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
  • A61K9/0087—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
• • 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
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• the present invention relates to a novel hydrophobic galenic system making it possible to improve the masking of the taste of the active principles that it contains, the stability of said active principles and, if necessary, to control their release.
• the galenic system according to the invention is suitable for the preparation of pharmaceutical or veterinary compositions, in particular for oral or injection administrations.
• the present invention thus relates to a galenic system, in the form of lipid particles without surfactants or emulsifiers comprising at least one active principle, characterized in that the particles consist of a nonionizable hydrophobic lipid matrix at physiological pH in which the active ingredient (s) such as the surface of the lipid particles is dispersed is devoid of active principle.
• the invention also relates to a method for masking the taste of the active principles and / or for protecting the active principles against the degradation reactions and / or for modulating the release rate of the active principles, characterized in that lipid particles are prepared. without surfactants or emulsifiers comprising a nonionizable hydrophobic lipid matrix at physiological pH in which the active principle (s) is dispersed.
• the matrix may advantageously be designated a "strictly hydrophobic" horn insofar as it contains no detectable traces of water.
• the hydrophobic matrix is non-ionizable since the constituent elements are not likely to be ionized at physiological pH, in particular do not include acidic or basic functions, such as organic or inorganic acids and organic or inorganic bases. More particularly, the particles of the galenic system according to the invention do not comprise fatty acids.
• the lipidic hydrophobic matrix is advantageously selected from natural or synthetic oils or waxes which are non-ionizable at physiological pH and their mixtures, and in particular triglycerides and derivatives thereof, palm oil, carnauba wax, candelilla wax, coconut wax and the like.
• oils or waxes which are non-ionizable at physiological pH and their mixtures, and in particular triglycerides and derivatives thereof, palm oil, carnauba wax, candelilla wax, coconut wax and the like.
• composition is more particularly free of traces of water or organic solvents. It is strictly hydrophobic.
• the active ingredient (s) are dispersed in the lipid matrix, substantially distributed at a constant concentration in said matrix. Depending on the hydrophilic or hydrophobic nature of the active ingredient, it will be solubilized in whole or in part in the hydrophobic matrix or simply dispersed.
• the particles advantageously have a loading rate of active ingredient of between 0.10 and 2 grams / gram of hydrophobic lipid matrix, more preferably between 0.5 and 2 grams / gram of hydrophobic lipid matrix, more preferably between 1 and 2 grams. / gram of hydrophobic lipid matrix.
• They preferably have a melting point of between 15 and 85 ° C, more preferably between 30 and 45 ° C.
• the particles are spherical, more preferably.
• Their size is advantageously between 0.5 and 1500 ⁇ m, preferably between 100 and 400 ⁇ m for oral administration, preferably between 0.5 and 5 ⁇ m for administration by injection.
• the invention also relates to a pharmaceutical or veterinary composition in the form of an oral powder, cachet, tablet, capsule, capsule, gum, oral liquid, drops, syrup, suspension, solution, solution or suspension for injection or implantation, and containing particles according to the invention. 'invention.
• compositions in accordance with the invention consist essentially of waxes or mixtures of waxes, vegetable, animal or mineral, natural, synthetic or semisynthetic, oils, non-amphiphilic and hydrophobic compounds allowing adjust the melting point and physicochemical properties such as hardness. They may also contain oily, pasty or solid additives, liposoluble or water-soluble active ingredients. Mixtures having a melting point between 15 ° C and 85 ° C can be used. In a particular form of the invention, a hydrophobic composition is used, the melting point of which, after incorporation of the active principle, is between 15 and 50 ° C., more preferably between 30 and 45 ° C. An appropriate composition should be chosen, with oral absorption or any other method of administration.
• the components will preferably be chosen from the components already used for oral administration and described in the list of excipients published by the European Pharmacopoeia or the GRAS list published by the FDA and in such a way that the particles formed retain their properties. incorporation, taste masking and stabilization of the active components.
