Powder mixture comprising repalisin

Abstract

The present invention relates to a powder mixture of repariocin which is suitable, when in use, to produce a reconstituted liquid suspension in an aqueous vehicle.

Description

Technical Field

[0001] The present invention relates to a powder mixture comprising reparixin suitable for producing a liquid suspension for reconstitution at the time of use. Prior 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 the prevention or treatment of 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 (YRMahkla 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 the activation of leukocyte recruitment and inflammation. The effects of Reparixin include inhibition of neutrophil stimulation and downstream effects of neutrophils during inflammatory responses, such as NETosis, i.e., the formation of NETs (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] A phase 2, multicenter, open-label, randomized clinical trial was conducted from May 5, 2020 to November 27, 2020 to evaluate the efficacy and safety of reparixin compared with available treatment considered standard of care (SOC) in hospitalized patients with severe COVID-19 pneumonia. The trial showed that treatment with reparixin 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).

[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 not suitable for achieving satisfactory patient compliance, particularly 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 that has 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 heterogeneous dispersion systems, and most pharmaceutical suspensions have an aqueous dispersion medium.

[0009] Suspensions can be sold in the form of ready-to-use liquid suspensions or as powder mixtures to be reconstituted in a suitable liquid carrier at the time of use. Such powder mixtures typically contain a suitable suspending and dispersing agent and an active pharmaceutical ingredient (API) diluted and stirred with a specific amount of a carrier, which is typically an aqueous carrier.

[0010] The preparation and distribution of such dosage forms are associated with several advantages: efficient distribution of hydrophobic drugs; avoidance of cosolvents; masking of unpleasant tastes; 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).

[0011] Suspensions are thermodynamically unstable systems due to the free energy of the internal phase of the suspension, which results in particle aggregation and sedimentation to reduce the energy of the system.

[0012] The main challenge in developing a powder mixture that can be suspended in a suitable vehicle at the time of use to obtain a liquid suspension after manual shaking is to ensure rapid dispersion upon reconstitution in water. In addition, the powder must be flowable and the API must be uniformly dispersed in the powder mixture, and physical stability and redispersibility must be ensured, preferably for at least one month after reconstitution.

[0013] In order to achieve the above mentioned properties, several aspects must be considered when formulating a powder mixture suitable for producing a liquid suspension to be reconstituted at the time of use.

[0014] The preparation of suspensions containing Reparixin is particularly difficult due to the specific characteristics of this active pharmaceutical ingredient (API).

[0015] First, Reparixin is produced in the form of a powder consisting of particles with a large particle size. Therefore, a potential suspension containing Reparixin is a coarse suspension, i.e. a suspension characterized by an internal phase with a particle size greater than about 0.5 μm (Edman, P., Journal of Aerosol Medicine 1994, 7, S-3-S-6).

[0016] In the case of a coarse suspension, the internal phase with the API tends to settle under gravity and produces a sedimentation phenomenon due to its particle size. In terms of absolute value, the increase in zeta potential produces an increase in sedimentation rate. This shows that sedimentation is driven by gravity rather than electrostatic interaction, which is not enough 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 usually set near zero to ensure physical stability. This value of zeta potential corresponds to the situation where the particles are surrounded by a hydration layer, which hides its charge, and in the case of particle aggregation and precipitation, it is possible to prevent the formation of dense precipitates, and on the contrary promote the formation of loose precipitates, 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.

[0017] In addition, Reparixin has low wettability, which makes it complicated to prepare it into a powder mixture suitable for producing a reconstructed liquid suspension when used. In fact, the wettability of dispersed particles is important for ensuring homogeneity and content uniformity (Kwok, DYet al., Advances in Colloid and Interface Science 1999, 81, 167–249). Wettability is the tendency of a fluid to diffuse or adhere to a solid surface when the fluid is immiscible; 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 or a powder mixture reconstructed in an aqueous carrier when used, a common method for improving the wettability of a solid is to use a wetting agent that can reduce the solid-liquid interfacial tension, such as a surfactant.

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

[0019] In view of the above, there is a clear need to develop powder mixtures containing Reparixin that, when reconstituted in an aqueous vehicle at the time of use, yield a suspension with satisfactory characteristics. However, this is particularly challenging for this API, for the reasons discussed above. Summary of the invention

[0020] The present inventors have developed a powder mixture comprising Reparixin which is suitable for producing a reconstituted liquid suspension having satisfactory characteristics in terms of stability, wettability and uniformity of API distribution. For use, reconstitution is carried out in an aqueous vehicle.

[0021] In particular, the inventors have unexpectedly discovered that the type and amount of sweetener included in a powder mixture to mask the unpleasant taste of Reparixin affects the zeta potential value and rheological properties of a liquid suspension reconstituted from such a mixture, and thus affects its stability.

[0022] Furthermore, the present inventors have found that the use of polyvinylpyrrolidone or poloxamer 188 as wetting agent allows obtaining satisfactory wettability of Reparixin. The selected wetting agent ensures a homogeneous dispersion of Reparixin in the aqueous vehicle.

[0023] The present inventors have also determined the type and range of viscosity agents and colloidal silicon dioxide that must be included in the powder mixture in order to obtain a flowable powder and a stable liquid suspension of Reparixin after reconstitution of the powder in an aqueous vehicle.

[0024] Therefore, a first object of the present invention is a powder mixture comprising:

[0025] - Reparixin in an amount ranging from 3.5% w / w to 28.2% w / w,

[0026] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 3% w / w to 8.3% w / w,

[0027] - sucrose in an amount of 63% w / w to 89% w / w,

[0028] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w,

[0029] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.4% w / w,

[0030] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0031] Another object of the present invention is a process for producing a liquid suspension comprising Reparixin, comprising the step of suspending the powder mixture according to the first object of the present invention in an aqueous vehicle, preferably water.

[0032] Another object of the present invention is a powder mixture according to the first object of the present invention or a reconstituted liquid suspension thereof, 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, glomerulonephritis, COVID-19, pneumonia caused by SARS-CoV-2 or its variants.

[0033] Another object of the present invention is the powder mixture according to the first object of the present invention or its reconstituted liquid suspension for use in preventing diabetes or delaying the onset and progression of diabetes.

[0034] Another object of the present invention is the powder mixture according to the first object of the present invention or its reconstituted liquid suspension for use in the prevention or treatment of epileptic seizures.

[0035] Another object of the invention is a kit comprising:

[0036] a) a powder mixture according to the first object of the invention, and

[0037] b) an aqueous carrier, preferably water.

