0003] For example, IL-8 is involved in neutrophil infiltration in pathological conditions such as psoriasis (B.J. Nickoloff et al., Am. J. Pathol., 1991, 138, 129), rheumatoid arthritis (M. Selz et al., J. Clin. Invest., 1991, 87, 463), ulcerative colitis (Y.R. Mahkla et al., Clin. Sci., 1992, 82, 273), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (P.C. Carre et al., J. Clin. Invest., 1991, 88, 1802, and E.J. Miller et al., Am. Rev. Respir. Dis., 1992, 146: 427-432) and glomerulonephritis (T. Wada et al., J. Exp. Med., 1994, 180, 1135).

[0004] In vitro and preclinical small animal experiments have demonstrated that the binding of repalixine to CXCR1 / CXCR2 can prevent leukocyte mobilization and activation of inflammation. The actions of repalixine include inhibition of neutrophil stimulation and downstream actions of neutrophils during an inflammatory response, such as NETosis, formation of NETs, etc. (Cheng OZ, Palaniyar N., Front Immunol., 2013; 4: 1).

[0005] The dosage, safety, and pharmacokinetics of repalixine have been investigated in clinical studies of patients with metastatic breast cancer (Schott AF, et al., Clin Cancer Res. 2017;23(18):5358-65; Goldstein LJ et al., Breast Cancer Res Treat. 2021;190(2):265-75).

[0006] A phase 2, multi-center, open-label, randomized, clinical trial was conducted from May 5, 2020, to November 27, 2020, to evaluate the efficacy and safety of repalixine in hospitalized patients with severe COVID-19 pneumonia, compared with available treatments considered as standard of care (SOC). This trial showed that treatment with repalixine in patients with severe COVID-19 pneumonia resulted in improved clinical outcomes compared with standard of care (Landoni G., et al., Infect Dis Ther, 2022, 26:1-16).

[0007] At that time, repalixine was formulated only in the form of tablets for oral administration or solutions for i.v. administration. However, these types of administration are invasive and / or not appropriate for achieving satisfactory medication compliance, especially in pediatric patients or patients who cannot swallow solid tablets. As a result, it is necessary to develop a new pharmaceutical dosage form containing repalixine that can overcome these problems and can be administered to subjects of all conditions and ages. For this purpose, a suspension is an ideal candidate.

[0008] A suspension is a pharmaceutical dosage form having two phases, namely an external liquid phase (also known as the continuous phase or dispersion medium) and an internal phase (also known as the dispersed phase) containing particulate matter insoluble in the external phase. Suspensions are recognized as heterogeneous dispersion systems, and most pharmaceutical suspensions have an aqueous dispersion medium.

[0009] The formulation and dispensing of this type of dosage form is associated with several advantages, namely, efficient formulation of hydrophobic drugs; avoidance of the use of co-solvents; masking of unpleasant taste; provision of resistance to drug degradation by hydrolysis, oxidation or microbial activity; and ease of administration for young or elderly patients. In addition, higher concentrations of drugs can be incorporated into suspensions than into solutions (Doye, P. et al., Int J Curr Pharm Sci, 2017, 9, 8).

[0010] The main challenge in the development of suspensions is to ensure the physical stability of these over time in order to ensure the homogeneity of the contents. In fact, suspensions are thermodynamically unstable systems due to the free energy of these internal phases, which results in particle aggregation and sedimentation, reducing the energy of the system. When formulating suspensions, several aspects must be considered.

[0011] First, based on the particle size of the internal phase, suspensions can be classified into two groups, namely, suspensions characterized by an internal phase with a particle size greater than about 0.5 μm, known as coarse suspensions, and suspensions characterized by an internal phase with a particle size smaller than 0.5 μm, known as colloidal dispersions (Edman, P., Journal of Aerosol Medicine, 1994, 7, S-3-S-6). Different parameters must be considered to ensure stability, depending on the type of suspension.

[0012] The preparation of suspensions containing repalixine is particularly difficult due to the specific characteristics of this active pharmaceutical ingredient (API). First, repalixine is produced in the form of a powder composed of particles with a large particle size. Therefore, any possible suspension containing repalixine is a coarse suspension.

[0013] In the case of a coarse suspension, the internal phase containing the API tends to sediment under gravity, causing a sedimentation phenomenon depending on its particle size. An increase in the zeta potential as an absolute value leads to an increase in the sedimentation rate. This suggests that sedimentation is driven rather by gravitational force than by electrostatic interaction, and in this electrostatic interaction, due to the particle size of the internal phase, it is insufficient to bring about stability and kinetic stabilization. For this reason, the zeta potential value of a coarse suspension is usually set around zero to ensure physical stability. This zeta potential value corresponds to the state where the particles are surrounded by a hydration layer that hides these charges. When the particles aggregate and sediment, the hydration layer can prevent the formation of a compact precipitate and instead promote the formation of a loose precipitate that can be easily redispersed by manually shaking. To adjust the zeta potential value of a suspension, ionic or non-ionic surfactants and different types of electrolytes (e.g., salts) are commonly used. For example, PEG (polyethylene glycol) is included in many commercially available suspensions for this purpose.

[0014] Furthermore, reparixin has low wettability, which makes it more complicated to formulate reparixin into a stable liquid suspension. In fact, the wettability of the dispersed particles is important to ensure homogeneity and uniformity of the content (Kwok, D.Y. et al., Advances in Colloid and Interface Science, 1999, Vol. 81, pp. 167 - 249). Wettability is the tendency of a fluid to spread or adhere on a solid surface when the fluids are immiscible. As a result of the weak wettability of the powder solid, the powder solid flows on the surface of the liquid medium. The weak wettability of the internal phase is mainly due to the high interfacial tension between the dispersed particles and the dispersion medium, and a decrease in the interfacial tension increases the stability of the suspension. When formulating a suspension, a common way to improve the wettability of a solid is the use of a wetting agent, such as a surfactant, which can reduce the solid - liquid interfacial tension.

[0015] Another requirement necessary to ensure the stability of the suspension is the presence of a so-called yield stress (τ0), which is a material property and can be defined as the stress corresponding to the yield point at which the material begins to flow or deform plastically.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0016] In view of the above, it is clear that there is a need to develop a suspension containing repalixine with satisfactory characteristics. However, this is particularly difficult for this API considering the reasons discussed above.

MEANS FOR SOLVING THE PROBLEMS

[0017] The inventors of the present invention have developed a stable liquid suspension of repalixine. In particular, the inventors have found that using sucrose as a sweetening agent and polyvinylpyrrolidone as a wetting agent in the formulation enables the production of a stable, ready-to-use liquid suspension of repalixine.

[0018] Specifically, the inventors have surprisingly found that the type and amount of sweetening agent included in the formulation to mask the unpleasant taste of repalixine affect the zeta potential value and, consequently, the stability of the suspension. Furthermore, the inventors have identified that the use of polyvinylpyrrolidone as a wetting agent enables the attainment of satisfactory wettability of repalixine.

[0019] The inventors have also identified the type and range of viscosity modifiers for obtaining a stable and ready-to-use liquid suspension of repalixine when used in combination with the above excipients. Therefore, the object of the present invention is - Repalixine in an amount between 2% w / w and 13% w / w, - Xanthan gum in an amount between 0.15% w / w and 0.3% w / w, - Sucrose in an amount between 25% w / w and 55% w / w, - A quantity of polyvinylpyrrolidone between 1.8% w / w and 3.2% w / w, - A quantity of water-insoluble polymer between 2.25% w / w and 2.75% w / w is a liquid suspension containing the same.

[0020] A further object of the present invention is a liquid suspension according to the first object of the present invention for use in the treatment of diseases or conditions selected from psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis, glomerulonephritis, and COVID-19.

[0021] A further object of the present invention is a liquid suspension according to the first object of the present invention for use in the prevention of diabetes or the delay of the onset and progression of diabetes. A further object of the present invention is a liquid suspension according to the first object of the present invention for use in the prevention and / or treatment of seizures.

Brief Description of the Drawings

[0022]

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Mode for Carrying Out the Invention

[0023] Definition The term "antifoaming agent", as used herein, refers to a chemical additive that reduces and / or inhibits the formation of foamy substances in liquid formulations, such as liquid suspensions, by reducing the liquid-air surface tension.

[0024] The term "anti-caking agent", as used herein, refers to an excipient that can assist in stabilizing the suspension and improving the appearance of the final formulation. These agents are generally water-insoluble chemical compounds, including inorganic solids, insoluble cellulose derivatives, and insoluble synthetic polymers.

[0025] The term "wetting agent", as used herein, refers to an excipient that can reduce the API-water interfacial tension and improve the wettability and spreadability of the suspended API. As used herein in reference to the components of the liquid suspension according to the present invention, "% w / w" indicates the grams of the component contained in 100 grams of the suspension. For example, the expression "5% w / w amount of repalixine" indicates that 5 grams of repalixine are contained in 100 grams of the suspension.

[0026] As used herein, the term "Avicel CL-611" refers to a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose, in which sodium carboxymethylcellulose is present in an amount between 11.3% w / w and 18.8% w / w.

[0027] It is understood that terms such as "suspend" and "disperse", or "suspended" and "dispersed", can be used interchangeably in the context of the description of the present invention. As will be described in more detail in the experimental section, the inventors have identified qualitative and quantitative compositions that enable the production of a stable liquid suspension of repalixine.

