Repalysin liquid suspension

Abstract

The present invention relates to a stable, ready-to-use repalysin liquid suspension and a use thereof.

Description

Technical Field

[0001] The present invention relates to a liquid suspension comprising Reparixin. Background Art

[0002] Reparixin, also known as R-(-)-2-(4-isobutylphenyl)propionyl methanesulfonamide 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 in preventing or treating pathological conditions in which activation of this pathway is detrimental.

[0003] For example, IL-8 is involved in neutrophil infiltration in pathological conditions 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 (P.C. Carré 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 studies have shown that the binding of Reparixin to CXCR1 / CXCR2 can prevent leukocyte recruitment and inflammatory activation. The effects of Reparixin include inhibition of neutrophil stimulation and downstream effects of neutrophils during inflammatory responses, such as NETosis and NET formation (Cheng OZ, Palaniyar N., Front Immunol. 2013; 4: 1).

[0005] The dosage, safety, and pharmacokinetics of reparixin have been studied in clinical studies 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).

[0006] From May 5, 2020 to November 27, 2020, a Phase 2, multicenter, open-label, randomized clinical trial was conducted 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, which showed that treatment with Reparixin 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] Currently, Reparixin is formulated only in the form of tablets for oral administration or solutions for iv administration. However, these types of administration are invasive and / or unsuitable for achieving satisfactory patient compliance, especially in the case of pediatric patients or patients who cannot swallow solid tablets. Therefore, there is a need to develop new pharmaceutical dosage forms containing Reparixin that can overcome these problems and can be administered to subjects of all conditions and ages. For this purpose, suspensions are ideal candidates.

[0008] A suspension is a pharmaceutical dosage form with two phases: an external liquid phase, also called a continuous phase or dispersion medium; and an internal phase, also called a dispersed phase, which contains particulate matter that is insoluble in the external phase. Suspensions are considered multiphase dispersed systems, and most pharmaceutical suspensions have an aqueous dispersion medium.

[0009] The preparation and distribution of this type of dosage form is associated with several advantages: efficient distribution of hydrophobic drugs; avoiding the use of co-solvents; masking unpleasant taste; providing resistance to drug degradation due to hydrolysis, oxidation or microbial activity; easy ingestion by young or elderly patients. In addition, higher concentrations of drugs can be incorporated into suspensions than in solutions (Doye, P. et al., Int J Curr Pharm Sci 2017, 9, 8).

[0010] The main challenge in developing suspensions is to ensure their physical stability over time to ensure uniformity of content. In fact, suspensions are thermodynamically unstable systems due to the free energy of the internal phase of the suspension, which produces particle aggregation and sedimentation to reduce the energy of the system. Several aspects must be considered when formulating suspensions.

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

[0012] Due to the specific characteristics of Reparixin, the preparation of suspensions containing this active pharmaceutical ingredient (API) is particularly difficult.

[0013] First, Reparixin is produced in a powder form consisting of particles having a large particle size. Therefore, a potential suspension containing Reparixin is a coarse suspension.

[0014] In the case of a coarse suspension, the internal phase containing the API tends to settle under gravity and causes sedimentation due to its particle size. The increase in zeta potential (in terms of absolute value) causes an increase in sedimentation rate. This shows that sedimentation is driven by gravity rather than electrostatic interaction, which is insufficient to provide stability and kinetic stability due to the particle size of the internal phase. For this reason, the zeta potential value of a coarse suspension is generally set to about zero to ensure physical stability. The zeta potential value corresponds to a situation in which particles are surrounded by a hydration layer, which hides their charge and can prevent the formation of a dense precipitate and on the contrary promote the formation of a loose precipitate in the case of particle aggregation and sedimentation, which can be easily resuspended by manual shaking. In order to adjust the zeta potential value of a suspension, ionic or nonionic surfactants and different types of electrolytes (such as salts) are generally used. For example, for this purpose, PEG (polyethylene glycol) is included in many commercial suspensions.

[0015] In addition, Reparixin has low wettability, which makes it complicated to be formulated into a stable liquid suspension. In fact, the wettability of dispersed particles is very important for ensuring homogeneity and content uniformity (Kwok, DYet al., Advances in Colloid and Interface Science 1999, 81, 167-249). Wettability refers to the tendency of a fluid to diffuse or adhere to a solid surface when the fluid is immiscible with the solid surface; the result of poor wettability of a powdered solid is that it floats on the surface of a liquid medium. The poor wettability of the internal phase is mainly due to the high interfacial tension between the dispersed particles and the dispersion medium, and the reduction of the interfacial tension improves the stability of the suspension. When preparing a suspension, a common way to improve the wettability of a solid is to use a wetting agent (e.g., a surfactant), which can reduce the solid-liquid interfacial tension.

[0016] Another prerequisite necessary to ensure the stability of the suspension is the presence of the so-called yield stress (τ0), which is a property of the substance and can be defined as the stress corresponding to the yield point at which the substance starts to flow or deform plastically.

[0017] In view of the above, there is a clear need to develop suspensions containing Reparixin with desirable characteristics. However, this is particularly challenging for this API for the reasons discussed above. Summary of the invention

[0018] The present inventors have developed a stable liquid suspension of Reparixin.

[0019] In particular, the present inventors have found that the use of sucrose as a sweetener and polyvinylpyrrolidone as a wetting agent in the formulation allows for the production of a stable, ready-to-use liquid suspension of Reparixin.

[0020] In particular, the inventors have surprisingly found that the type and amount of sweetener included in the formulation to mask the unpleasant taste of Reparixin affects the zeta potential value of the suspension and, therefore, its stability. Furthermore, the inventors have determined that the use of polyvinylpyrrolidone as a wetting agent allows obtaining satisfactory wettability of Reparixin.

[0021] The present inventors have also determined the type and range of viscosity agents to be used in combination with the above excipients to achieve a stable, ready-to-use liquid suspension of Reparixin.

[0022] One object of the present invention is therefore a liquid suspension comprising:

[0023] - Reparixin in an amount of 2% w / w to 13% w / w,

[0024] - xanthan gum in an amount of 0.15% w / w to 0.3% w / w,

[0025] - sucrose in an amount of 25% w / w to 55% w / w,

[0026] - polyvinylpyrrolidone in an amount of 1.8% w / w to 3.2% w / w,

[0027] - A water insoluble polymer in an amount of 2.25% w / w to 2.75% w / w.

[0028] Another object of the present invention is a liquid suspension according to the first object of the present invention, for use in treating a disease or condition selected from the group consisting of psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome (ARDS), idiopathic fibrosis, glomerulonephritis, COVID-19.

[0029] Another object of the invention is a liquid suspension according to the first object of the invention for use in preventing diabetes or delaying the onset and progression of diabetes.

[0030] Another 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 epileptic seizures. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 A frequency scan spectrum of suspension 82 is shown.

[0032] Figure 2 A frequency scan spectrum of suspension 98 is shown.

[0033] Figure 3 A frequency scan spectrum of suspension 105 is shown.

[0034] Figure 4 A frequency scan spectrum of the suspension 106 is shown.

