Classifications

• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
  • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

• the present invention relates to a new process for the preparation of granules of active ingredients, as well as the granules as obtained.
• Such pharmacokinetic profiles involve the administration of large daily doses and / or concomitant doses repeated during the day, as well as limited efficacy due to the large variations in plasma concentration and a risk of intolerance due to these same variations. Moreover, this is detrimental to the observance of the treatment.
• the object of the present invention is to provide a process for the preparation of a new galenic form making it possible to circumvent the aforementioned drawbacks.
• the present invention aims to provide a new dosage form to reduce the daily dose and the number of daily doses, increasing the apparent half-life and bioavailability of active ingredients.
• the present invention aims to provide a new dosage form to reduce or eliminate side effects by reducing the plasma concentrations used.
• the purpose of the present invention is to provide a new galenic form which makes it possible to improve patient comfort and monitor treatment by reducing the number of daily doses.
• the purpose of the present invention is to provide a new galenic form which makes it possible to improve the safety of the product with a stable dosage form.
• the present invention relates to a method for preparing a granule of at least two active ingredients, comprising a step of application by dusting said active ingredients on a solid particulate carrier, characterized in that said active ingredients are not plant extracts.
• granule refers to a preparation consisting of dry solid grains, each forming an aggregate of powder particles of sufficient strength to allow various manipulations.
• the granules are in the form of small grains of substantially uniform size and irregular and angular shape.
• the granules according to the present invention have the particularity of having a fairly regular shape that is almost spherical and rather smooth. From the physical point of view, the granules are aggregates of crystallized or amorphous powders of various powders.
• the granules of the present invention are intended for oral administration, and more particularly to be swallowed as such.
• the method of the invention therefore consists of mixing the active ingredients in the form of powder in the presence of solid particles as a support.
• the solid particles of the support used form a core on which the particles of active ingredients are deposited.
• the implementation of the process of the invention thus makes it possible to obtain pellets of core-shell structure.
• the granules obtained by such a process have a very high specific surface area requiring large amounts of coating polymers according to conventionally used techniques.
• the granules of the present invention are characterized in that they have a lowered specific surface area. Moreover, in appearance, they are relatively smooth and have a rather regular shape.
• active ingredients there may be mentioned antimalarial drugs, antibiotics, antihypertensives, antivirals (and antiretrovirals), antiepileptics, active principles used in gastroenterology, active principles used in dermatology, anticancer drugs, especially of the type cisplatin or 5-flurouracil, as well as lipid-lowering agents.
• the core of the granules of the invention does not consist of particles of a neutral core.
• the solid core of the granules of the invention is not a neutral core.
• neutral nucleus refers to a spherical solid support having a homogeneous surface state.
• these supports are not advantageous because they cause, on the one hand, problems of solubility (too slow dissolution), and, on the other hand, because of their excessive regularity, do not allow not to obtain a homogeneous final product (granule).
• spherical supports tested such as, for example, the neutral nuclei of sucrose and starch, have not given satisfactory results in terms of the final dissolution of the form.
• their spherical surface is too regular, which represents an advantage in terms of coating but in this case does not allow the attachment of small particles of adjuvants (flavorings, sweeteners) and therefore ultimately is detrimental to good homogeneity.
• the mixture can then "catch" in the anfractuosities of the support grain during dusting operations in successive layers and thus participate in the rounding of the grain.
• the successive grinding and dusting operations are essential to obtain the targeted particle size dispersion which makes it possible to respond simultaneously to the various constraints listed above.
• the supports used in the context of the present invention have the advantage of having a poorly homogeneous surface state but presenting crevices in which the various active ingredients in the form of powder will be fixed. This choice is important for allow to obtain a homogeneous final product despite the mixture of at least two powders having distinct particle sizes.
• the solid core of the granules of the invention consists of particles having a mean diameter of from 300 .mu.m to 650 .mu.m, preferably from 400 to 600 .mu.m.
• Granulated mannitol support and more particularly 400-500 grade, is preferred because such a support has a sufficiently large size to be able to attach smaller particles (less than 100 microns).
• this granule has the following particle size distribution: 20% of the particles have a diameter of less than 710 ⁇ m, 70% of the particles have a diameter of less than 500 ⁇ m and 25% of the particles have a diameter of less than 315 ⁇ m.