[0028] In particular, it was unexpectedly found that the type and amount of sweetener contained in the liquid suspension of repalixine to mask the unpleasant taste of this API affect the zeta potential value and rheological properties of the resulting suspension, and thus its stability. Specifically, based on the results reported in the experimental section, sucrose in an amount between 25% w / w and 55% w / w was selected as the sweetener to be included in the liquid suspension of repalixine to achieve the desired stability.

[0029] The inventors also selected polyvinylpyrrolidone as the wetting agent to be included in the liquid suspension of repalixine to achieve satisfactory wettability of this API. Furthermore, the inventors selected the types / amounts of the viscosity modifier (xanthan gum) and the anti-caking agent (water-insoluble polymer) used in combination with sucrose and polyvinylpyrrolidone to obtain a stable liquid suspension of repalixine.

[0030] Therefore, a first object of the present invention is - Repalixine in an amount between 2% w / w and 13% w / w, preferably between 3% w / w and 13% w / w, more preferably between 4% w / w and 13% w / w, more preferably between 4.5% w / w and 12.5% w / w, more preferably between 4.8% w / w and 12.2% w / w, even more preferably between 4.9% w / w and 12.1% w / w, and most preferably between 5% w / w and 12% w / w - Xanthan gum in an amount between 0.15% w / w and 0.3% w / w, preferably between 0.18% w / w and 0.27% w / w, more preferably between 0.18% w / w and 0.23% w / w, even more preferably between 0.19% w / w and 0.21% w / w, and most preferably 0.2% w / w - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, and most preferably between 30% w / w and 50% w / w, - Polyvinylpyrrolidone in an amount between 1.8% w / w and 3.2% w / w, preferably between 1.9% w / w and 3.1% w / w, more preferably between 2% w / w and 3% w / w, preferably polyvinylpyrrolidone K30, - A water-insoluble polymer in an amount between 2.25% w / w and 2.75% w / w is a liquid suspension containing the same.

[0031] Repalixine (CAS No.: 266359-83-5) is also known as R-(-)-2-(4-isobutylphenyl)propionylmethanesulfonamide and Repeltaxine, and has the following chemical formula:

[0032] [Chemical formula]

[0033] is a compound having the same. Preferably, the liquid suspension according to the first object of the present invention is - Repalixine in an amount between 5% w / w and 12% w / w, - Xanthan gum in an amount between 0.15% w / w and 0.3% w / w, - Sucrose in an amount between 30% w / w and 50% w / w, - Polyvinylpyrrolidone in an amount between 1.8% w / w and 3.2% w / w, preferably polyvinylpyrrolidone K30, - A water-insoluble polymer in an amount between 2.25% w / w and 2.75% w / w contains the same.

[0034] Preferably, the liquid suspension according to the first object of the present invention is - Repalixine in an amount between 5% w / w and 12% w / w, - Xanthan gum in an amount of 0.2% w / w, - Sucrose in an amount between 30% w / w and 50% w / w, - Polyvinylpyrrolidone in an amount between 2% w / w and 3% w / w, preferably polyvinylpyrrolidone K30, - An amount of water-insoluble polymer between 2.25% w / w and 2.75% w / w and containing.

[0035] Preferably, the water-insoluble polymer is selected from microcrystalline cellulose and crospovidone. Preferably, the water-insoluble polymer is crospovidone, preferably crospovidone in an amount of 2.5% w / w.

[0036] In one embodiment, and in combination with any of the above embodiments, the liquid suspension according to the first object of the present invention further comprises a buffering agent, preferably a buffering agent in an amount between 0.1% w / w and 3% w / w, and / or an antifoaming agent, preferably an antifoaming agent in an amount between 0.003% w / w and 5% w / w, more preferably between 0.005% w / w and 5% w / w, and / or a preservative, preferably a preservative in an amount between 0.01% w / w and 0.5% w / w.

[0037] Preferably, the antifoaming agent is a silicone derivative, preferably the silicone derivative is - Dimethicone in an amount between 0.5% w / w and 5% w / w, and - An amount between 0.003% w / w and 0.006% w / w, preferably an amount of 0.005% w / w of simethicone selected from.

[0038] Preferably, the buffering agent is selected from citrate buffer and phosphate buffer. Preferably, the buffering agent is a citrate buffer containing citric acid, preferably citric acid monohydrate, in an amount between 0.06% w / w and 0.6% w / w, preferably between 0.06% w / w and 0.3% w / w, more preferably an amount of 0.064% w / w, and sodium citrate, preferably sodium citrate dihydrate, in an amount between 0.2% w / w and 0.3% w / w, preferably an amount of 0.208% w / w.

[0039] Preferably, the preservative is selected from potassium sorbate, sodium benzoate, methyl paraben, and propyl paraben. Preferably, the preservative is potassium sorbate in an amount between 0.1% w / w and 0.2% w / w, preferably 0.15% w / w.

[0040] In one embodiment, the liquid suspension according to the first object of the present invention is - Reparixin in an amount between 2% w / w and 13% w / w, preferably between 3% w / w and 13% w / w, more preferably between 4% w / w and 13% w / w, more preferably between 4.5% w / w and 12.5% w / w, more preferably between 4.8% w / w and 12.2% w / w, even more preferably between 4.9% w / w and 12.1% w / w, and most preferably between 5% w / w and 12% w / w. - Xanthan gum in an amount between 0.15% w / w and 0.3% w / w, preferably between 0.18% w / w and 0.27% w / w, more preferably between 0.18% w / w and 0.23% w / w, even more preferably between 0.19% w / w and 0.21% w / w, and most preferably 0.2% w / w. - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, even more preferably between 29% w / w and 51% w / w, and most preferably between 30% w / w and 50% w / w. - Polyvinylpyrrolidone, preferably polyvinylpyrrolidone K30, in an amount between 1.8% w / w and 3.2% w / w, preferably between 1.9% w / w and 3.1% w / w, more preferably between 2% w / w and 3% w / w. - A water-insoluble polymer in an amount between 2.25% w / w and 2.75% w / w. - Preferably, a buffer in an amount between 0.1% w / w and 3% w / w. - Preferably, an antifoaming agent in an amount between 0.003% w / w and 5% w / w, more preferably between 0.005% w / w and 5% w / w. - Preferably, a preservative in an amount between 0.01% w / w and 0.5% w / w. - An aqueous solvent in an amount up to 100% w / w, preferably water and consisting of.

[0041] In one embodiment, the liquid suspension according to the first object of the present invention is - Reparixin in an amount between 2% w / w and 13% w / w, - Xanthan gum in an amount of 0.2% w / w, - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w, - Polyvinylpyrrolidone in an amount between 2% w / w and 3% w / w, preferably polyvinylpyrrolidone K30, - A water-insoluble polymer in an amount between 2.25% w / w and 2.75% w / w, - A buffer in an amount preferably between 0.1% w / w and 3% w / w, - An antifoaming agent in an amount preferably between 0.003% w / w and 5% w / w, more preferably between 0.005% w / w and 5% w / w, - A preservative in an amount preferably between 0.01% w / w and 0.5% w / w, - An aqueous solvent in an amount up to 100% w / w, preferably water and consisting of.

[0042] Preferably, the amount of repalixine in the liquid suspension according to any one of the above-described embodiments is 2% w / w, 2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w, 2.9% w / w, 3% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w, 3.7% w / w, 3.8% w / w, 3.9% w / w, 4% w / w, 4.1% w / w, 4.2% w / w, 4.3% w / w, 4.4% w / w, 4.5% w / w, 4.6% w / w, 4.7% w / w, 4.8% w / w, 4.9% w / w, 5% w / w, 5.1% w / w, 5.2% w / w, 5.3% w / w, 5.4% w / w, 5.5% w / w, 5.6% w / w, 5.7% w / w, 5.8% w / w, 5.9% w / w, 6% w / w, 6.1% w / w, 6.2% w / w, 6.3% w / w, 6.4% w / w, 6.5% w / w, 6.6% w / w, 6.7% w / w, 6.8% w / w, 6.9% w / w, 7% w / w, 7.1% w / w, 7.2% w / w, 7.3% w / w, 7.4% w / w, 7.5% w / w, 7.6% w / w, 7.7% w / w, 7.8% w / w, 7.9% w / w, 8% w / w, 8.1% w / w, 8.2% w / w, 8.3% w / w, 8.4% w / w, 8.5% w / w, 8.6% w / w, 8.7% w / w, 8.8% w / w, 8.9% w / w, 9% w / w, 9.1% w / w, 9.2% w / w, 9.3% w / w, 9.4% w / w, 9.5% w / w, 9.6% w / w, 9.7% w / w, 9.8% w / w, 9.9% w / w, 10% w / w, 10.1% w / w, 10.2% w / w, 10.3% w / w, 10.4% w / w, 10.5% w / w, 10.6% w / w, 10.7% w / w, 10.8% w / w, 10.9% w / w, 11% w / w, 11.1% w / w, 11.2% w / w, 11.3% w / w, 11.4% w / w, 11.5% w / w, 11.6% w / w, 11.7% w / w, 11.8% w / w, 11.9% w / w, 12% w / w, 12.1% w / w, 12.2% w / w, 12.3% w / w, 12.4% w / w, 12.5% w / w, 12.6% w / w, 12.7% w / w, 12.8% w / w, 12.9% w / w or 13% w / w.