[0035] Figure 5 A frequency scan spectrum of suspension 107 is shown.

[0036] Figure 6 The frequency scan spectrum of suspension 165 is shown.

[0037] Figure 7 The frequency scan spectrum of suspension 159 is shown.

[0038] Figure 8 A frequency scan spectrum of suspension 160 is shown.

[0039] Fig. 9 A frequency scan spectrum of suspension 166 is shown.

[0040] Fig.10 A frequency scan spectrum of suspension 168 is shown.

[0041] definition

[0042] As used herein, the term "antifoaming agent" refers to a chemical additive that reduces and / or hinders the formation of foam in liquid formulations (eg, liquid suspensions) by lowering the liquid-air surface tension.

[0043] The term "anti-caking agent" as used herein refers to an excipient that helps stabilize the suspension and improves the appearance of the final formulation. These agents are usually chemical compounds that are insoluble in water, and they include inorganic solids, insoluble cellulose derivatives, and insoluble synthetic polymers.

[0044] The term "wetting agent" as used herein refers to an excipient that is capable of reducing the API-water interfacial tension, improving the wettability and spreadability of the suspended API.

[0045] As used herein, "% w / w" with respect to a component of a liquid suspension according to the present invention means the number of grams of the component contained in 100 grams of the suspension. For example, the phrase "Reparixin in an amount of 5% w / w" means that 100 grams of the suspension contains 5 grams of Reparixin.

[0046] As used herein, the term "Avicel CL-611" refers to a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose, wherein the sodium carboxymethylcellulose is present in an amount of 11.3% w / w to 18.8% w / w.

[0047] It should be understood that the terms "suspended" and "dispersed" and variations thereof are used interchangeably in the context of this specification. DETAILED DESCRIPTION

[0048] As will be explained in more detail in the experimental section, the inventors have determined a qualitative-quantitative composition that allows the production of a stable liquid suspension of Reparixin.

[0049] In particular, it was unexpectedly found that the type and amount of sweetener included in the Reparixin liquid suspension to mask the unpleasant taste of the API affects the zeta potential value and rheological properties of the resulting suspension, and therefore its stability. Specifically, based on the results reported in the experimental section, sucrose in an amount of 25% w / w to 55% w / w was selected as a sweetener to be included in the Reparixin liquid suspension to achieve the desired stability.

[0050] Furthermore, the present inventors have selected polyvinylpyrrolidone as a wetting agent to be included in the Reparixin liquid suspension in order to achieve satisfactory wettability of this API.

[0051] Furthermore, the present inventors have selected the type / amount of viscosity agent (xanthan gum) and anti-caking agent (water-insoluble polymer) used in combination with sucrose and polyvinylpyrrolidone to obtain a stable liquid suspension of Reparixin.

[0052] Therefore, a first object of the present invention is a liquid suspension comprising:

[0053] - Reparixin in an amount of 2% w / w to 13% w / w, preferably 3% w / w to 13% w / w, more preferably 4% w / w to 13% w / w, more preferably 4.5% w / w to 12.5% ​​w / w, more preferably 4.8% w / w to 12.2% w / w, even more preferably 4.9% w / w to 12.1% w / w, most preferably 5% w / w to 12% w / w,

[0054] - xanthan gum in an amount of 0.15% w / w to 0.3% w / w, preferably 0.18% w / w to 0.27% w / w, more preferably 0.18% w / w to 0.23% w / w, even more preferably 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0055] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0056] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 1.8% w / w to 3.2% w / w, preferably 1.9% w / w to 3.1% w / w, more preferably 2% w / w to 3% w / w,

[0057] - A water insoluble polymer in an amount of 2.25% w / w to 2.75% w / w.

[0058] Reparixin (CAS No. 266359-83-5), also known as R-(-)-2-(4-isobutylphenyl)propionylmethanesulfonamide and repertaxin, is a compound having the following chemical formula:

[0059]

[0060] Preferably, the liquid suspension according to the first object of the present invention comprises:

[0061] - Reparixin in an amount of 5% w / w to 12% w / w,

[0062] - xanthan gum in an amount of 0.15% w / w to 0.3% w / w,

[0063] - sucrose in an amount of 30% w / w to 50% w / w,

[0064] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 1.8% w / w to 3.2% w / w,

[0065] - A water insoluble polymer in an amount of 2.25% w / w to 2.75% w / w.

[0066] Preferably, the liquid suspension according to the first object of the present invention comprises:

[0067] - Reparixin in an amount of 5% w / w to 12% w / w,

[0068] - xanthan gum in an amount of 0.2% w / w,

[0069] - sucrose in an amount of 30% w / w to 50% w / w,

[0070] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w to 3% w / w,

[0071] - A water insoluble polymer in an amount of 2.25% w / w to 2.75% w / w.

[0072] Preferably, the water-insoluble polymer is selected from microcrystalline cellulose and crospovidone.

[0073] Preferably, the water insoluble polymer is crospovidone, preferably in an amount of 2.5% w / w.

[0074] In one embodiment, which embodiment is also combined with any of the above embodiments, the liquid suspension according to the first object of the present invention further comprises: a buffer, preferably in an amount of 0.1% w / w to 3% w / w; and / or an antifoaming agent, preferably in an amount of 0.003% w / w to 5% w / w, more preferably 0.005% w / w to 5% w / w; and / or a preservative, preferably in an amount of 0.01% w / w to 0.5% w / w.

[0075] Preferably, the defoaming agent is a silicone derivative, which is preferably selected from:

[0076] - polydimethylsiloxane in an amount of 0.5% w / w to 5% w / w, and

[0077] - Simethicone in an amount of 0.003% w / w to 0.006% w / w, preferably in an amount of 0.005% w / w.

[0078] Preferably, the buffer is selected from a citrate buffer and a phosphate buffer. Preferably, the buffer is a citrate buffer comprising: citric acid, preferably citric acid monohydrate, in an amount of 0.06% w / w to 0.6% w / w, preferably in an amount of 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 0.2% w / w to 0.3% w / w, preferably in an amount of 0.208% w / w.

[0079] Preferably, the preservative is selected from potassium sorbate, sodium benzoate, methylparaben and propylparaben.

[0080] Preferably, the preservative is potassium sorbate in an amount of 0.1% w / w to 0.2% w / w, preferably in an amount of 0.15% w / w.

[0081] In one embodiment, the liquid suspension according to the first object of the present invention consists of:

[0082] - Reparixin in an amount of 2% w / w to 13% w / w, preferably 3% w / w to 13% w / w, more preferably 4% w / w to 13% w / w, more preferably 4.5% w / w to 12.5% ​​w / w, more preferably 4.8% w / w to 12.2% w / w, even more preferably 4.9% w / w to 12.1% w / w, most preferably 5% w / w to 12% w / w,

[0083] - xanthan gum in an amount of 0.15% w / w to 0.3% w / w, preferably 0.18% w / w to 0.27% w / w, more preferably 0.18% w / w to 0.23% w / w, even more preferably 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0084] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0085] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 1.8% w / w to 3.2% w / w, preferably 1.9% w / w to 3.1% w / w, more preferably 2% w / w to 3% w / w,

[0086] - a water-insoluble polymer in an amount of 2.25% w / w to 2.75% w / w,

[0087] - a buffer, preferably in an amount of 0.1% w / w to 3% w / w,

[0088] - 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,

[0089] - a preservative, preferably in an amount of 0.01% w / w to 0.5% w / w,

[0090] - an aqueous solvent, preferably water, in an amount up to 100% w / w.

