Powder mixture containing repalixine

Abstract

The present invention relates to a powder mixture of reparixin suitable for generating a reconstituted liquid suspension in an aqueous vehicle during use.

Description

Technical Field

[0001] The present invention relates to a powder mixture containing repalixine, which is suitable for generating a liquid suspension that is reconstituted during use.

Background Art

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

[0003] For example, IL-8 is involved in neutrophil infiltration in pathological conditions such as psoriasis (B.J. Nickoloff et al., Am. J. Pathol., 1991, 138, 12�), rheumatoid arthritis (M. Selz et al., J. Clin. Invest., 1991, 87, 463), ulcerative colitis (Y.R. Mahkla et al., Clin. Sci., , 1992, 82, 273), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (P.C. Carre et al., J. Clin. Invest., 1991, 88, 1802, and E.J. Miller et al., Am. Rev. Respir. Dis., 1992, 146: 427-432) and glomerulonephritis (T. Wada et al., J. Exp. Med., 1994, 180, 1135).

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

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

[0006] A phase 2, multi - center, open - label, randomized, draw - out clinical trial was conducted from May 5, 2020, to November 27, 2020, to evaluate the efficacy and safety of reparixin in hospitalized patients with severe COVID - 19 pneumonia compared with available treatments considered as standard of care (SOC). This trial 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] At that time, reparixin was only formulated in the form of tablets for oral administration or solutions for i.v. administration. However, these types of administration are invasive and / or not appropriate for achieving satisfactory medication compliance, especially in pediatric patients or patients who cannot swallow solid tablets. As a result, it is necessary to develop a new pharmaceutical formulation containing reparixin that can overcome these problems and can be administered to subjects of all conditions and ages. For this goal, a suspension is an ideal candidate.

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

[0009] Suspensions can be sold either in the form of a ready-to-use liquid suspension or as a powder mixture that is reconstituted in a suitable liquid vehicle at the time of use. Such powder mixtures generally contain an active pharmaceutical ingredient (API) as well as suitable suspending and dispersing agents, which are to be diluted with a specified amount of vehicle (usually an aqueous vehicle) and agitated.

[0010] The formulation and dispensing of this type of dosage form are associated with several advantages, namely, efficient formulation of hydrophobic drugs; avoidance of the use of co-solvents; masking of unpleasant tastes; provision of resistance to drug degradation by hydrolysis, oxidation or microbial activity; and ease of administration for pediatric or geriatric patients. In addition, higher concentrations of drugs can be incorporated into suspensions than into solutions (Doye, P. et al., Int J Curr Pharm Sci, 2017, 9, 8).

[0011] Suspensions are thermodynamically unstable systems due to the free energy of these internal phases, which results in particle aggregation and sedimentation, reducing the energy of the system. The main challenge in the development of a powder mixture that can be suspended in a suitable vehicle at the time of use and manually shaken to obtain a liquid suspension is to ensure rapid dispersion upon reconstitution in water. Also, the powder must be flowable, the API must be uniformly dispersed in the powder mixture, and preferably, physical stability and redispersibility must be ensured for at least one month after reconstitution.

[0012] When formulating a powder mixture suitable for generating a liquid suspension that is reconstituted at the time of use, several aspects must be considered to achieve the above-described properties. The preparation of a suspension containing repalixine is particularly difficult due to the specific characteristics of this active pharmaceutical ingredient (API).

[0013] First, repalixine is produced in the form of a powder composed of particles with large particle sizes. Therefore, a possible suspension containing repalixine is a coarse suspension, that is, a suspension characterized by an internal phase with a particle size larger than about 0.5 μm (Edman, P., Journal of Aerosol Medicine, 1994, Vol. 7, pp. S-3 - S-6).

[0014] In the case of a coarse suspension, the internal phase with the API settles under gravity and tends to cause a sedimentation phenomenon due to its particle size. An increase in the zeta potential as an absolute value results in an increase in the sedimentation rate. This suggests that sedimentation is driven more by gravity rather than electrostatic interactions, and in this electrostatic interaction, the particle size of the internal phase is not sufficient to bring about stability and kinetic stabilization. For this reason, the zeta potential value of a coarse suspension is usually set around zero to ensure physical stability. This zeta potential value corresponds to the state where the particles are surrounded by a hydration layer that hides these charges. When the particles aggregate and sediment, the hydration layer can prevent the formation of a compact precipitate and instead promote the formation of a loose precipitate that can be easily resuspended by manually shaking. To adjust the zeta potential value of the suspension, ionic or non-ionic surfactants and different types of electrolytes (such as salts) are generally used. For example, PEG (polyethylene glycol) is included in many commercially available suspensions for this purpose.

[0015] Furthermore, repalixine has low wettability, which makes it more complicated to formulate repalixine into a powder mixture suitable for generating a reconstituted liquid suspension during use. In fact, the wettability of dispersed particles is important to ensure homogeneity and uniformity of the contents (Kwok, D.Y. et al., Advances in Colloid and Interface Science, 1999, Vol. 81, pp. 167-249). Wettability is the tendency of a fluid to spread or adhere on a solid surface when the fluids are immiscible. As a result of the weak wettability of the powder solid, the powder solid flows on the surface of the liquid medium. The weak wettability of the internal phase is mainly due to the high interfacial tension between the dispersed particles and the dispersion medium, and the reduction of the interfacial tension increases the stability of the suspension. When formulating a suspension or a powder mixture that is reconstituted in an aqueous vehicle during use, a common way to improve the wettability of the solid is to use a wetting agent, such as a surfactant, which can reduce the solid-liquid interfacial tension.

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

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0017] Considering the above, it is clear that there is a need to develop a powder mixture containing repalixine that produces a suspension having satisfactory characteristics when reconstituted in an aqueous vehicle during use. However, this is particularly difficult for this API considering the reasons discussed above.

MEANS FOR SOLVING THE PROBLEM

[0018] The inventors have developed a powder mixture containing reparixin that is suitable for generating a reconstituted liquid suspension having satisfactory characteristics in terms of stability, wettability, and homogeneity of API distribution. Reconstitution is carried out in an aqueous vehicle during use.

[0019] Specifically, the inventors have surprisingly found that the type and amount of sweetener contained in the powder mixture to mask the unpleasant taste of reparixin affect the zeta potential value and rheological properties, and consequently the stability, of the liquid suspension reconstituted from such a mixture.

[0020] Furthermore, the inventors have found that the use of polyvinylpyrrolidone or poloxamer 188 as a wetting agent makes it possible to obtain satisfactory wettability of reparixin. The selected wetting agent ensures homogeneous dispersion of reparixin in the aqueous vehicle.

[0021] The inventors have further identified the type and range of viscosity modifiers and colloidal silica that must be included in the powder mixture in order to obtain a free-flowing powder and a stable liquid suspension of reparixin after reconstitution of the powder in an aqueous vehicle.

[0022] Accordingly, a first object of the present invention is - reparixin in an amount between 3.5% w / w and 28.2% w / w, - a viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 3% w / w and 8.3% w / w, - sucrose in an amount between 63% w / w and 89% w / w, - a wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.5% w / w and 1.5% w / w, - colloidal silica in an amount between 0.7% w / w and 1.4% w / w A powder mixture comprising, provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0023] A further object of the present invention is a method for producing a liquid suspension containing repalixine, the method comprising suspending a powder mixture according to the first object of the present invention in an aqueous vehicle, preferably water.