[0043] In two preferred embodiments, and in combination with any of the embodiments described above, the liquid suspension according to the first object of the present invention comprises repalixine, - in an amount between 2% w / w and 5.5% w / w, preferably between 3% w / w and 5.5% w / w, more preferably between 4% w / w and 5.5% w / w, more preferably between 4.5% w / w and 5.5% w / w, more preferably between 4.7% w / w and 5.3% w / w, more preferably between 4.9% w / w and 5.1% w / w, even more preferably in an amount of 5% w / w (this embodiment is suitable for administration to pediatric subjects, where the pediatric subjects are under 14 years of age), or - in an amount between 11.5% w / w and 12.5% w / w, preferably between 11.7% w / w and 12.3% w / w, even more preferably between 11.9% w / w and 12.1% w / w, most preferably in an amount of 12% w / w (this embodiment is suitable for administration to adult subjects, where the adult subjects are over 14 years of age).

[0044] In one embodiment, and in combination with any of the embodiments described above, the antifoaming agent is a silicone derivative, preferably selected from cyclomethicone, dimethicone and simethicone, more preferably dimethicone and simethicone.

[0045] The presence of the antifoaming agent in the liquid suspension is advantageous as it prevents and / or impedes the formation of foamy substances on the surface of the suspension. Preferably, the simethicone is in an amount between 0.003% w / w and 0.6% w / w, preferably between 0.003% w / w and 0.3% w / w, more preferably between 0.003% w / w and 0.009% w / w, even more preferably between 0.003% w / w and 0.007% w / w, even more preferably between 0.003% w / w and 0.006% w / w, most preferably in an amount of 0.005% w / w.

[0046] Preferably, the dimethicone is in an amount between 0.5% w / w and 5% w / w. In one embodiment, and in combination with any of the embodiments described above, the buffer can maintain the pH of the suspension at a value between 4 and 6, preferably between 4.5 and 5.5, more preferably at a value of 5. Preferably, the buffer is selected from a citrate buffer and a phosphate buffer, and more preferably, the buffer is a citrate buffer. Preferably, the citrate buffer contains, preferably consists of, citric acid, preferably citric acid monohydrate, in an amount between 0.06% w / w and 0.6% w / w, preferably between 0.06% w / w and 0.3% w / w, more preferably between 0.06% w / w and 0.1% w / w, even more preferably between 0.06% w / w and 0.07% w / w, most preferably in an amount of 0.064% w / w, and sodium citrate, preferably sodium citrate dihydrate, in an amount between 0.2% w / w and 2% w / w, preferably between 0.2% w / w and 1% w / w, more preferably between 0.2% w / w and 0.3% w / w, most preferably in an amount of 0.208% w / w. Preferably, within the above ranges, the relative amounts of citric acid monohydrate and sodium citrate dihydrate are selected, for example, to obtain a pH value between 4 and 6, preferably between 4.5 and 5.5, more preferably at pH 5.

[0047] In one embodiment, and in combination with any of the embodiments described above, the preservative is selected from potassium sorbate, sodium benzoate, methylparaben and propylparaben. The presence of a preservative in the formulation is advantageous as the preservative prevents or delays the growth of microorganisms.

[0048] Preferably, the potassium sorbate is in an amount between 0.1% w / w and 0.2% w / w, more preferably in an amount of 0.15% w / w. Preferably, the sodium benzoate is in an amount between 0.02% w / w and 0.5% w / w.

[0049] Preferably, the methylparaben, propylparaben or a combination thereof is in an amount between 0.015% w / w and 0.2% w / w. In one embodiment, and in combination with any of the embodiments described above, the water-insoluble polymer is selected from microcrystalline cellulose and crospovidone. The water-insoluble polymer acts as an anti-caking agent and is used to prevent the fine particulate solid from aggregating into a lump or sticky cake, and to avoid and / or limit the formation of sediment.

[0050] Crospovidone, known as polyvinylpolypyrrolidone, is a highly cross-linked variant of polyvinylpyrrolidone (PVP). Due to cross-linking, crospovidone is insoluble in water.

[0051] In one embodiment, and in combination with any of the embodiments described above, the liquid suspension according to the present invention further comprises an aqueous solvent, preferably water, in an amount up to 100% w / w.

[0052] In one embodiment, the liquid suspension according to the first object of the present invention is - Repaglinide in an amount between 2% w / w and 13% w / w, - Xanthan gum in an amount of 0.2% w / w, - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w, - Polyvinylpyrrolidone in an amount between 2% w / w and 3% w / w, preferably polyvinylpyrrolidone K30, - Crospovidone in an amount between 2.25% w / w and 2.75% w / w, - Citric acid in an amount between 0.06% w / w and 0.6% w / w, preferably between 0.06% w / w and 0.3% w / w, more preferably between 0.06% w / w and 0.1% w / w, even more preferably between 0.06% w / w and 0.07% w / w, preferably citric acid monohydrate, - Sodium citrate in an amount between 0.2% w / w and 2% w / w, preferably between 0.2% w / w and 1% w / w, more preferably between 0.2% w / w and 0.3% w / w, preferably sodium citrate dihydrate, - An amount of simethicone between 0.003% w / w and 0.6% w / w, preferably between 0.003% w / w and 0.3% w / w, more preferably between 0.003% w / w and 0.009% w / w, even more preferably between 0.003% w / w and 0.007% w / w, - An amount of potassium sorbate between 0.1% w / w and 0.2% w / w, - Water up to 100% and consisting of.

[0053] In one embodiment, the liquid suspension according to the first object of the present invention is - An amount of reparixin between 2% w / w and 5.5% w / w, preferably between 3% w / w and 5.5% w / w, more preferably between 4% w / w and 5.5% w / w, more preferably between 4.5% w / w and 5.5% w / w, more preferably between 4.7% w / w and 5.3% w / w, more preferably between 4.9% w / w and 5.1% w / w, even more preferably an amount of 5% w / w, - An amount of xanthan gum between 0.15% w / w and 0.3% w / w, preferably between 0.18% w / w and 0.27% w / w, more preferably between 0.18% w / w and 0.23% w / w, even more preferably between 0.19% w / w and 0.21% w / w, most preferably an amount of 0.2% w / w, - An amount of sucrose between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, even more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w, - An amount of polyvinylpyrrolidone between 1.5% w / w and 2.5% w / w, preferably between 1.7% w / w and 2.3% w / w, more preferably between 1.9% w / w and 2.1% w / w, even more preferably an amount of 2% w / w, preferably polyvinylpyrrolidone K30, - An amount between 2.25% w / w and 2.75% w / w, preferably an amount of 2.5% w / w of crospovidone, - Optionally, one or more of the following components: simethicone in an amount between 0.003% w / w and 0.006% w / w, preferably between 0.004% w / w and 0.006% w / w, more preferably 0.005% w / w; citric acid monohydrate in an amount between 0.06% w / w and 0.6% w / w, preferably between 0.06% w / w and 0.3% w / w, more preferably between 0.06% w / w and 0.1% w / w, even more preferably between 0.06% w / w and 0.07% w / w, most preferably 0.064% w / w; sodium citrate dihydrate in an amount between 0.2% w / w and 2% w / w, preferably between 0.2% w / w and 1% w / w, more preferably between 0.2% w / w and 0.3% w / w, most preferably 0.208% w / w; potassium sorbate in an amount between 0.1% w / w and 0.2% w / w, preferably 0.15% w / w - An aqueous solvent, preferably water, in an amount up to 100% w / w Comprising, preferably consisting of these.

[0054] In one embodiment, the liquid suspension according to the first object of the present invention is - Reparixin in an amount between 2% w / w and 5.5% w / w, preferably between 3% w / w and 5.5% w / w, more preferably between 4% w / w and 5.5% w / w, more preferably between 4.5% w / w and 5.5% w / w, more preferably between 4.7% w / w and 5.3% w / w, more preferably between 4.9% w / w and 5.1% w / w, even more preferably 5% w / w - Xanthan gum in an amount between 0.15% w / w and 0.3% w / w, preferably between 0.18% w / w and 0.27% w / w, more preferably between 0.18% w / w and 0.23% w / w, even more preferably between 0.19% w / w and 0.21% w / w, most preferably 0.2% w / w - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, even more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w - An amount of polyvinylpyrrolidone between 1.8% w / w and 2.5% w / w, preferably between 1.8% w / w and 2.3% w / w, more preferably between 1.9% w / w and 2.1% w / w, even more preferably 2% w / w, preferably polyvinylpyrrolidone K30, - An amount between 2.25% w / w and 2.75% w / w, preferably 2.5% w / w of crospovidone It contains.

