Mesalazine microparticles

Abstract

The invention relates to microparticles comprising a solid core that comprises mesalazine and a polymeric binder, wherein the core has a particle size distribution with d50 of 20-100 µm and span lower than 2.5, and wherein the core comprises at least 75 wt% of mesalazine based on the total weight of the core. The invention also refers to a method for the manufacture of the microparticles, to a pharmaceutical composition comprising the microparticles and to the use of the microparticles in the prevention or treatment of an inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

Description

[0001] MESALAZINE MICROPARTICLES

[0002] Field of the Invention

[0003] The invention belongs to the field of pharmaceutical formulations, in particular to pharmaceutical compositions in the form of microparticles.

[0004] Background of the Invention

[0005] Ulcerative colitis is a long-term condition where the colon and rectum become inflamed. It is a chronic relapsing multifactorial gastrointestinal inflammatory bowel disease, characterized by bloody or mucus diarrhea, tenesmus, bowel distension and anemia.

[0006] Mesalazine (also known as mesalamine) is a compound regularly prescribed to treat this disease. However, to be effective it has to be delivered to the correct area of the colon. Consequently, there are a multitude of formulation techniques available, but all involve the mesalazine being coated in layers to ensure the drug first passes unabsorbed through the stomach, then through the upper part of the digestive system and finally is properly released in the colon.

[0007] The coatings needed to protect the active ingredient and deliver it to the colon result in a decrease of the ratio of mesalazine to excipients / coatings, leading also to dosage units larger than desired.

[0008] Currently marketed mesalazine formulations have a low content of mesalazine. As a consequence, patients need to take high amounts of the pills and this several times a day, which results in low treatment adherence.

[0009] Mesalazine is a tan to pink crystalline powder, whose individual crystals exhibit a needle-like morphology. Mesalazine shows low aqueous solubility which influences the way it is formulated. These properties pose problems in obtaining suitable mesalazine formulations. As a result, formulations with low content of active ingredient or which require several manufacturing steps or complex technologies are required, which make them not suitable for industrial production.

[0010] EP3131535 describes the need for ‘a process to manufacture mesalazine pellets that is faster, simple, robust and reproducible. Further, what is required is a process for manufacturing a mesalazine composition that possesses a high drug content suspension for layering processes and resulting in pellets having an aesthetic appearance.’ It describes a first drug layering suspension formed by mixing hypromellose (methocel E3), hot purified water, simethicone 30% emulsion, polysorbate 80 and mesalazine whilsthomogenizing. This first layer is sprayed onto sugar seeds. This method requires the use of several excipients and surfactant and the need of sugar pellets as cores.

[0011] The formulation of mesalazine in the form of small microparticles (of about 200 pm or lower) would be also desirable. Since the tongue does not detect particles with such particle size equal or lower than about 200 pm, such small microparticles would resemble to a liquid formulation and could be swallowed very easily.

[0012] Several documents report the preparation of mesalazine microparticles by spray drying compositions comprising mesalazine and a modified-release agent, such as chitosan, cross-linked xylan, xanthan gum, cross-linked pectin, biodegradable polymer etc. (see for example, Palma et al., Carbohydrate Polymers 2019, 212, 430-438; Mura et al., Colloids and Surface B: Biointerfaces 2012, 94, 199-205; Silva et al., Journal of Microencapsulation 2013, 30(8), 787-795; Walz et al., Carbohydrate Polymers 2018, 199, 102-108; Meneguin et al., Pharmaceutics 2021, 13, 1515; and WO 2013 / 134348). However, none of these documents allow the incorporation of high mesalazine contents in the microparticles. This is so because in these documents both solutions and dispersions of mesalazine and excipients were spray dried. For solutions, one is limited to the solubility of mesalazine in the used solvent. Therefore, to increase mesalazine load in the formulation, solid load of the liquid feed used for spray drying would have to be reduced, to ensure dissolution of the material, reducing the throughput of the process, which is not suitable for industrial production. Additionally, when a solution of mesalazine is used, it will convert to the amorphous state. In both cases, very low solid loads were used in the liquid feed for spray drying, which will be translated in low throughput of the process. Furthermore, the term ‘drug entrapment efficiency’ is used to describe the amount of drug recovered after processing. Such terminology is commonly used to describe how effectively a drug is encapsulated within systems or the efficacy of a nanocarrier to retain the drug / active ingredient, suggesting that the encapsulation of mesalazine within the used excipient was aimed, instead of a distribution of the excipient and mesalazine throughout the core. On top of this, obtained particles in these documents have a small particle size, with a D50 below 10 pm. Such particle size presents some disadvantages like poor flowability and electrostatic powders, which may be an issue for downstream processing and will hinder their use for coating applications.

[0013] Therefore, new mesalazine microparticles with a high load of the active ingredient are still needed. Specially, microparticles with minimal amounts of added excipients and which can be obtained by a fast, simple and industrially applicable method.Summary of the Invention

[0014] The invention is based on the finding by the inventors that mesalazine spherical microparticles (cores) with a very high load of the active ingredient, excellent flowability properties, can be obtained by spray drying a suspension of mesalazine and a polymeric binder.

[0015] These particles can be coated with controlled release coatings to regulate the disintegration time and site of delivery. Due to the excellent properties of the microparticles, the amount of coating required can be minimized. Consequently, the high content of mesalazine is preserved in the final coated particles.

[0016] Further, the mesalazine in the spray-dried particles disclosed herein maintains its crystalline structure. This is advantageous, since crystalline structures result in more stable particles, which do not suffer physical transformations over time and storage conditions that could affect their performance (e.g. solubility or dissolution rate). Crystalline structures provide robust and reliable particles suitable for pharmaceutical applications.

[0017] In addition to the high load of mesalazine, the microparticles can have a particle size equal to or lower than 200 pm, which make them highly advantageous for their oral administration. Since the tongue does not detect particles with this low particle size, the microparticles of the disclosure resemble to a liquid formulation and can be swallowed very easily, even without the need of a liquid to swallow them.

[0018] Thus, in a first aspect, the invention is concerned with microparticles comprising a solid core that comprises mesalazine and a polymeric binder, wherein the core has a particle size distribution with d50 of 20-100 pm and span lower than 2.5, and wherein the core comprises at least 75 wt% of mesalazine based on the total weight of the core.

[0019] In a second aspect, the invention is directed to a method for preparing the microparticles according to the first aspect, wherein the method comprises:

[0020] (i) preparing a solution of a polymeric binder in a solvent,

[0021] (ii) mixing the solution from step (i) with mesalazine to obtain a suspension, and (iii) spray-drying the suspension from step (ii).

[0022] A third aspect of the invention refers to microparticles obtainable by the method of the second aspect.

[0023] In a fourth aspect, the invention refers to a pharmaceutical composition comprising the microparticles according to the first or the third aspect and a pharmaceutically acceptable excipient.In a fifth aspect, the invention is concerned with the microparticles according to the first or the third aspect, or the pharmaceutical composition according to the fourth aspect, for use in medicine.

[0024] In a sixth aspect, the invention is concerned with the microparticles according to the first or the third aspect, or the pharmaceutical composition according to the fourth aspect, for use in the prevention or treatment of an inflammatory bowel disease.

[0025] Description of the figures

[0026] Figure 1 shows the SEM images of mesalazine microparticles obtained in Examples 1-12.

[0027] Figure 2 shows the SEM images of mesalazine (left) and spray-dried mesalazine / HPMC E585 / 15 (w / w) microparticles (right).

[0028] Figure 3 shows the SEM images of mesalazine microparticles obtained in Examples 15, 22, 24 and 27.

[0029] Figure 4 is an XRPD diffractogram of mesalazine and spray-dried microparticles of Examples 3, 7, 14 and 24.

[0030] Figure 5 is a graph with the dissolution profile of mesalazine microparticles in Examples 3, 7 and 15.

[0031] Figure 6 is a graph with the dissolution profile of mesalazine microparticles in Examples 16, 17, 18, 19 and 20.

[0032] Figure 7 is a graph with the dissolution profile of mesalazine microparticles in Example 24.

[0033] Figure 8 is a graph with the tableting profile of mesalazine and spray-dried microparticles of Examples 3, 7, 14 and 24.

[0034] Figure 9 shows the SEM images of uncoated Mesalazine / HPMC E5 85 / 15 (w / w) microparticles and Mesalazine / HPMC E585 / 15 (w / w) microparticles coated with EL100 or Eudragit FS30D.

[0035] Figure 10. Left: SEM images of uncoated Mesalazine / HPMC E5 90 / 10 (w / w) microparticles and Mesalazine / HPMC E590 / 10 (w / w) microparticles coated with EL100 (20% WG and 30%WG). Right: SEM images of uncoated Mesalazine / EC N100 90 / 10 (w / w) microparticles and Mesalazine / EC N100 90 / 10 (w / w) microparticles coated with EL100 (20% WG and 30%WG).

[0036] Figure 11 is a graph with the dissolution profile of uncoated Mesalazine / HPMC E5 85 / 15 (w / w) microparticles and Mesalazine / HPMC E585 / 15 (w / w) microparticles coated with EL100 or Eudragit FS30D.Figure 12 is a graph with the dissolution profile of uncoated Mesalazine / HPMC E5 90 / 10 (w / w) and Mesalazine / EC N10090 / 10 (w / w) microparticles and the corresponding microparticles coated with EL100.

[0037] Detailed Description of the Invention

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person having ordinary skill in the art to which this disclosure pertains.

[0039] As used herein, the singular forms “a” and “the” also include the plural form unless the context clearly dictates otherwise.

[0040] The terms “comprise(s)” and variations thereof, encompass the terms “consist(s) essentially of” and “consist(s) of”. Therefore, each time the term “comprise(s)” and variations thereof appear herein, they can be replaced with the terms “consist(s) essentially of” and “consist(s) of”.

[0041] When a range is indicated in the present document, both lower and upper limits are included in said range.