• the composition contains waxes or mixtures of waxes chosen preferentially from:
• glycerides semisynthetic glycerides and derivatives with medium or long chains, which can be hydrogenated - palm oil, sesame oil, Carnauba wax oil
• composition according to the invention may contain an oil or a mixture chosen from:
• oily compounds such as oleic alcohol, lanolin, sunflower oil, palm oil, olive oil may be used, but the resulting mixture must be characterized by hydrophobic behavior, no miscibility with water and a melting point between 15 ° C. and 85 ° C. It is also possible to adjust the consistency, to introduce into the composition of clays or their oily dispersions, phenyl silicone gums , starches, structuring of fats.
• the hydrophobic matrix consists only of nonionizable waxes at physiological pH.
• the matrix according to the invention is advantageously strictly hydrophobic.
• the preparation of the particles according to the invention is well known to those skilled in the art, in particular by following the procedures described in patent applications WO 99/65448, WO 2004/084856 and WO 2006/070117.
• the particles according to the invention are obtained by mixing with moderate heating. More specifically, these compositions are obtained by a process characterized by the fact that the melting temperature of the wax, the wax and the oil are mixed until a mixture characterized by a melting point below the temperature of the wax is obtained. melting of the wax. The initial ratio between the wax and the oil can be modulated so that the melting temperature of the final mixture is less than the degradation temperature of the compound to be incorporated, the most sensitive to heat. The final mixture must be solid at the temperature of use and have in one of these preferred shaping, a melting point of 37.5 ° C. The mixture is then cooled with appropriate stirring, at a temperature of 2 ° C or 3 ° C above its melting point, to allow the inclusion of pharmaceutical active ingredients. The mixture is then shaped into hydrophobic spherical particles called particles.
• mineral compounds such as talc, kaolin, will advantageously be chosen.
• the particles do not comprise mineral fillers.
• the particles have a size of between 0.5 and 1500 microns and contain, dissolved or dispersed in their matrix, cosmetic, pharmaceutical and biotechnological components.
• the mixture may contain components such as essential oils, flavors, pigments, fillers, dyes, enzymes and coenzymes and other active substances.
• the particle loading capacity can range from 0.02% to 75% based on the weight of particles.
• a suitable lipid composition should be chosen so that the process can be implemented and that the particles are solid at the temperature of use with a size preferably between 0.5 and 1500 micrometers and preferably between 100 and 400 microns during oral administration
• the components that can be used to be incorporated in the particles mention may be made of vitamins or provitamins A, B, C, D, E, PP and their esters, carotenoids, anti-radical substances, hydroxy acids, antiseptics, molecules acting on pigmentation, on inflammation, biological extracts.
• the particles may also contain preservatives, antioxidants, dyes and pigments, cells and cell organelles.
• these particles may contain pharmaceutical components intended to treat cutaneous or mucosal pathologies.
• active component is used to refer to any active therapeutic substance or mixture which can be advantageously administered to humans or other animals to diagnose, treat, reduce, treat or prevent the disease.
• active component examples include antibiotics, macrolides, antifungals, itraconazole, ketoconazole, antiparasitic agents, antimalarials, adsorbents, hormones and derivatives, nicotine, antihistamines, steroidal anti-inflammatories and non-steroids, ibuprofen, naproxen, cortisone and its derivatives, antiallergic agents, analgesics, local anesthetics, antivirals, antibodies and molecules acting on the immune system, cytostatic and anticancer drugs, analgesics, lipid-lowering agents , vasodilators, vasoconstrictors, angiotensin-converting enzyme inhibitors and phosphodiesterase, fenofibrate and derivatives, statins, nitrates and antiangiours, beta blockers, calcium channel blockers,
• the lipid particles according to the invention are devoid of active principle on their surface.
• the removal of the active ingredient from the surface of the particles is, for example, obtained by washing the particles or by any other appropriate method. Since the lipid particles are devoid of active principle on their surface, it is not necessary to use a coating of the particles to mask the taste of the active ingredients and / or to protect the active ingredients against degradation reactions and / or to modulate the release rate of the active ingredients.
• the lipid particles according to the invention can therefore be formulated directly into powders, compressed powders, aqueous suspensions or syrups.
• the particles of the invention can be used in any suitable galenic formulation.
• the particles of the invention are used in aqueous suspensions, syrups and sachets.