[0091] In one embodiment, the liquid suspension according to the first object of the present invention consists of:

[0092] - Reparixin in an amount of 2% w / w to 13% w / w,

[0093] - xanthan gum in an amount of 0.2% w / w,

[0094] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0095] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w to 3% w / w,

[0096] - a water-insoluble polymer in an amount of 2.25% w / w to 2.75% w / w,

[0097] - a buffer, preferably in an amount of 0.1% w / w to 3% w / w,

[0098] - 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,

[0099] - a preservative, preferably in an amount of 0.01% w / w to 0.5% w / w,

[0100] - an aqueous solvent, preferably water, in an amount up to 100% w / w.

[0101] Preferably, the amount of Reparixin in the liquid suspension according to any of the above embodiments is

[0102] 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

[0103] In two preferred embodiments, which are also combinable with any of the above embodiments, the liquid suspension according to the first object of the invention comprises rapamycin in the following amounts:

[0104] - 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 an amount of 5% w / w; this embodiment is suitable for administration to pediatric subjects, wherein the pediatric subject is less than 14 years old; or

[0105] - 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 an amount of 12% w / w; this embodiment is suitable for administration to adult subjects, wherein the age of the adult subject is greater than 14 years old.

[0106] In one embodiment, which also is combined with any of the above embodiments, the defoaming agent is a silicone derivative, preferably selected from cyclomethicone, dimethicone and simethicone, more preferably selected from dimethicone and simethicone.

[0107] The presence of an antifoaming agent in a liquid suspension is advantageous because it prevents and / or hinders the formation of foam on the surface of the suspension.

[0108] Preferably, the amount of simethicone is 0.003% w / w to 0.6% w / w, preferably 0.003% w / w to 0.3% w / w, more preferably 0.003% w / w to 0.009% w / w, even more preferably 0.003% w / w to 0.007% w / w, even more preferably 0.003% w / w to 0.006% w / w, most preferably 0.005% w / w.

[0109] Preferably, the amount of polydimethylsiloxane is from 0.5% w / w to 5% w / w.

[0110] In one embodiment, which embodiment is also combined with any of the above embodiments, the buffer is capable of maintaining the pH of the suspension at a value of 4 to 6, preferably 4.5 to 5.5, more preferably a value of 5. Preferably, the buffer is selected from a citrate buffer and a phosphate buffer, more preferably it is a citrate buffer. Preferably, the citrate buffer comprises, preferably consists of, citric acid, preferably citric acid monohydrate, in an amount of 0.06% w / w to 0.6% w / w, preferably 0.06% w / w to 0.3% w / w, more preferably 0.06% w / w to 0.1% w / w, even more preferably 0.06% w / w 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 0.2% w / w to 2% w / w, preferably 0.2% w / w to 1% w / w, more preferably 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w. Preferably, the relative amounts of citric acid monohydrate and sodium citrate dihydrate are selected within the above ranges, for example to obtain a pH of 4 to 6, preferably 4.5 to 5.5, more preferably a value of 5.

[0111] In one embodiment, which embodiment is also combined with any of the above embodiments, the preservative is selected from potassium sorbate, sodium benzoate, methylparaben and propylparaben.The presence of a preservative in the formulation is advantageous because it prevents or retards microbial growth.

[0112] Preferably, the amount of potassium sorbate is 0.1% w / w to 0.2% w / w, more preferably the amount is 0.15% w / w.

[0113] Preferably, the amount of sodium benzoate is 0.02% w / w to 0.5% w / w.

[0114] Preferably, the amount of methylparaben, propylparaben or a combination thereof is 0.015% w / w to 0.2% w / w.

[0115] In one embodiment, which is also combined with any of the above embodiments, the water-insoluble polymer is selected from microcrystalline cellulose and cross-linked polyvinylpyrrolidone. The water-insoluble polymer acts as an anti-caking agent and is used to prevent the particulate solid from agglomerating into a mass or cohesive cake, thereby avoiding and / or limiting the formation of precipitates.

[0116] Crospovidone, also known as polyvinylpolypyrrolidone, is a highly cross-linked modification of polyvinylpyrrolidone (PVP). Due to the cross-linking, crospovidone is insoluble in water.

[0117] In one embodiment, which also is combined with any of the above embodiments, the liquid suspension according to the invention further comprises an aqueous solvent, preferably water, in an amount of up to 100% w / w.

[0118] In one embodiment, the liquid suspension according to the first object of the present invention consists of:

[0119] - Reparixin in an amount of 2% w / w to 13% w / w,

[0120] - xanthan gum in an amount of 0.2% w / w,

[0121] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0122] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w to 3% w / w,

[0123] - crospovidone in an amount of 2.25% w / w to 2.75% w / w,

[0124] - citric acid, preferably citric acid monohydrate, in an amount of 0.06% w / w to 0.6% w / w, preferably 0.06% w / w to 0.3% w / w, more preferably 0.06% w / w to 0.1% w / w, even more preferably 0.06% w / w to 0.07% w / w,

[0125] - sodium citrate, preferably sodium citrate dihydrate, in an amount of 0.2% w / w to 2% w / w, preferably 0.2% w / w to 1% w / w, more preferably 0.2% w / w to 0.3% w / w,

[0126] - simethicone in an amount of 0.003% w / w to 0.6% w / w, preferably 0.003% w / w to 0.3% w / w, more preferably 0.003% w / w to 0.009% w / w, even more preferably 0.003% w / w to 0.007% w / w,

[0127] - potassium sorbate in an amount of 0.1% w / w to 0.2% w / w,

[0128] - Water, up to 100%.

[0129] In one embodiment, the liquid suspension according to the first object of the present invention comprises, preferably consists of:

[0130] - 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,

[0131] - xanthan gum in an amount of 0.15% w / w to 0.3% w / w, preferably 0.18% w / w to 0.27% w / w, more preferably 0.18% w / w to 0.23% w / w, even more preferably 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0132] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0133] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 1.5% w / w to 2.5% w / w, preferably 1.7% 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,

[0134] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0135] -Optionally one or more of the following components: 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; citric acid monohydrate in an amount of 0.06% w / w to 0.6% w / w, preferably 0.06% w / w to 0.3% w / w, more preferably 0.06% w / w to 0.1% w / w, or even More preferably, the amount is 0.06% w / w to 0.07% w / w, and the most preferred amount is 0.064% w / w; sodium citrate dihydrate, the amount is 0.2% w / w to 2% w / w, preferably 0.2% w / w to 1% w / w, more preferably 0.2% w / w to 0.3% w / w, and the most preferred amount is 0.208% w / w; potassium sorbate, the amount is 0.1% w / w to 0.2% w / w, preferably 0.15% w / w,

[0136] - an aqueous solvent, preferably water, in an amount up to 100% w / w.