[0055] In one embodiment, the liquid suspension according to the first object of the present invention is - An amount between 2% w / w and 5.5% w / w, preferably between 3% w / w and 5.5% w / w, more preferably between 4% w / w and 5.5% w / w, more preferably between 4.5% w / w and 5.5% w / w, more preferably between 4.7% w / w and 5.3% w / w, more preferably between 4.9% w / w and 5.1% w / w, even more preferably 5% w / w of reparixin, - An amount between 0.15% w / w and 0.3% w / w, preferably between 0.18% w / w and 0.27% w / w, more preferably between 0.18% w / w and 0.23% w / w, even more preferably between 0.19% w / w and 0.21% w / w, most preferably 0.2% w / w of xanthan gum, - An amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, even more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w of sucrose, - An amount between 1.8% w / w and 2.5% w / w, preferably between 1.8% w / w and 2.3% w / w, more preferably between 1.9% w / w and 2.1% w / w, even more preferably 2% w / w of polyvinylpyrrolidone, preferably polyvinylpyrrolidone K30, - An amount between 2.25% w / w and 2.75% w / w, preferably 2.5% w / w of crospovidone, - Optionally, one or more of the following components: simethicone in an amount between 0.003% w / w and 0.006% w / w, preferably between 0.004% w / w and 0.006% w / w, more preferably 0.005% w / w; citric acid in an amount between 0.06% w / w and 0.6% w / w, preferably between 0.06% w / w and 0.3% w / w, more preferably between 0.06% w / w and 0.1% w / w, even more preferably between 0.06% w / w and 0.07% w / w, most preferably 0.064% w / w, preferably citric acid monohydrate; sodium citrate in an amount between 0.2% w / w and 2% w / w, preferably between 0.2% w / w and 1% w / w, more preferably between 0.2% w / w and 0.3% w / w, most preferably 0.208% w / w, preferably sodium citrate dihydrate; potassium sorbate in an amount between 0.1% w / w and 0.2% w / w, preferably 0.15% w / w - An aqueous solvent, preferably water, in an amount up to 100% w / w It consists of

[0056] In one embodiment, the liquid suspension according to the first object of the present invention - Reparixin in an amount between 2% w / w and 5.5% w / w, preferably 5% w / w - Xanthan gum in an amount of 0.2% w / w - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, even more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w - Polyvinylpyrrolidone in an amount of 2% w / w, preferably polyvinylpyrrolidone K30 - Crospovidone in an amount between 2.25% w / w and 2.75% w / w, preferably 2.5% w / w It contains

[0057] In one embodiment, the liquid suspension according to the first object of the present invention - Reparixin in an amount between 2% w / w and 5.5% w / w, preferably 5% w / w - Xanthan gum in an amount of 0.2% w / w - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, and most preferably between 30% w / w and 50% w / w, - Polyvinylpyrrolidone in an amount of 2% w / w, preferably polyvinylpyrrolidone K30, - Crospovidone in an amount between 2.25% w / w and 2.75% w / w, preferably in an amount of 2.5% w / w, - Optionally, one or more of the following components: Dimethicone in an amount between 0.003% w / w and 0.006% w / w, preferably between 0.004% w / w and 0.006% w / w, more preferably in an amount of 0.005% w / w; Citric acid in an amount between 0.06% w / w and 0.6% w / w, preferably between 0.06% w / w and 0.3% w / w, more preferably between 0.06% w / w and 0.1% w / w, even more preferably between 0.06% w / w and 0.07% w / w, and most preferably in an amount of 0.064% w / w, preferably citric acid monohydrate; Sodium citrate in an amount between 0.2% w / w and 2% w / w, preferably between 0.2% w / w and 1% w / w, more preferably between 0.2% w / w and 0.3% w / w, and most preferably in an amount of 0.208% w / w, preferably sodium citrate dihydrate; Potassium sorbate in an amount between 0.1% w / w and 0.2% w / w, preferably in an amount of 0.15% w / w, - An aqueous solvent in an amount up to 100% w / w, preferably water and consisting of.

[0058] Preferably, within the above ranges, the relative amounts of citric acid monohydrate and sodium citrate dihydrate are selected, for example, between pH 4 and 6, preferably between 4.5 and 5.5, and more preferably selected to obtain a pH value of 5.

[0059] In an alternative embodiment, the liquid suspension according to the first object of the present invention is - An amount of Reparixin between 11.5% w / w and 12.5% w / w, preferably between 11.7% w / w and 12.3% w / w, more preferably between 11.9% w / w and 12.1% w / w, most preferably 12% w / w. - An amount of xanthan gum between 0.15% w / w and 0.3% w / w, preferably between 0.18% w / w and 0.27% w / w, more preferably between 0.18% w / w and 0.23% w / w, even more preferably between 0.19% w / w and 0.21% w / w, most preferably 0.2% w / w. - An amount of sucrose between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, even more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w. - An amount of polyvinylpyrrolidone between 2.5% w / w and 3.5% w / w, preferably between 2.7% w / w and 3.3% w / w, more preferably between 2.9% w / w and 3.1% w / w, even more preferably 3% w / w, preferably polyvinylpyrrolidone K30. - An amount between 2.25% w / w and 2.75% w / w, preferably 2.5% w / w of crospovidone. - Optionally, one or more of the following components: an amount of simethicone between 0.003% w / w and 0.006% w / w, preferably between 0.004% w / w and 0.006% w / w, more preferably 0.005% w / w; an amount of citric acid monohydrate between 0.06% w / w and 0.6% w / w, preferably between 0.06% w / w and 0.3% w / w, more preferably between 0.06% w / w and 0.1% w / w, even more preferably between 0.06% w / w and 0.07% w / w, most preferably 0.064% w / w; an amount of sodium citrate dihydrate between 0.2% w / w and 2% w / w, preferably between 0.2% w / w and 1% w / w, more preferably between 0.2% w / w and 0.3% w / w, most preferably 0.208% w / w; an amount of potassium sorbate between 0.1% w / w and 0.2% w / w, preferably 0.15% w / w. - An amount of aqueous solvent up to 100% w / w, preferably water. Comprising, preferably consisting of.

[0060] In an alternative embodiment, the liquid suspension according to the first object of the present invention is - Reparixin in an amount between 11.5% w / w and 12.5% w / w, preferably between 11.7% w / w and 12.3% w / w, more preferably between 11.9% w / w and 12.1% w / w, most preferably 12% w / w; - Xanthan gum in an amount between 0.15% w / w and 0.3% w / w, preferably between 0.18% w / w and 0.27% w / w, more preferably between 0.18% w / w and 0.23% w / w, even more preferably between 0.19% w / w and 0.21% w / w, most preferably 0.2% w / w; - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w; - Polyvinylpyrrolidone, preferably polyvinylpyrrolidone K30, in an amount between 2.5% w / w and 3.2% w / w, preferably between 2.7% w / w and 3.2% w / w, more preferably between 2.9% w / w and 3.1% w / w, even more preferably 3% w / w; - Crospovidone in an amount between 2.25% w / w and 2.75% w / w, preferably 2.5% w / w and comprises.

[0061] In an alternative embodiment, the liquid suspension according to the first object of the present invention is - Reparixin in an amount between 11.5% w / w and 12.5% w / w, preferably between 11.7% w / w and 12.3% w / w, more preferably between 11.9% w / w and 12.1% w / w; - Xanthan gum in an amount between 0.15% w / w and 0.3% w / w, preferably between 0.18% w / w and 0.27% w / w, more preferably between 0.18% w / w and 0.23% w / w; - sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, and most preferably between 30% w / w and 50% w / w, - polyvinylpyrrolidone in an amount between 2.5% w / w and 3.2% w / w, preferably between 2.7% w / w and 3.2% w / w, more preferably between 2.9% w / w and 3.1% w / w, and even more preferably 3% w / w, preferably polyvinylpyrrolidone K30, - crospovidone in an amount between 2.25% w / w and 2.75% w / w, preferably 2.5% w / w, - optionally, one or more of the following components: simethicone in an amount between 0.003% w / w and 0.006% w / w, preferably between 0.004% w / w and 0.006% w / w, more preferably 0.005% w / w; citric acid in an amount between 0.06% w / w and 0.6% w / w, preferably between 0.06% w / w and 0.3% w / w, more preferably between 0.06% w / w and 0.1% w / w, even more preferably between 0.06% w / w and 0.07% w / w, and most preferably 0.064% w / w, preferably citric acid monohydrate; sodium citrate in an amount between 0.2% w / w and 2% w / w, preferably between 0.2% w / w and 1% w / w, more preferably between 0.2% w / w and 0.3% w / w, and most preferably 0.208% w / w, preferably sodium citrate dihydrate; potassium sorbate in an amount between 0.1% w / w and 0.2% w / w, preferably 0.15% w / w, - an aqueous solvent in an amount up to 100% w / w, preferably water and consists of.

[0062] In an alternative embodiment, the liquid suspension according to the first object of the present invention is - leparaxine in an amount between 11.5% w / w and 12.5% w / w, preferably 12% w / w, - xanthan gum in an amount of 0.2% w / w, - sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, and most preferably between 30% w / w and 50% w / w, - polyvinylpyrrolidone in an amount of 3% w / w, preferably polyvinylpyrrolidone K30, - crospovidone in an amount between 2.25% w / w and 2.75% w / w, preferably in an amount of 2.5% w / w comprising.