[0038] definition

[0039] 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.

[0040] As used herein, the term "wetting agent" refers to an excipient that is capable of reducing the API-water interfacial tension by improving the wettability and spreadability of the suspended API.

[0041] "% w / w" as used herein in relation to a component of a powder mixture according to the invention means the number of grams of the component in 100 grams of the powder mixture. For example, the expression "Reparixin in an amount of 10.16% w / w" means that 10.16 grams of Reparixin are present in 100 grams of the powder mixture.

[0042] As used herein, "% w / w" with respect to a component of a liquid suspension means the number of grams of that component in 100 grams of the liquid suspension. For example, the phrase "Reparixin in an amount of 5% w / w" means that 5 grams of Reparixin are present in 100 grams of the liquid suspension.

[0043] The term "reconstituted liquid suspension" or "reconstituted liquid suspension thereof" as used herein with reference to a powder mixture means the liquid suspension that results when the powder mixture is suspended in an aqueous carrier, preferably water.

[0044] The term "aqueous carrier" as used herein refers to an aqueous solvent suitable for suspending the powder mixture according to the first object of the present invention. Preferably, the aqueous carrier is water.

[0045] 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.

[0046] It should be understood that the terms "suspending" and "dispersing" or "suspended" and "dispersed" are used interchangeably in the context of the present specification. DETAILED DESCRIPTION

[0047] As will be explained in more detail in the experimental section, the inventors have determined a quali-quantitative combination of excipients that must be included in a powder mixture containing Reparixin such that when the powder mixture is suspended in an aqueous vehicle, a homogeneous reconstituted liquid suspension is obtained that is stable for a sufficient amount of time.

[0048] In particular, it was unexpectedly found that the type and amount of sweetener included in the powder mixture of Reparixin to mask the unpleasant taste of the API affects the zeta potential value and rheological properties of the corresponding reconstituted liquid suspension and, therefore, its stability.

[0049] Furthermore, the present inventors have selected polyvinylpyrrolidone or poloxamer 188 as a wetting agent for inclusion in the powder mixture in order to achieve satisfactory wettability of the API and ensure uniform distribution in the reconstituted liquid suspension.

[0050] The reconstituted liquid suspension must be stable for at least one month after reconstitution and, in case a precipitate is formed, the precipitate must be easily resuspendable by manual shaking.

[0051] Therefore, a first object of the present invention is a powder mixture comprising:

[0052] - Reparixin in an amount ranging from 3.5% w / w to 28.2% w / w,

[0053] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 3% w / w to 8.3% w / w,

[0054] - sucrose in an amount of 63% w / w to 89% w / w,

[0055] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w,

[0056] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.4% w / w,

[0057] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

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

[0059]

[0060] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0061] - Reparixin in an amount ranging from 3.5% w / w to 28.2% w / w,

[0062] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 3% w / w to 8.3% w / w,

[0063] - sucrose in an amount of 63% w / w to 89% w / w,

[0064] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w,

[0065] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.4% w / w,

[0066] - a pH adjusting agent, preferably in an amount of 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount of 0.1% w / w to 0.5% w / w, with the proviso that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0067] In a preferred embodiment, the powder mixture according to the first object of the present invention comprises: - Reparixin in an amount ranging from 3.5% w / w to 28.2% w / w,

[0068] - Avicel CL-611 in an amount of 3% w / w to 8.3% w / w,

[0069] - sucrose in an amount of 63% w / w to 89% w / w,

[0070] - Poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w,

[0071] - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.4% w / w.

[0072] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0073] - Reparixin in an amount ranging from 3.5% w / w to 28.2% w / w,

[0074] - Avicel CL-611 in an amount of 3% w / w to 8.3% w / w,

[0075] - sucrose in an amount of 63% w / w to 89% w / w,

[0076] - Poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w,

[0077] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.4% w / w,

[0078] - a pH adjuster, preferably in an amount of 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount of 0.1% w / w to 0.5% w / w.

[0079] In a preferred embodiment, the powder mixture according to the first object of the present invention comprises: - Reparixin in an amount of 6.8% w / w to 28.2% w / w,

[0080] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 3% w / w to 8.3% w / w, preferably 3% w / w to 8% w / w,

[0081] - sucrose in an amount of 63% w / w to 88% w / w,

[0082] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w,

[0083] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w,

[0084] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0085] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0086] - Reparixin in an amount ranging from 6.8% w / w to 28.2% w / w,

[0087] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 3% w / w to 8.3% w / w, preferably 3% w / w to 8% w / w,

[0088] - sucrose in an amount of 63% w / w to 88% w / w,

[0089] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w,

[0090] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w,

[0091] - a pH adjuster, preferably in an amount of 0.1 to 0.2% w / w, and / or a preservative, preferably in an amount of 0.1 to 0.5% w / w,

[0092] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0093] In a preferred embodiment, the powder mixture according to the first object of the present invention comprises: - Reparixin in an amount of 6.8% w / w to 28.2% w / w,

[0094] - Avicel CL-611 in an amount of 3% w / w to 8.3% w / w, preferably 3% w / w to 8% w / w, - sucrose in an amount of 63% w / w to 88% w / w,

[0095] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w,

[0096] - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w.

[0097] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0098] - Reparixin in an amount ranging from 6.8% w / w to 28.2% w / w,

[0099] - Avicel CL-611 in an amount of 3% w / w to 8.3% w / w, preferably 3% w / w to 8% w / w, - sucrose in an amount of 63% w / w to 88% w / w,

[0100] - Poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w,

[0101] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w,

[0102] - a pH adjuster, preferably in an amount of 0.1 to 0.2% w / w, and / or a preservative, preferably in an amount of 0.1 to 0.5% w / w.

[0103] In a preferred embodiment, the powder mixture according to the first object of the present invention comprises: - Reparixin in an amount of 7.6% w / w to 26.8% w / w,

[0104] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 4.5% w / w to 7.8% w / w, - sucrose in an amount of 64.2% w / w to 85.2% w / w,

[0105] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w,

[0106] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w,

[0107] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0108] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0109] - Reparixin in an amount ranging from 7.6% w / w to 26.8% w / w,

[0110] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 4.5% w / w to 7.8% w / w, - sucrose in an amount of 64.2% w / w to 85.2% w / w,

[0111] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w,

[0112] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w,

[0113] - a pH adjusting agent, preferably in an amount of 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount of 0.2% w / w to 0.4% w / w,

[0114] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0115] In a preferred embodiment, the powder mixture according to the first object of the present invention comprises: - Reparixin in an amount of 7.6% w / w to 26.8% w / w,

[0116] - Avicel CL-611 in an amount of 4.5% w / w to 7.8% w / w,

[0117] - sucrose in an amount of 64.2% w / w to 85.2% w / w,

[0118] - Poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w,

[0119] - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w.

