Reparixin liquid suspensions

Abstract

FIELD: pharmaceuticals.SUBSTANCE: liquid suspension intended for the prevention or treatment of pathologies mediated by interleukin 8 (IL-8) receptors. The suspension contains: 2–13 wt.% reparixin; 0.15–0.3 wt.% xanthan gum; 25–55 wt.% sucrose; 1.8–3.2 wt.% polyvinylpyrrolidone; 2.25–2.75 wt.% water-insoluble polymer selected from microcrystalline cellulose and crospovidone.EFFECT: stable liquid suspensions of reparixin.15 cl, 10 dwg, 13 tbl, 3 ex

Description

[0001] FIELD OF INVENTION

[0002] The present invention relates to liquid suspensions containing reparixin.

[0003] STATE OF THE ART

[0004] Reparixin, also known as R-(-)-2-(4-isobutylphenyl)propionylmethanesulfonamide and repertaxin, 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). Reparixin has therapeutic potential for the prevention or treatment of pathologies in which activation of this pathway is detrimental.

[0005] For example, IL-8 has been implicated in neutrophil infiltration in pathologies such as psoriasis (BJ Nickoloff et al., Am. J. Pathol., 1991, 138, 129), rheumatoid arthritis (M Selz et al., J. Clin. Invest. 1991, 87, 463), ulcerative colitis (YR Mahkla et al., Clin. Sci., 1992, 82, 273), acute respiratory distress syndrome (ARDS), idiopathic fibrosis (PC Carré et al., J. Clin. Invest,. 1991, 88, 1802, and EJ Miller et al., Am. Rev. Respir. Dis. 1992, 146:427-432) and glomerulonephritis (T. Wada et al., J. Exp. Med., 1994, 180,1135).

[0006] In vitro studies and preclinical testing in small animals have demonstrated that reparixin binding to CXCR1 / CXCR2 can prevent leukocyte recruitment and inflammasome activation. Reparixin's actions include inhibition of neutrophil stimulation and subsequent neutrophil effects, such as NET formation, during the inflammatory response (Cheng OZ, Palaniyar N., Front Immunol. 2013; 4:1).

[0007] The dose, safety, and pharmacokinetics of reparixin were investigated in clinical trials in 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).

[0008] A multicenter, open-label, randomized, phase 2 clinical trial to evaluate the efficacy and safety of reparixin compared with available treatments considered standard of care (SOC) in hospitalized patients with severe COVID-19 pneumonia was conducted from May 5, 2020, to November 27, 2020, showing that treatment with reparixin resulted in improved clinical outcomes in patients with severe COVID-19 pneumonia compared with standard of care (Landoni G et al., Infect Dis Ther 2022, 26: 1-16).

[0009] Currently, reparixin is available only as tablets for oral administration or as an intravenous solution. However, these administration methods are invasive and / or unsuitable for achieving satisfactory patient compliance, particularly in children or patients who are unable to swallow solid tablets. Therefore, there is a need to develop new pharmaceutical dosage forms containing reparixin that overcome these issues and can be administered to individuals of all ages and conditions. Suspensions are ideal candidates for this purpose.

[0010] Suspensions are pharmaceutical dosage forms with two phases: an external liquid phase, also known as the continuous phase or dispersion medium, and an internal phase, also known as the dispersed phase, which contains solid particles insoluble in the external phase. Suspensions are recognized as heterogeneous dispersed systems, and most pharmaceutical suspensions have an aqueous dispersion medium.

[0011] The formulation and distribution of this type of dosage forms is associated with several advantages: efficient dosing of hydrophobic drugs; avoidance of the use of cosolvents; masking of unpleasant taste; ensuring resistance of drugs to degradation by hydrolysis, oxidation, or microbial activity; ease of oral administration for young and elderly patients. In addition, suspensions can include higher concentrations of drugs than solutions (Doye, P. et al., Int J Curr Pharm Sci 2017, 9, 8).

[0012] The primary challenge when developing suspensions is to ensure their physical stability over time to ensure content homogeneity. Indeed, suspensions are thermodynamically unstable systems due to the free energy of their internal phase, which causes particle aggregation and sedimentation, reducing the system's energy. Several aspects must be considered when formulating a suspension.

[0013] Based on the particle size of the internal phase, suspensions can be classified into two groups: suspensions characterized by an internal phase with a particle size greater than ~0.5 μm, known as coarse suspensions, and suspensions characterized by an internal phase with a particle size less than 0.5 μm, known as colloidal dispersions (Edman, P., Journal of Aerosol Medicine 1994, 7, S-3-S-6). Depending on the type of suspension, different parameters must be considered to ensure stability.

[0014] The preparation of suspensions containing reparixin is particularly challenging due to the specific properties of this active pharmaceutical ingredient (API).

[0015] Reparixin is primarily produced as a powder consisting of large particles. Therefore, potential suspensions containing reparixin are coarse suspensions.

[0016] In coarse suspensions, the internal phase containing the API tends to settle under gravity and cause sedimentation due to its particle size. An increase in the absolute zeta potential leads to an increase in the sedimentation rate. This suggests that sedimentation is driven by gravitational forces rather than electrostatic interactions, which are insufficient to ensure stability and kinetic stabilization due to the particle size of the internal phase. For this reason, to ensure physical stability, the zeta potential of coarse suspensions is typically achieved at a value near zero. This zeta potential value corresponds to a state in which the particles are surrounded by a hydration layer that conceals their charge and, in the event of particles aggregating and precipitating, can prevent the formation of a compact sediment and instead promotes the formation of a loose sediment that can be easily resuspended by hand shaking.To adjust the zeta potential of suspensions, ionic or nonionic surfactants and various types of electrolytes (e.g., salts) are typically used. For example, PEG (polyethylene glycol) is included in many commercial suspensions for this purpose.

[0017] Furthermore, reparixin has low wettability, which complicates its formulation into a stable liquid suspension. In fact, the wettability of dispersed particles is important for ensuring the homogeneity and uniformity of the content (Kwok, DY et al., Advances in Colloid and Interface Science 1999, 81, 167-249). Wettability is the tendency of a liquid to spread or adhere to a solid surface when they are immiscible; poor wettability of a powdered solid results in its floating on the surface of a liquid medium. Poor wettability of the internal phase is mainly due to the high interfacial tension between the dispersed particles and the dispersion medium, and reducing the interfacial tension increases the stability of the suspension.When formulating a suspension, a common method for improving the wettability of solids is the use of wetting agents such as surfactants, which can reduce the surface tension at the solid-liquid interface.

[0018] Another requirement necessary to ensure the stability of suspensions is the presence of the so-called yield strength (τ0), which is a property of the material and can be defined as the stress corresponding to the yield point at which the material begins to flow or plastically deform.

[0019] In light of the above, it is clear that there is a need to develop suspensions containing reparixin with satisfactory characteristics. However, this is particularly challenging for this API due to the reasons discussed above.

[0020] SUMMARY OF THE INVENTION

[0021] The present inventors have developed stable liquid suspensions of reparixin.

[0022] In particular, the inventors have discovered that the use of sucrose as a sweetener and polyvinylpyrrolidone as a wetting agent in the composition makes it possible to obtain stable ready-to-use liquid suspensions of reparixin.

[0023] In particular, the inventors unexpectedly discovered that the type and amount of sweetener included in the formulation to mask the unpleasant taste of reparixin affects the zeta potential and, consequently, the stability of the suspension. Furthermore, the inventors found that the use of polyvinylpyrrolidone as a wetting agent allows for satisfactory wettability of reparixin.

[0024] The inventors also established the type and range of viscosity modifier to be used in combination with the above-mentioned excipients to achieve a stable ready-to-use liquid suspension of reparixin.

[0025] Thus, the object of the present invention is a liquid suspension containing:

[0026] - reparixin in an amount from 2% w / w to 13% w / w,

[0027] - xanthan gum in an amount of from 0.15% w / w to 0.3% w / w,

[0028] - sucrose in an amount from 25% w / w to 55% w / w,

[0029] - polyvinylpyrrolidone in an amount of 1.8% w / w to 3.2% w / w,

[0030] - water-insoluble polymer in an amount of 2.25% w / w to 2.75% w / w.

[0031] A further object of the present invention is a liquid suspension according to the first object of the invention for use in the treatment of a disease or condition selected from psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome (ARDS), idiopathic fibrosis, glomerulonephritis, COVID-19.

[0032] A further object of the present invention is a liquid suspension according to the first object of the invention for use in the prevention of diabetes or delaying the onset and progression of diabetes.

[0033] A further object of the present invention is a liquid suspension according to the first object of the invention for use in the prevention and / or treatment of seizures.

[0034] BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 shows the frequency sweep profile of suspension 82.

[0036] Figure 2 shows the frequency sweep profile of suspension 98.

[0037] Figure 3 shows the frequency sweep profile of suspension 105.

[0038] Figure 4 shows the frequency sweep profile of suspension 106.

[0039] Figure 5 shows the frequency sweep profile of suspension 107.

[0040] Figure 6 shows the frequency sweep profile of suspension 165.

[0041] Figure 7 shows the frequency sweep profile of suspension 159.

[0042] Fig. 8 shows the frequency sweep profile of suspension 160.

[0043] Fig. 9 shows the frequency sweep profile of suspension 166.

[0044] Fig. 10 shows the frequency sweep profile of suspension 168.