[0042] The skilled person readily understands that, when a composition or material is defined by the weight percentage values of the components it comprises, these values can never sum up to a value which is greater than 100%. The amount of all components that said material or composition comprises adds up to 100% of the weight of the composition or material.

[0043] For the purposes of the invention the expressions "obtainable", "obtained" and equivalent expressions are used interchangeably, and in any case, the expression "obtainable" encompasses the expression "obtained".

[0044] Unless specifically stated otherwise, or unless they are clearly incompatible, all the embodiments disclosed in relation to an aspect of the invention are also applicable to the other aspects. Also, any combination of the embodiments and preferences described herein is encompassed by the present invention unless otherwise indicated herein, or otherwise clearly contradicted by context.

[0045] It should be understood that the scope of the present disclosure includes all the possible combinations of embodiments disclosed herein, either belonging to the same aspect or to different aspects of the invention.

[0046] The term "particle size" refers to the volume-based diameter. Volume-based particle size is defined as the diameter of a sphere that has the same volume as the given particle. The particle size distribution is therefore determined based on thesevolume-equivalent diameters, rather than the longest dimension of the particles. Throughout the present document, the term "particle size" is described by its distribution of particle sizes. The terms d10, d50, and d90 are known to those skilled in the art. The term “d10” refers to the particle size below which 10% of the particles (by volume) are smaller. The term “d50” refers to the median particle size, below which 50% of the particles (by volume) are smaller. The term “d90” refers to the particle size below which 90% of the particles (by volume) are smaller. The term particle size distribution span refers to the result of the calculation [(d90-d10) / d50]. The particle size distribution can be measured, for example, by laser diffraction (e.g., Sympatec RODOS / HELOS laser diffraction equipment).

[0047] The term "surface area" may refer to the total area of the surface of the particles per gram of particles. It can be determined by gas adsorption, for example using ISO 9277:2022.

[0048] The term "sphericity" as used herein shall be understood as (S), the ratio of the perimeter of the equivalent circle, PEQPC, to the real perimeter, Preal. The result is a value between 0 and 1. The smaller the value, the more irregular is the shape of the particle.

[0049] The term “aspect ratio” as used herein shall be understood as the ratio of the width to the length of the particle. It gives an indication for the elongation of the particle. It can be determined by static image analysis, for example using ISO 13322-1:2014.

[0050] The term "flowability" is intended to denote the ability of a powder to flow freely in a uniform and constant manner in the form of individual particles. It can be determined by flow through an orifice, for example using a powder flowability device, such as a FlowPro device.

[0051] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art. In certain embodiments, the term “about” or “approximately” means within 10%, or even within 5% of a given value or range.

[0052] In the context of the present disclosure, the term microparticle refers to a microsphere or to a decorated or coated microsphere.

[0053] By “microsphere” should be understood a solid core wherein the mesalazine and the polymeric binder are distributed, thus not featuring a distinct core / shell structure. The cores of the present disclosure, comprising mesalazine and a polymeric binder, are microspheres. By “decorated or coated microsphere” should be understood a microsphere as defined above, wherein the solid core is coated or decorated, forexample with a polymer. The microparticles of the present disclosure might be microspheres, when they do not comprise a coating, or they might be decorated / coated microparticles, when they comprise a coating on the surface of the core.

[0054] In an embodiment, the disclosure refers to a microparticle comprising a solid core that comprises mesalazine and a polymeric binder, wherein the core has a particle size distribution with d50 of 20-100 pm and span lower than 2.5, and wherein the core comprises at least 75 wt% of mesalazine based on the total weight of the core.

[0055] Core

[0056] In an embodiment, the mesalazine and the polymeric binder are distributed throughout the core without a distinct core / shell structure.

[0057] The mesalazine might be present both at the internal portion and at the surface of the core. In an embodiment, the mesalazine has a concentration gradient in which the mesalazine concentration gradually decreases from the center toward the surface of the core. That is, the surface of the particle comprises lower amount of mesalazine than the center of the particle.

[0058] In particular embodiments, the core is a solid continuous core; i.e. it is essentially not hollow.

[0059] In a particular embodiment, the core consists of mesalazine and the polymeric binder. That is, there are no further components in the core other than mesalazine and the polymeric binder.

[0060] The amount of mesalazine in the core is at least 75 wt% based on the weight of the core. In an embodiment, the core comprises at least 80 wt% of mesalazine based on the weight of the core. In a further embodiment, the core comprises at least 85 wt% of mesalazine based on the weight of the core. According to a particular embodiment, the core comprises at least 88 wt%, or even at least 90 wt%, of mesalazine based on the weight of the core.

[0061] In an embodiment, the amount of mesalazine in the core is 75-90 wt% based on the weight of the core. In a further embodiment, the core comprises 75-85 wt% of mesalazine based on the weight of the core.

[0062] The amount of mesalazine in the core can be 75-98 wt% based on the weight of the core. In an embodiment, the core comprises 80-98 wt% of mesalazine based on the weight of the core. In a further embodiment, the core comprises 85-98 wt% of mesalazine based on the weight of the core. According to a particular embodiment, the core comprises 88-98 wt%, or even 90-98 wt%, of mesalazine based on the weight of the core.The amount of mesalazine in the core can be 75-95 wt% based on the weight of the core. In an embodiment, the core comprises 80-95 wt% of mesalazine based on the weight of the core. In a further embodiment, the core comprises 85-95 wt% of mesalazine based on the weight of the core. According to a particular embodiment, the core comprises 88-95 wt%, or even 90-95 wt%, of mesalazine based on the weight of the core.

[0063] In another embodiment, the core comprises 75-90 wt% of mesalazine based on the weight of the core. In an embodiment, the core comprises 80-90 wt% of mesalazine based on the weight of the core. In a further embodiment, the core comprises 85-90 wt% of mesalazine based on the weight of the core.

[0064] The amount of polymeric binder in the core is equal to or less than 25 wt% based on the weight of the core. In an embodiment, the core comprises no more than 20 wt% of polymeric binder based on the weight of the core. In a further embodiment, the core comprises no more than 15 wt% of polymeric binder based on the weight of the core. According to a particular embodiment, the core comprises no more than 12 wt%, or even no more than 10 wt%, of polymeric binder based on the weight of the core.

[0065] In an embodiment, the amount of polymeric binder in the core is 10-25 wt% based on the weight of the core. In a further embodiment, the core comprises 15-25 wt% of polymeric binder based on the weight of the core.

[0066] The amount of polymeric binder in the core can be 5-25 wt% based on the weight of the core. In an embodiment, the core comprises 5-20 wt% of polymeric binder based on the weight of the core. In a further embodiment, the core comprises 5-15 wt% of polymeric binder based on the weight of the core. According to a particular embodiment, the core comprises 5-12 wt%, or even 5-10 wt%, of polymeric binder based on the weight of the core.

[0067] In another embodiment, the core comprises 10-25 wt% of polymeric binder based on the weight of the core. In an embodiment, the core comprises 10-20 wt% of polymeric binder based on the weight of the core. In a further embodiment, the core comprises IQ-15 wt% of polymeric binder based on the weight of the core.

[0068] The amounts of further components other than mesalazine and the polymeric binder, if any, in the core might be equal to or lower than 5 wt% based on the weight of the core. In an embodiment, the core comprises, if any, 0-3 wt% of components other than mesalazine and the polymeric binder based on the weight of the core. In a further embodiment, the core comprises, if any, 0-2 wt% of components other than mesalazine and the polymeric binder based on the weight of the core. According to a particularembodiment, the core comprises, if any, 0-1 wt% of components other than mesalazine and the polymeric binder based on the weight of the core.

[0069] According to an embodiment of the disclosure, the core comprises 80-95 wt% of mesalazine and 5-20 wt% of polymeric binder, based on the weight of the core. In an embodiment, the core comprises 85-95 wt% of mesalazine and 5-15 wt% of polymeric binder, based on the weight of the core.

[0070] In a further embodiment, the core comprises 75-90 wt% of mesalazine and 10-25 wt% of polymeric binder, based on the weight of the core. In an embodiment, the core comprises 75-85 wt% of mesalazine and 15-25 wt% of polymeric binder, based on the weight of the core.

[0071] In an embodiment, the mesalazine in the core is in crystalline form. In an embodiment, at least 80% of mesalazine in the core is in the crystalline form. In an embodiment, at least 85% of mesalazine in the core is in the crystalline form. In a further embodiment, at least 90%, or even at least 95%, of mesalazine in the core is in the crystalline form. The amount of crystalline mesalazine can be determined by X-Ray powder diffraction analysis (XRPD).

[0072] The core in the microparticles of the disclosure has a particle size distribution with d50 of 20-100 pm and span lower than 2.5, or even a span lower than 2.2.

[0073] In an embodiment, the core has a particle size distribution with a d10 of 4-60 pm. In a further embodiment, it has a d10 of 5-50 pm, or even 5-25 pm.

[0074] In an embodiment, the core has a particle size distribution with a d50 of 20-90 pm. In a further embodiment, it has a d50 of 25-85 pm. In another embodiment, it has a d50 of 25-80 pm, or even 25-65 pm.

[0075] In an embodiment, the core has a particle size distribution with a d90 of 40-150 pm. In a further embodiment, it has a d90 of 45-140 pm. In another embodiment, it has a d90 of 50-130 pm, or even 50-120 pm.

[0076] In an embodiment, the core has a particle size distribution with a span lower than 2.2. In a further embodiment, it has a span lower than 2.1. In another embodiment, it has a span lower than 2.0.

[0077] In an embodiment, the core has a particle size distribution with a span of 0.8-2.5, or even 0.9-2.5. In a further embodiment, it has a span of 0.9-2.2. In another embodiment, it has a span of 1.0-2.1. In a further embodiment, it has a span of 1.0-2.0.