[0063] In an alternative embodiment, the liquid suspension according to the first object of the present invention is - reparixin in an amount between 11.5% w / w and 12.5% w / w, preferably in an amount of 12% w / w, - xanthan gum in an amount of 0.2% w / w, - sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, and most preferably between 30% w / w and 50% w / w, - polyvinylpyrrolidone in an amount of 3% w / w, preferably polyvinylpyrrolidone K30, - crospovidone in an amount between 2.25% w / w and 2.75% w / w, preferably in an amount of 2.5% w / w, - Optionally, one or more of the following components: simethicone in an amount between 0.003% w / w and 0.006% w / w, preferably between 0.004% w / w and 0.006% w / w, more preferably 0.005% w / w; citric acid in an amount between 0.06% w / w and 0.6% w / w, preferably between 0.06% w / w and 0.3% w / w, more preferably between 0.06% w / w and 0.1% w / w, even more preferably between 0.06% w / w and 0.07% w / w, most preferably 0.064% w / w, preferably citric acid monohydrate; sodium citrate in an amount between 0.2% w / w and 2% w / w, preferably between 0.2% w / w and 1% w / w, more preferably between 0.2% w / w and 0.3% w / w, most preferably 0.208% w / w, preferably sodium citrate dihydrate; potassium sorbate in an amount between 0.1% w / w and 0.2% w / w, preferably 0.15% w / w - An aqueous solvent, preferably water, in an amount up to 100% w / w Consisting of

[0064] Preferably, within the above ranges, the relative amounts of citric acid monohydrate and sodium citrate dihydrate are selected, for example, between pH 4 and 6, preferably between 4.5 and 5.5, more preferably selected to obtain a pH value of 5

[0065] In one embodiment, the liquid suspension according to the first object of the present invention - Reparixin in an amount of 5% w / w - Xanthan gum in an amount of 0.2% w / w - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, even more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w - Polyvinylpyrrolidone in an amount of 2% w / w, preferably polyvinylpyrrolidone K30 - Crospovidone in an amount of 2.5% w / w Containing

[0066] In one embodiment, the liquid suspension according to the first object of the present invention - Reparixin in an amount of 5% w / w, - Xanthan gum in an amount of 0.2% w / w, - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, and most preferably between 30% w / w and 50% w / w, - Polyvinylpyrrolidone in an amount of 2% w / w, preferably polyvinylpyrrolidone K30, - Crospovidone in an amount of 2.5% w / w, - Simethicone in an amount between 0.003% w / w and 0.006% w / w, preferably between 0.004% w / w and 0.006% w / w, more preferably in an amount of 0.005% w / w, - Citric acid in an amount between 0.06% w / w and 0.6% w / w, preferably between 0.06% w / w and 0.3% w / w, more preferably between 0.06% w / w and 0.1% w / w, even more preferably between 0.06% w / w and 0.07% w / w, and most preferably in an amount of 0.064% w / w, preferably citric acid monohydrate, - Sodium citrate in an amount between 0.2% w / w and 2% w / w, preferably between 0.2% w / w and 1% w / w, more preferably between 0.2% w / w and 0.3% w / w, and most preferably in an amount of 0.208% w / w, preferably sodium citrate dihydrate, - Potassium sorbate in an amount between 0.1% w / w and 0.2% w / w, preferably in an amount of 0.15% w / w, - Water up to 100% and consisting of.

[0067] In one embodiment, the liquid suspension according to the first object of the present invention is - Reparixin in an amount of 5% w / w, - Xanthan gum in an amount of 0.2% w / w, - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, and most preferably between 30% w / w and 50% w / w, - Polyvinylpyrrolidone in an amount of 2% w / w, preferably polyvinylpyrrolidone K30, - Crospovidone in an amount of 2.5% w / w, - Dimethicone in an amount of 0.005% w / w, - Citric acid monohydrate in an amount of 0.064% w / w, - Sodium citrate dihydrate in an amount of 0.208% w / w, - Potassium sorbate in an amount of 0.15% w / w, - Water up to 100% and consisting of.

[0068] In one embodiment, the liquid suspension according to the first object of the present invention is - Reparixin in an amount of 12% w / w, - Xanthan gum in an amount of 0.2% w / w, - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w, - Polyvinylpyrrolidone in an amount of 3% w / w, preferably polyvinylpyrrolidone K30, - Crospovidone in an amount of 2.5% w / w and containing.

[0069] In another embodiment, the liquid suspension according to the first object of the present invention is - Reparixin in an amount of 12% w / w, - Xanthan gum in an amount of 0.2% w / w, - Sucrose in an amount between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w, - Polyvinylpyrrolidone in an amount of 3% w / w, preferably polyvinylpyrrolidone K30, - Crospovidone in an amount of 2.5% w / w, - Between 0.003% w / w and 0.006% w / w, preferably between 0.004% w / w and 0.006% w / w, more preferably an amount of 0.005% w / w of simethicone, - Between 0.06% w / w and 0.6% w / w, preferably between 0.06% w / w and 0.3% w / w, more preferably between 0.06% w / w and 0.1% w / w, even more preferably between 0.06% w / w and 0.07% w / w, most preferably an amount of 0.064% w / w of citric acid, preferably citric acid monohydrate, - Between 0.2% w / w and 2% w / w, preferably between 0.2% w / w and 1% w / w, more preferably between 0.2% w / w and 0.3% w / w, most preferably an amount of 0.208% w / w of sodium citrate, preferably sodium citrate dihydrate, - An amount between 0.1% w / w and 0.2% w / w, preferably an amount of 0.15% w / w of potassium sorbate, - Water up to 100% Comprising.

[0070] In another embodiment, the liquid suspension according to the first object of the present invention is - An amount of 12% w / w of repaloxine, - An amount of 0.2% w / w of xanthan gum, - Between 25% w / w and 55% w / w, preferably between 27% w / w and 53% w / w, even more preferably between 29% w / w and 51% w / w, most preferably between 30% w / w and 50% w / w of sucrose, - An amount of 3% w / w of polyvinylpyrrolidone, preferably polyvinylpyrrolidone K30, - An amount of 2.5% w / w of crospovidone, - An amount of 0.005% w / w of simethicone, - An amount of 0.064% w / w of citric acid monohydrate, - An amount of 0.208% w / w of sodium citrate dihydrate, - An amount of 0.15% w / w of potassium sorbate, - Water up to 100% Comprising.

[0071] In one embodiment, and in combination with any of the embodiments described above, the amount of sucrose in the liquid suspension according to the first object of the present invention is 30% w / w, 30.1% w / w, 30.2% w / w, 30.3% w / w, 30.4% w / w, 30.5% w / w, 30.6% w / w, 30.7% w / w, 30.8% w / w, 30.9% w / w, 31% w / w, 31.1% w / w, 31.2% w / w, 31.3% w / w, 31.4% w / w, 31.5% w / w, 31.6% w / w, 31.7% w / w, 31.8% w / w, 31.9% w / w, 32% w / w, 32.1% w / w, 32.2% w / w, 32.3% w / w, 32.4% w / w, 32.5% w / w, 32.6% w / w, 32.7% w / w, 32.8% w / w, 32.9% w / w, 33% w / w, 33.1% w / w, 33.2% w / w, 33.3% w / w, 33.4% w / w, 33.5% w / w, 33.6% w / w, 33.7% w / w, 33.8% w / w, 33.9% w / w, 34% w / w, 34.1% w / w, 34.2% w / w, 34.3% w / w, 34.4% w / w, 34.5% w / w, 34.6% w / w, 34.7% w / w, 34.8% w / w, 34.9% w / w, 35% w / w, 35.1% w / w, 35.2% w / w, 35.3% w / w, 35.4% w / w, 35.5% w / w, 35.6% w / w, 35.7% w / w, 35.8% w / w, 35.9% w / w, 36% w / w, 36.1% w / w, 36.2% w / w, 36.3% w / w, 36.4% w / w, 36.5% w / w, 36.6% w / w, 36.7% w / w, 36.8% w / w, 36.9% w / w, 37% w / w, 37.1% w / w, 37.2% w / w, 37.3% w / w, 37.4% w / w, 37.5% w / w, 37.6% w / w, 37.7% w / w, 37.8% w / w, 37.9% w / w, 38% w / w, 38.1% w / w, 38.2% w / w, 38.3% w / w, 38.4% w / w, 38.5% w / w, 38.6% w / w, 38.7% w / w, 38.8% w / w, 38.9% w / w, 39% w / w, 39.1% w / w, 39.2% w / w, 39.3% w / w, 39.4% w / w, 39.5% w / w, 39.6% w / w, 39.7% w / w, 39.8% w / w, 39.9% w / w, 40% w / w, 40.1% w / w, 40.2% w / w, 40.3% w / w, 40.4% w / w, 40.5% w / w, 40.6% w / w, 40.7% w / w, 40.8% w / w, 40.9% w / w, 41% w / w, 41.1% w / w, 41.2% w / w, 41.3% w / w, 41.4% w / w, 41.5% w / w, 41.6% w / w, 41.7% w / w, 41.8% w / w, 41.9% w / w, 42% w / w, 42.1% w / w, 42.2% w / w, 42.3% w / w, 42.4% w / w, 42.5% w / w, 42.6% w / w, 42.7% w / w, 42.8% w / w, 42.9% w / w, 43% w / w, 43.1% w / w, 43.2% w / w, 43.3% w / w, 43.4% w / w, 43.5% w / w, 43.6% w / w, 43.7% w / w, 43.8% w / w, 43.9% w / w, 44% w / w, 44.1% w / w, 44.2% w / w, 44.3% w / w, 44.4% w / w, 44.5% w / w, 44.6% w / w, 44.7% w / w, 44.8% w / w, 44.9% w / w, 45% w / w, 45.1% w / w, 45.2% w / w, 45.3% w / w, 45.4% w / w, 45.5% w / w, 45.6% w / w, 45.7% w / w, 45.8% w / w, 45.9% w / w, 46% w / w, 46.1% w / w, 46.2% w / w, 46.3% w / w, 46.4% w / w, 46.5% w / w, 46.6% w / w, 46.7% w / w, 46.8% w / w, 46.9% w / w, 47% w / w, 47.1% w / w, 47.2% w / w, 47.3% w / w, 47.4% w / w, 47.5% w / w, 47.6% w / w, 47.7% w / w, 47.8% w / w, 47.9% w / w, 48% w / w, 48.1% w / w, 48.2% w / w, 48.3% w / w, 48.4% w / w, 48.5% w / w, 48.6% w / w, 48.7% w / w, 48.8% w / w, 48.9% w / w, 49% w / w, 49.1% w / w, 49.2% w / w, 49.3% w / w, 49.4% w / w, 49.5% w / w, 49.6% w / w, 49.7% w / w, 49.8% w / w, 49.9% w / w or 50% w / w.

