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
  • A61K9/14—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
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • 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
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • 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
• • 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
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

• the invention relates to a process for the preparation of a rapidly dissolving Imidapril powder, particularly useful for the reconstitution of a solution for oral administration.
• Oral formulations are mainly solid forms (powders, tablets, capsules) or liquid forms (solutions, suspensions).
• the liquid forms are suitable, for example, in the case where the active ingredient is stable in solution or in suspension.
• a means consists in preparing a powder for reconstitution in a medium, for example an aqueous medium, before administration.
• the dissolution rate of the powder in the medium must then be as high as possible in order to facilitate the preparation of the solution by the user.
• This dissolution rate is a function of the temperature of the medium in which the powder is dissolved, as well as the particle size and the crystalline state of the powder.
• the powder thus obtained comprises Imidapril in a particular crystalline state which allows rapid reconstitution of a liquid solution, particularly for oral administration.
• Techniques for the preparation of fast dissolving powders have been widely developed. At the present time, the most used ones are co-precipitation, atomization, micronization and lyophilization.
• Micronization of the active substance or co-micronization with a water-soluble excipient are techniques well known to those skilled in the art to increase the rate of dissolution of a substance.
• micronized product is difficult to handle in the form of powders. In this case, it is then necessary to carry out additional operations such as granulation and drying, in order to obtain an appropriate powder.
• European patent EP 0 973 506 (filed in the name of Grother Léon, Michael Hall, Bryans Douglas, Green Richard and Kearney Patrick and published in 1997) describes a freeze-drying process for obtaining a fast dissolving solid dosage form. This method is based on the determination in suitable containers of a solution or a suspension comprising the active substance followed by its lyophilization.
• the cost of manufacture, the fragility of the product obtained, in particular its friability, as well as the need for a specific primary packaging represent significant disadvantages for the implementation of such a process on an industrial scale.
• the inventors have demonstrated that it is possible by spraying a solution of Imidapril on an excipient in a granulator, for example a fluidized air bed granulator, and by drying the Imidapril powder. resulting from Imidapril in a particular physical state and in particular a new crystalline state regardless of the initial physical state of Imidapril used.
• a granulator for example a fluidized air bed granulator
• This crystalline state differs from that of Imidapril by: an external morphology different from the crystal, in particular by its surface state; a lower melting temperature (-29 ° C.).
• This new crystalline state makes it possible to obtain a powder having a high dissolution rate which is at least comparable, if not greater, with respect to the dissolution rates described in the prior art for known Imidapril formulations (see Example 4 below).
• the first object of the invention is a process for the preparation of a fast-dissolving Imidapril powder, comprising at least the steps of spraying a solution of Imidapril on at least one excipient in a granulator, preferably a granulator. with air bed or fluidized inert gas, and drying the powder thus obtained.
• the powder obtained after drying has a ratio Imidapril / water-soluble excipient of between 1: 2 and 1:20, preferably between 1: 8 and 1:10 by weight of the total weight of said powder.
• the invention relates to a method for preparing an Imidapril powder comprising the steps of: a) preparing an Imidapril solution; b) heating said Imidapril solution; c) mixing and heating at least one excipient in a granulator, preferably an air bed granulator or fluidized inert gas; d) spraying in said granulator of said Imidapril solution of step b) on said excipient of step c); e) drying the powder obtained in the previous step.
• Imidapril can be in any form compatible with use in an air bed granulator or fluidized inert gas, particularly in the form of a solution.
• Said solution may be of any type compatible with the spray in an air bed granulator or fluidized inert gas, such as an alcoholic, aqueous-alcoholic or aqueous solution.
• the Imidapril solution is an aqueous solution.
• the Imidapril solution when the Imidapril solution is an aqueous solution, the Imidapril may be in the aqueous solution at a concentration between 1 and 16 I, preferably 10 to 13% by weight of the total weight of said solution.
• the aqueous solution of Imidapril can be heated at a temperature of between 30 ° and 70 ° C., preferably 55 ° C. to 60 ° C.
• the excipient may be heated to a temperature of between 30 ° C. and 70 ° C., preferably between 50 ° C. and 60 ° C.
• the granulator may be an apparatus in which granulation and drying can be carried out.
• Glatt® manufactured by Glatt Agen Germany and Okawara Seisakusho Co. in Japan
• Aeromatic® manufactured by Aeromatic AG in Switzerland and Fuji Industries Co. in Japan
• Calmic® manufactured by Calmic Engineering Co. in Great Britain
• Growmax® manufactured by Fuji Powdal Co. in Japan
• Flowcoater® manufactured by Freund Industries Co. in Japan