[0078] According to a particular embodiment of the disclosure, the core has a particle size distribution with d10 of 4-60 pm, d50 of 20-100 pm and d90 of 40-150 pm. In an embodiment, the core has a particle size distribution with d10 of 4-60 pm, d50 of 20-90m and d90 of 45-140 pm. In another embodiment, the core has a particle size distribution with d10 of 5-50 pm, d50 of 25-85 pm and d90 of 45-140 pm. In a further embodiment, the core has a particle size distribution with d10 of 5-50 pm, d50 of 25-80 pm and d90 of 50-130 pm. In an embodiment, the core has a particle size distribution with d10 of 5-25 pm, d50 of 25-65 pm and d90 of 50-120 pm.

[0079] The polymeric binder in the core might be selected from cellulosic and non-cellulosic polymers, including cellulose esters or cellulose ethers, such as alkylcelluloses (e.g., methylcellulose (MC) or ethylcellulose (EC)), hydroxyalkylcelluloses (e.g., hydroxypropylcellulose (HPC) or hydroxyethylcellulose (HEC)), hydroxyalkylalkylcelluloses (e.g., hydroxypropylmethylcellulose (HPMC)), carboxymethyl cellulose (CMC), cellulose acetate (CA), and cellulose phthalates or succinates (e.g., cellulose acetate phthalate (CAP) and hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose succinate (HPMCS), or hydroxypropylmethylcellulose acetate succinate (HPMCAS)); homopolymers or copolymers of N-vinyl lactams, such as homopolymers or copolymers of N-vinyl pyrrolidone (e.g., polyvinylpyrrolidone (PVP), or copolymers of N-vinyl pyrrolidone and vinyl acetate (PVPVA) or vinyl propionate (PVPVP); polyalkylene oxides, such as polyethylene oxide (PEO), polypropylene oxide (PPO), copolymers of ethylene oxide and propylene oxide, and polyethylene glycol (PEG); polyacrylates or polymethacrylates, such as methacrylic acid / ethyl acrylate copolymers, methacrylic acid / methyl methacrylate copolymers, acrylic acid / methyl methacrylate copolymers, poly(hydroxyalkyl acrylates), and poly(hydroxyalkyl methacrylates); vinyl acetate polymers (e.g. PVA, PVAc) and vinyl acetate phthalate polymers; polyalkylenes, such as polyethylene (PE); polylactides (e.g. PLGA); polycaprolactones; polyurethanes; polyacrylamides; oligo- or polysaccharides, such as chitosan, alginate, carrageenan, galactomannan, guar gum, and xanthan gum; or any mixture thereof.

[0080] In a particular embodiment, the polymeric binder in the core is selected from cellulose ethers (such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose acetate succinate and hydroxypropyl methyl cellulose), homopolymers or copolymers of N-vinyl pyrrolidone (such as polyvinylpyrrolidone and copolymers of N-vinyl pyrrolidone and vinyl acetate), and mixtures thereof.

[0081] In a particular embodiment, the polymeric binder in the core is selected from cellulose ethers (such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose acetate succinate and hydroxypropyl methyl cellulose), and mixtures thereof.In an embodiment, the polymeric binder in the core is selected from ethyl cellulose (EC N7, EC N10, EC N20, EC N22, EC N50, EC N100, EC N200, EC N300), hydroxypropyl cellulose (e.g. HPC ELF, HPC EF, HPC SSL, HPC SL, HPC L, HPC M, HPC H), hydroxypropylmethylcellulose acetate succinate (HPMCAS-LG, HPMCAS-MG, HPMCAS-HG), hydroxypropyl methyl cellulose (HPMC E3, HPMC E5, HPMC E6, HPMC E15, HPMC E50, HPMC P55), polyvinylpyrrolidone, (e.g. PVP K12, PVP K17, PVP K25, PVP K30, PVP K40, PVP K50, PVP K60, PVP K70, PVP K80, PVP K85, PVP K90, PVP K120) copolymer of N-vinyl pyrrolidone and vinyl acetate (e.g. PVPVA64), and mixtures thereof.

[0082] In a particular embodiment, the polymeric binder in the core is selected from hydroxypropylmethylcellulose acetate succinate, hydroxypropyl methyl cellulose, ethyl cellulose, and mixtures thereof.

[0083] In an embodiment, the polymeric binder in the core comprises a mixture of hydroxypropyl methyl cellulose and ethyl cellulose. For example, in a HPMC:EC ratio from 250:1 to 1:50, or from 200:1 to 1:2.

[0084] In an embodiment, the polymeric binder in the core comprises a mixture of hydroxypropylmethylcellulose acetate succinate, hydroxypropyl methyl cellulose and ethyl cellulose. For example, in a HPMCAS:HPMC:EC ratio 2-70:10-70:2-60 (w / w / w), or 5-60:20-60:5-50 (w / w / w). In an embodiment, the core comprises a mixture of HPMCAS:HPMC:EC in a ratio 30-40:30-40:20-30 (w / w / w).

[0085] In a further embodiment, the polymeric binder in the core is selected from hydroxypropyl methyl cellulose, polyvinylpyrrolidone and mixtures thereof.

[0086] In an embodiment, the polymeric binder in the core is hydroxypropyl methyl cellulose.

[0087] In an embodiment, the polymeric binder in the core is polyvinylpyrrolidone.

[0088] In an embodiment, the ethyl cellulose has a Brookfield viscosity of 5-500 mPa-s measured at25°C of a 5% w / w solution in a mixture of toluene / ethanol (80:20). In another embodiment, it has a viscosity of 10-300 mPa s, or even 50-250 mPa s. According to a particular embodiment, it has a viscosity of 80-120 mPa s.

[0089] In an embodiment, the hydroxypropyl cellulose has a Brookfield viscosity of 75-3000 mPa s measured at 25°C in an aqueous solution at 10% w / w. In another embodiment, it has a viscosity of 75-1000 mPa s, or even 100-600 mPa s. According to a particular embodiment, it has a viscosity of 100-350 mPa s.

[0090] Hydroxypropyl methyl cellulose (HPMC) is generally characterized by its viscosity in aqueous solution relative to that of water (2 wt% at 20°C). For example, HPMC E3refers to HPMC with a viscosity of about 3 mPa s, E5 refers to HPMC with a viscosity of about 5 (4 to 6) mPa s, E6 refers to HPMC with a viscosity of about 5 (4.5 to 7.5) mPa s, E15 refers to HPMC with a viscosity of about 15 (12 to 18) mPa s, E50 refers to HPMC with a viscosity of about 50 (40 to 60) mPa s. In an embodiment, the hydroxypropyl methyl cellulose has a Brookfield viscosity of 1-100 mPa s measured at 20°C in an aqueous solution at 2% w / w. In another embodiment, it has a viscosity of 2-50 mPa s, or even 2-20 mPa s. According to a particular embodiment, it has a viscosity of 3-6 mPa s.

[0091] Hydroxypropylmethylcellulose acetate succinate (HPMCAS) is a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethyl cellulose. It is commercially available in three chemical grades (LG, MG and HG), which vary in their acetyl and succinoyl group substitution. For example, HPMCAS-LG refers to HPMCAS with 5-9 wt% acetyl groups and 14-18 wt% succinoyl groups, HPMCAS-MG refers to HPMCAS with 7-11 wt% acetyl groups and 10-14 wt% succinoyl groups, and HPMCAS-HG refers to HPMCAS with 10-14 wt% acetyl groups and 4-8 wt% succinoyl groups. In a particular embodiment, the HPMCAS is HPMCAS-LG.

[0092] Polyvinylpyrrolidone (PVP) is generally characterized by its viscosity in aqueous solution relative to that of water and expressed as a K value. For example, a K-value of approximately 12 (PVP K12), of approximately 17 (PVP K17), of approximately 30 (PVP K30), of approximately 80 (PVP K80), of approximately 85 (PVP K85), of approximately 90 (PVP K90), of approximately 100 (PVP K100), of approximately 120 (PVP K120). In a particular embodiment, the polyvinylpyrrolidone used as polymeric binder in the core has a K value (1% water) in the range of 10-120 measured according to Fikentscher (Fikentscher, Cellulosechemie 13, 1932 (58)). In an embodiment, the polyvinylpyrrolidone has a K value (1% water) in the range of 20-120 measured according to Fikentscher. In a particular embodiment, it has a K value (1% water) in the range of 20-120 measured according to Fikentscher. In another embodiment, the polyvinylpyrrolidone has a K value (1% water) in the range of 70-120 measured according to Fikentscher. In a further embodiment, it has a K value (1% water) in the range of 80-100 measured according to Fikentscher. The polyvinylpyrrolidone used as polymeric binder in the core may have a weight average molecular weight (Mw) in the range of 2.000-1.500.000 Da determined by GPC using a polystyrene standard. In an embodiment, the polyvinylpyrrolidone has a weight average molecular weight in the range of 20.000-1.500.000 Da, or even 40.000-1.300.000 Da (GPC, PS standard). In a particular embodiment, it has a weight average molecular weight in the range of 30.000-60.000 Da (GPC, PS standard). In another embodiment, the polyvinylpyrrolidone has a weight average molecular weight in the range of 500.000-1.300.000 Da (GPC, PS standard). In a further embodiment, it has a weight average molecular weight in the range of 800.000-1.300.000 Da (GPC, PS standard). According to an embodiment, the polyvinylpyrrolidone has a K value (1% water) in the range of 10-120 measured according to Fikentscher and a weight average molecular weight in the range of 2.000-1.500.000 Da (GPC, PS standard). In a particular embodiment, it has a K value (1% water) in the range of 20-120 measured according to Fikentscher and a weight average molecular weight in the range of 20.000-1.500.000 Da (GPC, PS standard). In a further embodiment, it has a K value (1% water) in the range of 70-120 measured according to Fikentscher and a weight average molecular weight in the range of 500.000-1.300.000 Da (GPC, PS standard).

[0093] In an embodiment, the copolymer of N-vinyl pyrrolidone and vinyl acetate comprises 30-70 wt% of N-vinyl pyrrolidone and 70-30 wt% of vinyl acetate. In an embodiment, it comprises 50-70 wt% of N-vinyl pyrrolidone and 50-30 wt% of vinyl acetate (e.g. a copolymer of 60 wt% of N-vinyl pyrrolidone and 40 wt% of vinyl acetate, such as PVPVA64).

