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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/35—Allergens
  • A61K39/36—Allergens from pollen
• • 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
• • 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
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• • 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
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to a new process for the manufacture of transmucosal pharmaceutical formulations, as well as the formulations thus obtained.
• thermolabile active ingredients that is to say capable of being degraded by heat.
• thermolabile active ingredients used in the formulations obtained by the method according to the invention are chosen from the group of hormones, proteins, allergens or triptans, since these substances are sensitive to heat. These active ingredients are known to be fragile, so that the traditional methods of manufacturing pharmaceutical formulations containing them are not suitable because they lead to their degradation.
• the purpose of the process according to the invention is, in contrast to the aforementioned process, to dissolve the active ingredient in a binder with a low melting point.
• a first test was therefore carried out, aimed at dissolving the active ingredient in a binder in which the binder was an amphiphilic polymer of the polyethylene glycol (PEG) 1500 stearate type, hereinafter referred to as 1500 stearate, and the active ingredient is the adrenaline tartrate.
• PEG polyethylene glycol
• the first heating shows the melting of the polymer (endotherm at 50 ° C), followed by a plateau up to 116 ° C: beyond this, an endotherm starts up to the tartrate melting temperature adrenaline at 150 ° C.
• Another possibility is to go through the intermediate formation of an aqueous solution in which the polymer and adrenaline are dissolved.
• a soluble mannitol or insoluble microcrystalline cellulose (MCC) type support is added to the aqueous solution.
• the water contained in this mixture is then removed by a lyophilization-type low-temperature drying technique or by the use of a speedvac® type centrifugal evaporator so as not to degrade the adrenaline present. It leads to the formation of a compact white mass which is then milled and sieved after drying to give a grain of homogeneous appearance.
• the resulting mixture is then placed in a vacuum centrifuge overnight. 25 g of a white compact mass are obtained after drying which is then milled and sieved to give a homogeneous grain.
• HPLC analysis is in accordance with the adrenaline content namely 5.0% w / w (equivalent based on the dry matter).
• the loss on drying is between 0.2 and 0.3% for grains from mannitol.
• the first step was to check the feasibility of this ternary mixture.
• TPGS and stearate 1500 are miscible in all proportions. Above 45 ° C these 2 polymers melt and mix without any difficulty to form a homogeneous and stable mass.
• This ternary when brought to 50 ° C has a similar appearance and is handled identically to the two aforementioned polymers in the molten state.
• the second step consisted in producing a solid solution of adrenaline bitartrate in the aforementioned ternary mixture.
• adrenaline bitartrate is a very water-soluble compound, it was first necessary to check whether it was possible to directly dissolve solid adrenaline bitartrate in said ternary mixture.
• ternary mixture 10 g are prepared from 4.50 g of 1500 stearate, 500 mg of TPGS and 5 g of water at 50 ° C. This mixture is kept at 50 ° C. with stirring for 5 minutes. 4.54 g of powdered adrenaline bitartrate (equivalent to 2.5 g of adrenaline base) are then added. The dissolution is total and fast. After only a few seconds with stirring the mixture becomes translucent and homogeneous.
• a granular carrier was directly added to this melt.
• the supports selected are mannitol and ProSolv 90.
• Mannitol is a soluble carrier. However, assuming that the previous mixture contains a limited amount of water, it should be checked whether the grain will be handled after drying, which would open the way to obtaining a fully soluble sublingual tablet.
• the grains obtained according to the method described above and coming within the scope of the present invention will comprise between 0.5% and 10% equivalent epinephrine base, 35% to 45% 1500 stearate, 2% to 10% TPGS and 40% to 60% mannitol.
• the sublingual tablet envisaged comprises 5 mg of adrenaline (base equivalent) for a tablet of 200 to 300 mg with a disintegration time as short as possible and not exceeding 3 minutes.
• the compression operation is performed on a conventional compression machine.
• a set of cylindrical geometry punches with a diameter 11, 28 mm or a surface of 1 cm 2 , planar and not chamfered, is used.
• the height of the compression chamber at the time of filling is set to obtain the desired mass of the tablets.
• the tablets thus produced and analyzed are of course only prototypes, and do not have the final geometric characteristics.
• the press is equipped with two sensors for measuring the forces that the powder bed exerts on the upper and lower punches, as well as a sensor for moving the upper punch.