[0137] In one embodiment, the liquid suspension according to the first object of the present invention comprises:

[0138] - 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,

[0139] - xanthan gum in an amount of 0.15% w / w to 0.3% w / w, preferably 0.18% w / w to 0.27% w / w, more preferably 0.18% w / w to 0.23% w / w, even more preferably 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0140] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0141] - 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,

[0142] - Crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w.

[0143] In one embodiment, the liquid suspension according to the first object of the present invention consists of:

[0144] - 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,

[0145] - xanthan gum in an amount of 0.15% w / w to 0.3% w / w, preferably 0.18% w / w to 0.27% w / w, more preferably 0.18% w / w to 0.23% w / w, even more preferably 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0146] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0147] - 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,

[0148] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0149] - Optionally one or more of the following components: 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; citric acid, preferably citric acid monohydrate, in an amount of 0.06% w / w to 0.6% w / w, preferably 0.06% w / w to 0.3% w / w, more preferably 0.06% w / w to 0.1% w / w, or even More preferably, the amount is 0.06% w / w to 0.07% w / w, and the most preferred amount is 0.064% w / w; sodium citrate, preferably sodium citrate dihydrate, the amount is 0.2% w / w to 2% w / w, preferably 0.2% w / w to 1% w / w, more preferably 0.2% w / w to 0.3% w / w, and the most preferred amount is 0.208% w / w; potassium sorbate, the amount is 0.1% w / w to 0.2% w / w, preferably the amount is 0.15% w / w,

[0150] - an aqueous solvent, preferably water, in an amount up to 100% w / w.

[0151] In one embodiment, the liquid suspension according to the first object of the present invention comprises:

[0152] - Reparixin in an amount of 2% w / w to 5.5% w / w, preferably in an amount of 5% w / w,

[0153] - xanthan gum in an amount of 0.2% w / w,

[0154] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0155] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w,

[0156] - Crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w.

[0157] In one embodiment, the liquid suspension according to the first object of the present invention consists of:

[0158] - Reparixin in an amount of 2% w / w to 5.5% w / w, preferably in an amount of 5% w / w,

[0159] - xanthan gum in an amount of 0.2% w / w,

[0160] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0161] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w,

[0162] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0163] - Optionally one or more of the following components: 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; citric acid, preferably citric acid monohydrate, in an amount of 0.06% w / w to 0.6% w / w, preferably 0.06% w / w to 0.3% w / w, more preferably 0.06% w / w to 0.1% w / w, or even More preferably, the amount is 0.06% w / w to 0.07% w / w, and the most preferred amount is 0.064% w / w; sodium citrate, preferably sodium citrate dihydrate, the amount is 0.2% w / w to 2% w / w, preferably 0.2% w / w to 1% w / w, more preferably 0.2% w / w to 0.3% w / w, and the most preferred amount is 0.208% w / w; potassium sorbate, the amount is 0.1% w / w to 0.2% w / w, preferably the amount is 0.15% w / w,

[0164] - an aqueous solvent, preferably water, in an amount up to 100% w / w.

[0165] Preferably, the relative amounts of citric acid monohydrate and sodium citrate dihydrate are selected within the above range, for example to obtain a pH of 4 to 6, preferably 4.5 to 5.5, more preferably a value of 5.

[0166] In an alternative embodiment, the liquid suspension according to the first object of the present invention comprises, preferably consists of:

[0167] - 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 in an amount of 12% w / w,

[0168] - xanthan gum in an amount of 0.15% w / w to 0.3% w / w, preferably 0.18% w / w to 0.27% w / w, more preferably 0.18% w / w to 0.23% w / w, even more preferably 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0169] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0170] - 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 in an amount of 3% w / w,

[0171] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0172] -Optionally one or more of the following components: 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; citric acid monohydrate in an amount of 0.06% w / w to 0.6% w / w, preferably 0.06% w / w to 0.3% w / w, more preferably 0.06% w / w to 0.1% w / w, or even More preferably, the amount is 0.06% w / w to 0.07% w / w, and the most preferred amount is 0.064% w / w; sodium citrate dihydrate, the amount is 0.2% w / w to 2% w / w, preferably 0.2% w / w to 1% w / w, more preferably 0.2% w / w to 0.3% w / w, and the most preferred amount is 0.208% w / w; potassium sorbate, the amount is 0.1% w / w to 0.2% w / w, preferably 0.15% w / w,

[0173] - an aqueous solvent, preferably water, in an amount up to 100% w / w.

[0174] In an alternative embodiment, the liquid suspension according to the first object of the invention comprises:

[0175] - 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 in an amount of 12% w / w,

[0176] - xanthan gum in an amount of 0.15% w / w to 0.3% w / w, preferably 0.18% w / w to 0.27% w / w, more preferably 0.18% w / w to 0.23% w / w, even more preferably 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0177] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0178] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2.5% w / w to 3.2% w / w, preferably 2.7% w / w to 3.2% w / w, more preferably 2.9% w / w to 3.1% w / w, even more preferably in an amount of 3% w / w,

[0179] - Crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w.

[0180] In an alternative embodiment, the liquid suspension according to the first object of the invention consists of:

[0181] - 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 in an amount of 12% w / w,

[0182] - xanthan gum in an amount of 0.15% w / w to 0.3% w / w, preferably 0.18% w / w to 0.27% w / w, more preferably 0.18% w / w to 0.23% w / w, even more preferably 0.19% w / w to 0.21% w / w, most preferably in an amount of 0.2% w / w,

[0183] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0184] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2.5% w / w to 3.2% w / w, preferably 2.7% w / w to 3.2% w / w, more preferably 2.9% w / w to 3.1% w / w, even more preferably in an amount of 3% w / w,

[0185] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0186] - Optionally one or more of the following components: 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; citric acid, preferably citric acid monohydrate, in an amount of 0.06% w / w to 0.6% w / w, preferably 0.06% w / w to 0.3% w / w, more preferably 0.06% w / w to 0.1% w / w, or even More preferably, the amount is 0.06% w / w to 0.07% w / w, and the most preferred amount is 0.064% w / w; sodium citrate, preferably sodium citrate dihydrate, the amount is 0.2% w / w to 2% w / w, preferably 0.2% w / w to 1% w / w, more preferably 0.2% w / w to 0.3% w / w, and the most preferred amount is 0.208% w / w; potassium sorbate, the amount is 0.1% w / w to 0.2% w / w, preferably the amount is 0.15% w / w,

[0187] - an aqueous solvent, preferably water, in an amount up to 100% w / w.

[0188] In an alternative embodiment, the liquid suspension according to the first object of the invention comprises:

[0189] - Reparixin in an amount of 11.5% w / w to 12.5% ​​w / w, preferably in an amount of 12% w / w,

[0190] - xanthan gum in an amount of 0.2% w / w,

[0191] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0192] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 3% w / w,

[0193] - Crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w.