[0094] According to an embodiment, the polymeric binder in the core is selected from hydroxypropyl methyl cellulose with a Brookfield viscosity of 2-50 mPa s measured at 20°C in an aqueous solution at 2% w / w and polyvinylpyrrolidone with a Fikentscher K value in the range of 20-120 measured in an aqueous solution at 1% w / w. In an embodiment, the polymeric binder in the core is selected from hydroxypropyl methyl cellulose with a Brookfield viscosity of 2-20 mPa s measured at 20°C in an aqueous solution at 2% w / w and polyvinylpyrrolidone with a Fikentscher K value in the range of 70-120 measured in an aqueous solution at 1% w / w. In a further embodiment, the polymeric binder in the core is selected from hydroxypropyl methyl cellulose with a Brookfield viscosity of 3-6 mPa s measured at 20°C in an aqueous solution at 2% w / w (e.g. HPMC E5) and polyvinylpyrrolidone with a Fikentscher K value in the range of 80-100 measured in an aqueous solution at 1% w / w (e.g. PVP K90).

[0095] In a particular embodiment, the polymeric binder in the core is a polyvinylpyrrolidone with a Fikentscher K value in the range of 80-100 measured in an aqueous solution at 1% w / w.

[0096] In an embodiment, the polymeric binder in the core comprises a mixture of a hydroxypropyl methyl cellulose with a Brookfield viscosity of 2-50 mPa-s measured at 20°C in an aqueous solution at 2% w / w and an ethyl cellulose with a Brookfield viscosityof 5-500 mPa-s measured at 25°C of a 5% w / w solution in a mixture of toluene / ethanol (80:20). In a further embodiment, the polymeric binder in the core comprises a mixture of a hydroxypropyl methyl cellulose with a Brookfield viscosity of 2-20 mPa s measured at 20°C in an aqueous solution at 2% w / w and an ethyl cellulose with a Brookfield viscosity of 50-250 mPa s measured at 25°C of a 5% w / w solution in a mixture of toluene / ethanol (80:20). For example, in a HPMC:EC ratio from 250:1 to 1:50, or from 200:1 to 1:2.

[0097] In an embodiment, the polymeric binder in the core comprises a mixture of a hydroxypropylmethylcellulose acetate succinate with 5-9 wt% acetyl groups and 14-18 wt% succinoyl groups, a hydroxypropyl methyl cellulose with a Brookfield viscosity of 2-50 mPa s measured at 20°C in an aqueous solution at 2% w / w and an ethyl cellulose with a Brookfield viscosity of 5-500 mPa s measured at 25°C of a 5% w / w solution in a mixture of toluene / ethanol (80:20). In a further embodiment, the polymeric binder in the core comprises a mixture of a hydroxypropylmethylcellulose acetate succinate with 5-9 wt% acetyl groups and 14-18 wt% succinoyl groups, a hydroxypropyl methyl cellulose with a Brookfield viscosity of 2-20 mPa s measured at 20°C in an aqueous solution at 2% w / w and an ethyl cellulose with a Brookfield viscosity of 50-250 mPa s measured at 25°C of a 5% w / w solution in a mixture of toluene / ethanol (80:20). For example, in a HPMCAS:HPMC:EC ratio 2-70:10-70:2-60 (w / w / w), or 5-60:20-60:5-50 (w / w / w). In an embodiment, the core comprises a mixture of HPMCAS:HPMC:EC in a ratio 30-40:30-40:20-30 (w / w / w).

[0098] According to an embodiment, the core has an aspect ratio (mean) of at least 0.6. In a further embodiment, it has an aspect ratio of at least 0.75. For example, an aspect ratio of 0.6-0.9, or even 0.65-0.85.

[0099] According to an embodiment of the disclosure, the core has a surface area of at least 0.8 m2 / g, determined according to ISO 9277:2022. In an embodiment, it has a surface area of at least 0.85 m2 / g, determined according to ISO 9277:2022. For example, a surface area of 0.8-2.5 m2 / g, or even 0.8-2.3 m2 / g, determined according to ISO 9277:2022.

[0100] According to an embodiment, the core has a flowability of at least 15 mg / s, or even at least 20 mg / s, determined according to flow through an orifice method. For example, a flowability of 15-100 mg / s, or 20-60 mg / s. In an embodiment, it has a flowability of at least 30 mg / s. In a further embodiment, is has a flowability of at least 35 mg / s. For example, a flowability of 20-400 mg / s, or 30-350 mg / s. According to a particular embodiment, the core has a flowability of at least 100 mg / s, or even at least 200 mg / s.

[0101]

[0102] In a particular embodiment, the microparticles are uncoated. For example, they consist of the core comprising mesalazine and the polymeric binder.

[0103] In another embodiment, the microparticles are coated. For example, the microparticles can comprise a coating layer directly coating the core.

[0104] In an embodiment, the microparticles comprise a core that comprises mesalazine and a polymeric binder, and a coating layer. In an embodiment, the microparticles comprise a core that consists of mesalazine and a polymeric binder, and a coating layer. In another embodiment, the microparticles consist of a core that comprises mesalazine and a polymeric binder, and a coating layer. In another embodiment, the microparticles consist of a core that consists of mesalazine and a polymeric binder, and a coating layer.

[0105] Any pharmaceutically acceptable coating known in the art may be suitable. Such coating will become apparent to the skilled person upon reduction to practice of the invention. Suitable coatings thus include polymeric, lipidic, polysaccharide-based and inorganic coating materials commonly used in solid dosage forms. Such coatings may comprise cellulose-based polymers such as ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and hydroxypropyl methylcellulose phthalate; acrylic and methacrylic acid polymers and copolymers including polymethacrylates, methacrylic acid-methyl methacrylate copolymers, methacrylic acid-ethyl acrylate copolymers and ammonium methacrylate copolymers; vinyl polymers such as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone and polyvinyl acetate phthalate; polysaccharides and derivatives thereof such as starch, modified starches, dextrins, dextrans, alginates, pectins, carrageenans, chitosan and chitin; lipidic and waxy materials such as fatty acids, fatty alcohols, glycerides, hydrogenated vegetable oils, beeswax, carnauba wax and shellac; protein-based materials such as gelatin and zein; and inorganic or mineral materials such as silica, talc, calcium carbonate and titanium dioxide, optionally in combination with plasticizers, pore formers, stabilizers, pigments and surfactants, provided that all such materials are pharmaceutically acceptable.

[0106] In an embodiment, the coating layer is a polymeric coating layer. The coating layer can comprise an enteric polymer to prevent release of the mesalazine from occurring until after passage through the stomach. Coatings for masking taste may also be particularly used. Also, multiple coatings with different materials can be used to obtain release at different sites of the gastrointestinal tract.Coating layer as used herein refers to completely encasing or coating a core with a pharmaceutically acceptable coating.

[0107] In an embodiment, the coating layer provides a sustained-release profile or a controlled-release profile.

[0108] In an embodiment, the polymer in the coating layer of the coated microparticles can be selected from polyacrylates or polymethacrylates polymers, such as methacrylic acid / ethyl acrylate copolymers, methacrylic acid / methyl methacrylate copolymers, acrylic acid / methyl methacrylate copolymers, methylacrylate / methyl methacrylate / methacrylic acid copolymers, poly(hydroxyalkyl acrylates), and poly(hydroxyalkyl methacrylates); cellulose polymers, such as cellulose esters or cellulose ethers, including alkylcelluloses (e.g., methylcellulose or ethylcellulose), cellulose acetate, cellulose acetate trimellitate and cellulose phthalates or succinates (e.g., cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose succinate (HPMCS), or hydroxypropylmethylcellulose acetate succinate (HPMCAS)); polyvinyl-based polymers, such as polivinyl acetate and polyvinyl acetate phthalate; and mixtures thereof.

[0109] In a particular embodiment, the polymer in the coating layer is selected from ethylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, and copolymers of a (meth)acrylic acid and a (meth)acrylic acid C1-4 alkyl ester, including copolymers of methacrylic acid and methacrylic acid methyl ester, copolymers of methacrylic acid and acrylic acid ethyl ester, and copolymers of acrylic acid methyl ester, methacrylic acid methyl ester and methacrylic acid.

[0110] The coating layer can optionally comprise coating excipients, such as plasticizers (e.g. triethyl citrate, glyceryl triacetate, acetyl trimethyl citrate, diethyl phthalate, tributyl citrate, acetylated monoglycerides, stearic acid, oleic acid, polyethylene glycol, propylene glycol, glycerol, or mixtures thereof), detackifiers (talc, silicon dioxide, silica gel, fumed silica, glycerin monostearate, or mixtures thereof), antifoaming agents, lubricants (e.g. magnesium stearate), stabilizers, and mixtures thereof.

[0111] In an embodiment of the disclosure, the coating layer represents 0-30 wt%, or 0-25 wt% of the weight of the microparticles. In an embodiment, the coating layer represents 0-20 wt%, or even 0-15 wt%, with respect to the weight of the microparticles. In an embodiment, the microparticles are coated and the coating layer represents 5-25 wt% of the weight of the microparticles. In a further embodiment, it represents 5-20 wt%, or even 5-15 wt%, of the weight of the microparticles.According to a particular embodiment, the microparticles comprise at least 60 wt%, or even at least 65%, of mesalazine based on the total weight of the microparticles. In an embodiment, the microparticles comprise at least 70 wt% of mesalazine based on the weight of the microparticles. In a further embodiment, the microparticles comprise at least 75 wt%, or even at least 80%, of mesalazine based on the weight of the microparticles.

[0112] According to a particular embodiment, the microparticles comprise 60-95 wt%, or even 65-95%, of mesalazine based on the total weight of the microparticles. In a further embodiment, the microparticles comprise 75-95 wt%, or even 80-95%, of mesalazine based on the weight of the microparticles.

[0113] In a particular embodiment, the microparticles comprise 70-80 wt%, or even 75-80%, of mesalazine based on the total weight of the microparticles.