• the tablets produced are individually weighed, and their dimensions and their diametric breaking strength are measured on a Kraemer EL Ektronik HP 97 type durometer.
• the content uniformity test was performed under the terms of the European Pharmacopoeia 5th edition (2.9.5). It covers 10 tablets, individually weighed products.
• the disintegration test was performed on PTZ (Pharmatest) under the terms of the European Pharmacopoeia 5th edition (2.9.1). The size of the tablets does not exceed 18 mm, the test is carried out on 6 tablets.
• the sublingual tablets which are the subject of the present invention and obtained from the grains described above must comply with a number of constraints: hardness, friability, disintegration time, cohesion in particular.
• ProSolv will be used as an excipient; this product is a multifunctional composite excipient based on 98% microcrystalline cellulose (MCC) and 2% colloidal silica. These pharmacotechnical properties allow in difficult cases to increase very significantly the cohesion of the system. Moreover, this excipient, if it is not water-soluble, nevertheless remains very hydrophilic.
• a first mixture of 25 g of grain and 15 g of ProSolv 90 made it possible to obtain tablets having valuable pharmacotechnical properties.
• the system is thus very cohesive and the average hardness of the tablets obtained from this mixture is between 9 > 5 and 11 Kp depending on the consolidation force applied.
• a disintegrant such as for example starch glycolate (Explotab).
• This one acts according to 2 complementary mechanisms of disintegration namely, by capillarity by favoring the penetration of the water in the compressed when in the mouth and then swelling favoring rapid disintegration of the tablet.
• Explotab starch glycolate
• the addition of Explotab in a range of between 2 and 4% made it possible to obtain a disintegration time compatible with the fixed objective, that is to say less than 3 minutes.
• the addition of a disintegrant reduces the hardness of the tablet.
• the disintegration time varies very strongly for the same mixing composition with the applied consolidation force. There is therefore an optimum to be determined between the applied consolidation force making it possible to obtain cohesion and a satisfactory hardness while allowing a disintegration time compatible with the aforementioned constraints.
• Saccharin does not bring any benefit from a pharmacotechnical point of view, however it appeared that a tablet manufactured without saccharin had an unpleasant bitter taste. The amount of saccharin added (0.8%) masked this bitterness.
• thermosensitive substance in this case the recombinant allergen rBetvl, allergen characteristic of trees of the order of fagales and in particular birch.
• aqueous solution of rBetvl 1 ml of aqueous solution of rBetvl is then prepared at a concentration of 3 mg / ml. The dissolution is rapid and the resulting solution of rBetvl remains clear at room temperature.
• mannitol type Mannogen EZ for example
• Mannitol is a water-soluble carrier, however the previous mixture contains a limited amount of water that does not allow the dissolution of mannitol. This gives a homogeneous mass which is dried under reduced pressure at 25 ° C for 24 hours to form a grain which after grinding and sieving is perfectly homogeneous.
• thermolabile active principles other than adrenaline or rBetvl, such as for example triptans which are drugs intended for the acute treatment of seizures of migraine.
• triptans which are drugs intended for the acute treatment of seizures of migraine.
• the process which is the subject of the invention applies to allergens and proteins sensitive to heat.
• a third component which, in the examples given for adrenaline and rBetvl, is water.
• an aqueous solvent such as a hydroalcoholic solution or a water-soluble solvent, is very suitable.
• water-soluble solvent is meant in the present invention any water-soluble solvent of class III (within the meaning of the guidelines of the "European Medicines Agency" on residual solvents.
• the aforementioned grains can be compressed into sublingual tablets, as has been described for adrenaline bitartrate.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
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• Animal Behavior & Ethology (AREA)
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• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Molecular Biology (AREA)
• Biophysics (AREA)
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• Nutrition Science (AREA)
• Immunology (AREA)
• Microbiology (AREA)
• Mycology (AREA)
• Emergency Medicine (AREA)
• Zoology (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2013
  • 2013-12-11 FR FR1302904A patent/FR3014317B1/fr not_active Expired - Fee Related
• 2014
  • 2014-12-10 US US15/104,028 patent/US20160361251A1/en not_active Abandoned
  • 2014-12-10 EP EP14824036.9A patent/EP3079662A1/de not_active Withdrawn
  • 2014-12-10 WO PCT/FR2014/000265 patent/WO2015086918A1/fr active Application Filing

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