[0045] DEFINITIONS

[0046] The term "antifoaming agent" as used herein refers to a chemical additive that reduces and / or prevents the formation of foam in liquid formulations, such as liquid suspensions, by reducing the liquid-air surface tension.

[0047] The term "anti-caking agent," as used herein, refers to excipients that can help stabilize a suspension and improve the appearance of the final formulation. These agents are typically water-insoluble chemical compounds and include inorganic solids, insoluble cellulose derivatives, and insoluble synthetic polymers.

[0048] The term "wetting agent" as used herein refers to excipients capable of reducing the API-water surface tension, improving the wettability and spreadability of the suspended API.

[0049] As used herein in relation to a component of a liquid suspension, "% w / w" indicates the number of grams of that component in 100 grams of liquid suspension. For example, the formulation "reparixin at 5% w / w" indicates that 5 grams of reparixin are present in 100 grams of liquid suspension.

[0050] As used herein, the term "Avicel CL-611" refers to a spray-dried mixture of microcrystalline cellulose and sodium carboxymethylcellulose, in which sodium carboxymethylcellulose is present in an amount of from 11.3% w / w to 18.8% w / w.

[0051] It is understood that the terms "suspending" and "dispersing" or "suspended" and "dispersed" may be used interchangeably in the context of the present description.

[0052] DETAILED DESCRIPTION OF THE INVENTION

[0053] As will be explained in more detail in the experimental section, the inventors have identified a qualitative-quantitative composition that allows the production of stable liquid suspensions of reparixin.

[0054] In particular, it was unexpectedly discovered that the type and amount of sweetener included in the liquid suspension of reparixin to mask the unpleasant taste of this API affects the zeta potential value and rheological properties of the resulting suspension and, consequently, its stability. Specifically, based on the results presented in the experimental section, sucrose in an amount of 25% w / w to 55% w / w was selected as the sweetener for inclusion in liquid suspensions of reparixin to achieve the desired stability.

[0055] Furthermore, the inventors selected polyvinylpyrrolidone as a wetting agent to be included in liquid suspensions of reparixin in order to achieve satisfactory wettability of this API.

[0056] Furthermore, the inventors selected the type / amount of viscosity modifier (xanthan gum) and anti-caking agent (water-insoluble polymers) for use in combination with sucrose and polyvinylpyrrolidone to obtain stable liquid suspensions of reparixin.

[0057] Thus, the first object of the invention is a liquid suspension containing:

[0058] - reparixin in an amount of from 2% w / w to 13% w / w, preferably from 3% w / w to 13% w / w, more preferably from 4% w / w to 13% w / w, more preferably from 4.5% w / w to 12.5% ​​w / w, more preferably from 4.8% w / w to 12.2% w / w, even more preferably from 4.9% w / w to 12.1% w / w, most preferably from 5% w / w to 12% w / w,

[0059] - xanthan gum in an amount of from 0.15% w / w to 0.3% w / w, preferably from 0.18% w / w to 0.27% w / w, more preferably from 0.18% w / w to 0.23% w / w, even more preferably from 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0060] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0061] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of from 1.8% w / w to 3.2% w / w, preferably from 1.9% w / w to 3.1% w / w, more preferably from 2% w / w to 3% w / w,

[0062] - water-insoluble polymer in an amount of 2.25% w / w to 2.75% w / w.

[0063] Reparixin (CAS No. 266359-83-5), which is also known as R-(-)-2-(4-isobutylphenyl)propionylmethanesulfonamide and repertaxin, is a compound with the following chemical formula:

[0064]

[0065] Preferably, the liquid suspension according to the first object of the invention comprises:

[0066] - reparixin in an amount from 5% w / w to 12% w / w,

[0067] - xanthan gum in an amount of from 0.15% w / w to 0.3% w / w,

[0068] - sucrose in an amount from 30% w / w to 50% w / w,

[0069] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of from 1.8% w / w to 3.2% w / w,

[0070] - water-insoluble polymer in an amount of 2.25% w / w to 2.75% w / w.

[0071] Preferably, the liquid suspension according to the first object of the invention comprises:

[0072] - reparixin in an amount from 5% w / w to 12% w / w,

[0073] - xanthan gum in an amount of 0.2% w / w,

[0074] - sucrose in an amount from 30% w / w to 50% w / w,

[0075] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w to 3% w / w,

[0076] - water-insoluble polymer in an amount of 2.25% w / w to 2.75% w / w.

[0077] Preferably, said water-insoluble polymer is selected from microcrystalline cellulose and crospovidone.

[0078] Preferably, said water-insoluble polymer is crospovidone, preferably in an amount of 2.5% w / w.

[0079] In one embodiment, also in combination with any of the above embodiments, the liquid suspension according to the first object of the invention further comprises a buffering agent, preferably in an amount of from 0.1% w / w to 3% w / w, and / or an antifoaming agent, preferably in an amount of from 0.003% w / w to 5% w / w, more preferably from 0.005% w / w to 5% w / w, and / or a preservative, preferably in an amount of from 0.01% w / w to 0.5% w / w.

[0080] Preferably, said antifoaming agent is a silicone derivative, preferably selected from:

[0081] - dimethicone in an amount of from 0.5% w / w to 5% w / w, and

[0082] - simethicone in an amount of from 0.003% w / w to 0.006% w / w, preferably in an amount of 0.005% w / w.

[0083] Preferably, said buffering agent is selected from a citrate buffer and a phosphate buffer. Preferably, said buffering agent is a citrate buffer containing citric acid, preferably citric acid monohydrate, in an amount of from 0.06% w / w to 0.6% w / w, preferably in an amount of from 0.06% w / w to 0.3% w / w, more preferably in an amount of 0.064% w / w, and sodium citrate, preferably sodium citrate dihydrate, in an amount of from 0.2% w / w to 0.3% w / w, preferably in an amount of 0.208% w / w.

[0084] Preferably, the said preservative is selected from potassium sorbate, sodium benzoate, methylparabens and propylparabens.

[0085] Preferably, said preservative is potassium sorbate in an amount of from 0.1% w / w to 0.2% w / w, preferably in an amount of 0.15% w / w.

[0086] In one embodiment, the liquid suspension according to the first object of the invention consists of:

[0087] - reparixin in an amount of from 2% w / w to 13% w / w, preferably from 3% w / w to 13% w / w, more preferably from 4% w / w to 13% w / w, more preferably from 4.5% w / w to 12.5% ​​w / w, more preferably from 4.8% w / w to 12.2% w / w, even more preferably from 4.9% w / w to 12.1% w / w, most preferably from 5% w / w to 12% w / w,

[0088] - xanthan gum in an amount of from 0.15% w / w to 0.3% w / w, preferably from 0.18% w / w to 0.27% w / w, more preferably from 0.18% w / w to 0.23% w / w, even more preferably from 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0089] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0090] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of from 1.8% w / w to 3.2% w / w, preferably from 1.9% w / w to 3.1% w / w, more preferably from 2% w / w to 3% w / w,

[0091] - water-insoluble polymer in an amount of from 2.25% w / w to 2.75% w / w,

[0092] - a buffering agent, preferably in an amount of 0.1% w / w to 3% w / w,

[0093] - an antifoaming agent, preferably in an amount of 0.003% w / w to 5% w / w, more preferably in an amount of 0.005% w / w to 5% w / w,

[0094] - preservative, preferably in an amount of from 0.01% w / w to 0.5% w / w.

[0095] - aqueous solvent, preferably water, in an amount of up to 100% w / w.

[0096] In one embodiment, the liquid suspension according to the first object of the invention consists of:

[0097] - reparixin in an amount from 2% w / w to 13% w / w,

[0098] - xanthan gum in an amount of 0.2% w / w,

[0099] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0100] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w to 3% w / w,

[0101] - water-insoluble polymer in an amount of from 2.25% w / w to 2.75% w / w,

[0102] - a buffering agent, preferably in an amount of 0.1% w / w to 3% w / w,

[0103] - an antifoaming agent, preferably in an amount of 0.003% w / w to 5% w / w, more preferably in an amount of 0.005% w / w to 5% w / w,

[0104] - preservative, preferably in an amount of 0.01% w / w to 0.5% w / w,

[0105] - aqueous solvent, preferably water, in an amount of up to 100% w / w.

[0106] Preferably, the amount of reparixin in said 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% wt. / wt., 8.9% wt. / wt., 9% wt. / wt., 9.1% wt. / wt., 9.2% wt. / wt., 9.3% wt. / wt., 9.4% wt. / wt., 9.5% wt. / wt., 9.6% wt. / wt., 9.7% wt. / wt., 9.8% wt. / wt., 9.9% wt. / wt., 10% wt. / wt., 10.1% wt. / wt., 10.2% wt. / wt., 10.3% wt. / wt., 10.4% wt. / wt., 10.5% wt. / wt., 10.6% wt. / wt., 10.7% wt. / wt., 10.8% mass / mass, 10.9% mass / mass, 11% mass / mass, 11.1% mass / mass, 11.2% mass / mass, 11.3% mass / mass, 11.4% mass / mass, 11.5% mass / mass, 11.6% mass / mass, 11.7% mass / mass, 11.8% mass / mass, 11.9% mass / mass, 12% mass / mass, 12.1% mass / mass, 12.2% mass / mass, 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.