[0024] A further 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 psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis, glomerulonephritis, COVID-19, pneumonia caused by SARS-CoV-2 or a variant thereof.

[0025] A further 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 prevention of diabetes or the delay of the onset and progression of diabetes.

[0026] A further 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 prevention and / or treatment of seizures. A further object of the present invention is a) a powder mixture according to the first object of the present invention, and b) an aqueous vehicle, preferably water A kit comprising. Definitions As used herein, the term "antifoaming agent" refers to a chemical additive that reduces and / or inhibits the formation of foamy substances in a liquid formulation, such as a liquid suspension, by reducing the liquid-air surface tension.

[0027] As used herein, the term "wetting agent" refers to an excipient that can reduce the API-water interfacial tension by improving the wettability and spreadability of the suspended API.

[0028] As used herein with reference to the components of the powder mixture according to the present invention, "% w / w" indicates the grams of the component in 100 grams of the powder mixture. For example, the expression "10.16% w / w amount of repalixine" indicates that 10.16 grams of repalixine is present in 100 grams of the powder mixture.

[0029] As used herein with reference to the components of the liquid suspension, "% w / w" indicated the grams of the component in 100 grams of the liquid suspension. For example, the expression "5% w / w amount of repalixine" indicates that 5 grams of repalixine is present in 100 grams of the liquid suspension.

[0030] As used herein, the terms "reconstituted liquid suspension" or "reconstituted such liquid suspension" with reference to the powder mixture refer to the liquid suspension produced when the powder mixture is suspended in an aqueous vehicle, preferably water.

[0031] As used herein, the term "aqueous vehicle" refers to an aqueous solvent suitable for suspending the powder mixture according to the first object of the present invention. Preferably, the aqueous vehicle is water.

[0032] As used herein, the term "Avicel CL-611" refers to a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose, in which sodium carboxymethylcellulose is present in an amount between 11.3% w / w and 18.8% w / w.

[0033] It is understood that terms such as "suspend" and "disperse", or "suspended" and "dispersed", can be used interchangeably in the context of the description of the present invention.

Mode for Carrying Out the Invention

[0034] As will be described in more detail in the experimental section, when the powder mixture is suspended in an aqueous vehicle, the inventors have identified the qualitative and quantitative composition of the excipients that must be included in the powder mixture containing repalixine so that a homogeneous reconstituted liquid suspension that is stable for a sufficient time can be obtained.

[0035] In particular, it has unexpectedly been found that the type and amount of sweetener included in the powder mixture of repalixine to mask the unpleasant taste of this API affect the zeta potential value and rheological properties of the corresponding reconstituted liquid suspension, and thus its stability.

[0036] Also, the inventors have selected polyvinylpyrrolidone or poloxamer 188 as the wetting agent included in the powder mixture to achieve satisfactory wettability of the API and to ensure a homogeneous distribution in the reconstituted liquid suspension.

[0037] The reconstituted liquid suspension must be stable for at least one month after reconstitution, and if a precipitate is formed, the precipitate must be easily resuspendable by manual shaking.

[0038] Therefore, the first object of the present invention is - Repalixine in an amount between 3.5% w / w and 28.2% w / w - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 3% w / w and 8.3% w / w - Sucrose in an amount between 63% w / w and 89% w / w - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.5% w / w and 1.5% w / w - Colloidal silica in an amount between 0.7% w / w and 1.4% w / w A powder mixture comprising, provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0039] Repalixine (CAS No.: 266359-83-5) is also known as R-(-)-2-(4-isobutylphenyl)propionylmethanesulfonamide or Repeltaxine and has the following chemical structure:

[0040] [Chemical formula]

[0041] It is a compound having the following structure. In a preferred embodiment, the powder mixture according to the first object of the present invention is such that at least 98%, preferably at least 99% of the total weight of the powder mixture is - Repalixine in an amount between 3.5% w / w and 28.2% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 3% w / w and 8.3% w / w, - Sucrose in an amount between 63% w / w and 89% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.5% w / w and 1.5% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.4% w / w, - A pH adjuster, preferably a pH adjuster in an amount between 0.1% w / w and 0.2% w / w, and / or a preservative, preferably a preservative in an amount between 0.1% w / w and 0.5% w / w and provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0042] In a preferred embodiment, the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 3.5% w / w and 28.2% w / w, - Avicel CL-611 in an amount between 3% w / w and 8.3% w / w, - Sucrose in an amount between 63% w / w and 89% w / w, - Poloxamer 188 in an amount between 0.5% w / w and 1.5% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.4% w / w and comprising.

[0043] In a preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the invention is - Repaglinide in an amount between 3.5% w / w and 28.2% w / w, - Avicel CL-611 in an amount between 3% w / w and 8.3% w / w, - Sucrose in an amount between 63% w / w and 89% w / w, - Poloxamer 188 in an amount between 0.5% w / w and 1.5% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.4% w / w, - A pH adjuster, preferably a pH adjuster in an amount between 0.1% w / w and 0.2% w / w, and / or a preservative, preferably a preservative in an amount between 0.1% w / w and 0.5% w / w and consisting of.

[0044] In a preferred embodiment, the powder mixture according to the first object of the invention is - Repaglinide in an amount between 6.8% w / w and 28.2% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 3% w / w and 8.3% w / w, preferably between 3% w / w and 8% w / w, - Sucrose in an amount between 63% w / w and 88% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.5% w / w and 1.5% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.3% w / w provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0045] In a preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 6.8% w / w and 28.2% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 3% w / w and 8.3% w / w, preferably between 3% w / w and 8% w / w, - Sucrose in an amount between 63% w / w and 88% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.5% w / w and 1.5% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.3% w / w, - A pH adjuster, preferably a pH adjuster in an amount between 0.1 w / w and 0.2% w / w, and / or a preservative, preferably a preservative in an amount between 0.1% w / w and 0.5% w / w provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0046] In a preferred embodiment, the powder mixture according to the first object of the present invention - Repaglinide in an amount between 6.8% w / w and 28.2% w / w, - Avicel CL-611 in an amount between 3% w / w and 8.3% w / w, preferably between 3% w / w and 8% w / w, - Sucrose in an amount between 63% w / w and 88% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.5% w / w and 1.5% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.3% w / w and containing.

[0047] In a preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 6.8% w / w and 28.2% w / w, - Avicel CL-611 in an amount between 3% w / w and 8.3% w / w, preferably between 3% w / w and 8% w / w, - Sucrose in an amount between 63% w / w and 88% w / w, - Poloxamer 188 in an amount between 0.5% w / w and 1.5% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.3% w / w, - A pH adjuster, preferably a pH adjuster in an amount between 0.1 w / w and 0.2% w / w, and / or a preservative, preferably a preservative in an amount between 0.1% w / w and 0.5% w / w consisting of.