[0120] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0121] - Reparixin in an amount ranging from 7.6% w / w to 26.8% w / w,

[0122] - Avicel CL-611 in an amount of 4.5% w / w to 7.8% w / w,

[0123] - sucrose in an amount of 64.2% w / w to 85.2% w / w,

[0124] - Poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w,

[0125] - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w

[0126] - a pH adjuster, preferably in an amount of 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount of 0.2% w / w to 0.4% w / w.

[0127] In a preferred embodiment, the powder mixture according to the first object of the present invention comprises: - Reparixin in an amount ranging from 8.4% w / w to 26% w / w,

[0128] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 4.5% w / w to 7.7% w / w, - sucrose in an amount of 64.9% w / w to 84.5% w / w,

[0129] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w,

[0130] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w,

[0131] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0132] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0133] - Reparixin in an amount ranging from 8.4% w / w to 26% w / w,

[0134] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 4.5% w / w to 7.7% w / w, - sucrose in an amount of 64.9% w / w to 84.5% w / w,

[0135] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w,

[0136] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w,

[0137] - a pH adjusting agent, preferably in an amount of 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount of 0.2% w / w to 0.4% w / w, with the proviso that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0138] In a preferred embodiment, the powder mixture according to the first object of the present invention comprises: - Reparixin in an amount ranging from 8.4% w / w to 26% w / w,

[0139] - Avicel CL-611 in an amount of 4.5% w / w to 7.7% w / w,

[0140] - sucrose in an amount of 64.9% w / w to 84.5% w / w,

[0141] - Poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w,

[0142] - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w.

[0143] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0144] - Reparixin in an amount ranging from 8.4% w / w to 26% w / w,

[0145] - Avicel CL-611 in an amount of 4.5% w / w to 7.7% w / w,

[0146] - sucrose in an amount of 64.9% w / w to 84.5% w / w,

[0147] - Poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w,

[0148] - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w

[0149] - a pH adjuster, preferably in an amount of 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount of 0.2% w / w to 0.4% w / w.

[0150] In a preferred embodiment, the powder mixture according to the first object of the present invention comprises: - Reparixin in an amount of 7.6% w / w to 13.9% w / w,

[0151] - sucrose in an amount of 75.5% w / w to 85.2% w / w,

[0152] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 5% w / w to 7.8% w / w,

[0153] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.8% w / w to 1.3% w / w,

[0154] - colloidal silicon dioxide in an amount of 0.8% w / w to 1.3% w / w,

[0155] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0156] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0157] - Reparixin in an amount ranging from 7.6% w / w to 13.9% w / w,

[0158] - sucrose in an amount of 75.5% w / w to 85.2% w / w,

[0159] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 5% w / w to 7.8% w / w,

[0160] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.8% w / w to 1.3% w / w,

[0161] - a pH adjuster, preferably in an amount of 0.1% w / w to 0.17% w / w, and / or a preservative, preferably in an amount of 0.2% w / w to 0.4% w / w, wherein the pH adjuster is preferably citric acid monohydrate, and / or the preservative is preferably potassium sorbate,

[0162] - colloidal silicon dioxide in an amount of 0.8% w / w to 1.3% w / w,

[0163] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0164] In a preferred embodiment, the powder mixture according to the first object of the present invention comprises: - Reparixin in an amount of 7.6% w / w to 13.9% w / w,

[0165] - sucrose in an amount of 75.5% w / w to 85.2% w / w,

[0166] - Avicel CL-611 in an amount of 5% w / w to 7.8% w / w,

[0167] - Poloxamer 188 in an amount of 0.8% w / w to 1.3% w / w,

[0168] - Colloidal silicon dioxide in an amount of 0.8% w / w to 1.3% w / w.

[0169] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0170] - Reparixin in an amount ranging from 7.6% w / w to 13.9% w / w,

[0171] - sucrose in an amount of 75.5% w / w to 85.2% w / w,

[0172] - a preservative, preferably potassium sorbate, in an amount of 0.2% w / w to 0.4% w / w,

[0173] - Avicel CL-611 in an amount of 5% w / w to 7.8% w / w,

[0174] - Poloxamer 188 in an amount of 0.8% w / w to 1.3% w / w,

[0175] - a pH adjuster, preferably citric acid monohydrate, in an amount of 0.1% w / w to 0.17% w / w,

[0176] - Colloidal silicon dioxide in an amount of 0.8% w / w to 1.3% w / w.

[0177] In a preferred embodiment, the powder mixture according to the first object of the present invention comprises: - Reparixin in an amount of 8.4% w / w to 12.8% w / w,

[0178] - sucrose in an amount of 76.5% w / w to 84.5% w / w,

[0179] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 5% w / w to 7.7% w / w,

[0180] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.8% w / w to 1.3% w / w,

[0181] - colloidal silicon dioxide in an amount of 0.8% w / w to 1.3% w / w,

[0182] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0183] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0184] - Reparixin in an amount of 8.4% w / w to 12.8% w / w,

[0185] - sucrose in an amount of 76.5% w / w to 84.5% w / w,

[0186] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 5% w / w to 7.7% w / w,

[0187] - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.8% w / w to 1.3% w / w,

[0188] - a pH adjuster, preferably in an amount of 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount of 0.2% w / w to 0.4% w / w, wherein the pH adjuster is preferably citric acid monohydrate, and / or the preservative is preferably potassium sorbate,

[0189] - colloidal silicon dioxide in an amount of 0.8% w / w to 1.3% w / w,

[0190] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0191] In a preferred embodiment, the powder mixture according to the first object of the present invention comprises: - Reparixin in an amount of 8.4% w / w to 12.8% w / w,

[0192] - sucrose in an amount of 76.5% w / w to 84.5% w / w,

[0193] - Avicel CL-611 in an amount of 5% w / w to 7.7% w / w,

[0194] - Poloxamer 188 in an amount of 0.8% w / w to 1.3% w / w,

[0195] - Colloidal silicon dioxide in an amount of 0.8% w / w to 1.3% w / w.