[0107] In two preferred embodiments, also in combination with any of the embodiments described above, the liquid suspension according to the first objective of the invention comprises reparixin in:

[0108] - in an amount of 2% w / w to 5.5% w / w, preferably 3% w / w to 5.5% w / w, more preferably 4% w / w to 5.5% w / w, more preferably 4.5% w / w to 5.5% w / w, more preferably 4.7% w / w to 5.3% w / w, more preferably 4.9% w / w to 5.1% w / w, even more preferably in an amount of 5% w / w; this embodiment is suitable for administration to a pediatric individual, wherein the age of the pediatric individual is less than 14 years old; or

[0109] - in an amount of 11.5% w / w to 12.5% ​​w / w, preferably 11.7% w / w to 12.3% w / w, even more preferably 11.9% w / w to 12.1% w / w, most preferably in an amount of 12% w / w; this embodiment is suitable for administration to an adult individual, wherein the age of the adult individual is more than 14 years old.

[0110] In one embodiment, also in combination with any of the above-described embodiments, said antifoaming agent is a silicone derivative, preferably selected from cyclomethicone, dimethicone and simethicone, more preferably from dimethicone and simethicone.

[0111] The presence of an antifoaming agent in a liquid suspension is advantageous because it prevents and / or slows down the formation of foam on the surface of the suspension.

[0112] Preferably, said simethicone is present in an amount of from 0.003% w / w to 0.6% w / w, preferably from 0.003% w / w to 0.3% w / w, more preferably from 0.003% w / w to 0.009% w / w, even more preferably from 0.003% w / w to 0.007% w / w, even more preferably in an amount of from 0.003% w / w to 0.006% w / w, most preferably in an amount of 0.005% w / w.

[0113] Preferably, said dimethicone is present in an amount of from 0.5% w / w to 5% w / w.

[0114] In one embodiment, also in combination with any of the above-described embodiments, said buffering agent is capable of maintaining the pH of the suspension at a level of from 4 to 6, preferably from 4.5 to 5.5, more preferably at a level of 5. Preferably, said buffering agent is selected from a citrate buffer and a phosphate buffer, more preferably it is a citrate buffer. Preferably, said citrate buffer comprises, preferably consists of, citric acid, preferably citric acid monohydrate, in an amount of from 0.06% w / w to 0.6% w / w, preferably from 0.06% w / w to 0.3% w / w, more preferably from 0.06% w / w to 0.1% w / w, even more preferably from 0.06% w / w. up to 0.07% w / w, most preferably in an amount of 0.064% w / w, and sodium citrate, preferably sodium citrate dihydrate, in an amount of from 0.2% w / w to 2% w / w., preferably from 0.2% w / w to 1% w / w, more preferably from 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w. Preferably, among the above ranges, the relative amount of citric acid monohydrate and sodium citrate dihydrate is selected so as to achieve a pH of from 4 to 6, preferably from 4.5 to 5.5, more preferably at the level of 5.

[0115] In one embodiment, also in combination with any of the embodiments described above, said preservative is selected from potassium sorbate, sodium benzoate, methylparabens, and propylparabens. The presence of a preservative in the composition is advantageous because it inhibits or slows microbial growth.

[0116] Preferably, said potassium sorbate is present in an amount of 0.1% w / w to 0.2% w / w, more preferably in an amount of 0.15% w / w.

[0117] Preferably, said sodium benzoate is present in an amount of from 0.02% w / w to 0.5% w / w.

[0118] Preferably, said methylparabens, propylparabens or a combination thereof are present in an amount of from 0.015% w / w to 0.2% w / w.

[0119] In one embodiment, also in combination with any of the embodiments described above, said water-insoluble polymer is selected from microcrystalline cellulose and crospovidone. The water-insoluble polymer acts as an anticaking agent and is used to prevent the agglomeration of the particulate solid into lumps or sticky cakes, avoiding and / or limiting sedimentation.

[0120] Crospovidone, also known as polyvinylpolypyrrolidone, is a highly cross-linked modification of polyvinylpyrrolidone (PVP). Due to cross-linking, crospovidone is insoluble in water.

[0121] In one embodiment, also in combination with any of the above-described embodiments, the liquid suspension according to the present invention further comprises an aqueous solvent, preferably water, in an amount of up to 100% w / w.

[0122] In one embodiment, the liquid suspension according to the first object of the invention consists of:

[0123] - reparixin in an amount from 2% w / w to 13% w / w,

[0124] - xanthan gum in an amount of 0.2% w / w,

[0125] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0126] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of from 2% w / w to 3% w / w,

[0127] - crospovidone in an amount from 2.25% w / w to 2.75% w / w,

[0128] - citric acid, preferably citric acid monohydrate, in an amount of from 0.06% w / w to 0.6% w / w, preferably from 0.06% w / w to 0.3% w / w, more preferably from 0.06% w / w to 0.1% w / w, even more preferably from 0.06% w / w to 0.07% w / w,

[0129] - sodium citrate, preferably sodium citrate dihydrate, in an amount of from 0.2% w / w to 2% w / w, preferably from 0.2% w / w to 1% w / w, more preferably from 0.2% w / w to 0.3% w / w,

[0130] - simethicone in an amount of from 0.003% w / w to 0.6% w / w, preferably from 0.003% w / w to 0.3% w / w, more preferably from 0.003% w / w to 0.009% w / w, even more preferably from 0.003% w / w to 0.007% w / w,

[0131] - potassium sorbate in an amount of from 0.1% w / w to 0.2% w / w,

[0132] - water up to 100%.

[0133] In one embodiment, the liquid suspension according to the first object of the invention comprises, preferably consists of:

[0134] - reparixin in an amount of 2% w / w to 5.5% w / w, preferably 3% w / w to 5.5% w / w, more preferably 4% w / w to 5.5% w / w, more preferably 4.5% w / w to 5.5% w / w, more preferably 4.7% w / w to 5.3% w / w, more preferably 4.9% w / w to 5.1% w / w, even more preferably in an amount of 5% w / w,

[0135] - xanthan gum in an amount of from 0.15% w / w to 0.3% w / w, preferably from 0.18% w / w to 0.27% w / w, more preferably from 0.18% w / w to 0.23% w / w, even more preferably from 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0136] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0137] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of from 1.5% w / w to 2.5% w / w, preferably from 1.7% w / w to 2.3% w / w, more preferably from 1.9% w / w to 2.1% w / w, even more preferably in an amount of 2% w / w,

[0138] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0139] - optionally one or more of the following components: simethicone in an amount of from 0.003% w / w to 0.006% w / w, preferably from 0.004% w / w to 0.006% w / w, more preferably in an amount of 0.005% w / w, citric acid monohydrate in an amount of from 0.06% w / w to 0.6% w / w, preferably from 0.06% w / w to 0.3% w / w, more preferably from 0.06% w / w to 0.1% w / w, even more preferably from 0.06% w / w. up to 0.07% w / w, most preferably in an amount of 0.064% w / w, sodium citrate dihydrate in an amount of from 0.2% w / w to 2% w / w, preferably from 0.2% w / w to 1% w / w, more preferably from 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w, potassium sorbate in an amount of from 0.1% w / w to 0.2% w / w, preferably in an amount of 0.15% w / w,

[0140] - aqueous solvent, preferably water, in an amount of up to 100% w / w.

[0141] In one embodiment, the liquid suspension according to the first object of the invention comprises:

[0142] - reparixin in an amount of from 2% w / w to 5.5% w / w, preferably from 3% w / w to 5.5% w / w, more preferably from 4% w / w to 5.5% w / w, more preferably from 4.5% w / w to 5.5% w / w, more preferably from 4.7% w / w to 5.3% w / w, more preferably from 4.9% w / w to 5.1% w / w, even more preferably in an amount of 5% w / w,

[0143] - xanthan gum in an amount of from 0.15% w / w to 0.3% w / w, preferably from 0.18% w / w to 0.27% w / w, more preferably from 0.18% w / w to 0.23% w / w, even more preferably from 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0144] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0145] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of from 1.8% w / w to 2.5% w / w, preferably from 1.8% w / w to 2.3% w / w, more preferably from 1.9% w / w to 2.1% w / w, even more preferably in an amount of 2% w / w,

[0146] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w.

[0147] In one embodiment, the liquid suspension according to the first object of the invention consists of:

[0148] - reparixin in an amount of 2% w / w to 5.5% w / w, preferably 3% w / w to 5.5% w / w, more preferably 4% w / w to 5.5% w / w, more preferably 4.5% w / w to 5.5% w / w, more preferably 4.7% w / w to 5.3% w / w, more preferably 4.9% w / w to 5.1% w / w, even more preferably in an amount of 5% w / w,

[0149] - xanthan gum in an amount of from 0.15% w / w to 0.3% w / w, preferably from 0.18% w / w to 0.27% w / w, more preferably from 0.18% w / w to 0.23% w / w, even more preferably from 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0150] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0151] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 1.8% w / w to 2.5% w / w, preferably 1.8% w / w to 2.3% w / w, more preferably 1.9% w / w to 2.1% w / w, even more preferably in an amount of 2% w / w,

[0152] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0153] - optionally one or more of the following components: simethicone in an amount of from 0.003% w / w to 0.006% w / w, preferably from 0.004% w / w to 0.006% w / w, more preferably in an amount of 0.005% w / w, citric acid, preferably citric acid monohydrate, in an amount of from 0.06% w / w to 0.6% w / w, preferably from 0.06% w / w to 0.3% w / w, more preferably from 0.06% w / w to 0.1% w / w, even more preferably from 0.06% w / w. up to 0.07% w / w, most preferably in an amount of 0.064% w / w, sodium citrate, preferably sodium citrate dihydrate, in an amount of from 0.2% w / w to 2% w / w, preferably from 0.2% w / w to 1% w / w, more preferably from 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w, potassium sorbate in an amount of from 0.1% w / w to 0.2% w / w., preferably in an amount of 0.15% w / w.,.