[0048] In a preferred embodiment, the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 7.6% w / w and 26.8% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 4.5% w / w and 7.8% w / w, - Sucrose in an amount between 64.2% w / w and 85.2% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.7% w / w and 1.3% w / w, - An amount of colloidal silica between 0.7% w / w and 1.3% w / w including, provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0049] In a preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - An amount of leptin between 7.6% w / w and 26.8% w / w, - A viscosity modifier selected from an amount of xanthan gum between 0.3% w / w and 0.5% w / w, an amount of gum arabic between 0.3% w / w and 0.5% w / w, and an amount of Avicel CL-611 between 4.5% w / w and 7.8% w / w, - An amount of sucrose between 64.2% w / w and 85.2% w / w, - A wetting agent selected from an amount of polyvinylpyrrolidone between 3% w / w and 5% w / w, and an amount of poloxamer 188 between 0.7% w / w and 1.3% w / w, - An amount of colloidal silica between 0.7% w / w and 1.3% w / w, - A pH adjuster, preferably an amount of pH adjuster between 0.1% w / w and 0.2% w / w, and / or a preservative, preferably an amount of preservative between 0.2% w / w and 0.4% w / w and provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0050] In a preferred embodiment, the powder mixture according to the first object of the present invention is - An amount of leptin between 7.6% w / w and 26.8% w / w, - An amount of Avicel CL-611 between 4.5% w / w and 7.8% w / w, - An amount of sucrose between 64.2% w / w and 85.2% w / w, - An amount of poloxamer 188 between 0.7% w / w and 1.3% w / w, - An amount of colloidal silica between 0.7% w / w and 1.3% w / w is included.

[0051] In a preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - An amount of leparaxin between 7.6% w / w and 26.8% w / w, - An amount of Avicel CL-611 between 4.5% w / w and 7.8% w / w, - An amount of sucrose between 64.2% w / w and 85.2% w / w, - An amount of poloxamer 188 between 0.7% w / w and 1.3% w / w, - An amount of colloidal silica between 0.7% w / w and 1.3% w / w, - A pH adjuster, preferably an amount of pH adjuster between 0.1% w / w and 0.2% w / w, and / or a preservative, preferably an amount of preservative between 0.2% w / w and 0.4% w / w consisting of.

[0052] In a preferred embodiment, the powder mixture according to the first object of the present invention is - An amount of leparaxin between 8.4% w / w and 26% w / w, - A viscosity modifier selected from an amount of xanthan gum between 0.3% w / w and 0.5% w / w, an amount of gum arabic between 0.3% w / w and 0.5% w / w, and an amount of Avicel CL-611 between 4.5% w / w and 7.7% w / w, - An amount of sucrose between 64.9% w / w and 84.5% w / w, - A wetting agent selected from an amount of polyvinylpyrrolidone between 3% w / w and 5% w / w and an amount of poloxamer 188 between 0.7% w / w and 1.3% w / w, - An amount of colloidal silica between 0.7% w / w and 1.3% w / w is included, provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0053] In a preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 8.4% w / w and 26% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 4.5% w / w and 7.7% w / w, - Sucrose in an amount between 64.9% w / w and 84.5% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.7% w / w and 1.3% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.3% w / w, - A pH adjuster, preferably a pH adjuster in an amount between 0.1% w / w and 0.2% w / w, and / or a preservative, preferably a preservative in an amount between 0.2% w / w and 0.4% w / w and provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0054] In a preferred embodiment, the powder mixture according to the first object of the present invention - Contains repaglinide in an amount between 8.4% w / w and 26% w / w, - Contains Avicel CL-611 in an amount between 4.5% w / w and 7.7% w / w, - Contains sucrose in an amount between 64.9% w / w and 84.5% w / w, - Contains poloxamer 188 in an amount between 0.7% w / w and 1.3% w / w, - Contains colloidal silica in an amount between 0.7% w / w and 1.3% w / w .

[0055] In a preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - An amount of Reparixin between 8.4% w / w and 26% w / w, - An amount of Avicel CL-611 between 4.5% w / w and 7.7% w / w, - An amount of sucrose between 64.9% w / w and 84.5% w / w, - An amount of poloxamer 188 between 0.7% w / w and 1.3% w / w, - An amount of colloidal silica between 0.7% w / w and 1.3% w / w, - A pH adjuster, preferably an amount of pH adjuster between 0.1% w / w and 0.2% w / w, and / or a preservative, preferably an amount of preservative between 0.2% w / w and 0.4% w / w and consisting of.

[0056] In a preferred embodiment, the powder mixture according to the first object of the present invention is - An amount of Reparixin between 7.6% w / w and 13.9% w / w, - An amount of sucrose between 75.5% w / w and 85.2% w / w, - A viscosity modifier selected from an amount of xanthan gum between 0.3% w / w and 0.5% w / w, an amount of gum arabic between 0.3% w / w and 0.5% w / w, and an amount of Avicel CL-611 between 5% w / w and 7.8% w / w, - A wetting agent selected from an amount of polyvinylpyrrolidone between 3% w / w and 5% w / w and an amount of poloxamer 188 between 0.8% w / w and 1.3% w / w, - An amount of colloidal silica between 0.8% w / w and 1.3% w / w including, provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0057] In a preferred embodiment, the powder mixture according to the first object of the present invention has at least 98%, preferably at least 99% of the total weight of the powder mixture being - An amount of Reparixin between 7.6% w / w and 13.9% w / w, - An amount of sucrose between 75.5% w / w and 85.2% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 5% w / w and 7.8% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.8% w / w and 1.3% w / w, - A pH adjuster, preferably a pH adjuster in an amount between 0.1% w / w and 0.17% w / w, and / or a preservative, preferably a preservative in an amount between 0.2% w / w and 0.4% w / w (the pH adjuster is preferably citric acid monohydrate and / or the preservative is preferably potassium sorbate), - Colloidal silica in an amount between 0.8% w / w and 1.3% w / w consisting of, provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0058] In a preferred embodiment, the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 7.6% w / w and 13.9% w / w, - Sucrose in an amount between 75.5% w / w and 85.2% w / w, - Avicel CL-611 in an amount between 5% w / w and 7.8% w / w, - Poloxamer 188 in an amount between 0.8% w / w and 1.3% w / w, - Colloidal silica in an amount between 0.8% w / w and 1.3% w / w including.

[0059] In a preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 7.6% w / w and 13.9% w / w, - Sucrose in an amount between 75.5% w / w and 85.2% w / w, - A preservative, preferably potassium sorbate in an amount between 0.2% w / w and 0.4% w / w, - Avicel CL-611 in an amount between 5% w / w and 7.8% w / w, - poloxamer 188 in an amount between 0.8% w / w and 1.3% w / w, - A pH adjuster in an amount between 0.1% w / w and 0.17% w / w, preferably citric acid monohydrate, - Colloidal silica in an amount between 0.8% w / w and 1.3% w / w and consists of.