[0114] If the microparticles are uncoated, the particles size distribution of the microparticles might be the same as disclosed herein for the core.

[0115] Preferably, the microparticles (either coated or uncoated) have a particle size distribution with d90 equal to or lower than 200 pm.

[0116] In an embodiment, the microparticles have a particle size distribution with d90 of 45-200 pm. If the microparticles have a coating layer, they might have d90 of 100-200 pm, or even 120-200 pm.

[0117] In an embodiment, the microparticles have a particle size distribution with d50 of 20-150 pm. If the microparticles have a coating layer, they might have d50 of 40-150 pm, or even 50-150 pm.

[0118] In an embodiment, the microparticles have a particle size distribution with d10 of 4-80 pm. If the microparticles have a coating layer, they might have d10 of 20-80 pm, or even 30-80 pm.

[0119] According to a particular embodiment of the disclosure, the microparticles have a particle size distribution with d10 of 4-80 pm, d50 of 20-150 pm and d90 of 45-200 pm. If the microparticles have a coating layer, in an embodiment they have a particle size distribution with d10 of 20-80 pm, d50 of 40-150 pm and d90 of 100-200 pm. In another embodiment, if the microparticles have a coating layer they have a particle size distribution with d10 of 30-80 pm, d50 of 50-150 pm and d90 of 120-200 pm.

[0120] In an embodiment, the microparticles have a particle size distribution with a span lower than 2.5. In a further embodiment, they have a span lower than 2.2. In another embodiment, they have a span lower than 2.0.

[0121] Method of preparationAnother aspect of the invention refers to a method for preparing the microparticles as defined herein, wherein the method comprises:

[0122] (i) preparing a solution of the polymeric binder in a solvent,

[0123] (ii) mixing the solution from step (i) with mesalazine to obtain a suspension, and (iii) spray-drying the suspension from step (ii).

[0124] Optionally, the method comprises:

[0125] (iv) coating the product obtained after step (iii) to obtain microparticles with a coating layer.

[0126] The solvent in step (i) is selected so that the polymeric binder is solubilized, but not the mesalazine. In this way, a suspension is obtained after step (ii). When the spraydrying process is carried out under these conditions (suspension of mesalazine and solution of the polymeric binder), microparticles with the desired properties are obtained. In particular, no loss of mesalazine occurs during spray-drying and particles with a very high load of mesalazine are obtained. Further, the crystalline state of mesalazine is maintained during the process and so microparticles with crystalline mesalazine are obtained.

[0127] Suitable solvents to solubilize the polymeric binder and not the mesalazine can be readily identified by a skilled person in the art. In a particular embodiment, the solvent in step (i) is selected from C1-6 alcohols (e.g. methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, s-butanol, t-butanol), mixtures of water and C1-6 alcohols, (e.g. mixtures of water:Ci-6 alcohol from 1:1 (v / v) to 1:20 (v / v), or even from 1:1 (v / v) to 1:10 (v / v)).

[0128] In a particular embodiment, the C1-6 alcohol is selected from methanol and ethanol. In an embodiment, the C1-6 alcohol is ethanol.

[0129] According to an embodiment, the solvent is selected from EtOH and mixtures of waterEtOH (e.g. mixtures of waterEtOH from 1:1 (v / v) to 1:10 (v / v), or even from 1:1 (v / v) to 1 :5 (v / v)).

[0130] Step (i) can be carried out under stirring (e.g. under magnetic stirring). It can be carried out at a temperature of 10-50 °C. For example, at 10-30 °C.

[0131] Suitable polymeric binders for step (i) are as disclosed above in relation to the disclosure of the core of the microparticles.

[0132] In an embodiment, the mesalazine used in step (i) has a particle size d50 from 10 pm to 40 pm. In a further embodiment, it has a particle size with d50 from 5 pm to 35 pm.

[0133] In an embodiment, the ratio mesalazine:polymeric binder in the suspension of step(ii) is from 75:25 to 96:4 (w / w). In a particular embodiment, it is from 80:20 to 96:4 (w / w). In a further embodiment, it is from 85:15 to 95:5 (w / w). In a particular embodiment, the ratio mesalazine:polymeric binder in the suspension of step (ii) is from 75:25 to 85:15 (w / w).

[0134] According to an embodiment, the concentration of mesalazine in the suspension of step (ii) is from 6.0 to 20.0% (w / w), or even 7.0 to 18% (w / w).

[0135] The concentration (based on the total solid content, e.g. the sum of the amount of mesalazine and polymeric binder) in the suspension prepared in step (ii) might be from 5 to 25% w / w. In a particular embodiment, it is from 10 to 20% w / w. In a further embodiment, it is from 15 to 20% w / w.

[0136] In step (ii), the solution of the polymeric binder in the solvent and the mesalazine are mixed until a uniform suspension is obtained. This can be performed, for example, with a stirrer or a high-shear mixer.

[0137] Step (ii) can be carried out at a temperature of 10-50 °C. For example, at 10-30 °C. In a particular embodiment, the spray-drying in step (iii) is carried out at a temperature from 120°C to 200 °C. In a particular embodiment, it is carried out at a temperature from 120°C to 180°C or from 120°C to 160 °C. For example, at a temperature from 130°C to 150 °C.

[0138] In an embodiment, the spray-drying in step (iii) is carried out at a dosing speed from 2 to 10 g / min. For example, at a dosing speed from 3 to 8 g / min, or from 3 to 6 g / min. For example, at a dosing speed of 4 g / min.

[0139] In an embodiment, the spray-drying in step (iii) is carried out at an inlet airflow from 0.1 to 0.5 m3 / min. For example, at an inlet airflow from 0.2 to 0.4 m3 / min. For example, at an inlet airflow of 0.3 m3 / min.

[0140] In an embodiment, the spray-drying in step (iii) is carried out at an atomization gas from 1 to 5 L / min. For example, at an atomization gas from 2 to 4 L / min. For example, at an atomization gas of 3 L / min.

[0141] The spray-drying in step (iii) can be carried out using a nozzle, such as a bi-fluid nozzle or an ultrasonic nozzle.

[0142] During spray-drying in step (iii), the suspension can be continuously stirred (e.g. with magnetic stirring), so that no precipitation occurs.

[0143] In step (iii) cores or (uncoated) microparticles are formed by spray-drying. Optionally, said cores or uncoated microparticles can be subsequently coated in step (iv).

[0144] Particular and preferred embodiments for the cores or uncoated microparticlesobtained in step (iii) are as disclosed herein in relation to the disclosure of the core. In step (iv) a coating layer that surrounds the cores or uncoated microparticles resulting from step (iii) is formed so that coated microparticles are obtained. The coating layer is directly coating the core or uncoated microparticle.

[0145] Step (iv) can be carried out by any known methods such as by fluid bed coating, compression coating or spray coating. In a particular embodiment, step (iv) is carried out by fluid bed coating.

[0146] Suitable polymers for the coating layer and particulars of the coating layer and the resulting microparticles are as defined herein in relation to the disclosure of the microparticles.

[0147] In another aspect, the disclosure refers to a microparticle obtained by the method disclosed herein.

[0148] Pharmaceutical compositions

[0149] Another aspect of the invention refers to pharmaceutical compositions comprising the microparticles (either coated or uncoated) of the disclosure and a pharmaceutically acceptable excipient.

[0150] The term "pharmaceutically acceptable excipient" refers to a vehicle, diluent, carrier or adjuvant that is administered with the active ingredient. The excipients and auxiliary substances necessary to manufacture the desired pharmaceutical form of administration of the pharmaceutical composition of the invention will depend, among other factors, on the elected administration pharmaceutical form. Pharmaceutically acceptable excipients include, among others, binding agents, fillers, bulking agents, thickening agents, surfactants, diluents, lubricants, disintegrants, wetting agents, emulsifying agents, suspending agents, buffering agents, sterile liquids, solubilizing agents, dispersing agents, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, sweetening agents, flavouring agents, colouring agents or preserving agents.

[0151] The pharmaceutical composition may be in any form suitable for the application to humans and / or animals, preferably humans including infants, children and adults, and can be produced by standard procedures known to those skilled in the art. In an embodiment, the pharmaceutical composition is for oral administration.

[0152] The microparticles might have a particle size equal to or lower than 200 pm, for example a particle size distribution with d90 equal to or lower than 200 pm. These microparticles are highly advantageous for their oral administration. Since the tongue does not detect particles with this low particle size, the microparticles of the disclosureresemble to a liquid formulation and can be swallowed very easily, even without the need of a liquid to swallow them.

[0153] Therefore, in a particular embodiment, the pharmaceutical composition is in the form of a sachet that comprises the microparticles of the disclosure. Alternatively, the microparticles of the invention can be also formulated in other dose forms for oral administration, such as tablets, capsules, pills, caplets, lozenges, gel caps, chewing gums, powders, granules, drops, syrups, elixirs, emulsions, suspensions or solutions. Oral dosage forms may contain conventional excipients known in the art such as binding agents, fillers, diluents, lubricants, disintegrants, wetting agents, emulsifying agents, suspending agents, buffering agents, sweetening agents, flavouring agents, colouring agents or preserving agents.

[0154] In another embodiment, the pharmaceutical composition can be for rectal administration, for example in the form of suppositories.

[0155] Uses

[0156] Mesalazine is used to treat inflammatory bowel disease, including ulcerative colitis and Crohn's disease. Therefore, another aspect refers to the microparticles of the disclosure or to the pharmaceutical composition of the disclosure for use in medicine.

[0157] Another aspect refers to the microparticles of the disclosure or to the pharmaceutical composition of the disclosure, for use in the prevention or treatment of an inflammatory bowel disease, such as ulcerative colitis or Crohn’s disease.

[0158] Another aspect refers to the use of the microparticles of the disclosure or to the pharmaceutical composition of the disclosure for the manufacture of a medicament; for example, for the manufacture of a medicament for the prevention or treatment of an inflammatory bowel disease, such as ulcerative colitis or Crohn’s disease.