[0154] - aqueous solvent, preferably water, in an amount of up to 100% w / w.

[0155] In one embodiment, the liquid suspension according to the first object of the invention comprises:

[0156] - reparixin in an amount of 2% w / w to 5.5% w / w, preferably in an amount of 5% w / w,

[0157] - xanthan gum in an amount of 0.2% w / w,

[0158] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0159] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w,

[0160] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w.

[0161] In one embodiment, the liquid suspension according to the first object of the invention consists of:

[0162] - reparixin in an amount of 2% w / w to 5.5% w / w, preferably in an amount of 5% w / w,

[0163] - xanthan gum in an amount of 0.2% w / w,

[0164] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0165] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w,

[0166] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0167] - optionally one or more of the following components: simethicone in an amount of from 0.003% w / w to 0.006% w / w, preferably from 0.004% w / w to 0.006% w / w, more preferably in an amount of 0.005% w / w, citric acid, preferably citric acid monohydrate, in an amount of from 0.06% w / w to 0.6% w / w, preferably from 0.06% w / w to 0.3% w / w, more preferably from 0.06% w / w to 0.1% w / w, even more preferably from 0.06% w / w. up to 0.07% w / w, most preferably in an amount of 0.064% w / w, sodium citrate, preferably sodium citrate dihydrate, in an amount of from 0.2% w / w to 2% w / w, preferably from 0.2% w / w to 1% w / w, more preferably from 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w, potassium sorbate in an amount of from 0.1% w / w to 0.2% w / w., preferably in an amount of 0.15% w / w.,.

[0168] - aqueous solvent, preferably water, in an amount of up to 100% w / w.

[0169] Preferably, among the above ranges, the relative amount of citric acid monohydrate and sodium citrate dihydrate is selected so as to achieve a pH of 4 to 6, preferably 4.5 to 5.5, more preferably at the level of 5.

[0170] In an alternative embodiment, the liquid suspension according to the first object of the invention comprises, preferably consists of:

[0171] - reparixin in an amount of 11.5% w / w to 12.5% ​​w / w, preferably 11.7% w / w to 12.3% w / w, even more preferably 11.9% w / w to 12.1% w / w, most preferably 12% w / w,

[0172] - xanthan gum in an amount of from 0.15% w / w to 0.3% w / w, preferably from 0.18% w / w to 0.27% w / w, more preferably from 0.18% w / w to 0.23% w / w, even more preferably from 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0173] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0174] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2.5% w / w to 3.5% w / w, preferably 2.7% w / w to 3.3% w / w, more preferably 2.9% w / w to 3.1% w / w, even more preferably 3% w / w,

[0175] - crospovidone in an amount of from 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0176] - optionally one or more of the following components: simethicone in an amount of from 0.003% w / w to 0.006% w / w, preferably from 0.004% w / w to 0.006% w / w, more preferably in an amount of 0.005% w / w, citric acid monohydrate in an amount of from 0.06% w / w to 0.6% w / w, preferably from 0.06% w / w to 0.3% w / w, more preferably from 0.06% w / w to 0.1% w / w, even more preferably from 0.06% w / w. up to 0.07% w / w, most preferably in an amount of 0.064% w / w, sodium citrate dihydrate in an amount of from 0.2% w / w to 2% w / w, preferably from 0.2% w / w to 1% w / w, more preferably from 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w, potassium sorbate in an amount of from 0.1% w / w to 0.2% w / w, preferably in an amount of 0.15% w / w,

[0177] - aqueous solvent, preferably water, in an amount of up to 100% w / w.

[0178] In an alternative embodiment, the liquid suspension according to the first object of the invention comprises:

[0179] - reparixin in an amount of 11.5% w / w to 12.5% ​​w / w, preferably from 11.7% w / w to 12.3% w / w, even more preferably from 11.9% w / w to 12.1% w / w, most preferably in an amount of 12% w / w,

[0180] - xanthan gum in an amount of from 0.15% w / w to 0.3% w / w, preferably from 0.18% w / w to 0.27% w / w, more preferably from 0.18% w / w to 0.23% w / w, even more preferably from 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0181] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0182] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of from 2.5% w / w to 3.2% w / w, preferably from 2.7% w / w to 3.2% w / w, more preferably from 2.9% w / w to 3.1% w / w, even more preferably in an amount of 3% w / w,

[0183] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w.

[0184] In an alternative embodiment, the liquid suspension according to the first object of the invention consists of:

[0185] - reparixin in an amount of 11.5% w / w to 12.5% ​​w / w, preferably 11.7% w / w to 12.3% w / w, even more preferably 11.9% w / w to 12.1% w / w, most preferably 12% w / w,

[0186] - xanthan gum in an amount of from 0.15% w / w to 0.3% w / w, preferably from 0.18% w / w to 0.27% w / w, more preferably from 0.18% w / w to 0.23% w / w, even more preferably from 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0187] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0188] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of from 2.5% w / w to 3.2% w / w, preferably from 2.7% w / w to 3.2% w / w, more preferably from 2.9% w / w to 3.1% w / w, even more preferably in an amount of 3% w / w,

[0189] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0190] - optionally one or more of the following components: simethicone in an amount of from 0.003% w / w to 0.006% w / w, preferably from 0.004% w / w to 0.006% w / w, more preferably in an amount of 0.005% w / w, citric acid, preferably citric acid monohydrate, in an amount of from 0.06% w / w to 0.6% w / w, preferably from 0.06% w / w to 0.3% w / w, more preferably from 0.06% w / w to 0.1% w / w, even more preferably from 0.06% w / w. up to 0.07% w / w, most preferably in an amount of 0.064% w / w, sodium citrate, preferably sodium citrate dihydrate, in an amount of from 0.2% w / w to 2% w / w, preferably from 0.2% w / w to 1% w / w, more preferably from 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w, potassium sorbate in an amount of from 0.1% w / w to 0.2% w / w., preferably in an amount of 0.15% w / w.,.

[0191] - aqueous solvent, preferably water, in an amount of up to 100% w / w.

[0192] In an alternative embodiment, the liquid suspension according to the first object of the invention comprises:

[0193] - reparixin in an amount of 11.5% w / w to 12.5% ​​w / w, preferably in an amount of 12% w / w,

[0194] - xanthan gum in an amount of 0.2% w / w,

[0195] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0196] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 3% w / w,

[0197] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w.

[0198] In an alternative embodiment, the liquid suspension according to the first object of the invention consists of:

[0199] - reparixin in an amount of 11.5% w / w to 12.5% ​​w / w, preferably in an amount of 12% w / w,

[0200] - xanthan gum in an amount of 0.2% w / w,

[0201] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0202] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 3% w / w,

[0203] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0204] - optionally one or more of the following components: simethicone in an amount of from 0.003% w / w to 0.006% w / w, preferably from 0.004% w / w to 0.006% w / w, more preferably in an amount of 0.005% w / w, citric acid, preferably citric acid monohydrate, in an amount of from 0.06% w / w to 0.6% w / w, preferably from 0.06% w / w to 0.3% w / w, more preferably from 0.06% w / w to 0.1% w / w, even more preferably from 0.06% w / w. up to 0.07% w / w, most preferably in an amount of 0.064% w / w, sodium citrate, preferably sodium citrate dihydrate, in an amount of from 0.2% w / w to 2% w / w, preferably from 0.2% w / w to 1% w / w, more preferably from 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w, potassium sorbate in an amount of from 0.1% w / w to 0.2% w / w., preferably in an amount of 0.15% w / w.,.

[0205] - aqueous solvent, preferably water, in an amount of up to 100% w / w.

[0206] Preferably, among the above ranges, the relative amount of citric acid monohydrate and sodium citrate dihydrate is selected so as to achieve a pH of 4 to 6, preferably 4.5 to 5.5, more preferably at the level of 5.

[0207] In one embodiment, the liquid suspension according to the first object of the invention comprises:

[0208] - reparixin in an amount of 5% w / w,

[0209] - xanthan gum in an amount of 0.2% w / w,

[0210] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0211] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w,

[0212] - crospovidone in the amount of 2.5% w / w.

[0213] In one embodiment, the liquid suspension according to the first object of the invention consists of:

[0214] - reparixin in an amount of 5% w / w,

[0215] - xanthan gum in an amount of 0.2% w / w,

[0216] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0217] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w,

[0218] - crospovidone in the amount of 2.5% w / w,

[0219] - simethicone in an amount of 0.003% w / w to 0.006% w / w, preferably 0.004% w / w to 0.006% w / w, more preferably 0.005% w / w,

[0220] - citric acid, preferably citric acid monohydrate, in an amount of from 0.06% w / w to 0.6% w / w, preferably from 0.06% w / w to 0.3% w / w, more preferably from 0.06% w / w to 0.1% w / w, even more preferably from 0.06% w / w to 0.07% w / w, most preferably in an amount of 0.064% w / w,

[0221] - sodium citrate, preferably sodium citrate dihydrate, in an amount of from 0.2% w / w to 2% w / w, preferably from 0.2% w / w to 1% w / w, more preferably from 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w,

[0222] - potassium sorbate in an amount of from 0.1% w / w to 0.2% w / w, preferably in an amount of 0.15% w / w,

[0223] - water up to 100%.