[0194] In an alternative embodiment, the liquid suspension according to the first object of the invention consists of:

[0195] - Reparixin in an amount of 11.5% w / w to 12.5% ​​w / w, preferably in an amount of 12% w / w,

[0196] - xanthan gum in an amount of 0.2% w / w,

[0197] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0198] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 3% w / w,

[0199] - crospovidone in an amount of 2.25% w / w to 2.75% w / w, preferably in an amount of 2.5% w / w,

[0200] - Optionally one or more of the following components: 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; citric acid, preferably citric acid monohydrate, in an amount of 0.06% w / w to 0.6% w / w, preferably 0.06% w / w to 0.3% w / w, more preferably 0.06% w / w to 0.1% w / w, or even More preferably, the amount is 0.06% w / w to 0.07% w / w, and the most preferred amount is 0.064% w / w; sodium citrate, preferably sodium citrate dihydrate, the amount is 0.2% w / w to 2% w / w, preferably 0.2% w / w to 1% w / w, more preferably 0.2% w / w to 0.3% w / w, and the most preferred amount is 0.208% w / w; potassium sorbate, the amount is 0.1% w / w to 0.2% w / w, preferably the amount is 0.15% w / w,

[0201] - an aqueous solvent, preferably water, in an amount up to 100% w / w.

[0202] Preferably, the relative amounts of citric acid monohydrate and sodium citrate dihydrate are selected within the above range, for example to obtain the following pH: 4 to 6, preferably 4.5 to 5.5, more preferably a value of 5.

[0203] In one embodiment, the liquid suspension according to the first object of the present invention comprises:

[0204] - Reparixin in an amount of 5% w / w,

[0205] - xanthan gum in an amount of 0.2% w / w,

[0206] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0207] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w,

[0208] - Crospovidone in an amount of 2.5% w / w.

[0209] In one embodiment, the liquid suspension according to the first object of the present invention consists of:

[0210] - Reparixin in an amount of 5% w / w,

[0211] - xanthan gum in an amount of 0.2% w / w,

[0212] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0213] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w,

[0214] - crospovidone in an amount of 2.5% w / w,

[0215] - 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 in an amount of 0.005% w / w,

[0216] - citric acid, preferably citric acid monohydrate, in an amount of 0.06% w / w to 0.6% w / w, preferably 0.06% w / w to 0.3% w / w, more preferably 0.06% w / w to 0.1% w / w, even more preferably 0.06% w / w to 0.07% w / w, most preferably in an amount of 0.064% w / w,

[0217] - sodium citrate, preferably sodium citrate dihydrate, in an amount of 0.2% w / w to 2% w / w, preferably 0.2% w / w to 1% w / w, more preferably 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w,

[0218] - potassium sorbate in an amount of 0.1% w / w to 0.2% w / w, preferably in an amount of 0.15% w / w,

[0219] - Water, up to 100%.

[0220] In one embodiment, the liquid suspension according to the first object of the present invention consists of:

[0221] - Reparixin in an amount of 5% w / w,

[0222] - xanthan gum in an amount of 0.2% w / w,

[0223] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0224] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 2% w / w,

[0225] - crospovidone in an amount of 2.5% w / w,

[0226] - simethicone in an amount of 0.005% w / w,

[0227] - citric acid monohydrate in an amount of 0.064% w / w,

[0228] - sodium citrate dihydrate in an amount of 0.208% w / w,

[0229] - potassium sorbate in an amount of 0.15% w / w,

[0230] - Water, up to 100%.

[0231] In one embodiment, the liquid suspension according to the first object of the present invention comprises:

[0232] - Reparixin in an amount of 12% w / w,

[0233] - xanthan gum in an amount of 0.2% w / w,

[0234] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0235] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 3% w / w,

[0236] - Crospovidone in an amount of 2.5% w / w.

[0237] In another embodiment, the liquid suspension according to the first object of the present invention consists of:

[0238] - Reparixin in an amount of 12% w / w,

[0239] - xanthan gum in an amount of 0.2% w / w,

[0240] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0241] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 3% w / w,

[0242] - crospovidone in an amount of 2.5% w / w,

[0243] - 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 in an amount of 0.005% w / w,

[0244] - citric acid, preferably citric acid monohydrate, in an amount of 0.06% w / w to 0.6% w / w, preferably 0.06% w / w to 0.3% w / w, more preferably 0.06% w / w to 0.1% w / w, even more preferably 0.06% w / w to 0.07% w / w, most preferably in an amount of 0.064% w / w,

[0245] - sodium citrate, preferably sodium citrate dihydrate, in an amount of 0.2% w / w to 2% w / w, preferably 0.2% w / w to 1% w / w, more preferably 0.2% w / w to 0.3% w / w, most preferably in an amount of 0.208% w / w,

[0246] - potassium sorbate in an amount of 0.1% w / w to 0.2% w / w, preferably in an amount of 0.15% w / w,

[0247] - Water, up to 100%.

[0248] In another embodiment, the liquid suspension according to the first object of the present invention consists of:

[0249] - Reparixin in an amount of 12% w / w,

[0250] - xanthan gum in an amount of 0.2% w / w,

[0251] - sucrose in an amount of 25% w / w to 55% w / w, preferably 27% w / w to 53% w / w, even more preferably 29% w / w to 51% w / w, most preferably 30% w / w to 50% w / w,

[0252] - polyvinylpyrrolidone, preferably polyvinylpyrrolidone K 30, in an amount of 3% w / w,

[0253] - crospovidone in an amount of 2.5% w / w,

[0254] - simethicone in an amount of 0.005% w / w,

[0255] - citric acid monohydrate in an amount of 0.064% w / w,

[0256] - sodium citrate dihydrate in an amount of 0.208% w / w,

[0257] - potassium sorbate in an amount of 0.15% w / w,

[0258] - Water, up to 100%.

[0259] In one embodiment, which embodiment is also combined with any of the above embodiments, the amount of sucrose in the liquid suspension according to the first object of the present invention is

[0260] 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, 4 3.5% 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. .

[0261] In one embodiment, which embodiment is also combined with any of the above embodiments, the liquid suspension according to the first object of the present invention has a zeta potential value of -3 mV to +3 mV, preferably -2.5 mV to +2.5 mV, wherein the zeta potential value is measured by laser Doppler electrophoresis using a Zetasizer nano ZS (Malvern Instruments, Worcestershire, UK) according to the manufacturer's instructions.

[0262] In one embodiment, which embodiment is also combined with any of the above embodiments, the liquid suspension according to the first object of the present invention has a yield stress value of at least 8 Pa, wherein the yield stress value is measured by a rheometer MCR 102 (Anton Paar, Graz, Austria) according to the procedure described in Example 2 below.

[0263] In one embodiment, which embodiment is also combined with any of the above embodiments, the liquid suspension according to the first object of the present invention is stable over a period of at least one year, preferably at least two years, meaning that during this period the API remains homogeneously suspended in the external phase, thereby ensuring correct dosing of the API, or in case a precipitate is formed, can be easily resuspended by manual shaking.

