WO2021204883A1

WO2021204883A1 - Pharmaceutical composition for treating inflammatory bowel diseases

Info

Publication number: WO2021204883A1
Application number: PCT/EP2021/059076
Authority: WO
Inventors: Sylvie SABLAYROLLES; Bruno Le Grand; Maria Ines RÉ; Antoine PERRON
Original assignee: Cvasthera; Institut Mines Telecom
Priority date: 2020-04-08
Filing date: 2021-04-07
Publication date: 2021-10-14
Also published as: FR3109089B1; FR3109089A1; EP4132473A1

Abstract

The invention relates to a pharmaceutical composition suitable for oral administration, containing as active ingredient a compound chosen from the group consisting of vorapaxar, vorapaxar isomers, atopaxar and 3,2-(chlorophenyl)-1-[4-(4-fluorobenzyl)piperazin-1-yl]propenone, and pharmaceutically acceptable salts thereof. This composition contains particles comprising a core containing a mixture of the active ingredient and of a substance capable of inhibiting recrystallisation of the active ingredient at a pH which has become greater than or equal to 5; and a pH-dependent, controlled-release coating layer covering said core, said coating layer being formed of a gastro-resistant coating agent and being porous.

Description

PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF INFLAMMATORY INTESTINAL DISEASES

The present invention falls within the field of the formulation of active pharmaceutical ingredients, more particularly for the treatment of chronic intestinal diseases, in particular in mammals.

More particularly, the present invention relates to a human or veterinary pharmaceutical composition suitable for oral administration which contains, as an active principle, a compound selected from the group consisting of vorapaxar, isomers of vorapaxar, atopaxar and 3-2- (chloro-phenyl) -l - [4- (4-fluoro-benzyl) -piperazin-1 -yl] -propenone, as well as the use of this pharmaceutical composition as a medicament, in particular for prevent and / or treat chronic inflammatory bowel and colon disease. The invention also relates to a process for preparing such a pharmaceutical composition.

Chronic inflammatory bowel and colon disease, also known as inflammatory bowel disease, commonly referred to as MICIs, include, in humans, Crohn's disease and ulcerative colitis.

Crohn's disease can affect the entire digestive tract, either in contiguous sections or in isolated sections, but it primarily affects the small intestine and colon. The inflammation can affect the inner lining and even cross the entire thickness of the intestinal wall. It is manifested by edema, dilation of blood vessels and loss of fluid in the tissues. Crohn's disease is a pathology in young adults that generally begins between the ages of 20 and 30. There is a second frequency peak between 50 and 80 years old and 15% of cases concern children. Both sexes are equally affected. The affection is ubiquitous but its incidence is higher in the North than in the South of Europe. In France, the incidence of Crohn's disease is 5 to 6 cases per 100,000 inhabitants and as many ulcerative colitis. On the other hand, the prevalence is increasing exponentially in countries undergoing industrialization, such as the countries of the Maghreb, Asia, South Africa ... The origin of Crohn's disease is still unknown. It is probably multifactorial, associating a predisposed genetic background - it has recently been demonstrated in humans on chromosomes 12 and 16, a predisposition gene for chronic inflammatory intestinal diseases - and environmental factors which remain to be elucidated, for example. a triggering infection or pollution. In addition, the harmful role of tobacco is clearly established, increasing the risk of recurrence.

Ulcerative colitis, or ulcerative colitis, is a chronic inflammatory bowel disease that affects the distal end of the digestive tract, that is, the colon and rectum which is always affected. Its etiology is unknown, although a genetic component is a hypothesis. It is classified under autoimmune diseases. This disease cannot be cured, and requires lifelong drug treatment. The goal of treatment is for remissions to last as long as possible. Its diagnosis is mainly based on the cytological examinations that accompany the samples during a colonoscopy.

These chronic inflammatory bowel and colon diseases progress through inflammatory outbreaks of extremely variable duration and frequency depending on the patient. These outbreaks alternate with phases of remission. During inflammatory outbreaks, IBDs are most often characterized by abdominal pain, frequent diarrhea, sometimes bloody, or even damage to the anal region (fissure, abscess). These symptoms place a certain taboo on the disease. They are often accompanied by fatigue, anorexia and fever, or even extra-intestinal manifestations (articular, cutaneous, ocular, hepatic). In about 20% of patients, the attacks are severe: their intensity may require hospitalization, discontinuation of food and infusion therapy for a few days. In addition, the course of the disease can lead to the narrowing of the affected intestinal segment, followed by an obstruction or even an abscess. This can lead to the formation of a fistula, that is to say the opening of an abnormal communication path from the intestine to another organ. These complications require surgery. IBDs are associated with an increased risk of colorectal cancer, especially when lesions are present in the colon. The diagnosis of IBD is based on several clinical, biological and medical imaging criteria. When clinical symptoms suggest IBD, a biological workup is performed. It makes it possible to detect an inflammatory syndrome, the presence of specific markers of IBD, in particular the anti-Saccharomyces cerevisiae (ASCA) antibodies and the anti-neutrophilic cytoplasmic antibodies (ANCA). A digestive endoscopy makes it possible to search for the presence and localization of lesions in the digestive tract, as well as to take samples.

The management of a patient with IBD involves a large number of parameters related to the form of the disease and to the patient himself. Five categories of drugs are currently used in the basic treatment of IBD. These are salicylates, corticosteroids, immunosuppressants, biotherapies and antibiotics. Each of these drugs has drawbacks, and there is currently no cure for MICIS. The publication by Vergnolle et al., 2004, Journal of Clinical Investigation, 114 (10): 1444-1456 describes the role of the PAR-1 receptor in inflammatory bowel disease. This document indicates that a particular PAR-1 antagonist, L-arininamide-4-methoxy-N - [[[1- [92,6-dichlorophenyl-methyl] -3- (1-pyrrolidinylmethyl) -1 H- indol-6-yl] amino] carbonyl] -1-phenylalanyl-N- (phenylmethyl) - (5), improves the survival rate of animals in a model of induced colitis in mice, by reducing the phenomenon of 'inflammation.

It has recently been discovered by the present inventors that particular compounds make it possible to decrease the inflammatory phenomenon involved in chronic inflammatory diseases of the intestine and colon, and in particular Crohn's disease, and to reduce the pain associated therewith as well. than repairing the epithelial tissues of the intestine. These compounds are more precisely vorapaxar and its isomers, in particular its isomers exhibiting antagonist activity of the PAR-1 receptor, atopaxar and 3-2- (chloro-phenyl) -1- [4- (4- fluoro- benzyl) -piperazin-1-yl] -propenone, as well as their pharmaceutically acceptable salts.