[0072] In one embodiment, and in combination with any of the embodiments described above, the liquid suspension according to the first object of the present invention has a zeta potential value between -3 mV and +3 mV, preferably between -2.5 mV and +2.5 mV, and the zeta potential value is measured by laser Doppler electrophoresis using a Zetasizer nano ZS (Malvern Instruments, Worcestershire, UK) in accordance with the manufacturer's instructions.

[0073] In one embodiment, and in combination with any of the embodiments described above, the liquid suspension according to the first object of the present invention has a yield stress value of at least 8 Pa, and the yield stress value is measured by a Rheometer MCR 102 (Anton Paar, Graz, Austria) according to the procedure described in Example 2 below.

[0074] In one embodiment, and in combination with any of the above embodiments, the liquid suspension according to the first object of the present invention is stable for a period of at least 1 year, preferably at least 2 years, which means that the API remains homogeneously suspended in the external phase during this period and the correct dose of the API is reliably administered, or, if a precipitate is formed, it can be easily resuspended by manual shaking.

[0075] The second object of the present invention is a liquid suspension according to any one of the embodiments described above for use in the treatment of a disease or condition selected from psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis and glomerulonephritis.

[0076] A further object of the present invention is a liquid suspension according to any one of the embodiments described above for use in the prevention of diabetes or the delay of the onset and progression of diabetes, wherein the diabetes is preferably type I diabetes.

[0077] A further object of the present invention is a liquid suspension according to any one of the embodiments described above for the first object of the present invention for use in the treatment of an infection caused by SARS-CoV-2 or a variant thereof, preferably for use in the treatment of COVID-19, more preferably for use in improving respiratory function in a subject suffering from pneumonia caused by SARS-CoV-2 or a variant thereof.

[0078] In one embodiment, said improvement in respiratory function in the subject means reducing, delaying the onset of, or preventing the need for supplemental oxygen, the use of a ventilator, or the need for admission to an intensive care unit.

[0079] As used herein, the term "pneumonia caused by SARS-CoV-2 or a variant thereof" refers to the inflammatory condition of the lungs associated with an infection by SARS-CoV-2 or a variant thereof. This is a severe complication of COVID-19 that affects a certain percentage of subjects.

[0080] In one embodiment, a liquid suspension according to any one of the embodiments described above for the first object of the present invention for use in the treatment of COVID-19 is administered in combination with standard care treatment for COVID-19 patients.

[0081] As used herein, "standard care treatment for COVID-19 patients" means a pharmacological treatment comprising one or more of the drugs approved by the regulatory authorities as a treatment for COVID-19 or ii) as a treatment for other pathological conditions and their symptoms and used in clinical practice as a treatment for the symptoms and complications associated with COVID-19. Preferably, the standard care treatment is in the treatment of patients with at least one drug selected from the following: i) antiviral drugs, preferably remdesivir; ii) antipyretics, analgesics and anti-inflammatory drugs, preferably non-steroidal anti-inflammatory drugs, corticosteroids, cytokines, chemokines and interleukin inhibitors (more preferably selected from dexamethasone, paracetamol, anakinra, celecoxib, prednisone, prednisolone, methylprednisolone, piryrone, and tramadol); iii) antibiotics in combination with tazobactam, azithromycin and ceftriazone, preferably an antibiotic selected from piperacillin; and iv) anticoagulants and antithrombotic drugs (preferably selected from enoxaparin and acetylsalicylic acid).

[0082] Preferably, the subject suffering from pneumonia caused by SARS-CoV-2 or a variant thereof has lymphopenia. According to a preferred embodiment, the subject having lymphopenia is an adult patient (14 years of age or older) and has a lymphocyte blood concentration of less than 1000, less than 900, less than 850, less than 800 or less than 750 cells / microliter.

[0083] According to another preferred embodiment, the patient having lymphopenia is a pediatric patient (less than 14 years of age) and has a lymphocyte blood concentration of less than 3000, less than 2800, less than 2500, less than 2300 or less than 2000 cells / microliter.

[0084] A further object of the present invention is a liquid suspension according to any one of the embodiments described above for the purpose of preventing or treating seizures in an individual.

[0085] According to a preferred embodiment, the seizure is an acute symptomatic seizure (ASS). According to another preferred embodiment, the seizure is associated with established epilepsy (established epileptic seizure EES).

[0086] In one embodiment, and in combination with any of the embodiments described above, the liquid suspension for use according to the present invention is a ready-to-use liquid suspension, i.e., a suspension that has already been dispensed via a liquid vehicle. The liquid suspension can be for a single dose, i.e., for a single administration, or for multiple doses, i.e., for more than one administration.

[0087] In one embodiment, and in combination with any of the embodiments described above, the liquid suspension for use according to the present invention is administered orally to a subject, preferably a mammal, more preferably a human.

[0088] The present invention is further illustrated in the following examples, which do not limit the scope of the invention as defined in the claims.

Examples

[0089] All percentages shown in the following table are intended to be % w / w. Example 1 Preparation of a suspension containing repalixine Several suspensions containing repalixine were prepared. All suspensions contained at least the following excipients: - A viscosity modifier to adjust the viscosity of the composition to achieve optimal rheological properties; - A wetting agent necessary to increase the wettability of repalixine in water (which is low per se); - Used to mask the unpleasant taste of the sweetening agent, repaglinide; - Used to prevent and / or interfere with the formation of foamy substances on the surface of the suspension; - Used to prevent or delay the growth of microorganisms; - Used to maintain the pH of the suspension between 4 and 6, preferably between 4.5 and 5.5, more preferably at a value of 5.

[0090] The materials used to prepare the suspension are shown in Table 1.

[0091]

Table 1

[0092] The types and / or amounts of the following components vary depending on the suspension: - Viscosity modifiers. In particular, xanthan gum and Avicel CL-611 were tested as viscosity modifiers. Avicel CL-611 is a spray-dried blend of microcrystalline cellulose and sodium carboxymethyl cellulose, and sodium carboxymethyl cellulose is present in an amount between 11.3% w / w and 18.8% w / w in this blend; - Wetting agents. In particular, sodium lauryl sulfate (SLS), poloxamer 407, poloxamer 188, and polyvinylpyrrolidone (PVP) were tested as wetting agents. Poloxamer 407 was immediately rejected because of its insufficient ability to disperse repaglinide; - Sweetening agents. In particular, sucrose and sucralose were tested as sweetening agents. Sucrose has a high glycemic index, while sucralose is an artificial sweetener with a glycemic index of zero.

[0093] The procedure used to prepare the suspension is described below. An amount of antifoaming agent, wetting agent, preservative and buffer was added to 40 g of distilled water, and the mixture was maintained under a magnetic stirrer until a solution was obtained. Then, an amount of repalixine was added and dispersed. Once the API was homogeneously suspended, an amount of other excipients (if present, viscosity modifier, sweetener and anti-caking agent) was added and dissolved. Finally, water was added up to a final weight of 100 g.

[0094] In the following, the composition of the prepared liquid suspension is reported, and the respective characterization data are shown in Examples 2 and 3. The following Table 2 reports on the liquid suspension prepared by using SLS as the wetting agent. Specifically, the prepared suspension contained 0.11% w / w of SLS, 40% w / w of sucrose as the sweetener, 0.15% w / w of potassium sorbate as the preservative, citric acid monohydrate and sodium citrate dihydrate as the buffer, 0.005% w / w of simethicone as the antifoaming agent and water as the solvent.

[0095] The type / amount of viscosity modifier used (xanthan gum or Avicel CL-611) and the amount of buffer differed depending on the prepared suspension.

[0096]

Table 2

[0097] The following Table 3 reports on the liquid suspension prepared by using poloxamer 188 as the wetting agent in combination with xanthan gum as the viscosity modifier. The suspension contained 0.15% w / w of potassium sorbate as the preservative, 0.064% w / w of citric acid monohydrate and 0.208% w / w of sodium citrate dihydrate as the buffer, 0.005% w / w of simethicone as the antifoaming agent and water as the solvent.

