EP2043605A1 - Injectable slow-release formulation of active ingredients, method for the preparation thereof - Google Patents

Injectable slow-release formulation of active ingredients, method for the preparation thereof

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Publication number
EP2043605A1
EP2043605A1 EP07823540A EP07823540A EP2043605A1 EP 2043605 A1 EP2043605 A1 EP 2043605A1 EP 07823540 A EP07823540 A EP 07823540A EP 07823540 A EP07823540 A EP 07823540A EP 2043605 A1 EP2043605 A1 EP 2043605A1
Authority
EP
European Patent Office
Prior art keywords
composition
poly
fatty
esters
oleate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP07823540A
Other languages
German (de)
French (fr)
Inventor
Jerome Gaucheron
Gerard Trouve
Jerome Aucouturier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Societe dExploitation de Produits pour les Industries Chimiques SEPPIC SA
Original Assignee
Societe dExploitation de Produits pour les Industries Chimiques SEPPIC SA
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Application filed by Societe dExploitation de Produits pour les Industries Chimiques SEPPIC SA filed Critical Societe dExploitation de Produits pour les Industries Chimiques SEPPIC SA
Publication of EP2043605A1 publication Critical patent/EP2043605A1/en
Withdrawn legal-status Critical Current

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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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the invention relates to a novel formulation of pharmaceutical or veterinary active ingredients, intended to promote their release into the human or animal body, over a prolonged period of time.
  • the prolonged release of drugs is a method that allows the therapeutic effects of an active ingredient to be prolonged over time, to reduce the side effects and to minimize the risks associated with temporarily exceeding the threshold of toxicity in the patient.
  • Many formulations for the sustained release of oral, topical or injectable drugs have been described in the literature. Among these, there are solid injectable forms and liquid injectable forms.
  • Solid injectable forms are suspensions of microbeads or nanobeads, the average diameter of which is between 0.01 ⁇ m and 100 ⁇ m, in an isotonic aqueous solution. Such suspensions often tend to sediment and are therefore not very stable storage and homogeneity of the drug is not always guaranteed, which can cause problems to ensure the administration of a specific dose of active ingredient to the patient.
  • the microbeads or nanobeads of these suspensions generally consist of biodegradable polymers such as copolymers of lactic acid and / or glycolic acid, as described in the United States patent application published under the number 2005/048115 A1.
  • microbeads or nanobeads Major drawbacks in the implementation of these microbeads or nanobeads are the use of volatile organic solvents dangerous to human health to prepare them and the residual presence of toxic monomers in the final formulation.
  • Other authors have described microbeads of fatty substances, solid at room temperature as injectable active agent vectors, such as those described in the international application published under the number WO 94/26252.
  • the disadvantages lie in the fact that the suspensions can only be weakly loaded with microbeads, so active ingredient, to remain fluid and injectable.
  • modifications of the crystalline form of the fatty substances over time, or during cold storage have been observed, which results in unsatisfactory release profiles of the active principles also described.
  • microbeads can only be used with lipophilic active principles.
  • Liquid injectable forms stable, homogeneous and fluid, are preferred for administration by injection.
  • a particularly useful form is the emulsion, which is a mixture of an aqueous phase and a liquid lipid phase, stabilized with surfactants.
  • H / E an "oil-in-water" emulsion
  • Such emulsions have long been used for parenteral nutrition and have also been proposed for the injection of lipophilic active principles to ensure prolonged release into the human body.
  • fatty phases such as vegetable oils, medium chain triglycerides which have a low solvent power and solubilize only small amounts of well-chosen drugs.
  • compositions in the form of water-in-oil (W / O) emulsions for vaccines having a viscosity of preferably less than 100 mPas, in which the emulsifying agent is, for example, ARCACEL TM P135 [poly (12-hydroxystearic acid)] polyester-type emulsifiers in which the aqueous phase comprises at least one water-soluble active principle.
  • W / O water-in-oil
  • emulsifying agent is, for example, ARCACEL TM P135 [poly (12-hydroxystearic acid)] polyester-type emulsifiers in which the aqueous phase comprises at least one water-soluble active principle.
  • WO 96/40057 discloses a drug in the form of a water-in-oil inverse emulsion of low viscosity, the fatty phase comprising a fluorocarbon oil, and the aqueous phase at least one active ingredient.