• the aforementioned powdering step of the process for the preparation of the granules of the invention may also comprise a step of spraying an aqueous, alcoholic or aqueous-alcoholic solution of a binder. These spraying and dusting steps are preferably carried out simultaneously or alternately.
• the above-mentioned dusting step is carried out concomitantly with a step of spraying a binder in the form of a solution.
• An advantageous implementation of the process of the invention thus consists in applying the active ingredients in powder form to the above-mentioned particulate support (or core of the granules) by alternating binder spraying sequences in the form of a solution.
• binders mention may be made of most of the hydrophilic excipients which give viscous solutions: gum arabic and tragacanth, methylcellulose and carboxymethylcellulose, gelatin, starches, maltodextrins, PEG 4000 and 6000 in alcoholic solution, polyvidone in aqueous or alcoholic solution, and also solutions of sucrose, glucose or sorbitol.
• the above-mentioned method further comprises, after the dusting step, a step of coating the granule, in particular by depositing a coating agent in the form of a film on the granule by film-coating.
• This coating step thus makes it possible to consolidate the granules obtained and possibly ensures a masking of the taste of the active principles.
• the low specific surface area of the granules of the invention thus makes it possible, in case of coating, to reduce the amount of coating agent used and thus to dilute the active ingredients in said coated granules less.
• a preferred embodiment of the process of the invention consists of a process comprising, after the coating step, a step of mixing with a lubricant and / or a flavor and / or a sweetener and / or a dye.
• the aforementioned method may also comprise, before the dusting step, a step of grinding the active ingredients in the presence of a diluent.
• the process for preparing the granules of the invention comprises the following steps:
• a step of application by powdering of the active ingredients on a solid particulate support combined with a step of spraying an aqueous, alcoholic or aqueous-alcoholic solution of a binder, to obtain a granule, said granulate consisting of a core; corresponding to the abovementioned support on which particles of the active ingredients are deposited;
• one or more coating steps of the granule obtained in the preceding step by coating a coating film, to obtain a coated granule; and an optional step of mixing with a lubricant and / or a flavor and / or a sweetener and / or a colorant.
• a particularly advantageous process according to the present invention is a process in which the solid particulate carrier is selected from the group consisting of polyols such as mannitol, sorbitol, maltitol or xylitol, lactose, dicalcium phosphate, carbonates such as calcium carbonate, potassium carbonate, magnesium carbonate, sodium carbonate, gluconates, silicates, sugar crystals, sucrose and silica derivatives.
• polyols such as mannitol, sorbitol, maltitol or xylitol
• lactose lactose
• dicalcium phosphate carbonates such as calcium carbonate, potassium carbonate, magnesium carbonate, sodium carbonate, gluconates, silicates, sugar crystals, sucrose and silica derivatives.
• the solid particulate support does not comprise a cellulosic compound.
• the solid particulate support is not a neutral core.
• the solid particulate support consists of mannitol. The granules thus obtained consist of a core consisting of mannitol particles around which are deposited the active ingredient particles.
• the binder is chosen from the group consisting of polyvinylpyrrolidone (PVP or polyvidone), hydroxypropylmethylcellulose (HPMC), shellac, polyvinylpyrrolidone hydroxypropylcellulose (HPC), cellulose, polyols, alginates, polyglycolized glycerides (Gelucire ®) or macrogolglycerides, in particular stearoyl macrogolglycerides, and mixtures thereof.
• polystylitol there may be mentioned in particular mannitol, sorbitol, maltitol or xylitol.
• the binders used in the process according to the present invention are not cellulosic compounds. They are therefore preferably selected from the group consisting of polyvinylpyrrolidone, shellac, polyols or alginates, polyglycolysed glycerides or macrogolglycerides, especially stearoyl macrogolglycerides, as well as mixtures thereof.
• the coating agents used in the process of the invention are preferably used. or HPC, sucrose, alginate, methacrylic polymers and fatty acid glycerides, or any other pharmaceutically acceptable coating polymer.