In order for these compounds to fully produce their therapeutic effect, their absorption window must be located in the lower part of the gastrointestinal tract. intestinal, more particularly at the level of the duodenum, the intestine and the colon. These compounds are, however, insoluble at the pH values which prevail in these regions, that is to say pH values between 5 and 6.8, so that, thereby being there in solid form, their effectiveness of action is limited. Document CN 105919966 describes a galenic formulation for oral administration comprising vorapaxar sulfate as active principle, mixed with an adhesive material, such as polyvidone or cellulose derivatives. However, this formulation does not allow this active principle to be delivered to the lower part of the gastrointestinal tract. Solid oral dosage forms have been proposed by the prior art to ensure a targeted release of active principles in the lower part of the gastrointestinal tract, and thereby increase the therapeutic efficacy of these active principles. These dosage forms are particles of the heart-shell type, comprising a core in which the active principle is mixed with a mucoadhesive substance, and an enteric shell, allowing targeted release of the active principle in the intestine and the colon.

By way of example, document US 2014/199469 describes a prolonged-release tablet comprising a core containing, as active ingredient, a tetracycline, and an inactive ingredient, this core being covered by four successive continuous coating layers. , including a layer containing enteric material.

None of the dosage forms proposed by the prior art, however, provides a satisfactory solution to the problem of the lack of solubility of vorapaxar, its isomers, atopaxar and 3-2- (chloro-phenyl) -1- [ 4- (4-Fluoro-benzyl) -piperazin-1-yl] -propenone at enteric pH.

The present invention aims to remedy this shortcoming, and to provide a galenic form ensuring the targeted release, in the duodenum, the intestine and the colon, of these active principles in a solubilized form, thus promoting their effectiveness of action, by particularly for the treatment of inflammatory bowel diseases.

The invention also aims for this dosage form to be easy to prepare, moreover by means of equipment commonly used in the pharmaceutical industry. The present inventors have now discovered that these objectives are achieved by a particular pharmaceutical dosage form, which advantageously makes it possible to control the release profile of these active principles to ensure their release in the lower part of the gastrointestinal tract, and this under a soluble form in intestinal fluids.

More particularly, the present inventors have developed a galenic form which takes advantage of the property that such active principles have of dissolving at very acidic pH, in particular at the pH value of the stomach, to then ensure inhibition of the recrystallization of these active principles in the intestinal fluids, and consequently their presence in a soluble form in the latter.

Thus, according to a first aspect, there is proposed according to the present invention a pharmaceutical composition suitable for oral administration, containing as active principle a compound chosen from the group consisting of vorapaxar, isomers of vorapaxar, in particular isomers. showing antagonist activity of the PAR-1 receptor, atopaxar, 3- 2- (chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl] -propenone and their pharmaceutically acceptable salts. This pharmaceutical composition contains particles which comprise: a core containing a mixture of the active principle and of a substance, called an inhibiting substance, chosen from cellulose polymers, polymers derived from povidone and copolymers based on polyvinyl caprolactam, this inhibitory substance being capable of inhibiting, at least partially, the recrystallization of said active principle being in aqueous solution at pH less than 2, when the pH becomes greater than or equal to 5,

- And a pH-dependent controlled release coating layer covering said core, said coating layer being formed of a gastro-resistant coating agent having a solubilization pH value of between 4.5 and 7, and said coating layer being porous. All the constituents of the particles of the pharmaceutical composition according to the invention are of course chosen to be pharmaceutically compatible, that is to say that they do not produce any adverse, allergic or other adverse reaction when they are administered. to a subject, in particular to a mammal and in particular to a human.

In the present description, the term “gastro-resistant” is understood to mean, in a manner conventional in itself, the fact that the coating agent does not dissolve at the very acidic pHs prevailing in the stomach, so that the layer of coating that it forms or participates in forming does not break down in the stomach. The coating agent used according to the invention also has a solubilization pH value of between 4.5 and 7. This is understood to mean that it dissolves, in aqueous solution, and more precisely in the juices. gastrointestinal, from a pH value of 4.5, and that its solubilization is complete at a pH value of 7. Preferably, the gastro-resistant coating agent has a solubilization pH value of between 5.5 and 7.

Thus, the coating layer of the particles according to the invention remains intact during the passage of the particles in the stomach, and disintegrates when the particle reaches the intestine and the colon, in which the intestinal pH gradually increases to values comprised between 5 and 7. Such a coating layer can be qualified as enteric, in the sense that it allows release of the active principle contained in the core of the particles specifically in the intestine and the colon.

The pharmaceutical composition according to the invention may contain, in particular in the particles, one or more active principles other than vorapaxar, the isomers of vorapaxar, in particular the isomers exhibiting an antagonist activity of PAR-1, atopaxar, 3 -2- (chloro-phenyl) -1 - [4- (4-fluoro-benzyl) - piperazin-1 -yl] -propenone and their pharmaceutically acceptable salts.

In particular embodiments of the invention, the pharmaceutical composition is devoid of any active principle other than those listed above.

The particles of the pharmaceutical composition according to the invention prove to be particularly effective for, when they are administered to a subject orally, releasing a large amount of the active principle in dissolved form in the lower part of the gastrointestinal tract. Such an advantageous result is obtained by virtue of the particular combination of an enteric coating layer which is porous, and of the presence of the inhibiting substance in the core of the particles. In fact, when the particles pass through the stomach of the subject to whom they are administered orally, the porosity of the coating layer allows the active principle contained in the core of the particles to be brought into contact with the very gastric juices. acids which are in the stomach, this while ensuring the maintenance of a part of the active principle inside the coating layer. On contact with these gastric juices, the active principle, contained in the core of the particles, dissolves at this very acidic pH. When the particles reach the intestine, the active principle is thus found in dissolved form, in the core of the particles or outside them. The dissolution of the coating agent with a pH greater than 4.5, and even greater than 5.5, prevailing in the intestine, there causes the complete release of the active principle. The presence of the inhibiting substance, which is in an intimate mixture with the latter, then advantageously inhibits, at least partially, its recrystallization despite the fact that it is confronted with pH values between 5 and 7, which would otherwise have caused its complete recrystallization.

In the present description, the term “substance capable of inhibiting the recrystallization of the active principle in aqueous solution at a pH of less than 2, when the pH becomes greater than or equal to 5,” means the fact that, when the active principle is in solution in an aqueous composition with a pH of less than 2, and when the pH of this composition increases and becomes greater than or equal to 5, a value which normally causes recrystallization of the active principle, the inhibiting substance prevents this recrystallization, at least in part. Preferably, the inhibiting substance is chosen to ensure that at least 50% by weight of the active principle remains in solution in the aqueous composition at a pH greater than or equal to 5, preferably for at least 30 minutes, this percentage being expressed relative to the total weight of the active principle which is present in the composition.