[0159] In another aspect, the disclosure refers to a method for the prevention or treatment of an inflammatory bowel disease, such as ulcerative colitis or Crohn’s disease, which comprises the administration of the microparticles of the disclosure or to the pharmaceutical composition of the disclosure to a patient in need thereof.

[0160] It should be understood that the scope of the present disclosure includes all the possible combinations of embodiments disclosed herein.

[0161] The following materials and methods were used:

[0162] Materials:Mesalazine (Zhejiang Hengkang Pharmaceutical Co., Ltd.)

[0163] HPMC E5 (Shin-Etsu)

[0164] HPMC E15 (Shin-Etsu)

[0165] HPMCAS-LG (Shin-Etsu)

[0166] HPC ELF (Ashland)

[0167] EC N 100 (Ashland)

[0168] PVPVA64 (BASF)

[0169] PVP K30 (BASF)

[0170] PVP K90 (BASF)

[0171] Eudragit L100 (Evonik)

[0172] Eudragit FS 30D (Evonik)

[0173] Ethanol 99% Technisolv (VWR)

[0174] Isopropanol (VWR)

[0175] Acetone (VWR)

[0176] Magnesium Stearate (Peter Greven)

[0177] Talc (ABC Chemicals)

[0178] TEC (Aldrich)

[0179] Testing methods:

[0180] Scanning electron microscopy

[0181] The samples were visually evaluated using scanning electron microscopy (SEM) (Phenom Pro Suite, Phenom). A small amount of sample was placed on a carbon conductive tab on a sample holder. Next, the sample was coated with a thin layer of gold (approx. 10 nm) in a gold sputter coater (Quorum). Afterwards the sample could be analysed by SEM.

[0182] Particle size distribution (PSD)

[0183] The dry particle size (d10, d50, d90 - by volume) and distribution width (span) were measured using dry powder laser diffraction. The samples were dispersed with a RODOS dry dispersing unit (with compressed air at 1.5 bar) before sizing with a HELOS laser diffraction sensor (measurement range R3 = 0.9 - 175 pm, R5 = 4.5 - 875 pm) (both Sympatec).

[0184] Particle shape

[0185] The particle shape was analysed using dynamic image analysis. The samples were dispersed in free fall using a GRADIS dry dispersing unit before being optically capturedwith a QICPIC high resolution camera at a frequency of 80 Hz (both Sympatec). The width of the outlet slit of the fall shaft was set at 2.0 mm. Measurement range M6 (2.8 pm - 5632 pm) was used for all measurements.

[0186] Tabletting

[0187] The tableting instrument Styl'One Evolution (Medelpharm) was used for the hybrid modelling of direct compaction. The compaction simulator was equipped with a round shaped flat faced punch (0 11.28 mm). Automatic filling with a feed shoe was used to fill the powder into the die. The Styl'One Evolution is operated with a dedicated software (ANALIS, Version 2.08.8, Medelpharm).

[0188] Tablet weight, thickness and hardness

[0189] Tablet weight, thickness and hardness determination was carried out using a SOT AX tablet hardness tester ST50. The tablet hardness was measured using constant speed at 0.35 mm / s.

[0190] Flowability

[0191] The Flow Rate, measured by the FlowPro (iPAT, Turku, Finland), records the mass change over time for powder flow through an orifice (3 mm). Approximately 5 mL of sample was filled in the vessel. This vessel is mounted in the FlowPro, which undergoes a repeating cycle of a single upward motion breaking the powder arch until flow is complete (80% in down-position, allowing flow and 20% in up-position, breaks the powder arch).

[0192] X-ray powder diffraction of dry samples (XRPD)

[0193] XRPD experiments were carried out using an automated Aeris diffractometer (PANalytical, malvern) with a Cu tube (Ka A = 1.5418 A) with a generator of 40 kV and 15 mA. Samples were applied on spinning zero background sample holders. Measurements were performed in a continuous scan mode from 4° to 40° with 0.0217° step size and 500 s per step counting time.

[0194] Dissolution

[0195] The release profile of the sample was analysed using an AT Xtend semi-automatic dissolution bath (Sotax). An USP I (basket) method was used, whereby a pH shift of the medium was performed. Starting with HCI buffer pH 1.2, adding buffer pH 12.3 to obtain pH 6.8 and finally adding buffer pH 11.6 to obtain a final pH of 7.5 (media preparation as describe next). Dissolution media were at a temperature of 37°C. The basket was rotatedat 100 rpm. An amount of sample was brought into the vessel to obtain a final concentration (in final volume) of 0.28 mg eq. API / mL. Samples of the medium were taken at set time points and analysed using an UPLC system (chromatographic conditions as described below).

[0196] • Dissolution media preparation:

[0197] Buffer pH 1.2: 84 mL of 37% HCI was added to a 10 L flask. The flask was diluted to volume with water, pH was checked.

[0198] Buffer pH 12.3: 158.15 g potassium dihydrogen phosphate was weighed into a 5L flask. 1163 mL 2M NaOH was added. The flask was diluted to volume with water, pH was checked.

[0199] Buffer pH 11.6: 32.80 g potassium dihydrogen phosphate was weighed into a 5L flask.

[0200] 193 mL 2M NaOH was added. The flask was diluted to volume with water, pH was checked.

[0201] • Chromatographic conditions:

[0202] System: UPLC (PDA detector)

[0203] Wavelength: 240 nm

[0204] Column: Acquity HSS T3, 50 mm length x 2.1 mm i.d., 1.8 pm Flow rate: 0.45 mL / min

[0205] Column temperature: 33 °C

[0206] Sample tray temperature: 18 °C

[0207] Injection volume: 0.6 pL

[0208] Run time: 10 min

[0209] Mobile phase: A: Monosodium phosphate monohydrate 6.9 g / L pH 6.2.

[0210] B: 40 / 60 ACN / Monosodium phosphate monohydrate 6.9 g / L pH 6.2 (v / v)

[0211] Gradient

[0212]

[0213] Surface area

[0214] The adsorption analysis with N2 as adsorptive was recorded at 77 K on a Micromeritics Tristar II 3020. A relative pressure range from p / pO = 0.01 up to p / pO = 0.30 was applied. Prior to the actual adsorption investigations, the samples were pre-treated at 40°C in vacuum for 16 hours. The dry sample mass obtained after the pre-treatment was used in the various calculations according to ISO 9277:2022.1.1. Synthesis of mesalazine microparticles

[0215] Mesalazine microparticles were obtained by spray-drying. The spray drying experiments were performed on the 4M8-TriX spray drier (PROCEPT, Belgium). To atomize the feed solution into droplets, the bi-fluid (BF) nozzle with a nozzle diameter of 1mm or an ultrasonic nozzle (25kHz) was used depending on the used binder. An inlet temperature of 140°C, inlet airflow of 0.3 m3 / min and a cyclone gas flow of 400 L / min were used for all trials. An atomization gas of 3 L / min (for the bi-fluid nozzle) and a dosing speed of 4 g / min were used.

[0216] For preparation of the liquid feed for spray drying, when required, a solvent mixture of water and ethanol is first prepared in a 1 / 2 water / ethanol ratio (v / v), prepared in a volume ratio. Solvents were well mixed prior to use to addition of solids. When ready, first, the polymer was dissolved in the specified solvent and amount, as defined by the solid load (Table 1), by use of magnetic stirring. Afterwards, the required amount of mesalazine was added to mixture while continuous stirring. Lastly, high-shear mixing was applied (e.g. 20 min) until a uniform suspension was obtained.

[0217] During spray drying, suspension was continuously stirred (with magnetic stirring) to ensure that no precipitation occurs.

[0218] Different polymers, mesalazine (API):polymer ratios and spray-drying conditions were tested as shown in Table 1 below.

[0219] Table 1

[0220]

[0221]

[0222] Different types of polymers (HPMC E5, HPC ELF, EC N100, PVPVA64, PVP K30 and PVP K90) were tested and found to allow the preparation of spherical mesalazine particles at an 85:15 mesalazine:polymer ratio (w / w) via spray drying. Similar properties were observed for the spray-dried particles when prepared with 90% (w / w) mesalazine load using HPMC E5, HPC ELF, EC N100 and PVP K90. For PVP K90, a further increase in mesalazine load to 95% (w / w) still resulted in a high amount of spherical particles. Spherical particles with rough or wrinkled surface were obtained in Examples 1-12, with no or very low amounts of mesalazine needles (Figure 1).

[0223] On SEM pictures of the obtained microparticles, both crystalline mesalazine fractions and polymeric binder were observed at the surface.

[0224] Example 2 (mesalazine:HPMC E5, 85:15) was used as reference to produce bigger batches (Examples 13 and 14, Table 2) of spray-dried material to be used for additional characterization and coating testing (Figure 2). Stable processes, with similar results as for the small scale trial were obtained for both examples.

[0225] Table 2

[0226]

[0227] The term Assay (mg / g) refers to the amount of mesalazine in mg per gram of the microparticle. As shown in Table 2, it was found that the process of the disclosure allows the incorporation of 98-100% of the starting mesalazine into the particles. Importantly,no loss of mesalazine is happening during spray-drying, resulting in microparticles with a very high load of the active ingredient.

[0228] Process recovery refers to the amount of collected solids (i.e. after spray drying) divided by the amounts of dosed solids (i.e. weighed solids for feed preparation).

[0229] Mesalazine microparticles comprising mixtures of polymers as binder shown in Table 3 were obtained by spray-drying following the general method defined above (BF, solid load: 16.5 %w / w, solvent: H2O / EtOH (1 / 2 w / w).

[0230] Table 3

[0231]

[0232] Different combinations of polymers were tested and found to allow the preparation of spherical mesalazine particles mesalazine ratios higher than 75 wt% via spray drying. Figure 3 shows the SEM images of the microparticles obtained in Examples 15, 22, 24 and 27.