[0098] The amounts of poloxamer 188 and xanthan gum varied depending on the suspension to be prepared and the type / amount of sweetener (sucrose or sucralose).

[0099]

Table 3

[0100] The following Table 4 reports on liquid suspensions prepared by using poloxamer 188 as a wetting agent in combination with Avicel CL-611 as a viscosity modifier. The suspensions contained 0.25% poloxamer 188, 0.15% w / w potassium sorbate as a preservative, 40% w / w sucrose as a sweetener, 0.005% w / w simethicone as an antifoaming agent, and water as a solvent.

[0101] The amount of Avicel CL-611 and the type / amount of buffer (citric acid monohydrate / sodium citrate dihydrate or citric acid monohydrate / 1M NaOH) varied depending on the various suspensions prepared.

[0102] In addition to the suspensions reported in Table 4, suspension 80 was also prepared, which had a composition corresponding to suspension 79 but contained 1.00% w / w Blanose (sodium carboxymethylcellulose) instead of 3.00% w / w Avicel CL-611.

[0103]

Table 4

[0104] Table 5 below reports on a liquid suspension prepared by using polyvinylpyrrolidone as a wetting agent in combination with xanthan gum as a viscosity modifier. Specifically, the prepared suspension contained 2.00% w / w PVP K30 as a wetting agent, xanthan gum, 0.15% w / w potassium sorbate as a preservative, 40% w / w sucrose as a sweetening agent, 0.005% w / w simethicone as an antifoaming agent, 0.064% w / w citric acid monohydrate and 0.208% w / w sodium citrate dihydrate as buffering agents, and water as a solvent.

[0105] The amount of xanthan gum varied depending on the suspension and the amount of crospovidone (from 0% w / w to 2.50% w / w) used as an anti-caking agent.

[0106] [Table 5]

[0107] Table 6 below reports on a liquid suspension prepared by using polyvinylpyrrolidone as a wetting agent in combination with Avicel-CL611 as a viscosity modifier. Specifically, the prepared suspension contained 2.00% w / w PVP K30, Avicel CL-611, 0.15% w / w potassium sorbate as a preservative, 40% w / w sucrose as a sweetening agent, 0.005% w / w simethicone as an antifoaming agent, 0.064% w / w citric acid monohydrate and 0.208% w / w sodium citrate dihydrate as buffering agents, and water as a solvent.

[0108] The amount of Avicel CL-611 and the amount of crospovidone (from 0% w / w to 1% w / w) used as an anti-caking agent varied depending on the suspension being prepared.

[0109] [Table 6]

[0110] Finally, the effects of the type and amount of sweeteners contained in a suspension containing PVP as a wetting agent and crospovidone as an anti-caking agent were further investigated. Table 7 reports on a liquid suspension prepared using 2.00% w / w PVP K30, 2.50% w / w crospovidone, 0.20% w / w xanthan gum as a viscosity modifier, 0.15% w / w potassium sorbate as a preservative, 0.005% w / w simethicone as an anti-foaming agent, 0.064% w / w citric acid monohydrate and 0.208% w / w sodium citrate dihydrate as buffering agents, and water as a solvent.

[0111] The type / amount of sweetener (sucrose or sucralose) differed depending on the suspension prepared.

[0112]

Table 7

[0113] Example 2 Determination of zeta potential and rheological properties The zeta potential values and rheological properties of the liquid suspensions reported in Example 1 were determined to evaluate their stability.

[0114] Repaglinide is an insoluble active pharmaceutical ingredient that has a large particle size and produces a coarse suspension. Due to this large particle size, the stability level of the suspension is determined by attractive forces rather than electrostatic interactions, which are insufficient to provide stability and kinetic stabilization. To ensure the stability of the suspension containing repaglinide, the zeta potential value must be equal to or near zero, and the particles of the internal phase must be surrounded by a hydration layer that hides the charge of the particles of the internal phase and ensures that, even if a precipitate forms, it is a loose precipitate that can be easily redispersed rather than a compact precipitate that is difficult to redisperse. An increase in the zeta potential (in absolute value) corresponds to a state where this hydration layer around the particles of the internal phase is less or not present, resulting in an increase in the sedimentation rate.

[0115] Regarding rheological properties, to obtain information on the physical stability of the suspension, the yield stress and thixotropy of the prepared suspension were determined. The yield stress (τ0) is a material property that can be defined as the stress corresponding to the yield point at which the material begins to flow or deform plastically. A suspension is considered stable if the yield stress is higher than the sedimentation stress (τS), where the sedimentation stress can be defined as the stress exerted by the particles on the liquid. If τ0 is higher than τS, sedimentation does not occur and the suspension can be considered stable. Generally, a yield stress of 8 or higher is considered a good value for an immediately usable liquid suspension as a final formulation to counter sedimentation.

[0116] The physical stability of the suspension is also evaluated based on the thixotropy hysteresis area. Thixotropy is an inevitable property of the polymer system selected as the viscosity modifier. In fact, the viscosity (e.g., viscosity) of the external phase brought about by the suspending agent should decrease when shear stress such as manual shaking is applied to ensure the redispersibility of the precipitate. In the scientific literature, the thixotropy area is usually correlated with suspension stability. As demonstrated by E.C. Foernzler, the sedimentation rate is directly proportional to the reciprocal of the hysteresis area, which means that the physical stability is directly proportional to thixotropy (Ernest C. Foernzler et al., J. Am. Pharm. Assoc., Vol. 49 (1960), pp. 249 - 252).

[0117] Based on the above, the generated suspension was characterized for zeta potential value, rheological properties, and redispersion ability. The zeta potential value of the prepared suspension was measured by laser Doppler electrophoresis using a Zetasizer nano ZS (Malvern Instruments, Worcestershire, UK) according to the manufacturer's instructions.

[0118] Rheological properties, such as yield stress and thixotropy (hysteresis), were evaluated via a Rheometer MCR102 (Anton Paar, Graz, Austria).

[0119] To generate the flow curve (shear stress vs. shear rate), the shear rate was linearly increased stepwise from 0.1 to 100 s -1 to perform the determination of the yield stress. Subsequently, the generated flow curve was fitted to the Herschel-Bulkley regression model, and the yield point was determined by extrapolating the flow curve to zero shear rate.

[0120] The thixotropy of the suspension was evaluated via hysteresis. This measurement was first performed using pre-shear at 5 1 / s, then the shear rate was increased from 5 to 131 s -1 on a logarithmic scale to generate the ascending flow curve, and the descending flow curve was obtained by reducing the shear rate from 131 to 5 s -1 . The area between the ascending and descending curves was calculated. This correlates with the thixotropy of this system. All analyses were performed using a 25 mm measurement plate at room temperature with the gap set at 1 mm.

[0121] When a precipitate was present, the redispersibility was evaluated considering the number of 180° rotations enabling the redispersion of the precipitate. The following Table 8 reports the values of the zeta potential and rheological properties obtained for the suspensions reported in Table 2 above.

[0122]

Table 8

[0123] As can be seen, the zeta potential values of the suspensions with 0.11% w / w SLS as a wetting agent were all too high in absolute values that enabled the stability of the suspensions. The increase in the concentration of citrate buffer (sodium citrate dihydrate + citric acid monohydrate) slightly attenuated the absolute value of the zeta potential, but the value was still too high. Based on these results, SLS as a wetting agent was excluded because it could not produce a stable suspension of reparixin.

[0124] The following Table 9 reports the values of the zeta potential and rheological properties obtained for the suspensions reported in Table 3 above.

[0125]

Table 9

[0126] As can be seen, suspensions 73, 74 and 82 containing poloxamer 188 and 40% w / w sucrose had zeta potential values near zero. However, when the percentage of sucrose was reduced (suspension 84 had no sucrose, 89 contained 20.00% w / w sucrose) or when sucrose was replaced with sucralose (suspension 83), the absolute value of the zeta potential increased.

[0127] This trend indicated that the type and amount of sweetener contained in the formulation had a surprising effect on the zeta potential value of the suspension and, consequently, on its stability. As demonstrated, the amount of sucrose significantly affected the zeta potential and rheological properties. In fact, the increase in the amount of sucrose (from 0% w / w to 40% w / w) resulted in a reduction of the zeta potential in absolute value.

[0128] Although not bound by theory or principle, this tendency can be explained by the unexpected formation of a hydration layer of sucrose around the suspended particles, which enables this hydration layer to increase the distance between ions (cations and anions), thereby reducing the absolute value of the zeta potential. Due to this hydration layer, even when a precipitate is formed, the precipitate is loose and not compact, ensuring that this precipitate can be easily resuspended by manual shaking. At the same time, an increase in sucrose concentration results in an increase in both the yield stress and the hysteresis area, indicating an improvement in the stability of the suspension.

[0129] Regarding rheological properties, suspensions 74 and 82 showed the best values in terms of yield stress and hysteresis relative area. Suspension 74 showed a zeta potential value near zero and had appropriate values for yield stress and hysteresis area, but suspension 74 was not adopted because there were persistent suspended aggregates over time. As described in Example 3, suspension 82 was further characterized by frequency sweep analysis.

[0130] Table 10 below reports the zeta potential and rheological properties obtained for the suspensions reported in Table 4 above and the zeta potential and rheological property values of suspension 80 described above.