It is up to those skilled in the art to select the inhibiting substances making it possible to achieve such a result, depending on the particular active ingredient used.

For example, a person skilled in the art could carry out the following test for this purpose for a given substance to be tested. This substance will be found to be inhibitory in accordance with the present invention if, when 0.5 mg of the substance is added to 230 ml of an aqueous solution of pH 1, 1 -1, 2, for example a 0.1 M hydrochloric acid solution, containing 4 mg of active principle, the precipitation of the active principle is inhibited by 50% (w / w) within 30 minutes following the moment when the pH of the solution is increased to a value greater than or equal to 5. Preferably, the degree of porosity of the coating layer is between 5 and 50%, from preferably between 10 and 40%, more preferably between 10 and 30%, preferably between 10 and 25%, and more preferably still between 10 and 20%. A range of porosity rate of between 15 and 20% is particularly preferred in the context of the invention. This rate of porosity is a volume rate, expressed in volume of pores relative to the total volume of the coating layer.

Vorapaxar, also called ethyl N - [(1 R, 3aR, 4aR, 6R, 8aR, 9S, 9aS) -9 - [(E) - 2- [5- (3-fluorophenyl) pyridin-2-yl] ethenyl ] -1-methyl-3-oxo-3a, 4,4a, 5,6,7,8,8a, 9,9a-decahydro-1 H-benzo [f] [2] benzofuran-6-yl] carbamate ( SCH-530348, CAS n ° 618385-01 -6) corresponds to formula (I):

This compound is described in particular in document WO 03/089428. It is usually presented as a sulfate salt.

In the present description, by isomer of vorapaxar is meant any stereoisomer, that is to say any molecule corresponding to the same chemical formula as vorapaxar and exhibiting any possible combination of isomeric forms at the level of its asymmetric carbons, different from that of vorapaxar. From a mixture of isomers of vorapaxar, each isomer particular can be obtained by purification methods conventional in themselves for those skilled in the art. An isomer of vorapaxar exhibiting antagonist activity towards the PAR-1 receptor is, for example, the compound SCH 530348, described in the publication by Chackalamannil et al., 2008, J. Med. Chem. 51: 3061-3064.

It is within the competence of those skilled in the art to determine, among all the possible isomers of vorapaxar, which exhibit antagonistic activity towards the PAR-1 receptor. To this end, a person skilled in the art can in particular carry out protein binding tests against the PAR-1 agonist which is thrombin, as described in the publication by Chackalamannil et al., 2008, cited above.

Atopaxar, or 1 - (3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl) -2- (5,6-diethoxy-4-fluoro-3-imino-1 H-isoindol-2 -yl) ethanone (E5555, SCH-602539, CAS n ° 751475-53-3) corresponds to formula (II):

3-2- (Chloro-phenyl) -1 - [4- (4-fluoro-benzyl) -piperazin-1 -yl] -propenone has the formula (III):

The term “pharmaceutically acceptable salt” is understood in the present description to mean any salt of said compounds using, as counterion, a species which does not produce any adverse, allergic or other adverse reaction. when administered to a subject, particularly a mammal.

Any conventional non-toxic salt of the compounds used as an active principle according to the invention, whether it is formed from organic or inorganic acids, can be used according to the invention. By way of example, mention may be made of salts derived from inorganic acids such as hydrochloric, hydrobromic, phosphoric and sulfuric acids, and salts derived from organic acids such as acetic, trifluoroacetic, propionic, succinic, fumaric acids, malic, tartaric, citric, ascorbic, maleic, glutamic, benzoic, salicylic, toluenesulfonic, methanesulfonic, stearic, lactic, etc.

These salts can be synthesized from the corresponding compound and acid, using any conventional chemical method in itself. All of the above compounds exhibit significant therapeutic efficacy for the prevention and / or treatment of inflammatory bowel diseases, in particular Crohn's disease.

Preferably, the active principle used in the pharmaceutical composition according to the invention is vorapaxar or one of its pharmaceutically acceptable salts, in particular vorapaxar sulfate.

The particles contained in the pharmaceutical composition according to the invention can be of any size. These are in particular microparticles, that is to say particles having a size between 1 and 1000 miti, preferably between 5 and 100 miti and preferably between 10 and 70 miti.

The inhibitory substance is preferably hydrophilic, and in particular soluble in acidic aqueous media.

The inhibiting substance is chosen from cellulose polymers, polymers derived from povidone and polymers derived from the polyvinyl caprolactam copolymer.

Among the polymers derived from the polyvinyl caprolactam copolymer, particularly preferred are the polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol copolymers, which include a polymer comprising at least one caprolactam block, at least one polyvinyl acetate block and at least one polyethylene glycol block, and in which each block of a type is attached to a block of another type. According to the invention, the particularly preferred polymer in this family is the copolymer of polyvinyl caprolactam (57%), polyvinyl acetate (30%) and polyethylene glycol 6000 (13%), as sold under the name Soluplus®. The inhibitory substance is preferably chosen from hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copovidone and hydroxypropyl methyl cellulose acetate succinate, or any one of their mixtures.

The polyvinylpyrrolidone is preferably of type K12 to K30, these types being characterized by viscosity values K of 10.2-13.8 and 29-32, respectively. Such polymers are in particular marketed under the names

Kollidon®and Plasdone®.

An example of copovidone (polyvinylpyrrolidone / vinyl acetate copolymer) which can be used according to the invention is that marketed under the name Kollidon® VA64. The inhibitor substance can alternatively be selected from sodium caseinates, its water soluble hydrolysis derivatives, gelatin, collagen and their hydrolysates, or any of their mixtures.

The pharmaceutical composition according to the invention may also contain, preferably in the core of the particles, a mucoadhesive substance, which advantageously improves the biological adhesion of the active principle in the intestinal and colonic tissues.