[0233] The particles of Example 24 were prepared in a big batch using the following conditions and process parameters:

[0234]

[0235]

[0236] 2. Characterization of mesalazine microparticles

[0237] A. Particle size distribution, Bulk density and Flowability

[0238] The particle size (d10, d50, d90), distribution width (span), bulk density and flowability of the obtained mesalazine microparticles were determined and compared to mesalazine as such. The results are shown in Table 4.

[0239] Table 4

[0240]

[0241]

[0242] Pure mesalazine showed a broad distribution width (i.e. SPAN) with clear bimodal curve. Median particle size (d50) was found at 17 pm, however this value is biased by the presence of two population of particle sizes. It is important to note that the particle size distribution for pure mesalazine may not fully represent the sample morphology, as SEM images reveal the formation of needle-like structures rather than spherical particles (Figure 2). In contrast, the spray-dried particles of Examples 1-15, 24 and 27 showed a unimodal curve with a significantly lower SPAN.

[0243] The flowability of the samples was evaluated by measuring the flow rate of the powder through an orifice. The flow rate (mg / s) for pure mesalazine was found to be 3.4 mg / s. For all spray-dried materials, an improvement (5 to 85-fold) in flowability, compared to mesalazine as such, was obtained. HPMC E5, HPC ELF, PVPVA64 and PVP K30 showed similar PSD, bulk density and improved flowability (10-fold improvement vs. mesalazine). For EC N100, a lower density and flowability, compared to the other polymers, was obtained. On the other hand, particles prepared with PVP K90 showed the highest enhancement compared to mesalazine, with the highest PSD and a flowability improvement of 34-fold and 85-fold for materials prepared with 90% and 85% (w / w) mesalazine load, respectively. Therefore, the spray-dried samples have a clear improved flowability.B. Morphology

[0244] SEM analyses showed significant differences in morphology between the pure mesalazine and the samples according to the invention (Figures 1-3). In pure mesalazine a needle structure is visible with several agglomerates of needles. The spray-dried particles of Examples 1-15, 22, 24 and 26, on the other hand, consisted of spherical particles.

[0245] C. Sphericity

[0246] The sphericity of the particles was evaluated by means of the circularity parameter, which is a value for the roundness of the particles. Circularity refers to the ratio of the circumference of a circle equal to the object's projected area to the perimeter of the particle image. A perfectly circular particle has a circularity of 1 , while a rod-like particle has a lower circularity value. In order to present the most representative shape distribution as possible, “fines” (particles below D ) were filtered (Table 5).

[0247] Table 5

[0248]

[0249] Complementary, the aspect ratio was also calculated. This is the ratio of the width to the length of a particle, and, for these parameters, a circular or square particle, for example, will have both an aspect ratio of 1, since the width is equal to the length. Rod-like particles, on the other hand, will have a low aspect ratio as the width is much smaller compared to the length (Table 6).

[0250] The circularity and aspect ratio results show that mesalazine particles are elongate particles, as the circularity and mean aspect ratio are lower. The rather high circularity observed (0.71) is primarily due to the smallest particles included in the results, as typically, smaller particles are more rounded relative to the larger particles.

[0251] On the other hand, the four spray-dried samples showed a higher circularity around 0.89. In addition, also the aspect ratio of these samples is higher, averaged 0.69. Based on the found aspect ratio combined with the high circularity, it is suggested that particles are slightly oval in shape.Table 6

[0252]

[0253] D. Surface area

[0254] In order to determine the specific surface area of the powders, N2 adsportion investigation coupled to the samples masses was performed. Table 7 shows the textural properties of pure mesalazine and spray-dried mesalazine particles derived from adsorption isotherms.

[0255] Table 7

[0256]

[0257] The specific surface area of Example 7 was found the highest and Example 24, the lowest. Only the specific surface area of Example 7 was found lower compared to the neat API. This might be related to the fact that, compared to other spray-dried materials, these particles present less / no porous and a less wrinkled surface compared to the sample with EC 100 only.

[0258] E. Solid state characterization

[0259] To evaluate that the solid state of the mesalazine was not affected by the spray-drying process, the samples (mesalazine and Examples 3, 7, 14 and 24) were analyzed on XRPD. All powders were found to be crystalline and all characteristic peaks of pure mesalazine were found in the spray-dried mesalazine particles, confirming that spray drying process did not change mesalazine solid state (Figure 4).

[0260] F. DissolutionDissolution of pure mesalazine and the spray-dried powder of Examples 3, 7, 14-20 and 24 was performed to evaluate the release of mesalazine in the media. A pH shift was implemented during the dissolution tests. The initial pH of 1.2 was increased after 2 h to pH 6.5 and, after 2 hours, further increased to pH 7.1. The release of mesalazine is almost immediate in low pH (i.e. pH 1.2) for both powders and remains constant during the different phases of the dissolution. For Example 14, only a slightly lower start was noticed at the 30 minutes timepoint.

[0261] Figure 5 shows the dissolution profile of the particles of Examples 3, 7 and 15. Figure 6 shows the dissolution profile of the particles of Examples 16, 17, 18, 19 and 20. Addition of EC N 100 provided a positive effect for the sustained release of mesalazine.

[0262] Figure 7 shows the dissolution profile of the particles of Example 24. Sustained release of mesalazine for 24 h was obtained with these particles even without coating.

[0263] G. Tablet compression characterization

[0264] The tablet formulation composition of pure mesalazine and spray-dried mesalazine particles of Examples 3, 7, 14 and 24 is shown in Table 8.

[0265] Table 8

[0266]

[0267]

[0268] Tablet compression characterization was performed by applying different compression pressures to the powder blend to produce a tablet. For this, a compaction simulator was used (Styl'One Evolution, Medelpharm). The compaction simulator was equipped with a round shaped flat faced punch (0 11.28 mm). To evaluate tabletability, different compression pressures were tested and hardness (i.e. resistance of the tablets to breakage) of the tablets was measured. To minimize the impact of tablet dimension and weight, tensile strength (i.e. calculated value from hardness taking tablet dimension into account) was used during evaluation. The relationship between tensile strength and compression pressure was plotted in a tabletability plot for each powder blend (Figure 8). Generally, a tensile strength greater than 1.7 MPa is targeted as it is accepted this ensures that the tablet is mechanically strong enough to withstand commercial manufacture.

[0269] Tabletability of the formulation of pure mesalazine (sample 1) proved not to be successful as the tensile strength did not reach 1.7 MPa at any of the compression pressures used. Additionally, large variation was obtained for the compression pressure applied indicating that the powder could not be fed properly with the automatic feed shoe (i.e. poor flowability). On the other hand, the tabletability plot of all spray-dried powders showed a significant increased tensile strength of the tablets compared to that of the formulation of mesalazine, reaching the typical specification of 1.7 MPa starting from 100 MPa compression pressure already. Furthermore, the lower variations obtained for each applied compression pressure showed the proper filling of the punches with the automatic feed shoe.Table 9 shows an overview of the performed analyses and results for mesalazine and spray-dried particles of Example 14. It can be concluded that the spray-dried mesalazine particles have a spherical shape which results in a more uniform particle size distribution, a larger aspect ratio, larger surface area and unexpected clear improved flowability. Due to that, Example 14 powder could be easily compacted with a compaction simulator. In addition to these improvements, the characteristic elements of mesalazine, such as the solid state and full release in low pH, were preserved in the particles of Example 14. Table 9

[0270]

[0271] Table 10 shows an overview of the performed analyses and results for spray-dried particles of Examples 3, 7 and 24. Again, the spray-dried mesalazine particles have a spherical shape and a more uniform particle size distribution, a larger aspect ratio and unexpected clear improved flowability. Examples 3, 7 and 24 powders could be easily compacted with a compaction simulator. Also, the solid state of mesalazine was preserved during the process. In these examples, a much lower release of mesalazine was observed.

[0272] Table 10

[0273]

[0274]

[0275] H. Spatial distribution of components in the core

[0276] The distribution of mesalazine in the particles according to Examples 14 (Mesalazine / HPMC E5 85 / 15 w / w) and 24 (Mesalazine / HPMCAS-LG / HPMC E5 / EC N10080 / 7.35 / 7.35 / 5.30 w / w / w / w) was analyzed using energy-dispersive X-ray analysis. A semi-quantitative microanalysis and a mapping of the elemental composition distribution of the surface of the samples were carried out. Then, samples were ground with a mortar to also analyze the elemental composition of the granule interiors. The analysis was performed using an EDS Ultim®Max (Oxford Instruments, Abingdon, UK) controlled by INCA software (Oxford Instruments, Abingdon, UK).

[0277] Table 11

[0278]

[0279] Table 12

[0280]

[0281]

[0282] As shown in Tables 11 and 12, the amount of N (used as mesalazine marker) detected in the samples before crushing (at the surface of the particles) was lower than the amount of N after crushing. This means that mesalazine is present at the surface of the particles, but in an amount lower than in the inner part of the particles.

[0283] I . Helium Pycnometry

[0284] The density of the particles according to Examples 14 and 24 was determined using a helium pycnometer (Quantachrome, Boynton Beach, FL, USA) at a pressure of 1.2 Bar at room temperature. For each sample, 3 replicates were performed, and the average and standard deviation were calculated. The bulk density (p bulk) of the samples was calculated by weighing a determined amount and calculating its volume. For this, the helium pressure in the sample chamber (P1) and the final equilibrium pressure after opening the valve that connects the sample chamber with the reference chamber were measured.

[0285] With the collected data, the bulk density was calculated using the following equations:= (m * P2) / (V* (P1- P2))

[0286] The real density values indicate the compactness of the material. The more compact the material (denser particles) or with a smaller internal volume, the higher the values. Table 13

[0287]

[0288] 3. Coating of mesalazine microparticles

[0289] Mesalazine: H PMC E5 microparticles obtained by spray drying in Example 13 were coated by fluid bed coating.

[0290] Fluid bed coating experiments were performed using the 4M8Trix fluid bed (PROCEPT, Belgium) equipped with the 1 L vessel and a meshed bottom plate. The bi-fluid nozzle was inserted at the top of the vessel in order to perform (top-)coating.