• the spraying of the Imidapril solution can be carried out at a rate that will depend on the equipment used and the manufacturer's instructions.
• the inlet temperature of the air flow or of the inert gas may be between 35 ° C. and 90 ° C., preferably between 60 ° C. and 80 ° C.
• the drying of the powder obtained can be achieved by any known method of the prior art.
• said drying can be carried out in the same apparatus as the granulation.
• the drying of the powder may be carried out at a temperature between 50 0 C and 9O 0 C, preferably between 7O 0 C and 8O 0 C.
• the method may further comprise an additional step of calibrating the powder obtained after drying.
• the calibration of said powder can be carried out in any known apparatus, particularly by way of example, by a device marketed under the name Erweka® oscillating provided with a grid.
• the excipient may be chosen from any excipient for pharmaceutical use.
• the excipient is an inert excipient.
• the excipient is preferably a water-soluble excipient, even more preferably an inert water-soluble excipient, which may be chosen from dextrin, dextrose or glucose monohydrate, erythritol, fructose, lactitol, lactose, maltitol, maltose, maltodextrin, mannitol, povidone, polyoxyethylene glycols, sucrose or sucrose, sorbitol and xylitol, or a mixture thereof.
• an inert water-soluble excipient which may be chosen from dextrin, dextrose or glucose monohydrate, erythritol, fructose, lactitol, lactose, maltitol, maltose, maltodextrin, mannitol, povidone, polyoxyethylene glycols, sucrose or sucrose, sorbitol and xylitol, or a mixture thereof.
• the excipient may be chosen from lactose, maltodextrin, mannitol and povidone or a mixture thereof.
• At least one additional excipient which may advantageously be chosen from preservatives, antioxidants, antimicrobials, synthetic or natural origin flavorings, modifiers of pH and diluents.
• said additional excipient may be mixed with the Imidapril solution, with the water-soluble excipient or with the powder obtained by the process.
• the mixture of the additional excipient and Imidapril may be carried out previously at or during the spraying.
• the method of the invention makes it possible to obtain a powder such that 75 mg to 300 mg of active ingredient contained in said powder dissolve in 30 ml of water at room temperature in a time at least less than 2 minutes, preferably at 1 minute.
• the subject of the invention is also an Imidapril powder that can be obtained by the process according to the invention.
• the powder obtained by the process of the invention can be used directly either after the drying step or after the calibration step, particularly to be packaged for example in bottles, and especially glass ampoules, tubes or sachets or in the form of capsules or tablets.
• FIG. 1 shows an electron microscopic view (magnification 50) I 1 Imidapril in the raw state, that is that is, before incorporation into the process according to the invention
• FIG. 2 represents an electron microscope (magnification 50) view of the Imidapril powder as obtained after application of the process according to the invention (Example I)).
• EXAMPLE 1 Obtaining a powder basis of Imidapril f Lactose and Maltodextrin
• a powder based on Imidapril, Lactose and Maltodextrin having the following final proportions by weight:
• Maltodextrin 12 4% is prepared according to the following protocol: A starting aqueous solution comprising 13% by weight of Imidapril was heated to 60 ° C.
• the starting Imidapril solution was then sprayed into said granulator at a temperature of 60 ° C. at a flow rate of 9 g / min.
• the air inlet temperature in the granulator was 70 0 C.
• the temperature in the fluidization bowl was maintained at a temperature above 30 ° C. throughout the spraying step. Drying of the powder obtained after the spraying step was carried out in said granulator with an inlet air temperature of 70 ° C.
• the drying step was continued until a powder with a drying loss of less than 2% was obtained.
• Povidone 10.0% is prepared according to the protocol of Example 1.
• a powder based on Imidapril and Mannitol having the following final proportions by weight:
• Micronization of Imidapril was performed using an air jet micronizer.
• dv means "volume equivalent diameter” that is to say “diameter of a sphere of the same volume as the particle”.
• the forms of the particles being variable, they are, to be comparable, assimilated to spheres of fixed volume.
• the average value of the dv on the total sample is 4.85 ⁇ m, a sample in which 10% of the particles have a diameter less than 1.23 micrometers, 25% of the particles have a diameter less than 2.14 micrometers,

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• Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
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• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Veterinary Medicine (AREA)
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• Molecular Biology (AREA)
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• Heart & Thoracic Surgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2005
  • 2005-03-07 FR FR0502252A patent/FR2882655B1/fr not_active Expired - Fee Related
• 2006
  • 2006-03-07 EA EA200701903A patent/EA011559B1/ru unknown
  • 2006-03-07 US US11/885,806 patent/US20080167358A1/en not_active Abandoned
  • 2006-03-07 AU AU2006221875A patent/AU2006221875A1/en not_active Abandoned
  • 2006-03-07 CA CA002600178A patent/CA2600178A1/fr not_active Abandoned
  • 2006-03-07 WO PCT/FR2006/000508 patent/WO2006095085A1/fr active Application Filing
  • 2006-03-07 JP JP2008500231A patent/JP2008531745A/ja active Pending
  • 2006-03-07 EP EP06726040A patent/EP1855668A1/fr not_active Withdrawn
• 2007
  • 2007-09-03 IL IL185695A patent/IL185695A0/en unknown

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