This mucoadhesive substance can in particular be chosen from hydroxypropyl methyl cellulose (HPMC), sodium carboxymethylcellulose, crosslinked polyacrylic acid polymers, such as the polymer sold under the name Carbopol® 934, polycarbophil, tragacanth, poly (acrylic acid / divinylbenzene), sodium alginate, hydroxyethylcellulose, karaya gum, gelatin, guar gum, polyvinylpyrrolidone (PVP), chitosan, or any of their mixtures. In particularly preferred embodiments of the invention, the inhibitory substance and the mucoadhesive substance are one and the same substance, which on its own fulfills the two functions of mucoadhesiveness and of inhibiting the recrystallization of the active principle, found in aqueous solution at a pH less than 2, when the pH becomes greater than or equal to 5. Preferably, the inhibitory substance is hydroxypropyl methyl cellulose, also called hypromellose, which also has good gastrointestinal mucoadhesiveness properties. Type K hydroxypropyl methyl cellulose, exhibiting degrees of substitution, expressed by weight, of between 7 and 12% for hydroxypropyl groups, and of between 19 and 24% for methoxy groups, or of type E, exhibiting degrees substitution, expressed by weight, between 7 and 12% for the hydroxypropyl groups, and between 28 and 30% for the methoxy groups, can in particular be used in the context of the invention. Preferably, the hydroxypropyl methyl cellulose used according to the invention has a molecular weight of between 90 and 530 kDa, preferably between 400 and 520 kDa; and / or a viscosity, in a 2% m / v solution in water at 20 ° C, of between 15 and 15,000 mPa.s, preferably between 50 and 4000 mPa.s. The hydroxypropyl methyl cellulose may for example be of the K4M, K15M, E4M, E50 or E15 type.

The “active principle / inhibiting substance” weight ratio in the particles of the pharmaceutical composition according to the invention is preferably between 1/1 and 12/1, more preferably between 1/1 and 7/1, preferably between between 1, 5/1 and 7/1 and even more preferably between 1, 5/1 and 5/1, or even between 1, 5/1 and 3/1. A weight ratio in such value ranges increases the more the amount of active ingredient maintained in dissolved form in the duodenum, intestine and colon. The "active principle / coating agent" weight ratio is for its part preferably between 1/1 and 1/3, and preferably approximately equal to 1/2.

The particles of the pharmaceutical composition according to the invention may contain the following quantities of the following various constituents, these quantities being expressed by weight relative to the total weight of the particles: 5 to 50% of the active principle, in particular of vorapaxar sulphate ; 0.4 to 30% inhibitory substance, in particular hydroxypropyl methyl cellulose; and / or 25 to 94.5% coating agent.

The particles of the pharmaceutical composition according to the invention contain preferably the following amounts of the following various constituents, these amounts being expressed by weight relative to the total weight of the particles: 20 to 30%, for example 20 to 25%, of the active principle, in particular of vorapaxar sulfate; 10 to 20%, for example 10 to 15%, of inhibitory substance, in particular of hydroxypropyl methyl cellulose; and / or 50 to 70% coating agent.

The coating agent, allowing targeted release of the active principle in the lower part of the gastrointestinal tract, is preferably a polymer chosen from: copolymers of methacrylic acid and of ethyl acrylate, in particular of the type 1: 1, such as the copolymer marketed under the name Eudragit® L-100-55, or formulations containing such a copolymer mixed with one or more substances, in particular with plasticizing action, promoting its use in aqueous dispersion, such as formulations marketed under the names Eudragit® L30D-55 or Acryl-Eze®; copolymers of methacrylic acid and of methyl methacrylate, in particular of type 1: 1 or 1: 2; hypromellose phthalate (HPMCP), in particular of the HP-55 type; hydroxypropyl methyl cellulose aceto-succinate; and polyvinyl acetophthalate; or any of their mixtures.

Copolymers of methacrylic acid and ethyl acrylate, or formulations containing such copolymers, in particular of type 1: 1, are particularly preferred in the context of the invention.

The pharmaceutical composition according to the invention can consist only of particles as defined above. It may otherwise contain these particles in admixture with other pharmaceutically acceptable substances.

The pharmaceutical composition according to the invention may contain, in addition to the constituents defined above, any pharmaceutically acceptable excipient, this or these excipients may be present in the particles, in the core and / or the coating layer thereof, and / or be contained in the composition as a mixture with the particles.

By pharmaceutically acceptable is meant the fact that the excipient exhibits no adverse, allergic or other adverse reaction when it is administered to a mammal, in particular to a human. Such an excipient can be a diluent, an adjuvant or any other substance conventional in itself for the constitution of medicaments, such as a preservative, filling, disintegrating, wetting, emulsifying, dispersing, antibacterial or antifungal agent, etc., or any of their mixtures. The pharmaceutical composition according to the invention may also contain one or more other active agents, which may or may not act in synergy with the compound according to the invention, for example a painkiller. This or these active agent (s) may for example be contained in the particles, in particular in the heart of the latter. The pharmaceutical composition according to the invention can be of the human or veterinary type. It can be formulated in any galenic form suitable for oral administration in mammals, and in particular in humans.

It can in particular be provided in the form of powder, granules or oral suspension.

The pharmaceutical composition according to the invention is preferably packaged in the form of unit doses, each containing a therapeutically effective amount of active principle. The concentration of the active principle in each dose of the pharmaceutical composition according to the invention is thus preferably chosen to deliver to the subject, on each administration, an amount of active principle which is effective to obtain the desired therapeutic response.

The pharmaceutical composition according to the invention is for example packaged in the form of unit doses each comprising a quantity of between 0.05 and 1000 mg of the active principle, preferably between 1 and 100 mg of the active principle and preferably between 1 and 10 mg of the active principle. active ingredient.

The pharmaceutical composition according to the invention may for example be in the form of a capsule containing particles according to the invention in a capsule, and the wall of which is for example formed of gelatin. Such a capsule may for example contain between 0.05 and 1000 mg, preferably between 1 and 100 mg, preferably between 1 and 10 mg, for example approximately 2.5 mg, of active principle. The pharmaceutical composition according to the invention may otherwise be in the form of tablets or of powder packaged in sachets.

Another aspect of the present invention relates to the use of a pharmaceutical composition according to the invention as a medicament, in particular for the prevention and / or treatment of chronic inflammatory bowel and colon disease in a patient. subject affected or likely to be affected by the disease, and in particular to reduce pain and / or repair the epithelial tissues of the intestine in this subject.

This subject is in particular a mammal, in particular a human, or a non-human mammal.