  • the subject of the invention is a composition for the implementation of a therapeutic method of the human or animal body, comprising a fat phase (H) and an aqueous phase (E), in the form of a water - in - oil (W / O) type emulsion injectable in said human or animal body, wherein said aqueous phase (E) comprises at least a water-soluble pharmaceutical or veterinary active ingredient, characterized in that said fatty phase (H) comprises one or more surfactants having an overall HLB number of between 3 and 8, chosen from fatty acid esters with sorbitol or mannitol or esters of fatty acids with sorbitan or mannitane, triglycerides of (poly) alkoxylated fatty acids, (poly) alkoxylated polyglycerol esters of fatty acids and said composition has a viscosity measured at 25 ° C. in a beaker of 250 cm 3 having a diameter of about 7 cm, using a
  • the overall HLB of the mixture is the weighted sum of the HLBs of each surfactant.
  • the constituent fatty phase of the composition which is the subject of the present invention which must be liquid at 4 ° C., generally comprises one or more compounds chosen from oils of mineral, vegetable or animal origin, the alkyl esters of the said oils and the alkyl esters. of fatty acids or alkyl ethers of fatty alcohols, esters of fatty acids and polyols or ethers of fatty alcohols and polyols.
  • oils of mineral origin are petroleum oils, such as mineral white oils, such as MARCOL TM 52, MARCOL TM 82 or DRAKEOL TM 6 VR.
  • vegetable oils include peanut oil, olive oil sesame oil, soybean oil, wheat germ oil, coconut oil, grape seed, sunflower oil, castor oil, linseed oil, soybean oil, corn oil, coconut oil, palm oil, nuts, hazelnut oil, rapeseed oil or squalane or olive squalene.
  • oils of animal origin are spermaceti oil, tallow oil, squalane or squalene extracted from shark livers or fish oils.
  • alkyl esters of oils there are linear or branched or linear butyl, linear or branched methyl, propyl esters of said oils.
  • fatty acids suitable for the preparation of the esters mentioned above there are more particularly those having from 12 to 22 carbon atoms, such as, for example, myristic acid, palmitic acid, oleic acid, ricinoleic acid or isostearic acid and preferably a fatty acid liquid at 20 ° C.
  • fatty acid esters or fatty alcohol ethers are alkyl esters of fatty acids, such as ethyl oleate, methyl oleate, isopropyl myristate, and the like. or octyl palmitate, esters of fatty acids and polyols or ethers of fatty alcohols and polyols, such as monoglycerides of fatty acids, diglycerides of fatty acids, triglycerides of fatty acids, fatty acid esters with a polyglycerol or esters of fatty acids and of propylene glycol, and more particularly esters of fatty acids with a hexol, such as for example sorbitol or mannitol, esters of fatty acids with a hexol anhydride, such as sorbitan or mannitan.
  • alkyl esters of fatty acids such as ethyl oleate, methyl oleate, isopropyl myri
  • the fatty phase may comprise only one of the compounds mentioned above or a mixture of several of the compounds mentioned above.
  • the fatty phase (H) constituting the pharmaceutical composition is chosen from mineral white oils, liquid paraffin oils, squalane, squalene, ethyl oleate or a mixture of these oils.
  • the fatty phase comprises, for 100% of its mass, approximately between 1% and 15% by weight, preferably between 3% and 10% by weight of surfactants.
  • the invention more particularly relates to a composition as defined above in which the surfactant or the mixture of surfactants has an overall HLB number greater than or equal to 5 and less than 8.
  • the surfactants used are generally chosen from modified fatty substances.
  • the modified fatty substances used in the context of the present invention may be of plant or animal mineral origin.
  • mineral modified fatty substances there are oils of petroleum origin.
  • Vegetable modified modified fats include modified vegetable oils, for example modified peanut, olive, sesame, soy, wheat germ, sunflower seed castor, linseed, soybean, corn, copra, palm, walnuts, hazelnuts or rapeseed.
  • Modified fatty substances of animal origin include, for example, modified squalane, modified squalene, modified spermaceti oil or modified tallow oil.