[0224] In one embodiment, the liquid suspension according to the first object of the invention consists of:

[0225] - reparixin in the amount of 5% w / w,

[0226] - xanthan gum in an amount of 0.2% w / w,

[0227] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0228] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w,

[0229] - crospovidone in the amount of 2.5% w / w,

[0230] - simethicone in the amount of 0.005% w / w,

[0231] - citric acid monohydrate in an amount of 0.064% w / w,

[0232] - sodium citrate dihydrate in an amount of 0.208% w / w,

[0233] - potassium sorbate in an amount of 0.15% w / w,

[0234] - water up to 100%.

[0235] In one embodiment, the liquid suspension according to the first object of the invention comprises:

[0236] - reparixin in the amount of 12% w / w,

[0237] - xanthan gum in an amount of 0.2% w / w,

[0238] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0239] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 3% w / w,

[0240] - crospovidone in the amount of 2.5% w / w.

[0241] In another embodiment, the liquid suspension according to the first object of the invention consists of:

[0242] - reparixin in the amount of 12% w / w,

[0243] - xanthan gum in an amount of 0.2% w / w,

[0244] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0245] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 3% w / w,

[0246] - crospovidone in the amount of 2.5% w / w,

[0247] - simethicone in an amount of 0.003% w / w to 0.006% w / w, preferably 0.004% w / w to 0.006% w / w, more preferably 0.005% w / w,

[0248] - citric acid, preferably citric acid monohydrate, in an amount of from 0.06% w / w to 0.6% w / w, preferably from 0.06% w / w to 0.3% w / w, more preferably from 0.06% w / w to 0.1% w / w, even more preferably from 0.06% w / w to 0.07% w / w, most preferably in an amount of 0.064% w / w,

[0249] - sodium citrate, preferably sodium citrate dihydrate, in an amount of from 0.2% w / w to 2% w / w, preferably from 0.2% w / w to 1% w / w, more preferably from 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w,

[0250] - potassium sorbate in an amount of 0.1% w / w to 0.2% w / w, preferably in an amount of 0.15% w / w,

[0251] - water up to 100%.

[0252] In another embodiment, the liquid suspension according to the first object of the invention consists of:

[0253] - reparixin in the amount of 12% w / w,

[0254] - xanthan gum in an amount of 0.2% w / w,

[0255] - sucrose in an amount of from 25% w / w to 55% w / w, preferably from 27% w / w to 53% w / w, even more preferably from 29% w / w to 51% w / w, most preferably from 30% w / w to 50% w / w,

[0256] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 3% w / w,

[0257] - crospovidone in the amount of 2.5% w / w,

[0258] - simethicone in the amount of 0.005% w / w,

[0259] - citric acid monohydrate in an amount of 0.064% w / w,

[0260] - sodium citrate dihydrate in an amount of 0.208% w / w,

[0261] - potassium sorbate in an amount of 0.15% w / w,

[0262] - water up to 100%.

[0263] In one embodiment, also in combination with any of the above-described embodiments, the amount of sucrose in the liquid suspension according to the first object of the 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% mass. / mass., 49.7% mass. / mass., 49.8% mass. / mass., 49.9% mass. / mass. or 50% mass / mass.

[0264] In one embodiment, also in combination with any of the embodiments described above, the liquid suspension reconstituted from the powder mixture has a zeta potential value of -3 mV to +3 mV, preferably -2.5 mV to +2.5 mV, wherein said 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.

[0265] In one embodiment, also in combination with any of the above-described embodiments, the liquid suspension according to the first object of the invention has a yield strength value of at least 8 Pa, wherein said yield strength value is measured using an MCR 102 rheometer (Anton Paar, Graz, Austria) in accordance with the procedure described in Example 2 below.

[0266] In one embodiment, also in combination with any of the embodiments described above, the liquid suspension according to the first objective of the invention is stable for a period of at least one year, preferably at least two years, which means that during this period of time the API remains uniformly suspended in the external phase, ensuring the correct dose of administration of the API or, in the event of sedimentation, is easily resuspended by shaking by hand.

[0267] A second object of the invention is a liquid suspension according to any of the above-described embodiments for use in the treatment of a disease or condition selected from psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome (ARDS), idiopathic fibrosis and glomerulonephritis.

[0268] Another object of the invention is a liquid suspension according to any of the above-described embodiments of the first object of the invention for use in the prevention of diabetes or for delaying the onset and progression of diabetes, wherein said diabetes is preferably type I diabetes.

[0269] Another object of the present invention is a liquid suspension according to any of the above-described embodiments of the first object of the invention for use in the treatment of infection caused by SARS-CoV-2 or a variant thereof, preferably for use in the treatment of COVID-19, even more preferably for use in improving respiratory function in individuals suffering from pneumonia caused by SARS-CoV-2 or a variant thereof.

[0270] In one embodiment, said improvement in respiratory function in said individuals means a reduction, delay in the occurrence of, or prevention of the need for supplemental oxygen, the use of mechanical ventilation, or admission to an intensive care unit.

[0271] As used herein, the term "SARS-CoV-2 or variant pneumonia" refers to an inflammatory lung condition associated with infection with SARS-CoV-2 or its variant. It is a severe complication of COVID-19 that affects a certain percentage of individuals.

[0272] In one embodiment, the liquid suspension according to any of the above-described embodiments of the first objective of the invention for use in the treatment of COVID-19 is administered in combination with standard treatment for patients with COVID-19.

[0273] As used herein, "standard of care for patients with COVID-19" means a pharmacological treatment that includes one or more drugs that have been approved by regulatory authorities i) as a treatment for COVID-19 or ii) as a treatment for other pathological conditions and their symptoms and that are used in clinical practice as a treatment for the symptoms and complications associated with COVID-19.Preferably, said standard of treatment consists of treating the patient with at least one drug selected from: i) antiviral drugs, preferably remdesivir; ii) antipyretic, analgesic and anti-inflammatory drugs, preferably non-steroidal anti-inflammatory drugs, corticosteroids, cytokine, chemokine and interleukin inhibitors, more preferably selected from dexamethasone, paracetamol, anakinra, celecoxib, prednisone, prednisolone, methylprednisolone, pyrirone and tramadol; iii) antibiotics, preferably selected from piperacillin in combination with tazobactam, azithromycin and ceftriazone; and iv) anticoagulants and antithrombotic agents, preferably selected from enoxaparin and acetylsalicylic acid.

[0274] It is preferred that the specified individuals suspected of pneumonia caused by SARS-CoV-2 or its variant have lymphocytopenia.

[0275] According to a preferred embodiment, said individuals with lymphocytopenia are adult patients (14 years of age and older) and have a blood lymphocyte concentration of below 1000, below 900, below 850, below 800, or below 750 cells / microliter.

[0276] According to another preferred embodiment, said patients with lymphocytopenia are pediatric patients (under 14 years of age) and have a blood lymphocyte concentration of below 3000, below 2800, below 2500, below 2300, or below 2000 cells / microliter.

[0277] Another object of the present invention is a liquid suspension according to any of the above-described embodiments of the first object of the invention for use in the prevention or treatment of seizures in an individual.

[0278] According to a preferred embodiment, said seizures are acute symptomatic seizures (ASS).

[0279] According to another preferred embodiment, said seizures are associated with diagnosed epilepsy (diagnosed epileptic seizures EES).

[0280] In one embodiment, also in combination with any of the embodiments described above, the liquid suspension for use in accordance with the present invention is a ready-to-use liquid suspension, namely, a suspension already distributed in a liquid carrier. Said liquid suspension can be single-dose, i.e., intended for a single administration, or multi-dose, i.e., intended for more than one administration.

[0281] In one embodiment, also in combination with any of the above-described embodiments, the liquid suspension for use according to the present invention is administered orally to an individual, preferably a mammal, even more preferably a human.

[0282] The invention is further described in the following examples, which do not limit the scope of the invention as defined in the claims.

[0283] EXAMPLES

[0284] All percentages shown in the tables below are %w / w.

[0285] Example 1 - Preparation of suspensions containing reparixin

[0286] Several suspensions containing reparixin were prepared. All suspensions contained at least the following excipients:

[0287] - viscosity modifier, which regulates the viscosity of the composition to achieve optimal rheological properties;

[0288] - a wetting agent which is necessary to increase the wettability of reparixin in water which is low in itself;

[0289] - a sweetener used to mask the unpleasant taste of reparixin;

[0290] - antifoaming agent, which is used to prevent and / or slow down the formation of foam on the surface of the suspension;

[0291] - a preservative used to prevent or retard microbial growth.

[0292] - a buffering agent which is used to maintain the pH of the suspension at a level of 4 to 6, preferably 4.5 to 5.5, more preferably 5.

[0293] The materials used to prepare the suspensions are listed in Table 1.