[0291] Two different coatings were used for fluid bed coating. One was based on Eudragit L100 (EL100), that is soluble above pH 6.0, and a second based on Eudragit FS30D, which is soluble above pH 7.0. Coating was applied until a theoretical weight gain (WG) of 20% (w / w) was obtained for EL100 (Example 28), until a theoretical WG of 30% (w / w) was obtained for EL100 (Example 29) and until a theoretical WG of 20% (w / w) was obtained for Eudragit FS30D (Example 30).

[0292] Coating suspensions EL100 and Eudragit FS30D, used in Examples 28 to 29 as described in Table 14, were prepared as described in the “Technical Information -Quickstart” of the coating agents, available from their supplier (Evonik). Coating formulations can be found in Table 14.

[0293] Briefly, for EL100, a homogeneous solvent mixture consisting of acetone, isopropanol and water was first prepared in a ratio of 37.5 / 57.5 / 5 acetone / isopropanol / water (v / v). After, EL100 powder was slowly added into 50% (w / w) of the solvent mixture and stirred until the polymer was completely dissolved (approx. 30 - 60 minutes). Magnesium stearate (MgSt) and triethyl citrate (TEC) were added to the remaining diluent mixture and stirred for 10 minutes with a high shear mixer. Afterwards, the latest excipient suspension was slowly poured into the EL100 solution while stirring with a magnetic stirrer. Before use in fluid bed coating, spray suspension was passed through a 0.5 mm sieve. Coating suspension was continuously stirred during dosing.For Eudragit FS30D, first, triethyl citrate and talc were homogenized in water using a high shear mixer for 10 minutes. Afterwards, the excipient suspension was slowly poured into the EUDRAGIT® FS30D dispersion while stirring gently with a magnetic stirrer. Before use in fluid bed coating, spray suspension was passed through a 0.5 mm sieve. Coating suspension was continuously stirred during dosing.

[0294] A spray-dried batch of 75 g was coated in the 1 L vessel with the respective coating agent (Ex. 15 and 16 with EL100 and Ex. 17 with Eudragit FS30D). Coating addition was stopped when the theoretical weight gain (WG) of 20 or 30% (w / w) was achieved. WG is the increase in dry weight of the powder after coating, i.e. corresponds to the amount of solids added (w / w) of the coating agent to the spray-dried powder, that contributes to the increase in weight regarding the initial powder weight.

[0295] The coating parameters and formulations are shown in Table 14 and 15, respectively.

[0296] Table 14

[0297]

[0298] Table 15

[0299]

[0300]

[0301]

[0302] Table 16 shows the particle size distribution and morphology of the coated particles. No differences were observed between the two coating polymers used. SEM images showed the presence of non-porous, spherical particles (Figure 9). Particles were visually coated, with a rougher surface being obtained with coating with Eudragit FS30D. No differences could be detected between different WG for EL100 coating, based on PSD and SEM.

[0303] Table 16

[0304]

[0305] As shown in Table 16, 95-99% of the starting mesalazine is present in the coated particles. No loss of mesalazine is happening during the process, which allows to obtain microparticles with a very high load of mesalazine.Following the same process, mesalazine particles obtained by spray-drying in Examples 3 and 7 were coated by fluid bed coating with Eudragit L100 (EL100) until a theoretical weight gain (WG) of 20% (w / w) or 30% (w / w) was obtained.

[0306] Table 17 shows the coating parameters and the as well as the particle size distribution of the coated particles.

[0307] Table 17

[0308]

[0309] Figure 10 shows the SEM images of the uncoated particles of Examples 3 and 7 and the corresponding coated particles of Examples 31-34.

[0310] The quality of the delayed-release coating of the different polymers and WG was evaluated by in vitro dissolution. A pH shift was implemented during the dissolution tests. The initial pH of 1.2 was increased after 2 h to pH 6.8 and, after 2 hours, further increased to pH 7.5. As shown in Figure 11 and Table 18, mesalazine released from the coated microparticles in acidic media.

[0311] Table 18

[0312]

[0313] Figure 12 shows the dissolution profile of the uncoated particles of Examples 3 and 7 and the corresponding coated particles of Examples 32 and 34.

Claims

CLAIMS1. Microparticles comprising a solid core that comprises mesalazine and a polymeric binder, wherein the core has a particle size distribution with d50 of 20-100 pm and span lower than 2.5, and wherein the core comprises at least 75 wt% of mesalazine based on the total weight of the core.

2. Microparticles according to claim 1, wherein the core consists of mesalazine and a polymeric binder.

3. Microparticles according to any one of claims 1 or 2, wherein the core comprises at least 80 wt% of mesalazine based on the total weight of the core.

4. Microparticles according to any one of claims 1 to 3, wherein the microparticles have a particle size distribution with d90 equal to or lower than 200 pm.

5. Microparticles according to any one of claims 1 to 4, wherein the core has a particle size distribution with d90 lower than 150 pm.

6. Microparticles according to any one of claims 1 to 5, wherein the polymeric binder is selected from cellulose esters or cellulose ethers, such as alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, carboxymethyl cellulose, cellulose acetate, and cellulose phthalates or succinates; homopolymers or copolymers of N-vinyl lactams, such as homopolymers or copolymers of N-vinyl pyrrolidone, or copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate; polyalkylene oxides, such as polyethylene oxide, polypropylene oxide, copolymers of ethylene oxide and propylene oxide, and polyethylene glycol; polyacrylates or polymethacrylates, such as methacrylic acid / ethyl acrylate copolymers, methacrylic acid / methyl methacrylate copolymers, acrylic acid / methyl methacrylate copolymers, poly(hydroxyalkyl acrylates), and poly(hydroxyalkyl methacrylates); vinyl acetate polymers and vinyl acetate phthalate polymers; polyalkylenes, such as polyethylene; polylactides; polycaprolactones; polyurethanes; polyacrylamides; oligo- or polysaccharides, such as chitosan, alginate, carrageenan, galactomannan, guar gum, and xanthan gum; or mixtures thereof.

7. Microparticles according to any one of claims 1 to 6, wherein the polymeric binderis selected from ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, copolymer of N-vinyl pyrrolidone and vinyl acetate and mixtures thereof.

8. Microparticles according to any one of claims 1 to 7, wherein the polymeric binder comprises a mixture of ethyl cellulose, hydroxypropylmethyl cellulose acetate succinate and hydroxypropyl methyl cellulose.

9. Microparticles according to any one of claims 1 to 8, wherein mesalazine is in crystalline form.

10. Microparticles according to any one of claims 1 to 8, wherein the mesalazine has a concentration gradient in which the mesalazine concentration gradually decreases from the center toward the surface of the core.

11. Microparticles according to any one of claims 1 to 10, wherein the core has a flowability of at least 15 mg / s, or even at least 30 mg / s.

12. Microparticles according to any one of claims 1 to 11, wherein the microparticles further comprise a coating layer directly coating the core.

13. Microparticles according to any one of claims 1 to 12, wherein the coating layer comprises an polymer selected from polyacrylates or polymethacrylates polymers, such as methacrylic acid / ethyl acrylate copolymers, methacrylic acid / methyl methacrylate copolymers, acrylic acid / methyl methacrylate copolymers, methylacrylate / methyl methacrylate / methacrylic acid copolymers, poly(hydroxyalkyl acrylates), and poly(hydroxyalkyl methacrylates); cellulose polymers, such as cellulose esters or cellulose ethers, including alkylcelluloses, cellulose acetate, cellulose acetate trimellitate and cellulose phthalates or succinates; polyvinyl-based polymers, such as polivinyl acetate and polyvinyl acetate phthalate; and mixtures thereof.

14. Microparticles according to any one of claims 1 to 13, wherein the microparticles comprise at least 65 wt%, or even at least 70%, of mesalazine based on the total weight of the microparticles.

15. Method for preparing the microparticles according to any one of claims 1 to 14, comprising:(i) preparing a solution of a polymeric binder in a solvent,(ii) mixing the solution from step (i) with mesalazine to obtain a suspension, and (iii) spray-drying the suspension from step (ii).

16. Method according to claim 15, wherein the method further comprises:(iv) coating the product obtained after step (iii).

17. Method according to claim 16, wherein step (iv) is carried out by fluid bed coating.

18. Method according to any one of claims 15 to 17, wherein the solvent in step (i) is selected from a C1-6 alcohol and mixtures of water and a C1-6 alcohol.

19. Method according to any one of claims 15 to 18, wherein the mesalazine used in step (ii) has a particle size d50 from 10 to 40 pm, such as from 15 to 35 pm.

20. Method according to any one of claims 15 to 19, wherein the mesalazine concentration in the suspension of step (ii) is from 6.0 to 20.0% (w / w), or even 7.0 to 18% (w / w).

21. Method according to any one of claims 15 to 20, wherein the concentration of mesalazine and polymeric binder in the suspension of step (ii) is from 5 to 25 %w / w, such as from 10 to 20 %w / w.

22. Method according to any one of claims 15 to 21, wherein the ratio mesalazine:polymeric binder in the suspension of step (ii) is from 75:25 (w / w) to 96:4 (w / w).

23. Microparticles obtainable by the method according to any one of claims 15 to 22.

24. Pharmaceutical composition comprising the microparticles according to any one of claims 1 to 14 or 23 and a pharmaceutically acceptable excipient.

25. Pharmaceutical composition according to claim 24, wherein the composition is for oral administration.

26. Pharmaceutical composition according to any one of claims 24 or 25, wherein the composition is in the form of sachets, tablets, capsules, pills, caplets, lozenges, gel caps, chewing gums, powders, granules, drops, syrups, elixirs, emulsions, suspensions or solutions.

27. Microparticles according to any one of claims 1-14 or 23, or pharmaceutical composition according to any one of claims 24-26, for use in medicine.

28. Microparticles according to any one of claims 1-14 or 23, or pharmaceutical composition according to any one of claims 24-26, for use in the prevention or treatment of an inflammatory bowel disease, such as ulcerative colitis or Crohn’s disease.

Images