[0060] In a preferred embodiment, the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 8.4% w / w and 12.8% w / w, - Sucrose in an amount between 76.5% w / w and 84.5% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 5% w / w and 7.7% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.8% w / w and 1.3% w / w, - Colloidal silica in an amount between 0.8% w / w and 1.3% w / w including, provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0061] In a preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 8.4% w / w and 12.8% w / w, - Sucrose in an amount between 76.5% w / w and 84.5% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 5% w / w and 7.7% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w, and poloxamer 188 in an amount between 0.8% w / w and 1.3% w / w, - A pH adjuster, preferably a pH adjuster in an amount between 0.1% w / w and 0.2% w / w, and / or a preservative, preferably a preservative in an amount between 0.2% w / w and 0.4% w / w (the pH adjuster is preferably citric acid monohydrate, and / or the preservative is preferably potassium sorbate), - Colloidal silica in an amount between 0.8% w / w and 1.3% w / w and provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0062] In a preferred embodiment, the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 8.4% w / w and 12.8% w / w, - Sucrose in an amount between 76.5% w / w and 84.5% w / w, - Avicel CL-611 in an amount between 5% w / w and 7.7% w / w, - Poloxamer 188 in an amount between 0.8% w / w and 1.3% w / w, - Colloidal silica in an amount between 0.8% w / w and 1.3% w / w and contains.

[0063] In a preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 8.4% w / w and 12.8% w / w, - Sucrose in an amount between 76.5% w / w and 84.5% w / w, - A preservative, preferably potassium sorbate in an amount between 0.2% w / w and 0.4% w / w, - Avicel CL-611 in an amount between 5% w / w and 7.7% w / w, - poloxamer 188 in an amount between 0.8% w / w and 1.3% w / w, - A pH adjuster in an amount between 0.1% w / w and 0.2% w / w, preferably citric acid monohydrate, - Colloidal silica in an amount between 0.8% w / w and 1.3% w / w and consists of.

[0064] In another preferred embodiment, the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 17.5% w / w and 26.8% w / w, - Sucrose in an amount between 64.2% w / w and 76.1% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 4.5% w / w and 6.6% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.7% w / w and 1.1% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.1% w / w and includes, provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0065] In another preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 17.5% w / w and 26.8% w / w, - Sucrose in an amount between 64.2% w / w and 76.1% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 4.5% w / w and 6.6% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w, and poloxamer 188 in an amount between 0.7% w / w and 1.1% w / w, - A pH adjuster, preferably a pH adjuster in an amount between 0.1% w / w and 0.2% w / w, and / or a preservative, preferably a preservative in an amount between 0.2% w / w and 0.35% w / w (the pH adjuster is preferably citric acid monohydrate, and / or the preservative is preferably potassium sorbate), - Colloidal silica in an amount between 0.7% w / w and 1.1% w / w consisting of, provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0066] In another preferred embodiment, the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 17.5% w / w and 26.8% w / w, - Sucrose in an amount between 64.2% w / w and 76.1% w / w, - Avicel CL-611 in an amount between 4.5% w / w and 6.6% w / w, - Poloxamer 188 in an amount between 0.7% w / w and 1.1% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.1% w / w including.

[0067] In another preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 17.5% w / w and 26.8% w / w, - Sucrose in an amount between 64.2% w / w and 76.1% w / w, - A preservative, preferably potassium sorbate in an amount between 0.2% w / w and 0.35% w / w, - Avicel CL-611 in an amount between 4.5% w / w and 6.6% w / w, - poloxamer 188 in an amount between 0.7% w / w and 1.1% w / w, - A pH adjuster in an amount between 0.1% w / w and 0.2% w / w, preferably citric acid monohydrate, - Colloidal silica in an amount between 0.7% w / w and 1.1% w / w and consists of.

[0068] In another preferred embodiment, the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 18.1% w / w and 26% w / w, - Sucrose in an amount between 64.9% w / w and 75.6% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-61l in an amount between 4.5% w / w and 6.5% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w and poloxamer 188 in an amount between 0.75% w / w and 1.1% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.1% w / w including, provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0069] In another preferred embodiment, at least 98%, preferably at least 99% of the total weight of the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 18.1% w / w and 26% w / w, - Sucrose in an amount between 64.9% w / w and 75.6% w / w, - A viscosity modifier selected from xanthan gum in an amount between 0.3% w / w and 0.5% w / w, gum arabic in an amount between 0.3% w / w and 0.5% w / w, and Avicel CL-611 in an amount between 4.5% w / w and 6.5% w / w, - A wetting agent selected from polyvinylpyrrolidone in an amount between 3% w / w and 5% w / w, and poloxamer 188 in an amount between 0.75% w / w and 1.1% w / w, - A pH adjuster, preferably a pH adjuster in an amount between 0.1% w / w and 0.15% w / w, and / or a preservative, preferably a preservative in an amount between 0.2% w / w and 0.35% w / w (the pH adjuster is preferably citric acid monohydrate, and / or the preservative is preferably potassium sorbate), - Colloidal silica in an amount between 0.7% w / w and 1.1% w / w consisting of, provided that when the viscosity modifier is Avicel CL-611, the wetting agent is not polyvinylpyrrolidone.

[0070] In another preferred embodiment, the powder mixture according to the first object of the present invention is - Repaglinide in an amount between 18.1% w / w and 26% w / w, - Sucrose in an amount between 64.9% w / w and 75.6% w / w, - Avicel CL-611 in an amount between 4.5% w / w and 6.5% w / w, - Poloxamer 18's in an amount between 0.75% w / w and 1.1% w / w, - Colloidal silica in an amount between 0.7% w / w and 1.1% w / w including.

[0071] In another preferred embodiment, the powder mixture according to the first object of the present invention is at least 98%, preferably at least 99% of the total weight of the powder mixture, - Repaglinide in an amount between 18.1% w / w and 26% w / w, - Sucrose in an amount between 64.9% w / w and 75.6% w / w, - A preservative, preferably potassium sorbate in an amount between 0.2% w / w and 0.35% w / w, - Avicel CL-611 in an amount between 4.5% w / w and 6.5% w / w, - poloxamer 188 in an amount between 0.75% w / w and 1.1% w / w, - A pH adjuster in an amount between 0.1% w / w and 0.15% w / w, preferably citric acid monohydrate, - Colloidal silica in an amount between 0.7% w / w and 1.1% w / w and consisting of.

[0072] Preferably, when polyvinylpyrrolidone is used as a wetting agent, the polyvinylpyrrolidone is polyvinylpyrrolidone K30. In one embodiment, also in combination with any of the embodiments described above, the pH adjuster can adjust the pH of a liquid suspension reconstituted from the powder mixture to a value between 4 and 6, preferably between 4.5 and 5.5, more preferably 5.

[0073] In one embodiment, also in combination with any of the embodiments described above, the pH adjuster is selected from citric acid, preferably citric acid monohydrate, hydrochloric acid, sodium phosphate, preferably monobasic sodium phosphate, potassium phosphate, preferably monobasic potassium phosphate.

[0074] In one embodiment, also in combination with any of the embodiments described above, the pH adjuster is citric acid, preferably citric acid monohydrate, in an amount between 0.1% w / w and 0.2% w / w.

[0075] In one embodiment, also in combination with any of the embodiments described above, the preservative is selected from potassium sorbate, sodium benzoate, methylparaben and propylparaben. In a preferred embodiment, also in combination with any of the embodiments described above, the preservative is potassium sorbate in an amount between 0.1% w / w and 0.5% w / w.

[0076] Other preferred embodiments of the powder mixture according to the first object of the present invention are shown in Tables 1, 2, 3 and 4 below. All values in the tables are to be interpreted as % w / w as defined above.