The pharmaceutical composition according to the invention, in its veterinary application, is particularly useful for the treatment of non-human mammals, and in particular dogs and cats. Indeed, IBDs are chronic inflammatory bowel diseases common in dogs and cats, where they correspond to Crohn's disease in humans. These chronic conditions result from hypersensitivity to certain elements, such as antigens, present in the digestive tract. This hypersensitivity causes thickening and infiltration of the intestinal mucosa by inflammatory cells, as described in particular in the publication by Jergens et al, 2003, Vet Intern Med, 17 (3): 291-297. When this happens, the intestines are no longer able to absorb nutrients properly and digestive transit speeds up. IBD in cats can be associated with pancreatitis and inflammation of the bile ducts. We then speak of the feline triad. Certain breeds of dogs, such as German Shepherds, appear to be predisposed to IBDs. Symptoms associated with the disease in dogs and cats are similar to those of Crohn's disease in humans: chronic diarrhea, weight loss and appetite disturbances, chronic and intermittent vomiting, blood or mucus in the stomachs. stool. No drug therapy has been proposed by the prior art for the treatment of IBD in cats and dogs (Makielski et al, 2017, Journal of Veterinary Internai Medicine, 33: 11-22).

In the present description, the term treatment is intended to mean a curative treatment for the disease, and more particularly the reduction and / or inhibition of the disease. development of at least one of the symptoms of the disease, an increase in the remission phase and / or a decrease in the number of attacks or their frequency. The active principle according to the present invention makes it possible in particular, among other things, to effectively relieve the pain symptom associated with the disease. The term prevention is understood to mean the fact of reducing, or even completely avoiding, the onset of the disease.

By "repairing epithelial tissues" is meant, in a manner conventional to those skilled in the art, the fact of reducing intestinal epithelial hyperpermeability and restoring, at least partially, the mechanics of the intestine. The chronic inflammatory disease of the bowel and colon targeted by the present invention can be Crohn's disease as well as ulcerative colitis.

According to the invention, the pharmaceutical composition according to the invention is administered to the subject in need thereof orally, in a therapeutically effective amount.

The term “therapeutically effective amount” is understood to mean the amount of the composition, or more precisely of the active principle contained therein, which makes it possible, when the composition is administered to the subject, to obtain the desired level of therapeutic response, in particular, for the patient. particular case of chronic inflammatory bowel and colon disease, the level of pain reduction and / or the level of epithelial tissue repair of the intestine desired. The therapeutically effective dose level of the specific active ingredient for a particular subject will vary depending on many factors such as, for example, the exact condition and its severity, body weight, age, sex and general health of the subject, the duration of the treatment, the drugs possibly used in parallel, the sensitivity of the individual to be treated, etc.

Accordingly, the optimal dosage is determined by the physician based on the parameters he deems relevant.

The dosage for administration of the pharmaceutical composition according to the invention can, for example, be taken once or twice a day.

Although the effective doses may vary within wide proportions, the daily doses of the active principle according to the invention could range between 0.05 mg and 1000 mg per 24 hours, preferably between 1 and 100 mg per. 24 hours and preferably between 1 and 10 mg per 24 hours, in one or more doses, preferably in a single dose.

Preferably, the administration of the pharmaceutical composition according to the invention is started at the earliest upon diagnosis of the disease and, preferably, within the first 12 months following the acute event.

The present invention is also expressed in the form of a method for the prevention and / or treatment of a chronic inflammatory disease of the intestine and of the colon, in particular of Crohn's disease, in a subject, and in particular of a method for relieving pain and / or repairing epithelial tissues of the intestine in said subject with chronic inflammatory bowel and colon disease. The subject can be, in particular, a mammal, non-human such as a dog or a cat, and preferably a human being. This method comprises the administration, to said subject in need thereof, of a therapeutically effective amount of the pharmaceutical composition as defined above, containing in particular, as an active principle, vorapaxar or one of its pharmaceutically acceptable salts.

This method can meet one or more of the characteristics described above with reference to the use of the pharmaceutical composition according to the invention. The present invention is also expressed in terms of use, for the treatment and / or prevention of chronic inflammatory bowel and colon disease, and in particular for reducing pain and / or repairing tissue. epithelial cells of the intestine in a subject suffering from chronic inflammatory bowel and colon disease, in particular Crohn's disease, or for the manufacture of a medicament for such treatment and / or prevention, from particles to base of an active principle chosen from the group consisting of vorapaxar, isomers of vorapaxar, atopaxar, 3-2- (chloro-phenyl) -1- [4- (4- fluoro-benzyl) -piperazin -1-yl] -propenone and their pharmaceutically acceptable salts. These particles comprise: a core containing a mixture of said active principle and a substance, called an inhibitor substance, chosen from cellulose polymers, polymers derived from povidone and the polyvinyl caprolactam copolymer, this inhibiting substance being able to inhibit the recrystallization of said active principle is found in aqueous solution at pH less than 2, when the pH becomes greater than or equal to 5,

- And a pH-dependent controlled release coating layer covering said core, said coating layer being formed of a enteric coating agent having a solubilization pH value of between 4.5 and 7, and said coating layer being porous.

This use can meet one or more of the characteristics described above with reference to the pharmaceutical composition according to the invention and to its use. Another aspect of the present invention relates to a process for preparing a pharmaceutical composition according to the invention. This method comprises a step of preparing the particles by spray drying in an atomization device with a spray nozzle, the latter preferably being of the concentric type allowing the formation of capsules. To this end, a first aqueous formulation containing the active principle and the inhibiting substance is introduced into a central spray channel of the spray nozzle, and a second aqueous formulation containing the coating agent is introduced into a channel of the nozzle. peripheral spraying of said central channel. Such a process, called in situ coating, advantageously makes it possible to form the core and the coating layer of the particles at the same time.

It is within the competence of those skilled in the art to determine the exact operating parameters of this step of the process, as a function of the specific characteristics targeted for the particles, in particular their size and the desired active ingredient / coating agent weight ratio. , as well as the target porosity rate.

For the first aqueous formulation and / or the second aqueous formulation, the aqueous vehicle used may consist solely of water, or of a mixture of water and alcohol, in particular water and ethanol, in a volume ratio of between 10/90 and 99.9 / 0.1, in particular between 20/80 and 80/20, for example between 20/80 and 40/60. The presence of alcohol in the aqueous vehicle can advantageously improve the solubility of certain components of the aqueous formulations, and give rise to structures different physical core and / or coating layer.