• the particles can be used in conventional pharmaceutical formulations such as capsules, capsules, granules, oral powders, dispersible powders, tablets, water-dispersible and orodispersible tablets.
• the invention therefore also relates to processes for the preparation of powders, compressed powders, aqueous suspensions or syrups comprising lipid particles according to the invention.
• the taste-masked particles according to the invention can also be used for injectable administration and in particular for the preparation of sustained-release forms.
• the particles according to the invention are prepared to have a size preferably between 0.5 and 5 ⁇ m. It is best to sift them to obtain a size distribution consistent with the mode of administration.
• Their waxy composition is chosen to comply with the requirements of the injectable route. This dosage form makes it possible to eliminate the problems of toxicity encountered by the polymer particles obtained with emulsion polymerization processes, related to the use of solvents and surfactant compounds.
• the particles according to the invention make it possible to obtain loading rates of active ingredient of between 0.10 and 2 grams / gram of hydrophobic lipid matrix. Those skilled in the art know that encapsulation technologies do not achieve these rates. Finally, the degradation of the particles does not lead to an inflammatory reaction as can be encountered with the injectable particles based on polylactic-glycolic polymer.
• the following examples are not limiting, they serve only to illustrate the invention.
• taste masking tests were performed on a sample of 10 individuals. The results are expressed according to the following scale:
• Triglycerides of hydrogenated palm oil 24 g melting point 40 ° c
• the higher melting compound 2 ° C above its melting point
• the various compounds from the highest to the lowest melting point are gradually added.
• the temperature of the mixture is gradually lowered to be maintained 2 ° C to 3 ° C above the melting temperature of the new mixture obtained.
• ibuprofen is added.
• the dispersion of these components in the lipid phase is carried out using a stirring system equipped with a mobile anchor at a speed of 400 revolutions / min.
• the mixture When the mixture is homogeneous, it is added to 500 ml of aqueous gel 0.4% carbopol Ultrez 10, neutralized at pH 6.2 with sodium hydroxide, previously heated to the same temperature as the lipid mixture and contained in a reactor equipped with a quadripal propeller stirring system. During the addition of the composition, the stirring speed of the propeller is 400 revolutions / min. Stirring is maintained for 30 seconds after the end of the addition of the composition and then stopped. The dispersion is then cooled to 15 ° C. The particles are recovered by sieving and then washed with distilled water, then recovered and dried. The particles thus obtained have an average size of 285 microns.
• the taste masking test performed on the particles gives no detection of the active ingredient.
• an assay of ibuprofen is performed by HPLC Dionex Prontosil C18 150x4.6 mm column, 1 ml / min, isocratic UV detection mode 220 nm.
• the mobile phase (CH3CN / 0.2% orthophosphoric acid: 60/40) Tr ibuprofen 5.8 minutes.
• Talc 7 g After mixing, the whole is divided into a unit bag of 2.13 g containing 200 mg of ibuprofen. The recovery with 50 ml of water makes it possible to reconstitute an aqueous dispersion of rantiinflammatoire. The taste test performed on the dispersion gives no detection of the active ingredient.
• Composition Hydrogenated triglycerides of melting point 40 ° C 17 g
• Ibuprofen 1 1, 3 g The particles are prepared according to the protocol of Example No. 1. Finally, we obtain 35 g of particles containing 10 g of ibuprofen.
• Example 6 Particles containing copper sulphate and calcium ascorbate
• the taste masking test performed on the particles gives no detection.
• Triglycerides 60 g hydrogenated melting point 42 ° C.
• Clarythromycin 30 g The procedure is identical to that described in Example 1.
• the taste masking test performed on the particles gives no detection.

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• 2007
  • 2007-03-21 FR FR0753964A patent/FR2913884A1/fr active Pending
• 2008
  • 2008-03-21 WO PCT/EP2008/053451 patent/WO2008125423A1/fr not_active Ceased
  • 2008-03-21 US US12/532,164 patent/US20100086595A1/en not_active Abandoned
  • 2008-03-21 EP EP08718149A patent/EP2139454A1/de not_active Withdrawn

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