[0294] Table 1

[0295] Trade name Chemical name Supplier Sucrose Compri O Sucrose Südzucker Sucralose Sucralose Merck-Millipore Potassium sorbate Potassium sorbate Merck-Millipore Avicel CL-611 Microcrystalline cellulose + sodium carboxymethyl cellulose Dupont Xantural 75 Xanthan gum Kelco Kolliphor SLS Sodium lauryl sulfate Basf Kolliphor P188 (Poloxamer 188) polyoxyethylene-polyoxypropylene copolymer, average MM 7608-9510 Basf Kollidon 30 Polyvinylpyrrolidone Basf Kolliphor P407 (Poloxamer 407) polyoxyethylene-polyoxypropylene copolymer, average MM 9840-14600 Basf Simethicone Silicone antifoaming agent Wacker Citric acid monohydrate Citric acid monohydrate Merck Millipore Sodium citrate dihydrate Sodium citrate dihydrate Sigma-Aldrich Kollidon CL-M (crospovidone) 1-ethenyl-2-pyrrolidinone homopolymer Basf

[0296] The type and / or amount of the following components varied among suspensions:

[0297] - viscosity modifier. In particular, xanthan gum and Avicel CL-611 were tested as viscosity modifiers. Avicel CL-611 is a spray-dried mixture of microcrystalline cellulose and sodium carboxymethylcellulose, where sodium carboxymethylcellulose is present in an amount of 11.3% w / w to 18.8% w / w;

[0298] - wetting agent. Specifically, sodium lauryl sulfate (SLS), Poloxamer 407, Poloxamer 188, and polyvinylpyrrolidone (PVP) were tested as wetting agents. Poloxamer 407 was excluded due to its insufficient ability to disperse reparixin;

[0299] - sweetener. Specifically, sucrose and sucralose were used as sweeteners. Sucrose has a high glycemic index, while sucralose is an artificial sweetener with a zero glycemic index.

[0300] The procedure used to prepare the suspensions is described below.

[0301] Selected amounts of antifoam, wetting agent, preservative, and buffering agents were added to 40 g of distilled water, and the mixture was stirred magnetically until a solution was obtained. Then, the selected amount of reparixin was added and dispersed. After the API was homogeneously suspended, selected amounts of other excipients (viscosity modifier, sweetener, and anticaking agent, if present) were added and dissolved. Finally, water was added to a final weight of 100 g.

[0302] The composition of the obtained liquid suspensions is described below, while the corresponding characterization data are presented in Examples 2 and 3.

[0303] Table 2 below shows the liquid suspensions obtained using SLS as a wetting agent. Specifically, the resulting suspensions contained 0.11% w / w SLS, 40% w / w sucrose as a sweetener, 0.15% w / w potassium sorbate as a preservative, citric acid monohydrate and sodium citrate dihydrate as buffering agents, 0.005% w / w simethicone as an antifoaming agent, and water as a solvent.

[0304] The type / amount of viscosity modifier (xanthan gum or Avicel CL-611) and the amount of buffering agent used varied among the suspensions obtained.

[0305] Table 2

[0306] Suspension 41 55 56 57 58 59 Reparixin 5,00% 5,00% 5,00% 5,00% 5,00% 5,00% Sucrose 40,00% 40,00% 40,00% 40,00% 40,00% 40,00% Potassium sorbate 0,15% 0,15% 0,15% 0,15% 0,15% 0,15% Viscosity modifier Avicel CL-611 1.00% Xanthan gum 0.10% Xanthan gum 0.25% Avicel CL-611 1.00% Avicel CL-611 1.00% Avicel CL-611 1.00% Citric acid monohydrate 0,064% 0,064% 0,064% 0,320% 0,640% 1,240% Sodium citrate dihydrate 0,208% 0,208% 0,208% 1,040% 2,080% 4,140% Simethicone 0,005% 0,005% 0,005% 0,005% 0,005% 0,005% SLS 0,11% 0,11% 0,11% 0,11% 0,11% 0,11% Water Up to 100% Up to 100% Up to 100% Up to 100% Up to 100% Up to 100%

[0307] Table 3 below shows the liquid suspensions prepared using Poloxamer 188 as a wetting agent in combination with xanthan gum as a viscosity modifier. The suspensions contained 0.15% w / w potassium sorbate as a preservative, 0.064% w / w citric acid monohydrate and 0.208% w / w sodium citrate dihydrate as buffering agents, 0.005% w / w simethicone as an antifoaming agent, and water as a solvent.

[0308] The amounts of Poloxamer 188 and xanthan gum varied among the resulting suspensions, as did the type / amount of sweetener (sucrose or sucralose).

[0309] Table 3

[0310] Suspension 73 74 82 83 84 89 Reparixin 5,00% 5,00% 5,00% 5,00% 5,00% 5,00% Sweetener Sucrose 40.00% Sucrose 40.00% Sucrose 40.00% Sucralose 0.06% / Sucrose 20.00% Potassium sorbate 0,15% 0,15% 0,15% 0,15% 0,15% 0,15% Xanthan gum 0,20% 0,40% 0,40% 0,40% 0,40% 0,40% Citric acid monohydrate 0,064% 0,064% 0,064% 0,064% 0,064% 0,064% Sodium citrate dihydrate 0,208% 0,208% 0,208% 0,208% 0,208% 0,208% Simethicone 0,005% 0,005% 0,005% 0,005% 0,005% 0,005% Poloxamer 188 0,25% 0,25% 0,50% 0,50% 0,50% 0,50% Water Up to 100% Up to 100% Up to 100% Up to 100% Up to 100% Up to 100%

[0311] Table 4 below shows the liquid suspensions prepared 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.

[0312] The amounts of Avicel CL-611 and the type / amount of buffer (citric acid monohydrate / sodium citrate dihydrate or citric acid monohydrate / 1 M NaOH) varied among the different suspensions prepared.

[0313] In addition to the suspensions described 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.

[0314] Table 4

[0315] Suspension 68 69 70 71 72 78 79 Reparixin 5,00% 5,00% 5,00% 5,00% 5,00% 5,00% 5,00% Sucrose 40,00% 40,00% 40,00% 40,00% 40,00% 40,00% 40,00% Potassium sorbate 0,15% 0,15% 0,15% 0,15% 0,15% 0,15% 0,15% Avicel CL-611 1,00% 1,00% 1,00% 1,00% 1,00% 2,00% 3,00% Citric acid monohydrate 0,320% 0,10% 0,40% 0,40% 0,40% 0,064% 0,064% Other buffering agent Sodium citrate dihydrate 1.040% 1 M NaOH 0.03% 1 M NaOH 0.06% 1 M NaOH 0.126% 1 M NaOH 0.162% Sodium citrate dihydrate 0.208% Sodium citrate dihydrate 0.208% Simethicone 0,005% 0,005% 0,005% 0,005% 0,005% 0,005% 0,005% Poloxamer 188 0,25% 0,25% 0,25% 0,25% 0,25% 0,25% 0,25% Water Up to 100% Up to 100% Up to 100% Up to 100% Up to 100% Up to 100% Up to 100%

[0316] Table 5 below describes the liquid suspensions obtained using polyvinylpyrrolidone as a wetting agent in combination with xanthan gum as a viscosity modifier. Specifically, the obtained suspensions contained 2.00% w / w PVP K 30 as a wetting agent, xanthan gum, 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, 0.064% w / w citric acid monohydrate and 0.208% w / w sodium citrate dihydrate as buffering agents, and water as a solvent.

[0317] The amounts of xanthan gum varied among the suspensions, as did the amounts of crospovidone used as an anti-caking agent (from 0% w / w to 2.50% w / w).

[0318] Table 5

[0319] Suspension 91 93 98 105 106 107 Reparixin 5,00% 5,00% 5,00% 5,00% 5,00% 5,00% Sucrose 40,00% 40,00% 40,00% 40,00% 40,00% 40,00% Potassium sorbate 0,15% 0,15% 0,15% 0,15% 0,15% 0,15% Xanthan gum 0,40% 0,40% 0,20% 0,20% 0,20% 0,20% Citric acid monohydrate 0,064% 0,064% 0,064% 0,064% 0,064% 0,064% Sodium citrate dihydrate 0,208% 0,208% 0,208% 0,208% 0,208% 0,208% Simethicone 0,005% 0,005% 0,005% 0,005% 0,005% 0,005% PVP K 30 2,00% 2,00% 2,00% 2,00% 2,00% 2,00% Crospovidone / 2,50% 2,50% 0,50% 1,50% 2,00% Water Up to 100% Up to 100% Up to 100% Up to 100% Up to 100% Up to 100%

[0320] Table 6 describes the liquid suspensions obtained using polyvinylpyrrolidone as a wetting agent in combination with Avicel-CL611 as a viscosity modifier. Specifically, the obtained suspensions 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 sweetener, 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.

[0321] The amounts of Avicel CL-611 and the amount of crospovidone used as an anti-caking agent (0% w / w to 1% w / w) varied among the suspensions obtained.

[0322] Table 6

[0323] Suspension 99 104 108 Reparixin 5,00% 5,00% 5,00% Sucrose 40,00% 40,00% 40,00% Potassium sorbate 0,15% 0,15% 0,15% Avicel CL-611 1,00% 1,00% 2,00% Citric acid monohydrate 0,064% 0,064% 0,064% Sodium citrate dihydrate 0,208% 0,208% 0,208% Simethicone 0,005% 0,005% 0,005% PVP K 30 2,00% 2,00% 2,00% Crospovidone / 1,00% / Water Up to 100 Up to 100 Up to 100

[0324] Finally, the effect of the type and amount of sweetener included in suspensions containing PVP as a wetting agent and crospovidone as an anticaking agent was further investigated.

[0325] Table 7 describes the liquid suspensions prepared using 2.00% w / w PVP K 30, 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 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.