The degree of porosity of the coating layer can in particular be controlled by the speed of the drying step, and more particularly by the temperature of the gas stream, consisting of water vapor and dry particles, at the outlet of the device. . This temperature is controlled by several other process parameters, in particular the temperature of the hot air entering the drying chamber of the device and the volume flow rate of the formulation containing the coating agent which feeds the spray nozzle. . It is within the skill of those skilled in the art to adjust these parameters appropriately, to obtain the desired porosity rate for the particles. This adjustment is preferably carried out to obtain a drying temperature at the outlet of the atomization device, that is to say a temperature of the gas stream at the outlet of the device, which is between 50 and 110 ° C, in particular between 50 and 70 ° C or between 70 and 110 ° C, more particularly included: - when the aqueous vehicle of the first aqueous formulation and the aqueous vehicle of the second aqueous formulation comprise only water, between 70 and 110 ° C, preferably between 80 and 100 ° C and more preferably between 80 and 90 ° C;

- when the aqueous vehicle of the first aqueous formulation and / or the aqueous vehicle of the second aqueous formulation comprise a mixture of water and alcohol, in particular a mixture of water and ethanol, between 50 and 110 ° C, in particular between 80 and 100 ° C and for example between 80 and 90 ° C.

The higher temperatures favor the creation of more porous particles, with a porosity rate between 30 and 50%, while the lower temperatures favor the creation of less porous particles, with a porosity rate between 5 and 10%.

The characteristics and advantages of the invention will appear more clearly in the light of the examples of implementation below, provided for illustrative purposes only and in no way limiting of the invention, with the support of Figures 1 to 8, in which:

Figure 1 shows a scanning electron microscopy image of a particle according to the invention, at different magnifications.

Figure 2 is a bar graph showing the mass fraction (%) of vorapaxar sulphate dissolved in the dissolution medium, relative to the initial mass of vorapaxar sulphate, after different immersion times in successive solutions at pH 1, 2 (between 0 and 120 min), pH 5.6 ( between 120 and 240 min), pH 6.8 (between 240 and 360 min) and pH 3.0 (between 360 and 1440 min), for vorapaxar sulfate alone, for particles in accordance with the invention (P1, P2 , P3) and for comparative particles comprising a mixture of vorapaxar sulfate and HPMC, devoid of a coating layer.

Figure 3 is a bar graph showing the mass fraction (%) of vorapaxar sulfate dissolved in the dissolution medium, relative to the initial mass of vorapaxar sulfate, after different immersion times in successive solutions at pH 1 , 2 (between 0 and 120 min), pH 5.6 (between 120 and 240 min), pH 6.8 (between 240 and 360 min) and pH 3.0 (between 360 and 1440 min), for vorapaxar alone, for particles in accordance with the invention (P2) and for particles in accordance with the invention for which the immersion started at time t = 120 min, directly in the solution at pH 5.6 (P2 ') .

Figure 4 is a bar graph showing the mass fraction (%) of vorapaxar sulfate dissolved in the dissolution medium, relative to the initial mass of vorapaxar sulfate, after different immersion times in successive solutions at pH 1 , 2 (between 0 and 120 min), pH 5.6 (between 120 and 240 min), pH 6.8 (between 240 and 360 min) and pH 3.0 (between 360 and 1440 min), for vorapaxar alone and for particles not in accordance with the invention (C1, C2, C3) based on chitosan as a substance present in the core of the particles mixed with vorapaxar sulfate.

Figure 5 represents a bar graph showing the mass fraction (%) of vorapaxar sulfate dissolved in the dissolution medium, relative to the initial mass of vorapaxar sulfate, after different immersion times in successive solutions at pH 1 , 2 (between 0 and 120 min), pH 5.6 (between 120 and 240 min), pH 6.8 (between 240 and 360 min) and pH 3.0 (between 360 and 1440 min), for compliant particles to the invention (P3, P4) obtained by means of different vehicles and comprising substances of different core.

Figure 6 is a bar graph showing the mass fraction (%) of vorapaxar sulfate dissolved in the dissolution medium, relative to the initial mass of vorapaxar sulfate, after different immersion times in successive solutions at pH 1, 2 (between 0 and 120 min), pH 5.6 (between 120 and 240 min), pH 6.8 (between 240 and 360 min) and pH 3.0 (between 360 and 1440 min) ), for particles in accordance with the invention (P1, P5) obtained by means of different vehicles and comprising different coating layers. Figure 7 is a bar graph showing the mass fraction (%) of vorapaxar sulfate dissolved in the dissolution medium, relative to the initial mass of vorapaxar sulfate, after different immersion times in successive solutions at pH 1 , 2 (between 0 and 120 min), pH 5.6 (between 120 and 240 min), pH 6.8 (between 240 and 360 min) and pH 3.0 (between 360 and 1440 min), for compliant particles to the invention (P2, P3, P6) obtained by means of different vehicles and comprising substances of different core.

Figure 8 is a bar graph showing the mass fraction (%) of vorapaxar sulfate dissolved in the dissolution medium, relative to the initial mass of vorapaxar sulfate, after different immersion times in successive solutions at pH 1 , 2 (between 0 and 120 min), pH 5.6 (between 120 and 240 min), pH 6.8 (between 240 and 360 min) and pH 3.0 (between 360 and 1440 min), for compliant particles to the invention (P5, P7, P8) comprising different core substances. A / Materials and methods

Process for preparing the particles In the examples below, it is used:

- vorapaxar sulphate as an active principle;

- hydroxypropyl methylcellulose (HPMC) (Affinisol® HPMC 4M, molecular weight 552.8 KDa, or Affinisol® HPMC 100 LV and HPMC 15LV, molecular weights 180 kDa and 90 KDa respectively), polyvinyl caprolactam-polyvinyl copolymer acetate-polyethylene glycol (Soluplus®) or hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) (Aqoat® LF) or chitosan (Chitoclear® HQG-110 from Primex, 95% deacetylation, viscosity 26 mPa.s; or Chitoclear® HQG-800 from Primex, 95% deacetylation, viscosity 600 to 1200 mPa.s) as a substance present in the core of the particles, called core substance (substance inhibiting recrystallization and mucoadhesive for HPMC and HPMC-AS, substance recrystallization inhibitor for Soluplus®, a mucoadhesive substance only for chitosan);

- and the copolymer marketed under the name Acryl-Eze®93A18597 by the company Colorcon® (copolymer of methacrylic acid and ethyl acrylate 1: 1, methacrylic acid, talc, titanium dioxide (E171), sodium bicarbonate , colloidal anhydrous silica, sodium lauryl sulfate) or the copolymer of methacrylic acid and ethyl acrylate 1: 1, methacrylic acid alone (Eudragit® L100-55) as coating agent.

For each experiment, two distinct formulations are prepared: - Formulation 1: the desired amount of core substance is dispersed in deionized water, or in a water-ethanol mixture of 20:80 volume ratio, then the desired amount of sulfate vorapaxar is dispersed in the resulting solution, resulting in a suspension of vorapaxar crystals in an aqueous solution of the core substance; - Formulation 2: the desired amount of coating agent is dispersed in deionized water, or in a water-ethanol mixture with a volume ratio of 20:80.