  • modified fatty substances denotes, in particular, carboxylated, sulphated, phosphated or alkoxylated derivatives of fatty substances and more particularly (poly) alkoxylated derivatives of oils or (poly) alkoxylated derivatives of alkyl esters of oils and more particularly, (poly) ethoxylated and / or (poly) propoxylated derivatives of oils or (poly) ethoxylated and / or (poly) propoxylated derivatives of linear or branched, linear or branched or linear butyl, methyl, ethyl, propyl esters of said oils.
  • the invention more specifically relates to a composition as defined above, in which the modified fatty substance is chosen from ethoxylated derivatives of oils having an average degree of ethoxylation of between 1 and 10 (also referred to as the EO between 1 and 10).
  • Modified fatty substances also denote esters of fatty acids and polyols or ethers of fatty alcohols and polyols, and more particularly esters of fatty acids with a hexol, such as, for example, sorbitol or mannitol or esters of fatty acids with a hexol anhydride, such as sorbitan or mannitan, (poly) alkoxylated derivatives of fatty acid esters and polyols or (poly) alkoxylated derivatives of ethers of fatty alcohols and polyols, such as triglycerides of (poly) alkoxylated fatty acids, (poly) alkoxylated polyglycerol esters of
  • fatty acid and polyol esters denotes monoesters of fatty acids and of polyols or polyesters of fatty acids and of polyol, such as for example diesters of fatty acids and of polyols or triesters of fatty acids and polyols. It is the same for (poly) alkoxylated derivatives of said esters.
  • ethers of fatty alcohols and of polyols the term "monoethers of fatty alcohols and polyols or polyethers of fatty alcohols and of polyols such as, for example, the diethers of fatty alcohols, is meant in the context of the present invention.
  • the subject of the invention is more particularly a composition as defined above, in which the modified fatty substances are chosen from (poly) ethoxylated derivatives of fatty acid esters and of polyols or (poly) ethoxylated derivatives of ethers.
  • fatty alcohols and polyols and more particularly, the (poly) ethoxylated esters of fatty acids with glycerol with a hexol, such as for example sorbitol or mannitol or (poly) ethoxylated esters of fatty acids with a hexol anhydride, such as sorbitan or mannitan having an average degree of ethoxylation of between 5 and 10 (also referred to as an EO value between 5 and 10).
  • the (poly) ethoxylated esters of fatty acids with glycerol with a hexol such as for example sorbitol or mannitol
  • (poly) ethoxylated esters of fatty acids with a hexol anhydride such as sorbitan or mannitan having an average degree of ethoxylation of between 5 and 10 (also referred to as an EO value between 5 and 10).
  • Suitable fatty acids for the preparation of the modified fatty substances described above are those containing on average from 12 to 22 carbon atoms, for example those containing from 16 to 18 carbon atoms, such as oleic acid, ricinoleic acid, hydroxy stearic acid or isostearic acid and advantageously fatty acids that are liquid at 20 ° C.
  • the surfactant or the mixture of surfactants present in the fatty phase essentially consists of one or more esters chosen from the mannitan esters, the sorbitan esters, the mannitan esters. (poly) alkoxylated or (poly) alkoxylated sorbitan esters.
  • the surfactant present in the fatty phase consists of a mixture of mannitan oleate and (poly) ethoxylated mannitan oleate, a mixture of sorbitan oleate and sorbitan oleate (poly) ethoxylated, a mixture of sorbitan oleate and (poly) ethoxylated mannitan oleate or a mixture of mannitan oleate and (poly) ethoxylated sorbitan oleate, said mixtures having an overall HLB number is greater than or equal to 3 and less than 8.
  • the surfactant or the mixture of surfactants present in the fatty phase consists essentially of one or more compounds selected from lecithins, such as soy or egg lecithins, hydrogenated lecithins, phospholipids or sphingolipids.
  • lecithins such as soy or egg lecithins, hydrogenated lecithins, phospholipids or sphingolipids.
  • the composition as defined above comprises, for 100% of its mass, generally up to 50% by weight of aqueous phase, the aqueous phase consisting of water or any bioavailable aqueous solvent, such as water buffered with phosphate buffer added to the hydrophilic active ingredient (s) to be injected;
  • the composition as defined above is implemented in a curative therapeutic treatment method.
  • Suitable hydrophilic active ingredients for such an injectable formulation are, for example, water-soluble anti-cancer active ingredients, hormones, antibiotics, antivirals, analgesic agents, vasodilators, antidiabetic agents, anesthetics, sedatives, agents and the like.