[0196] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0197] - Reparixin in an amount of 8.4% w / w to 12.8% w / w,

[0198] - sucrose in an amount of 76.5% w / w to 84.5% w / w,

[0199] - a preservative, preferably potassium sorbate, in an amount of 0.2% w / w to 0.4% w / w,

[0200] - Avicel CL-611 in an amount of 5% w / w to 7.7% w / w,

[0201] - Poloxamer 188 in an amount of 0.8% w / w to 1.3% w / w,

[0202] - a pH adjuster, preferably citric acid monohydrate, in an amount of 0.1% w / w to 0.2% w / w,

[0203] - Colloidal silicon dioxide in an amount of 0.8% w / w to 1.3% w / w.

[0204] In another preferred embodiment, the first object powder mixture according to the present invention comprises:

[0205] - Reparixin in an amount ranging from 17.5% w / w to 26.8% w / w,

[0206] - sucrose in an amount of 64.2% w / w to 76.1% w / w,

[0207] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 4.5% w / w to 6.6% w / w, - a wetting agent selected from the group consisting of polyvinyl pyrrolidone in an amount of 3% w / w to 5% w / w, and poloxamer 188 in an amount of 0.7% w / w to 1.1% w / w,

[0208] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.1% w / w,

[0209] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0210] In another preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0211] - Reparixin in an amount ranging from 17.5% w / w to 26.8% w / w,

[0212] - sucrose in an amount of 64.2% w / w to 76.1% w / w,

[0213] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 4.5% w / w to 6.6% w / w, - a wetting agent selected from the group consisting of polyvinyl pyrrolidone in an amount of 3% w / w to 5% w / w, and poloxamer 188 in an amount of 0.7% w / w to 1.1% w / w,

[0214] - a pH adjuster, preferably in an amount of 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount of 0.2% w / w to 0.35% w / w, wherein the pH adjuster is preferably citric acid monohydrate, and / or the preservative is preferably potassium sorbate,

[0215] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.1% w / w,

[0216] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0217] In another preferred embodiment, the first object powder mixture according to the present invention comprises:

[0218] - Reparixin in an amount ranging from 17.5% w / w to 26.8% w / w,

[0219] - sucrose in an amount of 64.2% w / w to 76.1% w / w,

[0220] - Avicel CL-611 in an amount of 4.5% w / w to 6.6% w / w,

[0221] - Poloxamer 188 in an amount of 0.7% w / w to 1.1% w / w,

[0222] - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.1% w / w.

[0223] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0224] - Reparixin in an amount ranging from 17.5% w / w to 26.8% w / w,

[0225] - sucrose in an amount of 64.2% w / w to 76.1% w / w,

[0226] - a preservative, preferably potassium sorbate, in an amount of 0.2% w / w to 0.35% w / w,

[0227] - Avicel CL-611 in an amount of 4.5% w / w to 6.6% w / w,

[0228] - Poloxamer 188 in an amount of 0.7% w / w to 1.1% w / w,

[0229] - a pH adjuster, preferably citric acid monohydrate, in an amount of 0.1% w / w to 0.2% w / w,

[0230] - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.1% w / w.

[0231] In another preferred embodiment, the first object powder mixture according to the present invention comprises:

[0232] - Reparixin in an amount ranging from 18.1% w / w to 26% w / w,

[0233] - sucrose in an amount of 64.9% w / w to 75.6% w / w,

[0234] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 4.5% w / w to 6.5% w / w, - a wetting agent selected from the group consisting of polyvinyl pyrrolidone in an amount of 3% w / w to 5% w / w, and poloxamer 188 in an amount of 0.75% w / w to 1.1% w / w,

[0235] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.1% w / w,

[0236] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0237] In another preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0238] - Reparixin in an amount ranging from 18.1% w / w to 26% w / w,

[0239] - sucrose in an amount of 64.9% w / w to 75.6% w / w,

[0240] - a viscosity agent selected from the group consisting of xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and Avicel CL-611 in an amount of 4.5% w / w to 6.5% w / w, - a wetting agent selected from the group consisting of polyvinyl pyrrolidone in an amount of 3% w / w to 5% w / w, and poloxamer 188 in an amount of 0.75% w / w to 1.1% w / w,

[0241] - a pH adjuster, preferably in an amount of 0.1% w / w to 0.15% w / w, and / or a preservative, preferably in an amount of 0.2% w / w to 0.35% w / w, wherein the pH adjuster is preferably citric acid monohydrate, and / or the preservative is preferably potassium sorbate,

[0242] - colloidal silicon dioxide in an amount of 0.7% w / w to 1.1% w / w,

[0243] Provided that when the viscosity agent is Avicel CL-611, the wetting agent is not polyvinyl pyrrolidone.

[0244] In another preferred embodiment, the first object powder mixture according to the present invention comprises:

[0245] - Reparixin in an amount ranging from 18.1% w / w to 26% w / w,

[0246] - sucrose in an amount of 64.9% w / w to 75.6% w / w,

[0247] - Avicel CL-611 in an amount of 4.5% w / w to 6.5% w / w,

[0248] - Poloxamer 188 in an amount of 0.75% w / w to 1.1% w / w,

[0249] - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.1% w / w.

[0250] In a preferred embodiment, the powder mixture according to the first object of the present invention consists of at least 98%, preferably at least 99%, of the following by weight:

[0251] - Reparixin in an amount ranging from 18.1% w / w to 26% w / w,

[0252] - sucrose in an amount of 64.9% w / w to 75.6% w / w,

[0253] - a preservative, preferably potassium sorbate, in an amount of 0.2% w / w to 0.35% w / w,

[0254] - Avicel CL-611 in an amount of 4.5% w / w to 6.5% w / w,

[0255] - Poloxamer 188 in an amount of 0.75% w / w to 1.1% w / w,

[0256] - a pH adjuster, preferably citric acid monohydrate, in an amount of 0.1% w / w to 0.15% w / w,

[0257] - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.1% w / w.

[0258] Preferably, when polyvinylpyrrolidone is used as the wetting agent, the polyvinylpyrrolidone is polyvinylpyrrolidone K30.

[0259] In one embodiment, also in combination with any of the above embodiments, the pH adjusting agent is capable of adjusting the pH of the liquid suspension reconstituted from the powder mixture to a value between 4 and 6, preferably between 4.5 and 5.5, more preferably 5.

[0260] In one embodiment, also in combination with any of the above embodiments, the pH adjuster is selected from citric acid (preferably citric acid monohydrate), hydrochloric acid, sodium phosphate (preferably sodium dihydrogen phosphate), potassium phosphate (preferably potassium dihydrogen phosphate).