The particles are prepared by spray drying using a Büchi B-290 device equipped with a 3-fluid atomization nozzle. Formulation 1, containing vorapaxar sulfate and core substance, is introduced into the central spray channel of the nozzle, and Formulation 2, containing the coating agent, is introduced into a channel peripheral to this central channel. . The total flow rate of feed to the nozzle with these formulations is constant and equal to 0.3 kg / h, the ratio between the mass flow rates, in the atomization nozzle, of Formulation 2 / Formulation 1 varying according to the experiments. The operating parameters of the spray drying process are as follows: temperature of the air entering the device 130 ° C (Condition A) or 100 ° C (Condition B), temperature of the gas stream leaving the device 82 ° C ( Condition A) or 57 ° C (Condition B), drying air flow 33.2 m ³ / h, atomizing air flow 742 l / h (Condition A) or 740 l / h (Condition B) . For all the conditions tested, it is obtained, at the end of the process, a dry powder formed of particles of size between 5 and 100 miti, comprising a core containing a mixture of vorapaxar sulfate and the core substance, covered a coating layer containing the coating agent. This coating layer is not continuous, as can be confirmed by the presence of nanoscale beads which constitute the aqueous dispersion of the coating agent, visible in Figure 1. which shows scanning electron microscopy images. , at different magnifications, of an example of a particle in accordance with the invention obtained by this process (particle P1 described below). It is observed that the particles of vorapaxar sulfate are covered with a film which is strewn with nanometric-sized beads. These beads correspond to nanoparticles of the enteric polymer (copolymer of methacrylic acid and of ethyl acrylate 1: 1) in the aqueous dispersion of the Acryl-eze® product used. These nanoparticles coalesce during the formation of the film, in order to generate it. This coalescence is not complete, however, because of the rapidity of the drying step of the process for preparing the particles. The coating layer formed around the core of the particles is therefore porous, and allows the exchange between the coated interior of the particles and their exterior.

The porosity rates of the particles are evaluated from the release rates of the active principle at pH 1.2 compared to a formulation without a coating layer (Pcomp particles described below).

Dissolution test - In vitro study of the release profile of the active principle The dissolution profile of vorapaxar contained in the particles is determined in vitro in a set of media simulating the gastrointestinal environment. For this purpose, samples of particles containing the equivalent of 2.5 mg of vorapaxar sulfate are placed in a locking-cap gelatin capsule, which is then immersed in a dissolution medium consisting of the following successive solutions simulating the gastric and intestinal fluids, which cover the physiological pH range of gastrointestinal fluids from 1.2 to 6.8, then in a pH 3.0 solution to simulate the colonic pH of a person with inflammatory bowel disease (colonic pH is usually 6.4-7.0 for a healthy person, but may drop to 2.3-4.7 for someone with inflammatory bowel disease):

- 0.1 M aqueous hydrochloric acid solution HCl at pH 1.2 (231 ml) from time T0 to time T = 120 min; - then phosphate buffer at pH 5.6 from time T = 120 min to time T = 240 min; this solution is obtained by adding, to the previous solution, 54 ml of a 0.2M solution of Na3PO4;

- then phosphate buffer at pH 6.8 from time T = 240 min to time T = 360 min; this solution is obtained by adding 15 ml of a 0.2M solution of Na3PO4 to the previous solution;

- then solution at pH 3 (obtained by adding citric acid to the previous solution) over the next 24 hours; this solution is obtained by adding 2.90 g of citric acid monohydrate to the previous solution. The tests are carried out using an ERWEKA DT60 apparatus, using a paddle stirrer. A rotational speed of 75 rpm and an average temperature of 37 ± 0.5 ° C are maintained in each vessel containing the dissolution medium.

Aliquots are withdrawn at appropriate intervals from the containers and filtered using a sterile non-woven pad, centrifuged at 14,500 rpm for

10 minutes. The percentage of vorapaxar sulfate present therein in dissolved form, relative to the initial mass of vorapaxar sulfate, is determined by high performance liquid chromatography (HPLC) using an Agilent 1100 chromatograph equipped with a ProntoSIL column. KromaPlus C-18, 250mm x 4.6mm, particle size 5 miti (ICS). The mobile phase is formed from methanol: 0.1% acetic acid (80:20). The flow rate is 1 ml / min and the injection volume 20 mI. Detection is performed at 272 nm. A calibration curve, indicating the absorbance as a function of the vorapaxar concentration (in mg / ml) is produced from standard solutions containing vorapaxar at various increasing concentrations in methanol.

The average of two determinations is used to calculate this level of dissolved vorapaxar. The in vitro dissolution of crude vorapaxar crystals is also determined. B / Experiment 1 - HPMC

In this experiment, particles in accordance with the invention (P1, P2, P3) based on HPMC 4M as core substance (mucoadhesive and inhibitory recrystallization of vorapaxar), and particles not in accordance with the invention (Pcomp, comprising the single core based on vorapaxar and HPMC 4M, devoid of coating), are produced according to the operating parameters indicated in Table 1 below. below. The vehicle for each formulation is water only, and the conditions applied are Conditions A.

Table 1

These particles, as well as the vorapaxar sulfate alone, are subjected to the dissolution test described above. The results obtained are shown in figure 2.

It is observed in this figure that dissolution of vorapaxar sulfate occurs, for all the particles tested, in the solution at pH 1, 2, simulating the gastric environment, between 0 and 120 min. In solutions at pH 5.6 and 6.8, simulating the intestinal environment, between 120 and 360 min, predictably, vorapaxar sulfate does not dissolve in solution, it is found entirely there as of precipitate. Surprisingly, for all the particles tested, on the other hand, vorapaxar sulphate is found dissolved in the solutions at pH 5.6 and 6.8, which shows that the vorapaxar sulphate has dissolved in the solution at pH 1. , 2, while remaining at least partly inside the coating layer, then that, when the pH has been raised to a value greater than or equal to 5.6, the presence of 4M HPMC has inhibited, at least partially, the precipitation of vorapaxar sulfate in solutions. The level of vorapaxar sulphate dissolved in solutions at pH 5.6 and 6.8 is much greater for the particles according to the invention P1, P3 and especially P2, than for the Pcomp particles devoid of a coating layer.

Returning to pH 3, simulating a diseased colon, after 360 minutes, vorapaxar sulfate is again found in solution, for all the samples tested. These results demonstrate that the dosage form according to the invention allows a release of a large amount of vorapaxar sulfate in the lower part of the gastrointestinal tract.