[0077] [Table 1]

[0078] [Table 2]

[0079] [Table 3]

[0080] [Table 4]

[0081] In one embodiment, and in combination with any of the above embodiments, the powder mixture according to the first object of the present invention has a flowability index between 10 mm and 4 mm, preferably 6 mm, and the flowability index is measured by using a Flodex Apparatus, Teledyne Hanson Research, Chatsworth, California, USA, according to the procedure described in Example 2 below.

[0082] The second object of the present invention is a method for producing a liquid suspension containing repalixine, the method comprising suspending the powder mixture according to the first object of the present invention in an aqueous vehicle, preferably water. The amount of water in which repalixine is suspended may vary depending on the amount of repalixine, and those skilled in the art can determine such an amount of water.

[0083] In one embodiment, the liquid suspension reconstituted from the powder mixture has a zeta potential value between -5 mV and +5 mV, preferably between -3 mV and +3 mV, and 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.

[0084] In one embodiment, and in combination with any of the embodiments described above, the reconstituted liquid suspension has a yield stress value of at least 1.3 Pa, and the yield stress value is measured by a Rheometer MCR 102 (Anton Paar, Graz, Austria) according to the procedure described in Example 2 below.

[0085] A third object of the present invention is a powder mixture or a reconstituted liquid suspension thereof according to any one of the embodiments described above for use in the treatment of a disease or condition selected from psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis and glomerulonephritis.

[0086] A further object of the present invention is a powder mixture or a reconstituted liquid suspension thereof according to any one of the embodiments described above for use in the prevention of diabetes or the delay of the onset and progression of diabetes, wherein the diabetes is preferably type I diabetes.

[0087] A further object of the present invention is a powder mixture or a reconstituted liquid suspension thereof according to any one of the embodiments described above for use in the treatment of an infection caused by SARS-CoV-2 or a variant thereof, preferably for use in the treatment of COVID-19, more preferably for use in improving respiratory function in a subject suffering from pneumonia caused by SARS-CoV-2 or a variant thereof.

[0088] In one embodiment, the improvement of the respiratory function in the subject means reducing, delaying the onset of, or preventing the need for supplemental oxygen, the use of a ventilator, or the need for admission to an intensive care unit.

[0089] As used herein, the term "pneumonia caused by SARS-CoV-2 or a variant thereof" refers to the inflammatory condition of the lungs associated with an infectious disease caused by SARS-CoV-2 or a variant thereof. This is a severe complication of COVID-19 that affects a certain percentage of subjects.

[0090] In one embodiment, a liquid suspension according to any one of the above-described embodiments for use in the treatment of COVID-19 is administered in combination with standard care procedures for COVID-19 patients.

[0091] As used herein, "standard care procedures for COVID-19 patients" means a pharmacological treatment comprising one or more drugs that are approved by a regulatory authority as a treatment for COVID-19 or as a treatment for other pathological conditions and their symptoms and are used in clinical practice for the treatment of symptoms and complications associated with COVID-19. Preferably, the standard care procedure is the treatment of a patient with at least one drug selected from: i) an antiviral drug, preferably remdesivir; ii) an antipyretic, analgesic, and anti-inflammatory drug, preferably a non-steroidal anti-inflammatory drug, corticosteroid, cytokine, chemokine, and interleukin inhibitor (more preferably selected from dexamethasone, paracetamol, anakinra, celecoxib, prednisone, prednisolone, methylprednisolone, piryrone, and tramadol); iii) an antibiotic in combination with tazobactam, azithromycin, and ceftriazone, preferably an antibiotic selected from piperacillin; and iv) an anticoagulant and antithrombotic drug (preferably selected from enoxaparin and acetylsalicylic acid).

[0092] Preferably, the subject suffering from pneumonia caused by SARS-CoV-2 or a variant thereof has lymphopenia. According to a preferred embodiment, the subject having lymphopenia is an adult patient (14 years of age or older) and has a lymphocyte blood concentration of less than 1000, less than 900, less than 850, less than 800 or less than 750 cells / microliter.

[0093] According to another preferred embodiment, the patient having lymphopenia is a pediatric patient (less than 14 years of age) and has a lymphocyte blood concentration of less than 3000, less than 2800, less than 2500, less than 2300 or less than 2000 cells / microliter.

[0094] A further object of the present invention is a powder mixture or a reconstituted liquid suspension thereof according to any one of the above-described embodiments for use in preventing or treating seizures in an individual.

[0095] According to a preferred embodiment, the seizure is an acute symptomatic seizure (ASS). According to another preferred embodiment, the seizure is associated with established epilepsy (established epileptic seizure EES).

[0096] In one embodiment, the reconstituted liquid suspension for use according to the present invention is orally administered to a subject, preferably a mammal, more preferably a human. In one embodiment, a powder mixture according to the first object of the present invention and / or a reconstituted liquid suspension thereof containing leparexine in an amount between 7.6% w / w and 13.9% w / w is suitable for administration to a pediatric subject, the pediatric subject being less than 14 years of age.

[0097] In one embodiment, a powder mixture according to the first object of the present invention containing reparixin in an amount between 17.5% w / w and 26.8% w / w and / or its reconstituted liquid suspension is suitable for administration to adult subjects, where the adult subjects are over 14 years of age.

[0098] A further object of the present invention is a) a powder mixture according to any of the above embodiments of the first object of the present invention, and b) an aqueous vehicle, preferably water comprising, preferably consisting of, a kit.

[0099] 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 separated by a frangible barrier that can be broken during use to disperse the powder mixture in the aqueous vehicle.

[0100] The present invention is further illustrated in the following examples, which do not limit the scope of the present invention as defined in the claims.

Examples

[0101] All percentages shown in the following table are intended to be % w / w. Example 1 Preparation of a liquid suspension and a powder mixture containing reparixin The following experimental procedure was followed: a) A liquid suspension containing reparixin was prepared and characterized for zeta potential and rheological properties, b) Based on the results of the characterization, the best suspension was selected and the corresponding powder mixture was prepared.

[0102] The materials used to prepare the suspension are shown in Table 5.

[0103]

Table 5

[0104] The prepared suspension contained the following excipients: - A wetting agent, used to increase the wettability of repalixine in water (which is low in itself); - A sweetening agent, used to mask the unpleasant taste of repalixine; - A preservative, used to prevent or delay the growth of microorganisms; - A pH adjuster, used to adjust the pH of the solution to a desired value.

[0105] The type and / or amount of the following components varied depending on the suspension: - Wetting agent; In particular, sodium lauryl sulfate (SLS), poloxamer 407, polyvinylpyrrolidone, and poloxamer 188 were tested as wetting agents. Poloxamer 407 was immediately rejected because of its insufficient ability to disperse repalixine; - Sweetening agent; In particular, sucrose and sucralose were tested as sweetening agents. Sucrose has a high glycemic index, while sucralose is an artificial sweetening agent with a glycemic index of zero.

[0106] The procedure used for the preparation of the liquid suspension is described below. The selected amounts of defoamer (if present), wetting agent, preservative, and pH adjuster(s) were added to 40 g of distilled water, and the mixture was maintained under a magnetic stirrer until a solution was obtained. Then, the selected amount of repalixine was added and dispersed. Once the API was homogeneously suspended, the selected amounts of the other excipients (viscosity modifier and sweetening agent) were added and dissolved. Finally, water was added up to a final weight of 100 g.