[0264] A second object of the invention is a liquid suspension according to any one of the above embodiments for use in the treatment of a disease or condition selected from the group consisting of psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome (ARDS), idiopathic fibrosis and glomerulonephritis.

[0265] Another object of the present invention is a liquid suspension according to any of the above embodiments of the first object of the present invention for use in preventing diabetes or delaying the onset and progression of diabetes, wherein the diabetes is preferably type I diabetes.

[0266] Another object of the present invention is a liquid suspension according to any of the above embodiments of the first object of the present invention, for use in the treatment of infections caused by SARS-CoV-2 or variants thereof, preferably for the treatment of COVID-19, and even more preferably for improving respiratory function in subjects affected by pneumonia caused by SARS-CoV-2 or variants thereof.

[0267] In one embodiment, the improvement in the subject's respiratory function means reducing, delaying the onset of, or preventing the need for supplemental oxygen, use of mechanical ventilation, or admission to an intensive care unit.

[0268] As used herein, the term "pneumonia caused by SARS-CoV-2 or its variants" refers to an inflammatory condition of the lungs associated with infection by SARS-CoV-2 or its variants. This is a serious complication of COVID-19 that affects a certain percentage of subjects.

[0269] In one embodiment, the liquid suspension according to any of the above embodiments of the first object of the invention for treating COVID-19 is administered in combination with standard of care treatment for COVID-19 patients.

[0270] As used herein, "standard of care treatment for COVID-19 patients" means a pharmacological treatment comprising 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 is used in clinical practice to treat symptoms and complications associated with COVID-19. Preferably, the standard of care treatment comprises 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, cytokines, chemokines and interleukin inhibitors, more preferably selected from dexamethasone, paracetamol, anakinra, celecoxib, prednisone, prednisolone, methylprednisolone, piryrone and tramadol; iii) antibiotics, preferably selected from piperacillin in combination with tazobactam, azithromycin and ceftriaxone; and iv) anticoagulants and antithrombotic drugs, preferably selected from enoxaparin and acetylsalicylic acid.

[0271] Preferably, the subject affected by pneumonia caused by SARS-CoV-2 or a variant thereof suffers from lymphocytopenia.

[0272] According to a preferred embodiment, the subject suffering from lymphocytopenia is an adult patient (14 years and 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.

[0273] According to another preferred embodiment, said patient suffering from lymphocytopenia is a pediatric patient (under 14 years old) 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.

[0274] Another object of the present invention is a liquid suspension according to any of the above embodiments of the first object of the present invention for use in preventing or treating epileptic seizures in an individual.

[0275] According to a preferred embodiment, the epileptic seizure is an acute symptomatic seizure (ASS).

[0276] According to another preferred embodiment, the epileptic seizures are associated with established epilepsy (Es (Established Epilepsy Seizures)).

[0277] In one embodiment, which is also combined with any of the above embodiments, the liquid suspension used according to the invention is a ready-to-use liquid suspension, i.e. a suspension that has been distributed by a liquid carrier. The liquid suspension may be monodose, i.e. intended for a single administration, or multidose, i.e. intended for more than one administration.

[0278] In one embodiment, which also is combined with any of the above embodiments, the liquid suspension for use according to the present invention is orally administered to a subject, preferably a mammal, even more preferably a human.

[0279] The present invention will be further described in the following examples, which do not limit the scope of the invention as defined in the claims.

[0280] Example

[0281] All percentages shown in the following tables are to be considered as % w / w.

[0282] Example 1 - Preparation of a suspension containing Reparixin

[0283] Several suspensions containing Reparixin were prepared. All suspensions contained at least the following excipients:

[0284] - Viscosity agents, which adjust the viscosity of the composition in order to obtain optimal rheological properties;

[0285] - wetting agents, which are necessary to increase the wettability of Reparixin in water, which is inherently low;

[0286] - sweeteners, which serve to mask the unpleasant taste of Reparixin;

[0287] - antifoaming agents, which are used to prevent and / or hinder the formation of foam on the surface of the suspension;

[0288] - Preservatives, which are used to prevent or retard the growth of microorganisms.

[0289] - a buffer for maintaining the pH of the suspension at a value between 4 and 6, preferably between 4.5 and 5.5, more preferably 5.

[0290] The materials used to prepare the suspensions are shown in Table 1.

[0291] Table 1

[0292]

[0293]

[0294] In suspensions, the types and / or amounts of the following components are varied:

[0295] - Viscosity agents. In particular, xanthan gum and Avicel CL-611 were tested as viscosity agents. Avicel CL-611 is a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose, wherein the sodium carboxymethylcellulose is present in an amount of 11.3% w / w to 18.8% w / w;

[0296] - Wetting agents. In particular, sodium lauryl sulfate (SLS), poloxamer 407, poloxamer 188 and polyvinylpyrrolidone (PVP) were tested as wetting agents. Poloxamer 407 was immediately ruled out due to its insufficient ability to disperse Reparixin;

[0297] - Sweeteners. In particular, sucrose and sucralose were tested as sweeteners. Sucrose has a high glycemic index, while sucralose is an artificial sweetener with a zero glycemic index.

[0298] The procedure for preparing the suspension is described below.

[0299] Selected amounts of defoamers, wetting agents, preservatives and buffers are added to 40 g of distilled water and the mixture is maintained under a magnetic stirrer until a solution is obtained. Then, the selected amount of Reparixin is added and dispersed. Once the API is uniformly suspended, the selected amounts of other excipients (viscosity agents, sweeteners and anti-caking agents, if present) are added and dissolved. Finally, water is added up to a final weight of 100 g.

[0300] In the following, the composition of the prepared liquid suspensions will be reported, whereas the corresponding characterization data will be shown in Examples 2 and 3.

[0301] Table 2 below reports the liquid suspensions prepared by using SLS as a wetting agent. Specifically, the prepared 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 buffers, 0.005% w / w simethicone as a defoaming agent, and water as a solvent.

[0302] In the prepared suspensions, the type / amount of viscosity agent (xanthan gum or Avicel CL-611) and the amount of buffer used were varied.

[0303] Table 2

[0304]

[0305] Table 3 below reports a liquid suspension prepared by using Poloxamer 188 as a wetting agent in combination with xanthan gum as a viscosity agent. The suspension 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 buffers, 0.005% w / w simethicone as a defoaming agent, and water as a solvent.

[0306] The amounts of poloxamer 188 and xanthan gum were varied in the prepared suspensions, as well as the type / amount of sweetener (sucrose or sucralose).

[0307] Table 3

[0308]

[0309] Table 4 below reports a liquid suspension prepared by using Poloxamer 188 as a wetting agent in combination with Avicel CL-611 as a viscosity agent. The suspension contains 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.

[0310] The amount of Avicel CL-611 and the type / amount of buffer (citric acid monohydrate / sodium citrate dihydrate or citric acid monohydrate / NaOH 1 M) were varied in the different suspensions prepared.