C / Experiment 2

The P2 particles are subjected to the in vitro dissolution test, but some of them (P2 ’) start with exposure to pH 5.6. These latter conditions are representative of what would occur in the case of particles similar to those of the invention but with a continuous enteric coating layer (that is to say non-porous), this coating layer preventing the setting. in contact with the active principle with gastric juices as it passes through the stomach (at pH 1, 2 - 2.0).

The results obtained are presented in figure 3.

It is observed in this figure that, predictably and consistent with the results of Experiment 1 above, vorapaxar sulfate alone is dissolved at pH 1, 2 and pH 3, but present as a precipitate at pH 5 , 6 and 6.8.

The particles in accordance with the invention P2 release a significant amount of vorapaxar in dissolved form in solutions at pH 5.6, 6.8 and 3.0.

On the other hand, as regards the particles P2 ′, which were not subjected to the initial pH of 1, 2, the vorapaxar sulfate is solubilized at pH 3 (after 360 min), but is in the form of crystals, undissolved, in solutions at pH of 5.6 and 6.8.

These results demonstrate that the release of vorapaxar sulphate in dissolved form in solutions reproducing the pH of the intestine, requires its prior presence with a solution of acidic pH, so as to allow the initial dissolution of vorapaxar sulphate in this solution. solution, the presence of 4M HPMC then advantageously preventing it from recrystallizing when the pH rises. The particles in accordance with the invention, of which the coating layer coating the core containing the vorapaxar sulphate is not continuous, advantageously allow such a succession of phenomena to occur when the particles progress in the succession of solutions simulating the gastrointestinal tract. On the contrary, in the example simulating the conditions undergone by particles with a non-porous enteric coating layer, that is to say starting with the bringing together of vorapaxar sulfate with a solution at pH 5.6, the vorapaxar sulphate, which has not been solubilized beforehand by passage in a solution at pH 1, 2, that is to say under the pH conditions of the stomach, is not found in active dissolved form at pH of 5.6 and 6.8 to which it is subjected.

D / Experiment 3 - Chitosan In this experiment, particles (C1, C2, C3) based on chitosan as core substance are manufactured by the process described above for Experiment 1, according to the operating parameters defined in Table 2 below. For the preparation of Formulation 1, water is added with acetic acid.

Table 2

These particles, as well as the vorapaxar sulfate alone, are subjected to the dissolution test described above. The results obtained are shown in figure 4.

It can be seen in this figure that the amount of vorapaxar sulfate dissolved at pH between 5.6 and 6.8 is much lower than that obtained in Examples 1 and 2, when the core substance is HPMC.

E / Experiment 4 - mixture of water and ethanol as vehicle In this experiment, particles (P4, P5, P6, P7, P8) are produced according to the operating parameters defined in Table 3 below. The vehicle for each formulation is a 20/80 water / ethanol mixture, and the conditions applied are Conditions B.

Table 3

These particles are subjected to the dissolution test described above. The results obtained are shown respectively in figure 5 for the particles

P4 (compared to particles P3), in figure 6 for particles P5 (compared to particles P1), in figure 7 for particles P6 (compared to particles P2 and P3) and in figure 8 for particles P5, P7 and P8.

For all of these particles in accordance with the invention, vorapaxar sulfate dissolved in solutions at pH 5.6 and 6.8, as well as at pH 3, simulating a diseased colon, is observed after 360 minutes, demonstrating here again that the galenic form according to the invention allows a release of a large quantity of vorapaxar sulphate in the lower part of the gastrointestinal tract, variable according to the different formulation methods proposed.

Claims

1. Pharmaceutical composition suitable for oral administration, containing as active ingredient a compound selected from the group consisting of vorapaxar, isomers of vorapaxar, atopaxar, 3-2- (chloro-phenyl) - 1- [4- (4-fluoro-benzyl) -piperazin-1-yl] -propenone and their pharmaceutically acceptable salts, characterized in that it contains particles comprising:

a core containing a mixture of said active principle and a substance, called an inhibiting substance, chosen from cellulose polymers, polymers derived from povidone and copolymers based on polyvinyl caprolactam, said inhibiting substance being capable of inhibiting the recrystallization of said active principle in aqueous solution at pH less than 2, when the pH becomes greater than or equal to 5,

2. A pharmaceutical composition according to claim 1, wherein the volume ratio of porosity of the coating layer is between 5 and 50%.

3. Pharmaceutical composition according to one of claims 1 or 2, wherein the inhibitory substance is chosen from hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copovidone and hydroxypropyl methyl cellulose acetate succinate, or any one of their mixtures.

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the core of the particles contains a mucoadhesive substance.

5. Pharmaceutical composition according to claim 4, in which the mucoadhesive substance is chosen from hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, crosslinked polyacrylic acid polymers, polycarbophil, tragacanth, poly (acrylic acid / divinylbenzene). ), sodium alginate, hydroxyethylcellulose, karaya gum, gelatin, guar gum, polyvinylpyrrolidone, chitosan or any of their mixtures.

6. Pharmaceutical composition according to any one of claims 1 to 5, in which the “active principle / inhibiting substance” weight ratio is between 1/1 and 12/1, preferably between 1/1 and 7/1.

7. Pharmaceutical composition according to any one of claims 1 to 6, in which the "active ingredient / coating agent" weight ratio is between 1/1 and 1/3.

8. Pharmaceutical composition according to any one of claims 1 to 7, wherein the active ingredient is vorapaxar sulfate.

9. Pharmaceutical composition according to any one of claims 1 to 8, wherein the coating agent is a polymer selected from copolymers of methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and methyl methacrylate, hypromellose phthalate, hydroxypropyl methyl cellulose aceto-succinate and polyvinyl acetophthalate, or any mixture thereof.

10. Pharmaceutical composition according to any one of claims 1 to 9, for its use as a medicament.

11. A pharmaceutical composition for its use according to claim 10, for the prevention and / or treatment of chronic inflammatory bowel and colon disease, particularly Crohn's disease, in a subject.

12. A pharmaceutical composition for its use according to claim 10 or 11 in a human or non-human mammal, in particular a dog or a cat.

13. A method of preparing a pharmaceutical composition according to any one of claims 1 to 9, characterized in that it comprises a step of preparing said particles by spray drying in an atomization device with a spray nozzle, a first aqueous formulation containing said active principle and said inhibiting substance being introduced into a central spray channel of said spray nozzle, and a second aqueous formulation containing said coating agent being introduced into a channel of said spray nozzle peripheral to said central channel .

14. The method of claim 13, wherein the drying temperature at the outlet of said atomization device is between 50 and 110 ° C.