[0326] The type / amount of sweetener (sucrose or sucralose) varied among the suspensions obtained.

[0327] Table 7

[0328] Suspension 165 159 160 166 168 Reparixin 5,00% 5,00% 5,00% 5,00% 5,00% Sweetener Sucrose 20.00% Sucrose 30.00% Sucrose 50.00% Sucrose 60.00% Sucralose 0.60% Potassium sorbate 0,15% 0,15% 0,15% 0,15% 0,15% Xanthan gum 0,20% 0,20% 0,20% 0,20% 0,20% Citric acid monohydrate 0,064% 0,064% 0,064% 0,064% 0,064% Sodium citrate dihydrate 0,208% 0,208% 0,208% 0,208% 0,208% Simethicone 0,005% 0,005% 0,005% 0,005% 0,005% PVP K30 2,00% 2,00% 2,00% 2,00% 2,00% Crospovidone 2,50% 2,50% 2,50% 2,50% 2,50% Water Up to 100% Up to 100% Up to 100% Up to 100% Up to 100%

[0329] Example 2 - Determination of zeta potential and rheological properties

[0330] The zeta potential values ​​and rheological properties of the liquid suspensions described in Example 1 were determined to evaluate their stability.

[0331] Reparixin is an insoluble active pharmaceutical ingredient with a large particle size, forming coarse suspensions. Due to its large particle size, suspension stability is determined by gravitational forces rather than electrostatic interactions, which are insufficient to ensure stability and kinetic stabilization. To ensure the stability of suspensions containing reparixin, the zeta potential must be equal to or close to zero, and the internal phase particles must be surrounded by a hydration layer that masks their charge and ensures that even if sedimentation occurs, it will be a loose sediment that is easily resuspended, rather than a dense sediment that is difficult to resuspend. An increase in the zeta potential (in absolute value) corresponds to a state in which this hydration layer surrounding the internal phase particles is present in smaller quantities or is absent, resulting in an increased sedimentation rate.

[0332] Regarding the rheological properties, the yield stress and thixotropy of the resulting suspensions were determined to obtain information on the physical stability of the suspensions. 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), which can be defined as the stress exerted by a particle on the liquid. If τ0 is higher than τS, sedimentation will not occur, and the suspension can be considered stable. Generally, a yield stress of approximately 8 Pa or more is considered good anti-sedimentation value for ready-to-use liquid suspensions as final formulations.

[0333] The physical stability of a suspension is also assessed based on the thixotropy hysteresis area. Thixotropy is a mandatory property of a polymer system selected as a viscosity modifier. Indeed, the stability (e.g., viscosity) of the external phase provided by the suspending agent must decrease upon application of shear stress, such as manual shaking, to ensure redispersibility of the sediment. In the literature, the thixotropy area is usually correlated with suspension stability. As E.C. Foernzler showed, the sedimentation rate is directly proportional to the reciprocal of the hysteresis area, which means that physical stability is directly proportional to thixotropy (Ernest C. Foernzler et al., J. Am. Pharm. Assoc. 49 (1960) 249-252).

[0334] Based on the above, the obtained suspensions were characterized in terms of zeta potential value, rheological properties and redispersibility.

[0335] The zeta potential values ​​of the obtained suspensions were measured by laser Doppler electrophoresis using a Zetasizer nano ZS (Malvern Instruments, Worcestershire, UK) according to the manufacturer's instructions.

[0336] Rheological properties such as yield strength and thixotropy (hysteresis) were evaluated using an MCR 102 rheometer (Anton Paar, Graz, Austria).

[0337] The yield strength was determined by linearly increasing the shear rate in a stepwise manner from 0.1 to 100 s -1 to obtain a flow curve (shear stress versus shear rate). The resulting flow curve was then fitted to the Herschel-Bulkley regression model, and the yield strength was determined by extrapolating the flow curve to zero shear rate.

[0338] The thixotropy of the suspensions was assessed using hysteresis. This measurement was performed using an initial pre-shear at 5 1 / s, followed by an ascending flow curve increasing the shear rate from 5 to 131 s -1 (logarithmic scale), and the downward flow curve was obtained by decreasing the shear rate from 131 to 5 s -1 The area between the ascending and descending curves was calculated and correlated with the system's thixotropy. All analyses were performed at room temperature using a 25 mm measuring plate and a 1 mm gap setting.

[0339] If sediment was present, the redispersibility was assessed by taking into account the number of 180° rotations that allowed the sediment to be redispersed.

[0340] Table 8 below shows the zeta potential values ​​and rheological properties obtained for the suspensions listed in Table 2 above.

[0341] Table 8

[0342] Suspension Zeta potential (mV) Yield strength (Pa) Relative hysteresis area (|Pa / s|) Redispegging after storage for 1 month (number of rotations by 180°) 41 -13,63 0,00 281,31 > 30 (the sediment was redispersed only after vigorous shaking by hand) 55 -21,3 1,64 190,95 10 56 -17,6 1,81 84,18 5 57 -13,5 0,19 43,39 3 58 -10,57 0,68 26,172 3 59 -7,46 0,00 2,26 2

[0343] As can be seen, the zeta potential values ​​of suspensions with 0.11% w / w SLS as a wetting agent were too high in absolute value to ensure suspension stability. Increasing the concentration of citrate buffer (sodium citrate dihydrate + citric acid monohydrate) slightly decreased the absolute zeta potential value, which, however, was still too high. Based on these results, SLS was excluded as a wetting agent due to its inability to form stable reparixin suspensions.

[0344] Table 9 below shows the zeta potential values ​​and rheological properties obtained for the suspensions listed in Table 3 above.

[0345] Table 9

[0346] Suspension Zeta potential (mV) Yield strength (Pa) Relative hysteresis area (|Pa / s|) Redispegging after storage for 1 month (number of rotations by 180°) 73 -0,43 1,06 104,96 20 (vigorous manual shaking is required to redisperse the sediment) 74 -0,23 14,30 1376,90 No sediment 82 -0,5 14,00 760,6 No sediment 83 -21,2 2,56 153,9 20 84 -15,96 NA NA 30 89 -3,37 NA NA 10

[0347] As can be seen, suspensions 73, 74, and 82, which contained Poloxamer 188 and 40% w / w sucrose, had zeta potential values ​​near zero. However, when the percentage of sucrose was reduced (suspensions 84, without sucrose, and 89, with 20.00% w / w sucrose) or when sucrose was replaced with sucralose (suspension 83), the absolute value of the zeta potential increased.

[0348] This trend indicated an unexpected influence of the type and amount of sweetener included in the formulation on the zeta potential of the suspension and, consequently, its stability. As demonstrated, the amount of sucrose significantly influenced the zeta potential and rheological properties. Indeed, increasing the amount of sucrose (from 0% w / w to 40% w / w) resulted in a decrease in the absolute value of the zeta potential.

[0349] Without being tied to a theory or principle, this trend can be explained by the unexpected formation of a sucrose hydration layer surrounding the suspended particles, which increases the distance between ions (cations and anions), thereby reducing the absolute value of the zeta potential. This hydration layer ensures that, even if a precipitate forms, it is easily resuspended by manual shaking, as it is loose and not dense. At the same time, increasing the sucrose concentration led to an increase in both the yield stress and the hysteresis area, indicating increased suspension stability.

[0350] In terms of rheological properties, suspensions 74 and 82 showed the best values ​​in terms of yield strength and relative hysteresis area.

[0351] Even though suspension 74 exhibited a zeta potential near zero and had suitable yield stress and hysteresis area values, it was excluded due to the presence of suspended aggregates that persisted over time. Suspension 82 was further characterized using frequency sweep analysis, as described in Example 3.

[0352] Table 10 below presents the zeta potential values ​​and rheological properties obtained for the suspensions described in Table 4 above and the suspension 80 described above.

[0353] Table 10

[0354] Suspension Zeta potential (mV) Yield strength (Pa) Relative hysteresis area (|Pa / s|) Redispegging after storage for 1 month (number of rotations by 180°) 68 -1,30 0,84 48,173 >20 (vigorous manual shaking is required to redisperse the sediment) 69 -1,60 <0,01 3,20 20 70 -1,10 <0,01 45,91 >20 (vigorous manual shaking is required to redisperse the sediment) 71 -1,10 0,40 86,88 10 72 -0,96 0,00 21,70 8 78 -1,26 5,09 99,69 NA 79 -1,6 5,88 1205,70 NA 80 -0,83 3,04 46,79 Non-redispersible sediment

[0355] As can be seen, all suspensions listed in Table 4 demonstrated zeta potential values ​​near zero, confirming that the use of 40% sucrose as a sweetener enabled this trend to be achieved. However, all suspensions had yield stress values ​​that were too low for a ready-to-use liquid suspension as the final formulation. Based on these results, the use of Avicel CL-611 as a viscosity modifier was excluded. The use of this viscosity modifier resulted in a suspension with inadequate rheological properties in terms of yield stress and hysteresis loop (thixotropy).

[0356] Table 11 presents the zeta potential values ​​and rheological properties obtained for the suspensions described in Table 5 above.