• the present invention also relates to a method for preparing a granule comprising an enteric coating, said method comprising a step of applying a coating agent consisting of HPMCP (hydroxypropyl-methylcellulosephthalate-hypromellose phthalate), or methacrylic polymers, especially Eudragit ® L30D, or shellac.
• HPMCP hydroxypropyl-methylcellulosephthalate-hypromellose phthalate
• methacrylic polymers especially Eudragit ® L30D, or shellac.
• the present invention also relates to a process for the preparation of a granule comprising a coating for sustained release, said process comprising one or more steps of application of a coating agent consisting of methacrylate copolymers and Eudragit ® RL acrylates, Eudragit ® L100, shellac, cellulose derivatives, especially ethylcellulose, and acrylic derivatives.
• a coating agent consisting of methacrylate copolymers and Eudragit ® RL acrylates, Eudragit ® L100, shellac, cellulose derivatives, especially ethylcellulose, and acrylic derivatives.
• the presence of this coating for modified release makes it possible in particular to increase the apparent half-life of the active principles.
• the present invention also relates to a granule obtainable by the process as defined above.
• the present invention also relates to a granule of at least two active principles, characterized in that it comprises a solid core on which said active principles are supported and in that the active principles are not plant extracts.
• the granules of the present invention have a characteristic structure of heart-bark type, the heart not being of the same nature as the active principles forming the bark.
• these granules have a multilayer structure. Indeed, the active ingredients are deposited on the heart and thus form a layer (or bark) deposited around this heart (or support).
• the heart of the granules can also be considered as a support on which the particles of the active ingredients will be fixed.
• the core consists of solid particles and the active ingredients supported by said core are also in solid form.
• the present invention is therefore based on the development of a new multi-particle oral form.
• the originality of the form presented here consists of a granule intended for the oral route, allowing the administration of at least two active principles other than plant extracts in doses large enough to require only one or two administrations per day, the granule of the invention being highly concentrated in active principles.
• the granules of the present invention have the advantage of reducing the number of daily intakes.
• the amount of active ingredients per unit dosage is preferably greater than or equal to 500 mg, advantageously greater than or equal to 1 g, and preferably greater than or equal to 1, 5 g.
• the core of the granules of the invention consists of particles of a compound selected from the group consisting of polyols such as mannitol, sorbitol, maltitol or xylitol, lactose, dicalcium phosphate. , carbonates such as calcium carbonate, potassium carbonate, magnesium or sodium carbonate, gluconates, silicates, especially magnesium aminosilicate (Neusilin ® ), sugar crystals or sucrose.
• polyols such as mannitol, sorbitol, maltitol or xylitol
• lactose dicalcium phosphate
• carbonates such as calcium carbonate, potassium carbonate, magnesium or sodium carbonate
• gluconates such as silicates, especially magnesium aminosilicate (Neusilin ® ), sugar crystals or sucrose.
• the core of the granules of the invention consists of mannitol.
• the present invention therefore relates to granules comprising particles of active ingredients deposited on a core consisting of mannitol particles.
• the granules according to the present invention may also comprise a binder.
• the role of the binder is to bind the particles together, that is to say, to perfect the cohesion of the granule.
• the binders make it possible to ensure good cohesion of the active ingredients and the heart in the granules and to round off the granules.
• the binders are, like the active ingredients, deposited around the heart of the granules.
• the binders of the granules of the invention are preferably selected from the group consisting of starch, sucrose, gum arabic, polyvinylpyrrolidone (PVP or polyvidone), hydroxypropyl methylcellulose
• HPMC hydroxypropylcellulose
• HPC hydroxypropylcellulose
• HPC hydroxypropylcellulose
• HPC hydroxypropylcellulose
• cellulose polyols or alginates
• polyglycolysed glycerides Gelucire ®
• macrogolglycerides especially stearoyl macrogolglycerides, and mixtures thereof.
• the binders used in the granules of the present invention are not cellulosic compounds.
• the granules of the invention are coated.
• the coated granules consist of grains coated with one or more layers of mixtures of various excipients.
• the preferred coated granules according to the present invention comprise the active ingredients deposited on a core consisting of mannitol particles, as well as an additional layer consisting of or coating agents.
• the granules of the invention have a multilayer structure and consist of a core, preferably based on mannitol, on which are deposited the active ingredients and the binder, themselves coated with one or more layers of coating agent (s).