[0261] In one embodiment, also in combination with any of the above embodiments, the pH adjuster is citric acid, preferably citric acid monohydrate, in an amount of 0.1% w / w to 0.2% w / w.

[0262] In one embodiment, also in combination with any of the above embodiments, the preservative is selected from potassium sorbate, sodium benzoate, methylparaben and propylparaben. In a preferred embodiment, also in combination with any of the above embodiments, the preservative is potassium sorbate in an amount of 0.1% w / w to 0.5% w / w.

[0263] Further preferred embodiments of the powder mixture according to the first object of the present invention are shown in the following Table 1, Table 2, Table 3 and Table 4. All values ​​in the tables are to be interpreted as % w / w as defined above.

[0264] Table 1

[0265]

[0266] Table 2

[0267]

[0268] Table 3

[0269]

[0270] Table 4

[0271]

[0272] In one embodiment, also in combination with any of the above embodiments, the powder mixture according to the first object of the present invention has a flowability index of 10 mm to 4 mm, preferably 6 mm, wherein the flowability index is measured according to the procedure described in Example 2 below by using a Flodex Apparatus, Teledyne Hanson Research, Chatsworth, California, USA.

[0273] A second object of the present invention is a method for producing a liquid suspension comprising Reparixin, comprising the step of suspending the powder mixture according to the first object of the present invention in an aqueous carrier, preferably water. The amount of water in which Reparixin is suspended may vary based on the amount of Reparixin, and a skilled person is able to determine such amount of water.

[0274] In one embodiment, the liquid suspension reconstituted from the powder mixture has a zeta potential value of -5 mV to +5 mV, preferably -3 mV to +3 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.

[0275] In one embodiment, also in combination with any of the above embodiments, the reconstituted liquid suspension has a yield stress value of at least 1.3 Pa, wherein the yield stress value is measured by rheometer MCR 102 (Anton Paar, Graz, Austria) according to the procedure described in Example 2 below.

[0276] A third object of the present invention is a powder mixture or its reconstituted 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.

[0277] Another object of the present invention is a powder mixture according to any of the above embodiments or a reconstituted liquid suspension thereof for use in preventing diabetes or delaying the onset and progression of diabetes, wherein the diabetes is preferably type I diabetes.

[0278] Another object of the present invention is a powder mixture or a reconstituted liquid suspension thereof according to any of the above embodiments, for use in treating an infection caused by SARS-CoV-2 or a variant thereof, preferably for treating COVID-19, and even more preferably for improving respiratory function affected by pneumonia caused by SARS-CoV-2 or a variant thereof in a subject.

[0279] In one embodiment, said improvement in respiratory function in said subject means reducing, delaying the initiation of, or preventing the need for supplemental oxygen, the use of mechanical ventilation, or admission to an intensive care unit.

[0280] The term "pneumonia caused by SARS-CoV-2 or its variants" as used herein refers to an inflammatory condition of the lungs associated with infection with SARS-CoV-2 or its variants. This is a serious complication of COVID-19, affecting a certain percentage of subjects.

[0281] In one embodiment, the liquid suspension for treating COVID-19 according to any of the above embodiments is administered in combination with standard of care treatment for COVID-19 patients.

[0282] As used herein, “standard of care treatment for patients with COVID-19” means 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 is used in clinical practice as a treatment for symptoms and complications associated with COVID-19. Preferably, the standard of care treatment comprises treating the patient with at least one drug selected from the group consisting of: 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.

[0283] Preferably, the subject affected by pneumonia caused by SARS-CoV-2 or a variant thereof suffers from lymphocytopenia.

[0284] According to a preferred embodiment, the subject suffering from lymphocytopenia is an adult patient (14 years and above) and the blood concentration of lymphocytes is less than 1000 cells / μl, less than 900 cells / μl, less than 850 cells / μl, less than 800 cells / μl or less than 750 cells / μl.

[0285] According to another preferred embodiment, the subject suffering from lymphocytopenia is a pediatric patient (under 14 years old) and the blood concentration of lymphocytes is less than 3000 cells / μl, less than 2800 cells / μl, less than 2500 cells / μl, less than 2300 cells / μl or less than 2000 cells / μl.

[0286] Another object of the invention is a powder mixture or a reconstituted liquid suspension thereof according to any of the above embodiments for use in preventing or treating epileptic seizures in an individual.

[0287] According to a preferred embodiment, the epileptic seizure is an acute symptomatic seizure (ASS).

[0288] According to another preferred embodiment, the epileptic seizure is associated with an established epilepsy (Established Epilepsy Seizure (EES)).

[0289] In one embodiment, the reconstituted liquid suspension for use according to the present invention is orally administered to a subject, preferably a mammal, even more preferably a human.

[0290] In one embodiment, the powder mixture according to the first object of the invention and / or its reconstituted liquid suspension comprising Reparixin in an amount of 7.6% w / w to 13.9% w / w is suitable for administration to pediatric subjects, wherein the pediatric subject is less than 14 years old.

[0291] In one embodiment, the powder mixture according to the first object of the invention and / or its reconstituted liquid suspension comprising Reparixin in an amount of 17.5% w / w to 26.8% w / w is suitable for administration to adult subjects, wherein the adult subject is older than 14 years old.

[0292] Another object of the present invention is a kit comprising, preferably consisting of:

[0293] a) a powder mixture according to any of the above embodiments according to the first aspect of the invention, and

[0294] b) an aqueous carrier, preferably water.

[0295] In one embodiment, a) and b) are contained in separate containers. In an alternative embodiment, a) and b) are contained in the same container and are separated by a destructible barrier that can be broken at the time of use to disperse the powder mixture in the aqueous carrier.

[0296] The invention will be further described in the following examples, which do not limit the scope of the invention as defined in the claims.

[0297] Experimental Section

[0298] All percentages shown in the following tables are intended as % w / w.

[0299] Example 1 - Preparation of liquid suspensions and powder mixtures containing Reparixin

[0300] Follow these experimental steps:

[0301] a) a liquid suspension containing Reparixin was prepared and characterized based on zeta potential and rheological properties;

[0302] b) Based on the results of the characterization, the best suspension was selected and the corresponding powder mixture was prepared.

[0303] The materials used to prepare the suspensions are shown in Table 5.