[0357] Table 11

[0358] Suspension Zeta potential (mV) Yield strength (Pa) Relative hysteresis area (|Pa / s|) Redispegging after storage for 1 month (number of rotations by 180°) 91 -2,37 8,92 951,16 NA (No sediment - presence of suspended aggregate) 93 -0,13 20,06 894,08 NA (No sediment - dispersion was too viscous) 98 -0,60 10,25 612,760 NA (No sediment) 105 -0,66 2,30 62,70 NA (No sediment) 106 -1,03 8,82 109,54 NA (No sediment) 107 -0,53 8,45 158,2 NA (No sediment)

[0359] As can be seen, when 40% sucrose was used as a sweetener with PVP K 30 as a wetting agent, suspensions with zeta potential values ​​near zero were obtained, thus confirming the trend of the results reported regarding the role of sucrose in stabilizing the zeta potential values ​​of suspensions. The addition of crospovidone as an anticaking agent improved the rheological properties of the suspensions, particularly at high percentages (suspensions 93 and 98 containing 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). When the amount of xanthan gum was reduced to 0.20% w / w, this problem was solved and the suspension was easy to handle.

[0360] Table 12 presents the zeta potential values ​​and rheological properties obtained for the suspensions described in Table 6 above.

[0361] Table 12

[0362] Suspension Zeta potential (mV) Yield strength (Pa) Relative hysteresis area (|Pa / s|) Redispegging after storage for 1 month (number of rotations by 180°) 99 -0,30 4,14 1542,2 5 (Continuous presence of floating foam at time t0, as well as after 1 month) 104 This suspension was not characterized due to the constant presence of floating foam (reparixin was not completely wetted) 108 -1,30 0,23 40,97 NA (Non-stop floating foam)

[0363] As can be seen, the use of Avicel CL-611 as a viscosity modifier in combination with PVP K 30 as a wetting agent resulted in suspensions with unsuitable rheological properties.

[0364] Table 13 below presents the zeta potential values ​​and rheological properties obtained for the suspensions described in Table 7 above.

[0365] Table 13

[0366] Suspension Zeta potential (mV) Yield strength (Pa) Relative hysteresis area (|Pa / s|) Appearance 165 -7,42 1,48 36,057 Uniform appearance, presence of foam on the surface 159 -2,58 11,70 395,70 Uniform appearance 160 -1,26 8,72 2519,4 Uniform appearance 166 -0,068 0,00 4791,7 Uniform appearance, presence of a constant layer of foam on the surface 168 -5,77 0,43 23,447 Uniform appearance, presence of a constant layer of foam on the surface

[0367] This experiment was conducted to further investigate and confirm the influence of the type / amount of the selected sweetener on the stabilization of the zeta potential values ​​of the suspensions. As can be seen, when 20% w / w sucrose was used as a sweetener (suspension 165), the absolute zeta potential value was too high and the yield point was too low, indicating that the resulting suspension was not stable. The same trend was observed when 0.60% sucralose was used as a sweetener (suspension 168).

[0368] When 60% w / w (suspension 166) was used as a sweetener, a constant foam layer was observed on the surface.

[0369] When 30% w / w and 50% w / w sucrose were used as a sweetener (suspensions 159 and 160, respectively), suspensions with a zeta potential of about zero and suitable rheological properties were obtained.

[0370] These results confirmed the unexpected impact of the type and amount of sweetener added to the reparixin suspension to mask the unpleasant taste on the zeta potential values ​​and rheological properties, and consequently on the stability of the suspension. Specifically, based on these results, sucralose and amounts of 20% w / w and 60% w / w sucrose were excluded from the preparation of stable liquid suspensions of reparixin.

[0371] Example 3 - Frequency Response Analysis

[0372] Frequency sweep analysis is used to predict the long-term physical stability of suspensions. Specifically, frequency sweeps are used to describe the time-dependent behavior of suspensions in the non-destructive strain range (e.g., the linear viscoelastic region previously determined by amplitude analysis). High frequencies are used to simulate rapid motion on short time scales, while low frequencies simulate slow motion on long time scales. The storage modulus can be used as a measure of the elastic (solid-like) component of a sample, while the loss modulus is considered the viscous (fluid-like) component of the sample. Whichever modulus is dominant at a particular frequency will indicate whether the fully structured material will be elastic or viscous.When the storage modulus is higher than the loss modulus, the suspension has more elasticity than viscosity, meaning it behaves like a solid, and in this state, sedimentation is unlikely to occur (suspension stability). On the other hand, when the viscous modulus is higher than the elastic modulus, sedimentation may occur.

[0373] Frequency sweep analysis was performed using an MCR 102 rheometer (Anton Paar, Graz, Austria). The frequency sweep analysis was performed at decreasing angular frequencies (from 62.8 to 0.0628 rad / s, corresponding to 10-0.01 Hz) and constant strain, which was selected in the LVER (linear viscoelastic region) using oscillatory measurements. All analyses were performed at room temperature using a 25 mm measuring plate and a gap setting of 1 mm.

[0374] Figures 2 (suspension 98) and 3 (suspension 105) show the frequency sweep profiles of the systems in which the storage modulus is higher than the loss modulus, suggesting that these suspensions are stable over time. In addition, both suspensions are characterized by a storage modulus value recorded at low frequency (approximately 0.1 rad / s) above 10 Pa, suggesting possible dispersion stability (T.G. Mezger, “The Rheology Handbook,” 2nd Ed., Vincentz Network, Hannover, 2006). Figures 2 and 3 show an increase in both the loss modulus and the storage modulus with decreasing frequency values, suggesting that the corresponding suspensions may become more structured and packed over time.

[0375] As for suspension 105, despite a good frequency sweep profile, it was characterized by low yield strength and hysteresis region values ​​(Table 11 above). Figure 7 (suspension 159) and Figure 8 (suspension 160) show profiles associated with a system in which the storage modulus dominates over the loss modulus, suggesting the stability of the suspension, even though at low frequencies the difference between the loss modulus and storage modulus becomes smaller.

[0376] Fig. 1 (suspension 82), Fig. 5 (suspension 107) and Fig. 9 (suspension 166) are associated with systems in which, at high frequency values ​​(from 10 to 100 rad / s), the loss modulus is higher than the storage modulus, which indicates possible instability of the suspension, which may occur during short-term storage.

[0377] Figs. 4, 6 and 10 (suspensions 106, 165 and 168) are associated with systems in which, at low frequency values, the loss modulus is higher than the storage modulus, which indicates a possible sedimentation phenomenon over time (during long-term storage).

Claims

1. Liquid suspension for the prevention or treatment of pathologies mediated by interleukin 8 (IL-8) receptors, containing: - reparixin in an amount from 2 to 13 wt.%, - xanthan gum in an amount of 0.15 to 0.3 wt.%, - sucrose in an amount from 25 to 55 wt.%, - polyvinylpyrrolidone in an amount from 1.8 to 3.2 wt.%, - a water-insoluble polymer selected from microcrystalline cellulose and crospovidone in an amount of 2.25 to 2.75 wt.%.

2. A liquid suspension according to claim 1, containing reparixin in an amount of 4 to 13 wt.%.

3. A liquid suspension according to claim 1 or 2, wherein said water-insoluble polymer is crospovidone, which is preferably contained in an amount of 2.5% by weight.

4. A liquid suspension according to any one of the preceding claims, further comprising an antifoaming agent, preferably a silicone derivative.

5. The liquid suspension according to claim 4, wherein said antifoaming agent is selected from: - dimethicone, which is contained in an amount of 0.5 to 5 wt.%, and - simethicone, which is contained in an amount of 0.003 to 0.006 wt.%, preferably in an amount of 0.005 wt.%.

6. A liquid suspension according to any one of the preceding claims, further comprising a buffering agent, preferably selected from a citrate buffer and a phosphate buffer.

7. The liquid suspension according to claim 6, wherein said buffering agent is a citrate buffer containing citric acid monohydrate in an amount of 0.06 to 0.6 wt.%, preferably in an amount of 0.064 wt.%, and sodium citrate dihydrate in an amount of 0.2 to 0.3 wt.%, preferably in an amount of 0.208 wt.%.

8. A liquid suspension according to any one of the preceding claims, further containing a preservative, preferably selected from potassium sorbate, sodium benzoate, methylparabens and propylparabens.

9. The liquid suspension according to claim 8, wherein said preservative is potassium sorbate, which is contained in an amount of 0.1 to 0.2 wt.%, preferably in an amount of 0.15 wt.%.

10. A liquid suspension according to any one of the preceding claims, wherein the amount of reparixin is from 2 to 5.5 wt.%, preferably from 3 to 5.5 wt.%, more preferably from 4.5 to 5.5 wt.%, more preferably from 4.7 to 5.3 wt.%, more preferably from 4.9 to 5.1 wt.%, even more preferably 5 wt.%.

11. A liquid suspension according to any one of claims 1 to 9, wherein the amount of reparixin is from 11.5 to 12.5 wt.%, preferably from 11.7 to 12.3 wt.%, more preferably from 11.9 to 12.1 wt.%, even more preferably 12 wt.%.

12. A liquid suspension according to claim 10, containing: - xanthan gum in the amount of 0.2 wt.%, - polyvinylpyrrolidone in an amount of 2 wt.%.

13. A liquid suspension according to claim 11, containing: - xanthan gum in the amount of 0.2 wt.%, - polyvinylpyrrolidone in an amount of 3 wt.%.

14. A liquid suspension according to any of the preceding claims, further containing an aqueous solvent, preferably water, in an amount of up to 100% by weight.

15. A liquid suspension according to any one of the preceding claims, wherein the pathology mediated by interleukin 8 (IL-8) receptors is 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 a variant thereof, diabetes, preferably type I diabetes, or seizures in an individual.

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