Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

• 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.
• MICIs 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.
• 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.
• 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).
• ASCA anti-Saccharomyces cerevisiae
• ANCA anti-neutrophilic cytoplasmic antibodies
• 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.
• 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.
• 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.
• 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.
• 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.
• 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,
• 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.
• 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.
• the gastro-resistant coating agent has a solubilization pH value of between 5.5 and 7.
• 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.
• the pharmaceutical composition is devoid of any active principle other than those listed above.
• 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.
• 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.
• copovidone polyvinylpyrrolidone / vinyl acetate copolymer
• 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 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.
• the inhibitory substance is hydroxypropyl methyl cellulose, also called hypromellose, which also has good gastrointestinal mucoadhesiveness properties.
• 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 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.
• HPMCP hypromellose phthalate
• 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.
• 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.
• the dosage for administration of the pharmaceutical composition according to the invention can, for example, be taken once or twice a day.
• 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,
• 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.
• 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.
• 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.
• 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;
• 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%.
• 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 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 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.
• HPMC - hydroxypropyl methylcellulose
• HPMC 4M Addensity-polyvinyl copolymer acetate-polyethylene glycol
• HPMC-AS hydroxypropyl methyl cellulose acetate succinate
• chitosan Choat® LF
• Chitoclear® HQG-110 from Primex, 95% deacetylation, viscosity 26 mPa.s
• Chitoclear® HQG-800 from Primex, 95% deacetylation, viscosity 600 to 1200 mPa.s
• core substance substance inhibiting recrystallization and mucoadhesive for HPMC and HPMC-AS, substance
• 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 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 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.
• 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.

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• 2020
  • 2020-04-08 FR FR2003496A patent/FR3109089B1/fr not_active Expired - Fee Related
• 2021
  • 2021-04-07 WO PCT/EP2021/059076 patent/WO2021204883A1/fr not_active Ceased
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