[0107] In the following, the compositions of the prepared liquid suspension and powder mixture are reported, and the respective characterization data are shown and discussed in Example 2 below. Table 6 below reports on 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 sweetening agent, 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 an antifoaming agent, and water as a solvent.

[0108] The amounts of the pH adjusters (citric acid monohydrate and sodium citrate dihydrate) and the type / amount of the viscosity modifier (xanthan gum or Avicel CL-611) varied depending on the various suspensions prepared.

[0109] [Table 6]

[0110] Table 7 below reports on liquid suspensions prepared by using poloxamer 188 as a wetting agent. Specifically, the prepared suspensions contained 0.25% w / w poloxamer 188, Avicel CL-611 as a viscosity modifier, 0.15% w / w potassium sorbate as a preservative, 40% w / w sucrose as a sweetening agent, 0.005% w / w simethicone as an antifoaming agent, and water as a solvent.

[0111] The amount of Avicel CL-611 and the type / amount of the pH adjuster (citric acid monohydrate / sodium citrate dihydrate or citric acid monohydrate / 1 M NaOH) varied depending on the various suspensions prepared.

[0112] In addition to the suspensions reported in Table 7, suspension 80 was also prepared, which had a composition corresponding to suspension 79 but had 1.00% w / w Blanose (sodium carboxymethyl cellulose) instead of 3.00% w / w Avicel CL-611.

[0113] [Table 7]

[0114] The following Table 8 reports on liquid suspensions prepared by using polyvinylpyrrolidone as a wetting agent and Avicel CL-611 as a viscosity modifier. 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 sweetening agent, 0.005% w / w simethicone as an antifoaming agent, 0.064% w / w citric acid monohydrate and 0.208% w / w sodium citrate dihydrate as pH adjusters, and water as a solvent.

[0115] The amount of Avicel CL-611 varied depending on the suspension. Furthermore, suspension 104 also contained 1.00% w / w crospovidone used as an anti-caking agent.

[0116]

Table 8

[0117] The following Table 9 reports on other liquid suspensions prepared by using poloxamer 188 as a wetting agent and Avicel CL-611 as a viscosity modifier. For the suspensions reported in Table 7 above, the amounts of both poloxamer 188 and Avicel CL-611 were increased. 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 sweetening agent, 0.064% w / w citric acid monohydrate and 0.208% w / w sodium citrate dihydrate as pH adjusters, and water as a solvent.

[0118] The amounts of Avicel CL-611 and simethicone used as antifoaming agents in some suspensions, and the amount of sodium citrate dihydrate (0.208% w / w or 0%) used in combination with citric acid monohydrate as a pH adjuster varied depending on the suspension prepared.

[0119]

Table 9

[0120] Table 10 below reports on powder mixtures prepared via geometric dilution using a Turbula T2 F powder mixer (WAB Group, Muttenz, Switzerland) according to the manufacturer's instructions.

[0121] Aliquots of the powder mixture that could provide the desired amount of repalixine and the desired amount of other components in the corresponding reconstituted liquid suspension were placed in glass bottles and then reconstituted with water until a final volume of 100 g was reached. In some powder mixtures, different amounts of colloidal silica were introduced to examine its effect on the fluidity of the powder mixture.

[0122]

Table 10

[0123] Table 11 below reports on additional powder mixtures prepared by varying the percentage of repalixine and the percentage of 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 as an abbreviation for "powder mixture" and "lq" is used as an abbreviation for "liquid".

[0124]

Table 11

[0125]

Table 12

[0126] Example 2 Characterization of the generated liquid suspensions and powder mixtures The zeta potential values and rheological properties of the liquid suspensions reported in Example 1 were determined. In the case of the powder mixtures, the flowability was evaluated.

[0127] 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 attractive forces rather than electrostatic interactions, which are insufficient to provide stability and kinetic stabilization. To ensure the stability of the suspension, the zeta potential value should be equal to or near zero, and the particles of the internal phase should be surrounded by a hydration layer that hides the charge of the particles of the internal phase and ensures that, even if a precipitate forms, it is a loose precipitate that can be easily redispersed rather than a compact precipitate that is difficult to redisperse. An increase in the zeta potential (in absolute value) corresponds to a situation where this hydration layer around the particles of the internal phase is less or not present, resulting in an increase in the sedimentation rate.

[0128] Regarding rheological properties, to obtain information about the physical stability of the suspension, the yield stress and thixotropy of the prepared suspension were determined. The yield stress (τ0) is a material property that can be defined as the stress corresponding to the yield point at which the material starts to flow or deform plastically. The suspension is considered stable if the yield stress is higher than the sedimentation stress (τS), where the sedimentation stress can be defined as the stress exerted by the particles on the liquid. If τ0 is higher than τS, sedimentation does not occur and the suspension can be considered stable. Generally, a yield stress around or above 1.3 Pa is considered a satisfactory value for a liquid suspension reconstituted during use by suspending a powder mixture in a suitable vehicle to resist sedimentation.

[0129] The physical stability of the suspension is also evaluated based on the thixotropy hysteresis area. Thixotropy is an inevitable property of the polymer system selected as the viscosity modifier. In fact, the viscosity (e.g., viscosity) of the external phase brought about by the suspending agent should decrease when shear stress such as manual shaking is applied to ensure the redispersibility of the precipitate. In the literature, the thixotropy area is usually correlated with the suspension stability. As demonstrated by E.C. Foernzler, the sedimentation rate is directly proportional to the reciprocal of the hysteresis area, which means that the physical stability is directly proportional to thixotropy (Ernest C. Foernzler et al., J. Am. Pharm. Assoc., Vol. 49 (1960), pp. 249 - 252).

[0130] Based on the above, the generated suspension was characterized for zeta potential value, rheological properties, and redispersion ability. The zeta potential value of the prepared suspension was measured by laser Doppler electrophoresis using a Zetasizer nano ZS (Malvern Instruments, Worcestershire, UK) according to the manufacturer's instructions.

[0131] The rheological properties, such as yield stress and thixotropy (hysteresis), were evaluated via a Rheometer MCR102 (Anton Paar, Graz, Austria).

[0132] To generate the flow curve (shear stress vs. shear rate), the shear rate was linearly increased step - by - step between 0.1 and 100 s -1 to perform the determination of the yield stress. Then, the generated flow curve was fitted to the Herschel - Bulkley regression model, and the yield point was determined by extrapolating the flow curve to zero shear rate.

[0133] The thixotropy of the suspension was evaluated via hysteresis. This measurement was first performed using pre-shearing at 5 1 / s, and then the shear rate was increased from 5 to 13 1 / s (logarithmic scale) to generate the upward flow curve, and the downward flow curve was obtained by reducing the shear rate from 13 to 5 1 / s. The area between the upward and downward curves was calculated. This correlates with the thixotropy of this system. All analyses were performed using a 25 mm measurement plate at room temperature with a gap set at 1 mm. -1 to generate the upward flow curve, and the shear rate was reduced from 13 to 5 1 / s -1 to obtain the downward flow curve. The area between the upward and downward curves was calculated. This correlates with the thixotropy of this system. All analyses were performed using a 25 mm measurement plate at room temperature with a gap set at 1 mm.