[0311] In addition to the suspensions reported in Table 4, Suspension 80 was prepared having a composition corresponding to Suspension 79 but containing 1.00% w / w Blanose (sodium carboxymethylcellulose) instead of 3.00% w / w Avicel CL-611.

[0312] Table 4

[0313]

[0314]

[0315] Table 5 below reports liquid suspensions prepared using a combination of polyvinylpyrrolidone as a wetting agent and xanthan gum as a viscosity agent. In particular, the prepared suspensions comprised 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 buffers, and water as a solvent.

[0316] The amount of xanthan gum in the suspension was varied, as well as the amount of crospovidone used as an anti-caking agent (from 0% w / w to 2.50% w / w).

[0317] Table 5

[0318]

[0319]

[0320] Table 6 reports the liquid suspensions prepared using a combination of polyvinylpyrrolidone as a wetting agent and Avicel-CL611 as a viscosity agent. Specifically, the prepared 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 buffers, and water as a solvent.

[0321] In the prepared suspensions, the amount of Avicel CL-611 and the amount of crospovidone used as an anti-caking agent were varied (from 0% w / w to 1% w / w).

[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 anti-caking agent was further investigated.

[0325] Table 7 reports a liquid suspension prepared using 2.00% w / w PVP K 30, 2.50% w / w crospovidone, 0.20% w / w xanthan gum as viscosity agent, 0.15% w / w potassium sorbate as preservative, 0.005% w / w simethicone as defoaming agent, 0.064% w / w citric acid monohydrate and 0.208% w / w sodium citrate dihydrate as buffers and water as solvent.

[0326] The type / amount of sweetener (sucrose or sucralose) was varied in the prepared suspensions.

[0327] Table 7

[0328]

[0329] Example 2 - Determination of Zeta Potential and Rheological Properties

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

[0331] Reparixin 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 gravity rather than by electrostatic interactions, which are insufficient to provide stability and kinetic stability. In order to ensure the stability of the suspension containing Reparixin, the zeta potential value must be equal to or close to zero, and the particles of the internal phase must be surrounded by a hydration layer that hides their charge and ensures that even when a precipitate is formed, it is a loose precipitate that is easy to resuspend, rather than a dense precipitate that is difficult to resuspend. An increase in the zeta potential (in terms of absolute value) corresponds to a situation in which this hydration layer surrounding the particles of the internal phase is less present or absent, resulting in an increase in the sedimentation rate.

[0332] About rheological properties, the yield stress and thixotropy of the prepared suspension are determined to obtain information about the physical stability of the suspension. Yield stress (τ0) is a material property, which can be defined as the stress corresponding to the yield point at which the material begins to flow or plastic deformation. If the yield stress is higher than the sedimentation stress (τS), it is believed that the suspension is stable, and the sedimentation stress can be defined as the stress that the particle produces to the liquid. If τ0 is higher than τS, no sedimentation will occur, and it can be believed that the suspension is stable. In general, for the instant liquid suspension as the final formulation, a yield stress of about 8 or more is considered to be a good value for anti-sedimentation.

[0333] The physical stability of suspension is also evaluated based on the thixotropy hysteresis area. Thixotropy is a necessary characteristic of the polymer system selected as a viscosity agent. In fact, when shear stress is applied (e.g., manually shaken), the consistency (e.g., viscosity) of the external phase caused by the suspending agent should be reduced to ensure the redispersibility of the precipitate. In the scientific literature, the thixotropy area is usually related to suspension stability. As shown by E.C. Foernzler, the sedimentation rate is proportional to the inverse of the hysteresis area, which means that physical stability is proportional to thixotropy (Ernest C. Foernzler et al., J. Am. Pharm. Assoc. 49 (1960) 249-252).

[0334] Based on the above, the produced suspensions were characterized with respect to zeta potential values, rheological properties and redispersibility.

[0335] Zeta potential values ​​of the prepared 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 stress and thixotropy (hysteresis) were evaluated by means of a rheometer MCR 102 (Anton Paar, Graz, Austria).

[0337] 0.1 to 100 seconds -1 The yield stress is determined by linearly increasing the shear rate stepwise between the steps to generate a flow curve (shear stress vs. shear rate). The resulting flow curve is then fitted with a Herschel-Bulkley regression model and the yield point is determined by extrapolating the flow curve to zero shear rate.

[0338] The thixotropy of the suspension was evaluated by hysteresis. The measurement was performed using an initial pre-shear of 5 1 / sec, and then the shear rate was increased from 5 to 131 sec. -1 (logarithmic scale) to generate an up-flow curve and reduce the shear rate from 131 to 5 seconds -1 The down-flow curve is obtained. The area between the upper and lower curves is calculated and related to the thixotropy of the system. All analyses were performed at room temperature using a 25 mm measuring plate and a gap set to 1 mm.

[0339] If a precipitate is present, the redispersibility is evaluated in terms of the number of 180° rotations that allow the precipitate to redisperse.

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

[0341] Table 8

[0342]

[0343] As can be seen, the zeta potential values ​​of the suspensions with 0.11% w / w SLS as a wetting agent were too high in absolute terms to make the suspensions stable. Increasing the concentration of citrate buffer (sodium citrate dihydrate + citric acid monohydrate) slightly reduced the absolute value of the zeta potential, but it was still too high. Based on these results, SLS was ruled out as a wetting agent due to its inability to produce a stable suspension of Reparixin.

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

[0345] Table 9

[0346]

[0347] As can be seen, the zeta potential values ​​of suspensions 73, 74 and 82 containing poloxamer 188 and 40% w / w sucrose are close to zero. However, when the sucrose percentage is reduced (sucrose-free suspension 84, and suspension 89 containing 20.00% w / w sucrose) or when sucrose is replaced by sucralose (suspension 83), the absolute value of the zeta potential increases.

[0348] This trend indicates that the type and amount of sweetener included in the formulation has an unexpected effect on the zeta potential value of the suspension, and therefore also on its stability. As shown, the amount of sucrose has a significant effect on the zeta potential and rheological properties. In fact, an increase in the amount of sucrose (from 0% w / w to 40% w / w) leads to a decrease in the zeta potential (in terms of absolute value).

[0349] Without being bound by 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), in this way reducing the absolute value of the zeta potential. This hydration layer ensures that even in the case of the formation of a precipitate, the precipitate is easily resuspended by manual shaking because it is loose rather than dense. At the same time, the increase in sucrose concentration causes an increase in both yield stress and hysteresis area, indicating an improvement in suspension stability.

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

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

[0352] Table 10 below reports the values ​​of zeta potential and rheological properties obtained for the suspensions reported in Table 4 and Suspension 80 described above.

[0353] Table 10

[0354]

[0355]

[0356] As can be seen, all suspensions in Table 4 exhibit zeta potential values ​​close to zero, confirming that the use of 40% sucrose as a sweetener is allowed to achieve this trend. However, all suspensions are characterized by yield stress values ​​that are too low for a ready-to-use liquid suspension as a final formulation. Based on these results, the use of Avicel CL-611 as a viscosity agent was excluded. The suspensions produced using this viscosity agent do not have adequate rheological properties in terms of yield stress and hysteresis loop (thixotropy).