• the granules of the invention are preferably coated with one or more coating agents selected from the group consisting of shellac, polyvinylpyrrolidone, polyethylene glycol (PEG), cellulose derivatives such as HPMC or HPC, sucrose , alginate and glycerides of fatty acids.
• coating agents selected from the group consisting of shellac, polyvinylpyrrolidone, polyethylene glycol (PEG), cellulose derivatives such as HPMC or HPC, sucrose , alginate and glycerides of fatty acids.
• the granules of the invention are coated with shellac.
• the granules of the invention may also be coated with one or more coating films in which one or more excipients such as lubricants, dyes or sweeteners are added.
• the granules of the invention may also contain one or more plasticizers such as those conventionally used by those skilled in the art.
• the granules of the invention may also comprise an enteric coating for gastric protection. Such granules are therefore gastroresistant.
• Such a coating is obtained with coating agents including HPMCP (hydroxypropylmethylcellulosephthalate - hypromellose phthalate) or methacrylic polymers, including Eudragit ® L30D, or shellac.
• the granules of the invention may also comprise a coating for sustained release.
• Such granules allow a modified or delayed release of the active ingredients (modified release granules).
• Such a coating is obtained with coating agents in particular consisting of copolymers of methacrylates and acrylates Eudragit ® RL, Eudragit ®
• L100 shellac
• cellulose derivatives especially ethylcellulose, and acrylic derivatives.
• the granules according to the present invention may also comprise a lubricant and / or an aroma and / or a sweetener and / or a colorant.
• a lubricant and / or an aroma and / or a sweetener and / or a colorant are in particular as defined above.
• the granules according to the present invention are characterized in that the core represents from 10 to 70%, and preferably from 25 to 55% by weight relative to the total weight of the granule.
• a granulate according to the present invention comprises at least
• the granules of the invention preferably comprise less than 2% by weight of flavor.
• the granules of the invention preferably comprise less than 1.5% by weight of dye.
• the granules of the invention preferably comprise less than 2% by weight of sweetener.
• the granules of the invention preferably comprise less than 4% by weight of lubricant.
• the ingredients are weighed one by one, then the active ingredients are introduced into a cubic mixer (CMS type).
• CMS type cubic mixer
• the amount of diluent is in turn weighed (mannitol 160) and introduced into the mixer.
• the mixer is then started.
• the mixture obtained (A) is satisfactory after 10 minutes.
• the mixture is then introduced into a Forplex FLO mill and the entire mixture is milled so as to reduce the particle size of the assembly (active ingredients + diluent).
• This makes it possible to increase the difference in size of the particles of mannitol (support) (approximately 300 ⁇ ) and of the ground mixture (less than 100 ⁇ and preferably 25 ⁇ ).
• the next step of the process is a dusting step using a conventional turbine as a material.
• the support mannitol is introduced into a tank, it is then rotated (about 20 revolutions per minute) and the mixture A is deposited by sequential dusting on the support mannitol, alternatively with spraying phases of the binding solution (PVP / HPMC / OH / H ⁇ O).
• This step is done sequentially to allow evaporation and drying of the granules.
• a drying phase is carried out in order to circulate hot air over the mass of granules at about 40 ° C. for about 14 hours.
• the product is sieved so as to select the particles obtained.
• the mixture is then returned to the tank.
• the next step is the coating step.
• the solutions (or suspensions) containing the coating agents are placed successively in a low pressure tank with stirring.
• the mass of granules obtained is then placed in the tank of a fluidized air bed and the coating solutions are then sprayed successively in a continuous manner on the granules. Drying / coating steps can also be performed.
• a fluidised air bed apparatus (or related technology) is preferably used for the coating step for their high efficiency in terms of evaporation, which makes it possible to reduce the coating times considerably.
• additives such as sweeteners, lubricants, flavorings and dyes can be added to the granules in a mixer.
• the last step is to distribute the granules in individual packaging bags such as plastic ampoules or sachets.

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• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
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• Pharmacology & Pharmacy (AREA)
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• Public Health (AREA)
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• Animal Behavior & Ethology (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
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• Diabetes (AREA)
• Obesity (AREA)
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