[0131]

Table 10

[0132] As can be seen, all the suspensions in Table 4 showed zeta potential values near zero, and it was confirmed that the use of 40% sucrose as a sweetening agent made it possible to achieve this trend. However, all the suspensions had the characteristic that the yield stress value was too low for an immediately usable liquid suspension as the final formulation. Based on these results, the use of Avicel CL-611 as a viscosity modifier was excluded. When using this viscosity modifier, suspensions with insufficient rheological properties in terms of yield stress and hysteresis loop (thixothropy) were produced.

[0133] The values of zeta potential and rheological properties obtained for the suspensions reported in Table 5 above are reported in Table 11 below.

[0134]

Table 11

[0135] As can be seen, when 40% sucrose was used as a sweetening agent together with PVP K30 as a wetting agent, suspensions characterized by zeta potential values near zero were obtained, and thus the tendency of the results reported above regarding the role of sucrose in stabilizing the zeta potential value of the suspensions was confirmed. The addition of crospovidone as an anti-caking agent improved the rheological properties of the suspensions, especially at a high percentage (Suspensions 93 and 98 contained 2.50% w / w crospovidone). When 40% w / w xanthan gum was used as a viscosity modifier, the suspension was too viscous and thus difficult to handle (Suspension 93). Reducing the amount of xanthan gum to 0.20% w / w solved this problem and the suspension became easier to handle.

[0136] The values of zeta potential and rheological properties obtained for the suspensions reported in Table 6 above are reported in Table 12 below.

[0137]

Table 12

[0138] As can be seen, the use of Avicel CL-611 as a viscosity modifier in combination with PVP K30 as a wetting agent resulted in a suspension with inappropriate rheological properties.

[0139] The values of zeta potential and rheological properties obtained for the suspensions reported in Table 7 above are reported in Table 13 below.

[0140] [Table 13]

[0141] This experiment was conducted to further investigate and confirm the effect of the type / amount of selected sweeteners on the stabilization of the zeta potential value of the suspension. As can be seen, when 20% w / w of sucrose was used as the sweetener (Suspension 165), the absolute value of the zeta potential was too high and the yield stress value was too low, which meant that the resulting suspension was not stable. When 0.60% of sucralose was used as the sweetener (Suspension 168), the same tendency was observed.

[0142] When 60% w / w was used as the sweetener (Suspension 166), the presence of a layer of persistent foamy substance was observed on the surface. When 30% w / w and 50% w / w of sucrose were used as sweeteners (Suspensions 159 and 160 respectively), suspensions with zeta potential values near zero and appropriate rheological properties were produced.

[0143] These results confirmed the unexpected effect of the type and amount of sweetener added to the suspension to mask the unpleasant taste of rebaudioside A on the values of zeta potential and rheological properties and, as a result, on the stability of the suspension. In particular, based on these results, sucrose as well as 20% w / w and 60% w / w amounts of sucrose were excluded for the production of a stable liquid suspension of rebaudioside A.

[0144] Example 3 Frequency sweep analysis Frequency sweep analysis is utilized to predict the long-term physical stability of the suspension. Specifically, the frequency sweep is used to account for the time-dependent behavior of the suspension in the non-destructive deformation range (e.g., the linear viscoelastic region previously determined via amplitude analysis). High frequencies are used to simulate fast motions on short time scales, while low frequencies simulate slow motions on long time scales. The storage modulus can be used as a measure of the elastic component (solid-like) of the sample, while the loss modulus is considered as a measure of the viscous component (liquid-like) of the sample. Which modulus is dominant at a particular frequency indicates whether a fully structured material appears elastic or viscous. If the storage modulus is higher than the loss modulus, the suspension is more elastic than viscous, which means that they are characterized by solid-like behavior and there is a low likelihood of sedimentation occurring under this condition (stability of the suspension). On the other hand, if the viscous modulus is higher than the elastic modulus, sedimentation can occur.

[0145] Frequency sweep analysis was performed using a Rheometer MCR 102 (Anton Paar, Graz, Austria). The frequency sweep analysis was carried out with a decreasing angular frequency (from 62.8 to 0.0628 rad / s, corresponding to 10 to 0.01 Hz) and a constant strain, which was selected within the LVER (linear viscoelastic region) via oscillatory measurements. All analyses were performed at room temperature using a 25 mm measurement plate with a gap set to 1 mm.

[0146] Figures 2 (suspension 98) and 3 (suspension 105) show the frequency sweep profiles of systems where the storage modulus is higher than the loss modulus, indicating that these suspensions are stable over time. In addition, both suspensions are characterized by values of the storage modulus higher than 10 Pa recorded at low frequencies (around 0.1 rad / s), which means that the possibility of dispersion stability can be assumed (T.G. Mezger, "The Rheology Handbook", 2nd edition, Vincentz Network, Hannover, 2006). Figures 2 and 3 show that both the loss modulus and the storage modulus increase as the frequency value decreases, which means that the corresponding suspensions are further structured and densified over time.

[0147] Regarding suspension 105, despite the good profile of the frequency sweep, it was characterized by low values of the yield stress and the hysteresis area (Table 11 above). Figures 7 (suspension 159) and 8 (suspension 160) show profiles related to systems where the storage modulus is superior to the loss modulus, indicating that the suspension is stable even if the difference between the loss modulus and the storage modulus becomes less at low frequency values.

[0148] Figures 1 (suspension 82), 5 (suspension 107) and 9 (suspension 166) are all related to systems where the loss modulus is higher than the storage modulus at high frequency values (between 10 and 100 rad / s), indicating the possibility of instability of the suspension that can occur during short-term storage.

[0149] Figures 4, 6 and 10 (suspensions 106, 165 and 168) are related to systems where the loss modulus is higher than the storage modulus at low frequency values, indicating here the possibility of sedimentation phenomena occurring over time (during long-term storage).

Claims

1. - reparixin in an amount ranging from 2% w / w to 13% w / w, preferably ranging from 4% w / w to 13% w / w, xanthan gum in an amount ranging from 0.15% w / w to 0.3% w / w, sucrose in an amount ranging from 25% w / w to 55% w / w, - polyvinylpyrrolidone in an amount ranging from 1.8% w / w to 3.2% w / w, - a water-insoluble polymer in an amount ranging from 2.25% w / w to 2.75% w / w A liquid suspension comprising:

2. 10. The liquid suspension of claim 1, wherein the water-insoluble polymer is selected from microcrystalline cellulose and crospovidone.

3. 3. A liquid suspension according to claim 1 or claim 2, wherein the water-insoluble polymer is crospovidone, preferably in an amount of 2.5% w / w.

4. 2. The liquid suspension according to claim 1, further comprising an antifoaming agent, preferably a silicone derivative.

5. The antifoaming agent is dimethicone in an amount ranging from 0.5% w / w to 5% w / w, and simethicone in an amount ranging from 0.003% w / w to 0.006% w / w, preferably in an amount of 0.005% w / w 5. The liquid suspension of claim 4, wherein the liquid suspension is selected from:

6. 2. The liquid suspension of claim 1, further comprising a buffer, preferably selected from citrate buffers and phosphate buffers.

7. 7. The liquid suspension according to claim 6, wherein the buffer is a citrate buffer comprising citric acid monohydrate in an amount ranging from 0.06% w / w to 0.6% w / w, preferably in an amount of 0.064% w / w, and sodium citrate dihydrate in an amount ranging from 0.2% w / w to 0.3% w / w, preferably in an amount of 0.208% w / w.

8. 10. The liquid suspension of claim 1, further comprising a preservative, preferably selected from potassium sorbate, sodium benzoate, methylparaben and propylparaben.

9. 9. A liquid suspension according to claim 8, wherein the preservative is potassium sorbate in an amount ranging from 0.1% w / w to 0.2% w / w, preferably in an amount of 0.15% w / w.

10. 2. The liquid suspension of claim 1, wherein the amount of reparixin is in the range of 2% w / w to 5.5% w / w, preferably in the range of 3% w / w to 5.5% w / w, more preferably in the range of 4.5% w / w to 5.5% w / w, more preferably in the range of 4.7% w / w to 5.3% w / w, more preferably in the range of 4.9% w / w to 5.1% w / w, and even more preferably in an amount of 5% w / w.

11. 2. The liquid suspension of claim 1, wherein the amount of reparixin is in the range of 11.5% w / w to 12.5% ​​w / w, preferably in the range of 11.7% w / w to 12.3% w / w, more preferably in the range of 11.9% w / w to 12.1% w / w, and even more preferably in an amount of 12% w / w.

12. xanthan gum in an amount of 0.2% w / w, - polyvinylpyrrolidone in an amount of 2% w / w 11. The liquid suspension of claim 10, comprising:

13. xanthan gum in an amount of 0.2% w / w, - polyvinylpyrrolidone in an amount of 3% w / w 12. The liquid suspension of claim 11, comprising:

14. 2. The liquid suspension of claim 1, further comprising an aqueous solvent, preferably water, in an amount of up to 100% w / w.

15. - treatment of a disease or condition selected from psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome (ARDS), idiopathic fibrosis, glomerulonephritis, COVID-19, pneumonia caused by SARS-CoV-2 or variants thereof; - prevention or delay of the onset and progression of diabetes, preferably type 1 diabetes, - prevention or treatment of seizures in an individual 2. The liquid suspension of claim 1 for use in

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