[0357] Table 11 below reports the values ​​of zeta potential and rheological properties obtained for the suspensions reported in Table 5 above.

[0358] Table 11

[0359]

[0360]

[0361] As can be seen, when using 40% sucrose as sweetener and PVP K 30 as wetting agent, a suspension characterized by a ζ-potential value close to zero is obtained, thereby confirming the above result trend about the effect of sucrose in stabilizing the ζ-potential value of the suspension. Adding cross-linked polyvinylpyrrolidone as an anti-caking agent improves the rheological properties of the suspension, especially at high percentages (suspensions 93 and 98, containing 2.50% w / w cross-linked polyvinylpyrrolidone). When using 40% w / w xanthan gum as a viscosity agent, the suspension is too viscous and therefore difficult to handle (suspension 93). When the amount of xanthan gum is reduced to 0.20% w / w, this problem is solved and the suspension is easy to handle.

[0362] Table 12 below reports the values ​​of zeta potential and rheological properties obtained for the suspensions reported in Table 6 above.

[0363] Table 12

[0364]

[0365] As can be seen, the use of Avicel CL-611 as viscosity agent in combination with PVP K 30 as wetting agent results in a suspension with inappropriate rheological properties.

[0366] Table 13 below reports the values ​​of zeta potential and rheological properties obtained for the suspensions reported in Table 7 above.

[0367] Table 13

[0368]

[0369]

[0370] This experiment was conducted to further investigate and determine the effect of the type / amount of the selected sweetener on the zeta potential values ​​of the stable suspensions. As can be seen, when 20% w / w 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, meaning that the resulting suspension was unstable. The same trend was observed when 0.60% sucralose was used as the sweetener (Suspension 168).

[0371] When 60% w / w was used as sweetener (suspension 166), a persistent foam layer on the surface was observed.

[0372] When sucrose 30% w / w and 50% w / w were used as sweetener (suspensions 159 and 160, respectively), suspensions with zeta potential values ​​close to zero and suitable rheological properties were produced.

[0373] These results identified the unexpected effects of the type and amount of sweetener added to the suspension to mask the unpleasant taste of Reparixin on the zeta potential values ​​and rheological properties, and therefore on the stability of the suspension. In particular, based on these results, sucralose and amounts of 20% w / w and 60% w / w sucrose were excluded to produce a stable Reparixin liquid suspension.

[0374] Example 3 - Frequency Sweep Analysis

[0375] Frequency sweep analysis is used to predict the long-term physical stability of suspensions. To be precise, frequency sweeps are used to describe the time-dependent behavior of suspensions within a non-destructive deformation range (e.g., a linear viscoelastic region predetermined by amplitude analysis). High frequencies are used to simulate fast motions on a short time scale, while low frequencies are used to simulate slow motions on a long time scale. The storage modulus can be used as a measure of the elastic component of a sample (solid-like), while the loss modulus is considered to be the viscous component of a sample (liquid-like). At a specific frequency, whichever modulus is dominant will indicate whether a fully structured material is elastic or viscous. When the storage modulus is higher than the loss modulus, the elasticity of the suspension is greater than the viscosity, meaning that they are characterized by solid-like behavior, and in this case, sedimentation (stability of the suspension) is not likely to occur. On the other hand, when the viscous modulus is higher than the elastic modulus, sedimentation may occur.

[0376] Frequency sweep analysis was performed using a rheometer MCR 102 (Anton Paar, Graz, Austria). Frequency sweep analysis was performed with decreasing angular frequency (from 62.8 to 0.0628 rad / s, corresponding to 10 to 0.01 Hz) and constant strain, which was selected in the LVER (linear viscoelastic region) by oscillatory measurement. All analyses were performed at room temperature using a 25 mm measuring plate and with the gap set to 1 mm.

[0377] Figure 2 (Suspension 98) and Figure 3 (Suspension 105) shows the frequency sweep spectrum of a system in which the storage modulus is higher than the loss modulus, indicating that these suspensions are stable over time. In addition, both suspensions are characterized by storage modulus values ​​higher than 10 Pa recorded at low frequencies (about 0.1 rad / sec), meaning that possible dispersion stability can be assumed (TGMezger, "The Rheology Handbook", 2nd Ed., Vincentz Network, Hannover, 2006). Figure 2 and Figure 3 It is shown that at decreasing frequency values ​​both loss modulus and storage modulus increase, meaning that the corresponding suspension becomes more structured and dense over time.

[0378] Regarding suspension 105, despite having a good frequency sweep spectrum, it is characterized by low values ​​of yield stress and hysteresis area (Table 11 above). Figure 7 (Suspension 159) and Figure 8 (Suspension 160) shows a spectrum associated with a system where the storage modulus dominates the loss modulus, indicating that the suspension is stable, although the difference between the loss modulus and the storage modulus becomes lower at low frequency values.

[0379] Figure 1 (Suspension 82), Figure 5 (Suspension 107) and Fig. 9 (Suspension 166) are all related to systems where the loss modulus is higher than the storage modulus at high frequency values ​​(10 to 100 rad / sec), indicating possible instability of the suspensions that may occur during short storage times.

[0380] Figure 4 , 6 and 10 (suspensions 106, 165 and 168) are associated with systems where the loss modulus is higher than the storage modulus at low frequency values, indicating a possible sedimentation phenomenon over time (during long-term storage).

Claims

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

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

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. The 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 the defoaming agent is selected from: - polydimethylsiloxane in an amount of 0.5% w / w to 5% w / w, and - Simethicone in an amount of 0.003% w / w to 0.006% w / w, preferably in an amount of 0.005% w / w.

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

7. The liquid suspension according to claim 6, wherein the buffer is a citrate buffer comprising: citric acid monohydrate in an amount of 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 of 0.2% w / w to 0.3% w / w, preferably in an amount of 0.208% w / w.

8. The liquid suspension according to any one of the preceding claims, further comprising a preservative, preferably selected from potassium sorbate, sodium benzoate, methylparaben and propylparaben.

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

10. The liquid suspension according to any one of the preceding claims, wherein the amount of Reparixin is 2% w / w to 5.5% w / w, preferably 3% 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 an amount of 5% w / w.

11. The liquid suspension according to any one of claims 1 to 9, wherein the amount of Reparixin is 11.5% w / w to 12.5% ​​w / w, preferably 11.7% w / w to 12.3% w / w, more preferably 11.9% w / w to 12.1% w / w, even more preferably the amount is 12% w / w.

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

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

14. A liquid suspension according to any one of the preceding claims, further comprising an aqueous solvent, preferably water, in an amount of up to 100% w / w.

15. A liquid suspension according to any one of the preceding claims, for use in: - treating a disease or condition selected from the group consisting of: psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome (ARDS), idiopathic fibrosis, glomerulonephritis, COVID-19, pneumonia caused by SARS-CoV-2 or its variants, - preventing or delaying the onset and progression of diabetes, preferably type 1 diabetes, -Preventing or treating epileptic seizures in an individual.

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