[0304] Table 5

[0305]

[0306]

[0307] The prepared suspension contained the following excipients:

[0308] - wetting agents, which serve to increase the wettability of Reparixin in water, which itself is low;

[0309] - sweeteners, which serve to mask the unpleasant taste of Reparixin;

[0310] - preservatives, which are used to prevent or retard the growth of microorganisms;

[0311] - pH adjusting agents, which are used to adjust the pH of the solution to a desired value.

[0312] The types and / or amounts of the following components varied between suspensions:

[0313] - Wetting agents; in particular, sodium lauryl sulfate (SLS), poloxamer 407, polyvinylpyrrolidone and poloxamer 188 were tested as wetting agents. Poloxamer 407 was immediately rejected due to its insufficient ability to disperse Reparixin;

[0314] - Sweeteners; in particular, sucrose and sucralose were tested as sweeteners. Sucrose has a high glycemic index, while sucralose is an artificial sweetener with a glycemic index of zero.

[0315] The procedure for preparing the liquid suspension is described below.

[0316] Selected amounts of defoamer (when present), wetting agent, preservative and pH adjuster were added to 40 g of distilled water and the mixture was kept under a magnetic stirrer until a solution was obtained. Then, selected amount of Reparixin was added and dispersed. After the API was uniformly suspended, selected amounts of other excipients (viscosity agent and sweetener) were added and dissolved. Finally, water was added until the final weight was 100 g.

[0317] In the following, the compositions of the prepared liquid suspensions and powder mixtures will be reported, while the corresponding data for characterization will be shown and discussed in Example 2 below.

[0318] Table 6 below reports the liquid suspension prepared by using SLS as a wetting agent. Specifically, the prepared suspension 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 pH adjusters, 0.005% w / w simethicone as a defoaming agent, and water as a solvent.

[0319] The amount of pH adjuster (citric acid monohydrate and sodium citrate dihydrate) and the type / amount of viscosity agent (xanthan gum or Avicel CL-611) were varied between the different suspensions prepared.

[0320] Table 6

[0321]

[0322] Table 7 below reports a liquid suspension prepared by using poloxamer 188 as a wetting agent. Specifically, the prepared suspension contained 0.25% w / w poloxamer 188, Avicel CL-611 as a viscosity agent, 0.15% w / w potassium sorbate as a preservative, 40% w / w sucrose as a sweetener, 0.005% w / w simethicone as a defoaming agent, and water as a solvent.

[0323] The amount of Avicel CL-611 and the type / amount of pH adjuster (citric acid monohydrate / sodium citrate dihydrate or citric acid monohydrate / NaOH 1 M) were varied between the different suspensions prepared.

[0324] In addition to the suspensions reported in Table 7, suspension 80 was prepared having a composition corresponding to suspension 79, but with 1.00% w / w Blanose (sodium carboxymethylcellulose) instead of 3.00% w / w Avicel CL-611.

[0325] Table 7

[0326]

[0327] Table 8 below reports the liquid suspensions prepared by using polyvinylpyrrolidone as a wetting agent and Avicel CL-611 as a viscosity agent. Specifically, the prepared suspensions contained 2.00% w / w polyvinylpyrrolidone (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 a defoaming agent, 0.064% w / w citric acid monohydrate and 0.208% w / w sodium citrate dihydrate as pH adjusters, and water as a solvent.

[0328] The amount of Avicel CL-611 varied between suspensions. In addition, Suspension 104 also contained 1.00% w / w crospovidone, which served as an anti-caking agent.

[0329] Table 8

[0330]

[0331] Table 9 below reports other liquid suspensions prepared by using Poloxamer 188 as a wetting agent and Avicel CL-611 as a viscosity agent. The amounts of both Poloxamer 188 and Avicel CL-611 were increased relative to the suspensions reported in Table 7 above. Specifically, the prepared suspensions contained 0.50% w / w Poloxamer 188, Avicel CL-611, 0.15% w / w potassium sorbate as a preservative, 40.00% w / w sucrose as a sweetener, 0.064% w / w citric acid monohydrate 0.208% w / w sodium citrate dihydrate as pH adjusters and water as a solvent.

[0332] The amount of simethicone and the amount of Avicel CL-611 used as antifoaming agents in some suspensions, as well as the amount of sodium citrate dihydrate used as a pH adjuster in combination with citric acid monohydrate (0.208% w / w or 0%) varied between the suspensions prepared.

[0333] Table 9

[0334]

[0335] Table 10 below reports the powder mixtures prepared by geometric dilution using a powder mixer Turbula T2 F (WAB Group, Muttenz, Switzerland) according to the manufacturer's instructions.

[0336] The powder mixture (in an amount capable of producing the desired amount of Reparixin and other components in the corresponding reconstituted liquid suspension) was aliquoted into glass bottles and subsequently reconstituted with water until a final volume of 100 g was reached. In some powder mixtures, different amounts of colloidal silicon dioxide were introduced to study its effect on the flowability of the powder mixture.

[0337] Table 10

[0338]

[0339] Table 11 below reports additional powder mixtures prepared by varying the percentages of Reparixin and sucrose. The powder mixture designated "141pd" in Table 11 corresponds to the powder mixture designated "141" in Table 10. The corresponding reconstituted liquid suspensions are shown in Table 12. The abbreviation "pd" is used to indicate "powder mixture", while the abbreviation "lq" is used to indicate "liquid".

[0340] Table 11

[0341]

[0342] Table 12

[0343]

[0344] Example 2 - Characterization of the resulting liquid suspension and powder mixture

[0345] Zeta potential values ​​and rheological properties were determined for the liquid suspensions reported in Example 1. In the case of powder mixtures, flow properties were evaluated.

[0346] 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 containing Reparixin 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, 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 easily resuspendable 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 a hydration layer surrounding the particles of the internal phase is less present or absent, resulting in an increase in the sedimentation rate.

[0347] With regard to rheological properties, the rheological properties, 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 when the material begins to flow or plastic deformation. If the yield stress is higher than the sedimentation stress (τS), the suspension is considered to be stable, and the sedimentation stress can be defined as the stress applied by the particles to the liquid. If τ0 is higher than τS, no sedimentation will occur, and the suspension can be considered to be stable. Generally speaking, for a liquid suspension reconstructed by suspending the powder mixture in a suitable carrier when in use, a yield stress of about 1.3 Pa or more is considered to be a satisfactory value to prevent sedimentation.

[0348] 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 (such as manual shaking) is applied, the viscosity (such as viscosity) of the external phase caused by the suspensoid should be reduced to ensure the redispersibility of the precipitate. In the literature, the thixotropy area is usually related to the suspension stability. As shown by E.C. Foernzler, the sedimentation velocity 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).