[0134] When a precipitate was present, the redispersibility was evaluated considering the number of 180° rotations enabling redispersion of the precipitate. The values of the zeta potential and rheological properties obtained for the suspensions reported in Table 6 above are reported in Table 13 below.

[0135]

Table 13

[0136] As can be seen, the zeta potential values of the suspensions with 0.11% w / w SLS as the wetting agent were all too high in absolute value to enable the stability of the suspension. The increase in the concentration of the pH adjuster (sodium citrate dihydrate + citric acid monohydrate) slightly attenuated the absolute value of the zeta potential, but the value was still too high. Based on these results, SLS was excluded from the wetting agents to be included in the powder mixture because it could not generate a stable reconstituted liquid suspension of repalixine.

[0137] The values of the zeta potential and rheological properties obtained for the suspensions reported in Table 7 above and suspension 80 described above are reported in Table 14 below.

[0138]

Table 14

[0139] As can be seen, all the suspensions reported in Table 7 were characterized by zeta potential values near zero. Based on these data, the inventors hypothesized that the use of sucrose as a sweetening agent might surprisingly be involved in achieving this trend.

[0140] 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 this hydration layer to increase the distance between ions (cations and anions), thereby reducing the absolute value of the zeta potential. Due to this hydration layer, even when a precipitate is formed, the precipitate is loose and not compact, ensuring that this precipitate can be easily redispersed by manual shaking. The increase in the amount of the viscosity modifier (Avicel CL-611) brought about an improvement in the rheological properties. In fact, suspensions 78 and 79, which contained the largest amounts of Avicel CL-611 among the suspensions reported in Table 7, were suspensions characterized by the best rheological properties (higher yield stress and hysteresis area). Suspension 80 was characterized by the presence of a non-redispersible precipitate despite having appropriate zeta potential and yield stress values.

[0141] The following Table 15 reports the zeta potential and rheological property values obtained for the suspensions reported in Table 8 above.

[0142]

Table 15

[0143] As can be seen, when Avicel CL-611 as a viscosity modifier was used in combination with PVP K30 as a wetting agent, the resulting suspensions were characterized by persistent foam-like substances on these surfaces, probably due to the incomplete wettability of repalxin. Based on these results, it was decided not to use Avicel CL-611 as a viscosity modifier and PVP as a wetting agent in combination in the powder mixture according to the invention.

[0144] The values of the zeta potential and rheological properties obtained for the suspensions reported in Table 9 above are reported in Table 16 below.

[0145] [Table 16]

[0146] As can be seen, all suspensions were characterized by appropriate zeta potential values and rheological properties. Overall, suspensions 131 and 133 were characterized by the best properties. The powder mixtures reported in Table 10 above were characterized for fluidity via Flodex using a Flodex Apparatus, Teledyne Hanson Research, Chatsworth, California, USA. This analysis is based on the ability of the powder to freely enter the disk through the holes. For each substance, a fluidity index corresponding to the diameter of the holes in the disk is reported (scale between 4 mm and 34 mm). The apparatus is formed by a cylinder fixed to a shaft. The selected disk is fixed to the cylinder. The holes in the disk are closed by the device. Approximately 50 g of powder is injected into the center of the disk via a funnel. Once filling is complete, wait 30 seconds to allow any individual floes or large-scale flocculation that may occur in the entire filling to form. Then, operate the device to quickly open the holes in the disk without vibration. Highly fluid powders flow slowly through small-diameter holes, leaving a cavity in the shape of an inverted truncated cone. On the other hand, powders with extremely low fluidity may come out of the holes or fall rapidly. In this case, the powder must be retested using a disk with larger holes.

[0147] The flodex values of the powder mixtures reported in Table 10 above are reported in Table 17 below.

[0148] [Table 17]

[0149] As can be seen from the above results, the powder mixtures 141, 144 and 145 are characterized by appropriate flodex values, suggesting that in order to achieve the desired fluidity, the powder mixture of the present invention must contain colloidal silica. Conversely, there is no colloidal silica in the powder mixture 138, and this mixture is characterized by inappropriate flodex values.

[0150] Table 18 below reports the zeta potential and rheological property values obtained for the suspensions reported in Table 12 above, i.e., for the liquid suspensions reconstituted from the powder mixtures reported in Table 11 above.

[0151] [Table 18]

[0152] This experiment was conducted to further investigate and confirm the effect of the type / amount of sweetener contained in the formulation on the stabilization of the zeta potential value of the reconstituted liquid suspension. As can be seen, when 20% w / w sucrose was contained in the reconstituted liquid suspension (suspension 163lq), the absolute value of the zeta potential was too high. This means that the suspension was not stable. When 0.60% sucralose was contained in the reconstituted liquid suspension instead of sucrose, the same tendency was observed (suspension 167lq).

[0153] When 60% w / w sucrose was contained in the reconstituted liquid suspension (suspension 164lq), the presence of a layer of persistent foamy substance on the surface was observed, and the suspension was too viscous to be handled and injected.

[0154] When sucrose was contained in the reconstituted liquid suspension in amounts of 30% w / w, 40% w / w and 50% w / w in the reconstituted suspension (suspensions 161lq, 141lq and 162lq respectively), zeta potential values near zero and satisfactory rheological properties were obtained.

[0155] These results confirmed an unexpected influence of the type and amount of sweetener contained in the powder mixture on the zeta potential and rheological properties values of the reconstituted liquid suspension, and consequently on its stability. Therefore, sucrose was selected as the sweetener to be included in the powder mixture of the present invention.

[0156] The values of the zeta potential and rheological properties obtained for suspension 150lq reported in Table 12 above are reported in Table 19 below.

[0157] [Table 19]

[0158] The suspensions were characterized by optimal zeta potential values and rheological properties. These data further confirmed the suitability of sucrose to stabilize the zeta potential value even in the case of reconstituted liquid suspensions containing higher amounts of reparaxine, particularly those suitable for administration in adult subjects.

Claims

1. reparixin in an amount ranging from 3.5% w / w to 28.2% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% to 0.5% w / w, gum arabic in an amount ranging from 0.3% to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 3% to 8.3% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% to 18.8% w / w, sucrose in an amount ranging from 63% w / w to 89% w / w, a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w, and poloxamer 188 in an amount ranging from 0.5% w / w to 1.5% w / w, colloidal silica in an amount ranging from 0.7% w / w to 1.4% w / w with the proviso that when the viscosity modifier is the spray-dried blend of microcrystalline cellulose and sodium carboxymethyl cellulose, the wetting agent is not polyvinylpyrrolidone.