[0349] Based on the above, the prepared suspensions were characterized according to zeta potential values, rheological properties and redispersibility.

[0350] The 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.

[0351] Rheological properties such as yield stress and thixotropy (hysteresis) were evaluated by means of a rheometer MCR 102 (Anton Paar, Graz, Austria).

[0352] 0.1 to 100 s -1 The yield stress was determined by linearly increasing the shear rate stepwise to generate a flow curve (shear stress vs. shear rate). The resulting flow curve was then fitted with a Herschel-Bulkley regression model and the yield point was determined by extrapolating the flow curve to zero shear rate.

[0353] The thixotropy of the suspension was evaluated by hysteresis. The measurement was performed with an initial pre-shear at 5 1 / s, and then the shear rate was increased from 5 to 131 s. -1 (logarithmic scale), the upper flow curve is generated, and the shear rate is reduced from 131 to 5s -1 , the lower flow curve was obtained. The area between the upper and lower curves was calculated and related to the thixotropy of the system. All analyses were performed at room temperature using a 25 mm measuring plate and the gap was set to 1 mm.

[0354] If a precipitate was present, the ability to redisperse was assessed taking into account the number of 180° rotations that allowed the precipitate to redisperse.

[0355] Table 13 below reports the values ​​of zeta potential and rheological properties obtained for the suspensions reported in Table 6 above.

[0356] Table 13

[0357]

[0358] 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 pH adjuster (sodium citrate dihydrate + citric acid monohydrate) slightly reduced the absolute value of the zeta potential, however, the absolute value of the zeta potential was still too high. Based on these results, SLS was excluded from inclusion in the powder mixture as a wetting agent as it did not produce a stable reconstituted liquid suspension of Reparixin.

[0359] Table 14 below reports the values ​​of zeta potential and rheological properties obtained for the reported suspensions reported in Table 7 above and for Suspension 80 described above.

[0360] Table 14

[0361]

[0362]

[0363] As can be seen, all suspensions reported in Table 7 are characterized by zeta potential values ​​close to zero. Based on these data, the inventors hypothesized that, unexpectedly, the use of sucrose as sweetener might be involved in the realization of this trend.

[0364] Without being bound by theory or principle, this trend can be explained by the unexpected formation of a hydration layer of sucrose around the suspended particles, which allows to increase 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, it is easily resuspendable by manual shaking, because it is loose and not dense. The increase in the amount of viscosity agent (Avicel CL-611) leads to an improvement in the rheological properties. In fact, suspensions 78 and 79, which contain the highest amount of Avicel CL-611 among the suspensions reported in Table 7, are the suspensions characterized by the best rheological properties (higher yield stress and hysteresis area). Although suspension 80 is characterized by suitable zeta potential and yield stress values, it is characterized by the presence of non-redispersible precipitates.

[0365] Table 15 below reports the values ​​of zeta potential and rheological properties obtained for the suspensions reported in Table 8 above.

[0366] Table 15

[0367]

[0368] As can be seen, when Avicel CL-611 was used as viscosity agent, in combination with PVP K30 as wetting agent, the resulting suspension was characterized by persistent foaming on its surface, probably due to incomplete wettability of Reparixin. Based on these results, it was decided not to use Avicel CL-611 as viscosity agent and PVP as wetting agent in combination in the powder mixture according to the invention.

[0369] Table 16 below reports the values ​​of zeta potential and rheological properties obtained for the suspensions reported in Table 9 above.

[0370] Table 16

[0371]

[0372]

[0373] As can be seen, all suspensions are characterized by suitable zeta potential values ​​and rheological properties. Overall, suspensions 131 and 133 are characterized by the best properties.

[0374] The powder mixtures reported in Table 10 above were characterized by the flowability of the Flodex using the Flodex Apparatus, Teledyne Hanson Research, Chatsworth, California, USA. The analysis is based on the ability of the powder to fall freely through the holes in the disk. For each material, a flowability index is reported, corresponding to the diameter of the hole in the disk (scaled from 4 mm to 34 mm). The instrument is formed by a cylinder fixed on a shaft. The selected disk is fixed to the cylinder. The hole in the disk is closed by the device. About 50 g of powder is poured into the middle of the disk through a funnel. When the loading is completed, 30 seconds must be allowed to pass so that individual flocculations or large flocculations of the entire load may form. The device is then operated to open the holes in the disk quickly and without vibration. Very fluid powders will slowly flow through small diameter holes, leaving a cavity shaped like an inverted truncated cone. On the other hand, powders with very low flowability may come out of the hole or may fall suddenly. In this case, the powder must be tested again with a disk with larger holes.

[0375] Table 17 below reports the flodex values ​​for the powder blends reported in Table 10 above.

[0376] Table 17

[0377] preparation Flodex(mm) 138 20 141 6 144 10 145 9

[0378] As can be seen from the above results, powder mixtures 141, 144 and 145 are characterized by suitable flodex values, indicating that colloidal silicon dioxide must be included in the powder mixtures of the present invention to obtain the desired flowability. In contrast, powder mixture 138, in which colloidal silicon dioxide is not present, is characterized by an inappropriate flodex value.

[0379] Table 18 below reports the values ​​of zeta potential and rheological properties obtained for the suspensions reported in Table 12 above, ie for the liquid suspensions reconstituted from the powder mixtures reported in Table 11 above.

[0380] Table 18

[0381]

[0382]

[0383] This experiment was conducted to further study and confirm the effect of the type / amount of sweeteners included in the formulation on the stability of the zeta potential value of the reconstructed liquid suspension. As can be seen, when 20% w / w sucrose was contained in the reconstructed liquid suspension (suspension 163lq), the absolute value of the zeta potential was too high, meaning that the suspension was unstable. When 0.60% sucralose was contained instead of sucrose in the reconstructed liquid suspension (suspension 167lq), the same trend was observed.

[0384] When the reconstituted liquid suspension (suspension 164 1q) contained 60% w / w sucrose, a persistent foam layer was observed on the surface and the suspension was too viscous to handle and pour.

[0385] When sucrose was included in the reconstituted liquid suspension in an amount of 30% w / w, 40% w / w and 50% w / w, zeta potential values ​​close to zero and satisfactory rheological properties were obtained in the reconstituted liquid suspensions (suspensions 1611q, 1411q and 1621q, respectively).

[0386] These results demonstrate the unexpected influence of the type and amount of sweetener comprised in the powder mix on the zeta potential value and the rheological properties of the reconstituted liquid suspension and thus on its stability. Therefore, sucrose was selected as the sweetener comprised in the powder mix of the present invention.