2. reparixin in an amount ranging from 6.8% w / w to 28.2% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% to 0.5% w / w, gum arabic in an amount ranging from 0.3% to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 3% to 8.3% w / w, preferably from 3% to 8% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% to 18.8% w / w, sucrose in an amount ranging from 63% w / w to 88% w / w, a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w and poloxamer 188 in an amount ranging from 0.5% w / w to 1.5% w / w, colloidal silica in an amount ranging from 0.7% w / w to 1.3% w / w 2. The powder mixture of claim 1, comprising:

3. reparixin in an amount ranging from 7.6% w / w to 26.8% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% to 0.5% w / w, gum arabic in an amount ranging from 0.3% to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 4.5% to 7.8% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% to 18.8% w / w, sucrose in an amount ranging from 64.2% w / w to 85.2% w / w, a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w, and poloxamer 188 in an amount ranging from 0.7% w / w to 1.3% w / w, colloidal silica in an amount ranging from 0.7% w / w to 1.3% w / w 3. The powder mixture of claim 1 or claim 2, comprising:

4. reparixin in an amount ranging from 8.4% w / w to 26% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% to 0.5% w / w, gum arabic in an amount ranging from 0.3% to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 4.5% to 7.7% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% to 18.8% w / w, sucrose in an amount ranging from 64.9% w / w to 84.5% w / w, a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w, and poloxamer 188 in an amount ranging from 0.7% w / w to 1.3% w / w, colloidal silica in an amount ranging from 0.7% w / w to 1.3% w / w 2. The powder mixture of claim 1, comprising:

5. reparixin in an amount ranging from 7.6% w / w to 13.9% w / w, sucrose in an amount ranging from 75.5% w / w to 85.2% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% to 0.5% w / w, gum arabic in an amount ranging from 0.3% to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 5% to 7.8% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% to 18.8% w / w, a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w, and poloxamer 188 in an amount ranging from 0.8% w / w to 1.3% w / w, colloidal silica in an amount ranging from 0.8% w / w to 1.3% w / w 2. The powder mixture of claim 1, comprising:

6. reparixin in an amount ranging from 17.5% w / w to 26.8% w / w, sucrose in an amount ranging from 64.2% w / w to 76.1% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% w / w to 0.5% w / w, gum arabic in an amount ranging from 0.3% w / w to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 4.5% w / w to 6.6% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% w / w to 18.8% w / w, - a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w, and poloxamer 188 in an amount ranging from 0.7% w / w to 1.1% w / w, colloidal silica in an amount ranging from 0.7% w / w to 1.1% w / w 3. The powder mixture of claim 1 or claim 2, comprising:

7. At least 98%, preferably at least 99%, of the total weight of the powder mixture reparixin in an amount ranging from 3.5% w / w to 28.2% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% to 0.5% w / w, gum arabic in an amount ranging from 0.3% to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 3% to 8.3% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% to 18.8% w / w, sucrose in an amount ranging from 63% w / w to 89% w / w, a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w, and poloxamer 188 in an amount ranging from 0.5% w / w to 1.5% w / w, colloidal silica in an amount ranging from 0.7% w / w to 1.4% w / w, a pH adjusting agent, preferably in an amount ranging from 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount ranging from 0.1% w / w to 0.5% w / w 2. The powder mixture of claim 1, consisting of:

8. At least 98%, preferably at least 99%, of the total weight of the powder mixture reparixin in an amount ranging from 6.8% w / w to 28.2% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% to 0.5% w / w, gum arabic in an amount ranging from 0.3% to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 3% to 8.3% w / w, preferably from 3% to 8% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% to 18.8% w / w, sucrose in an amount ranging from 63% w / w to 88% w / w, a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w, and poloxamer 188 in an amount ranging from 0.5% w / w to 1.5% w / w, colloidal silica in an amount ranging from 0.7% w / w to 1.3% w / w, a pH adjusting agent, preferably in an amount ranging from 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount ranging from 0.1% w / w to 0.5% w / w 3. The powder mixture of claim 2, consisting of:

9. At least 98%, preferably at least 99%, of the total weight of the powder mixture reparixin in an amount ranging from 7.6% w / w to 26.8% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% to 0.5% w / w, gum arabic in an amount ranging from 0.3% to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 4.5% to 7.8% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% to 18.8% w / w, sucrose in an amount ranging from 64.2% w / w to 85.2% w / w, a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w, and poloxamer 188 in an amount ranging from 0.7% w / w to 1.3% w / w, colloidal silica in an amount ranging from 0.7% w / w to 1.3% w / w, a pH adjusting agent, preferably in an amount ranging from 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount ranging from 0.2% w / w to 0.4% w / w 4. The powder mixture of claim 3, consisting of:

10. At least 98%, preferably at least 99%, of the total weight of the powder mixture reparixin in an amount ranging from 8.4% w / w to 26% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% to 0.5% w / w, gum arabic in an amount ranging from 0.3% to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 4.5% to 7.7% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% to 18.8% w / w, sucrose in an amount ranging from 64.9% w / w to 84.5% w / w, a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w, and poloxamer 188 in an amount ranging from 0.7% w / w to 1.3% w / w, colloidal silica in an amount ranging from 0.7% w / w to 1.3% w / w, a pH adjusting agent, preferably in an amount ranging from 0.1% w / w to 0.2% w / w, and / or a preservative, preferably in an amount ranging from 0.2% w / w to 0.4% w / w 5. The powder mixture of claim 4, consisting of:

11. At least 98%, preferably at least 99%, of the total weight of the powder mixture reparixin in an amount ranging from 7.6% w / w to 13.9% w / w, sucrose in an amount ranging from 75.5% w / w to 85.2% w / w, a preservative, preferably in an amount ranging from 0.2% w / w to 0.4% w / w, and / or a pH adjuster, preferably in an amount ranging from 0.10% w / w to 0.17% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% to 0.5% w / w, gum arabic in an amount ranging from 0.3% to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 5% to 7.8% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% to 18.8% w / w, a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w, and poloxamer 188 in an amount ranging from 0.8% w / w to 1.3% w / w, colloidal silica in an amount ranging from 0.8% w / w to 1.3% w / w 6. The powder mixture of claim 5, consisting of:

12. At least 98%, preferably at least 99%, of the total weight of the powder mixture reparixin in an amount ranging from 17.5% w / w to 26.8% w / w, sucrose in an amount ranging from 64.2% w / w to 76.1% w / w, a preservative, preferably in an amount ranging from 0.2% w / w to 0.35% w / w, and / or a pH adjuster, preferably in an amount ranging from 0.1% w / w to 0.2% w / w, - a viscosity modifier selected from xanthan gum in an amount ranging from 0.3% w / w to 0.5% w / w, gum arabic in an amount ranging from 0.3% w / w to 0.5% w / w, and a spray-dried blend of microcrystalline cellulose and sodium carboxymethylcellulose in an amount ranging from 4.5% w / w to 6.6% w / w, wherein the sodium carboxymethylcellulose is present in the blend in an amount ranging from 11.3% w / w to 18.8% w / w, - a wetting agent chosen from polyvinylpyrrolidone in an amount ranging from 3% w / w to 5% w / w, and poloxamer 188 in an amount ranging from 0.7% w / w to 1.1% w / w, colloidal silica in an amount ranging from 0.7% w / w to 1.1% w / w 7. The powder mixture of claim 6, consisting of:

13. 8. The powder mixture of claim 7, 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, monobasic sodium phosphate and monobasic potassium phosphate.

14. A method for producing a liquid suspension reconstituted from the powder mixture of claim 1, comprising suspending the powder mixture in an aqueous vehicle, preferably water.

15. - treatment of a disease or condition selected from psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome (ARDS), idiopathic fibrosis, glomerulonephritis, COVID-19, pneumonia caused by SARS-CoV-2 or variants thereof; - prevention or delay of the onset and progression of diabetes, preferably type 1 diabetes, - prevention or treatment of seizures in an individual 10. The powder mixture or reconstituted liquid suspension thereof of claim 1 for use in