[0387] Table 19 below reports the values ​​of zeta potential and rheological properties obtained for the suspension 150 lq reported in Table 12 above.

[0388] Table 19

[0389]

[0390] The suspension is characterized by optimal zeta potential values ​​and rheological properties. These data further demonstrate the suitability of sucrose for stabilizing zeta potential values, even in reconstituted liquid suspensions containing higher amounts of Reparixin, particularly suitable for administration in adult subjects.

Claims

1. A powder mixture comprising: - Reparixin in an amount ranging from 3.5% w / w to 28.2% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 3% w / w to 8.3% w / w, - sucrose in an amount of 63% w / w to 89% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w, - colloidal silicon dioxide in an amount of 0.7% w / w to 1.4% w / w, Provided that when the viscosity agent is the spray-dried blend of microcrystalline cellulose and sodium carboxymethyl cellulose, the wetting agent is not polyvinyl pyrrolidone.

2. The powder mixture according to claim 1, comprising: - Reparixin in an amount ranging from 6.8% w / w to 28.2% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 3% w / w to 8.3% w / w, preferably 3% w / w to 8% w / w, - sucrose in an amount of 63% w / w to 88% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w, - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w.

3. A powder mixture according to claim 1 or claim 2, comprising: - Reparixin in an amount of 7.6% w / w to 26.8% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 4.5% w / w to 7.8% w / w, - sucrose in an amount of 64.2% w / w to 85.2% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w, - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w.

4. A powder mixture according to any one of the preceding claims, comprising: - Reparixin in an amount ranging from 8.4% w / w to 26% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 4.5% w / w to 7.7% w / w, - sucrose in an amount of 64.9% w / w to 84.5% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w, - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w.

5. A powder mixture according to any one of claims 1 to 3, comprising: - Reparixin in an amount of 7.6% w / w to 13.9% w / w, - sucrose in an amount of 75.5% w / w to 85.2% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 5% w / w to 7.8% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.8% w / w to 1.3% w / w, - Colloidal silicon dioxide in an amount of 0.8% w / w to 1.3% w / w.

6. A powder mixture according to any one of claims 1 or 2, comprising: - Reparixin in an amount ranging from 17.5% w / w to 26.8% w / w, - sucrose in an amount of 64.2% w / w to 76.1% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 4.5% w / w to 6.6% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.7% w / w to 1.1% w / w, - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.1% w / w.

7. A powder mixture according to claim 1, wherein at least 98%, preferably at least 99%, of the total weight of the mixture consists of: - Reparixin in an amount ranging from 3.5% w / w to 28.2% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 3% w / w to 8.3% w / w, - sucrose in an amount of 63% w / w to 89% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w, - colloidal silicon dioxide in an amount of 0.7% w / w to 1.4% w / w, - a pH adjuster, preferably in an amount of 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount of 0.1% w / w to 0.5% w / w.

8. A powder mixture according to claim 2, wherein at least 98%, preferably at least 99%, of the total weight of the mixture consists of: - Reparixin in an amount ranging from 6.8% w / w to 28.2% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 3% w / w to 8.3% w / w, preferably 3% w / w to 8% w / w, - sucrose in an amount of 63% w / w to 88% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.5% w / w to 1.5% w / w, - colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w, - a pH adjuster, preferably in an amount of 0.1 to 0.2% w / w, and / or a preservative, preferably in an amount of 0.1 to 0.5% w / w.

9. A powder mixture according to claim 3, wherein at least 98%, preferably at least 99%, of the total weight of the mixture consists of: - Reparixin in an amount ranging from 7.6% w / w to 26.8% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 4.5% w / w to 7.8% w / w, - sucrose in an amount of 64.2% w / w to 85.2% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w, - colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w, - a pH adjuster, preferably in an amount of 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount of 0.2% w / w to 0.4% w / w.

10. A powder mixture according to claim 4, wherein at least 98%, preferably at least 99%, by total weight thereof consists of: - Reparixin in an amount ranging from 8.4% w / w to 26% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 4.5% w / w to 7.7% w / w, - sucrose in an amount of 64.9% w / w to 84.5% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.7% w / w to 1.3% w / w, - colloidal silicon dioxide in an amount of 0.7% w / w to 1.3% w / w, - a pH adjuster, preferably in an amount of 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount of 0.2% w / w to 0.4% w / w.

11. A powder mixture according to claim 5, wherein at least 98%, preferably at least 99%, of the total weight of the mixture consists of: - Reparixin in an amount of 7.6% w / w to 13.9% w / w, - sucrose in an amount of 75.5% w / w to 85.2% w / w, - a preservative, preferably in an amount of 0.2% w / w to 0.4% w / w, and / or a pH adjuster, preferably in an amount of 0.10% w / w to 0.17% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 5% w / w to 7.8% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.8% w / w to 1.3% w / w, - Colloidal silicon dioxide in an amount of 0.8% w / w to 1.3% w / w.

12. A powder mixture according to claim 6, wherein at least 98%, preferably at least 99%, of the total weight of the mixture consists of: - Reparixin in an amount ranging from 17.5% w / w to 26.8% w / w, - sucrose in an amount of 64.2% w / w to 76.1% w / w, - a preservative, preferably in an amount of 0.2% w / w to 0.35% w / w, and / or a pH adjuster, preferably in an amount of 0.1% w / w to 0.2% w / w, - a viscosity agent selected from xanthan gum in an amount of 0.3% w / w to 0.5% w / w, gum arabic in an amount of 0.3% w / w to 0.5% w / w, and 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, the blend being in an amount of 4.5% w / w to 6.6% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount of 3% w / w to 5% w / w and poloxamer 188 in an amount of 0.7% w / w to 1.1% w / w, - Colloidal silicon dioxide in an amount of 0.7% w / w to 1.1% w / w.

13. A powder mixture according to any one of claims 7 to 12, wherein the preservative is selected from potassium sorbate, sodium benzoate, methylparaben and propylparaben, and / or the pH adjuster is selected from citric acid monohydrate, hydrochloric acid, sodium dihydrogen phosphate and potassium dihydrogen phosphate.

14. Process for producing a reconstituted liquid suspension from a powder mixture according to any one of claims 1 to 13, comprising the step of suspending the powder mixture in an aqueous carrier, preferably water.

15. A powder mixture according to any one of claims 1 to 13 or a reconstituted liquid suspension thereof 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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