  • the subject of the invention is a method for preparing a composition as defined above, characterized in that it comprises the following successive stages:
  • the subject of the invention is a method for allowing the prolonged release into the human or animal body of an active ingredient characterized in that said active ingredient is administered by injection in the form of a water-in-oil emulsion such as than previously defined.
  • an active ingredient characterized in that said active ingredient is administered by injection in the form of a water-in-oil emulsion such as than previously defined.
  • the caffeine is dissolved beforehand at the desired concentration, in particular of 1 mg / ml, but more generally from 0.1 to 10 mg / ml, in physiological saline, the necessary quantities of oil and the necessary surfactants are put under stirring until a homogeneous mixture.
  • the proportions of fatty phase (oil plus surfactants) and of aqueous caffeine solution are maintained equal to 70% of fatty phase and 30% by weight of aqueous phase.
  • the aqueous phase is poured onto the oily phase and the stirring is maintained for 3 minutes by means of a stator rotor stator of the laboratory type.
  • Silverson TM L4R Six samples of W / O emulsions were prepared with caffeine as the hydrophilic active principle and the ingredients indicated in the following tables: The surfactant mixtures used are characterized by their physicochemical specifications as indicated in the table below.
  • the caffeine emulsions obtained have the following characteristics: 2 - In vitro evaluation of emulsions in their ability to prolonged release of active principles
  • the results obtained are recorded in the following table in terms of percentage of caffeine released:
  • the pharmacokinetics of caffeine were evaluated in four groups of 4 animals by subcutaneous injection of emulsions No. 1 and 2, a physiological solution of caffeine (SC solution) and a physiological solution of intravenous caffeine (Solution IV). For these four groups, the dose of caffeine injected is
  • the concentration of caffeine in the blood is periodically determined (in ⁇ g / ml of blood) and the following results are obtained:
  • A.U.C. Area Under the Curve, that is the measurement of the area under the curve plotted by placing the abscissa duration (in hours, h) and the ordinate the concentration in ⁇ g / mL of blood.
  • the absorption phase of the caffeine emulsion is three times slower and the time to reach the maximum plasma concentration is delayed by one hour.
  • the maximum plasma concentrations obtained with the emulsions according to the invention are reduced by 20% to 35% of those obtained with the caffeine solution.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composition for the implementation of a therapeutic method for the human or animal body, comprising a fatty phase (O) and an aqueous phase (W), in the form of an 5 emulsion of the water-in-oil (W/O) type, in which said aqueous phase (W) comprises at least one hydrosoluble active ingredient, characterized in that said composition has a viscosity, measured at 25 °C in a 250-cm3 beaker having a diameter of about 7 cm, using a Brookfield LVT viscosimeter equipped with a No. 2 spindle turning at a speed of 30 or 60 revolutions per minute, of less than or equal to 10 [sic] 2000 mPas, and preferably less than 200 mPas.

Description

Formulation injectable à libération prolongée de principes actifs, procédé pour sa préparation Injection formulation with sustained release of active ingredients, process for its preparation
L'invention se rapporte à une nouvelle formulation de principes actifs pharmaceutiques ou vétérinaires, destinée à favoriser leur libération dans le corps humain ou animal, de façon prolongée dans le temps.The invention relates to a novel formulation of pharmaceutical or veterinary active ingredients, intended to promote their release into the human or animal body, over a prolonged period of time.
La libération prolongée de médicaments est une méthode qui permet de prolonger dans le temps les effets thérapeutiques d'un principe actif, d'en réduire les effets secondaires et de minimiser les risques liés au dépassement temporaire du seuil de toxicité chez le patient. De nombreuses formulations permettant la libération prolongée de médicaments par voie orale, topique ou injectables ont été décrites dans la littérature. Parmi ces dernières, on distingue les formes injectables solides et les formes injectables liquides.The prolonged release of drugs is a method that allows the therapeutic effects of an active ingredient to be prolonged over time, to reduce the side effects and to minimize the risks associated with temporarily exceeding the threshold of toxicity in the patient. Many formulations for the sustained release of oral, topical or injectable drugs have been described in the literature. Among these, there are solid injectable forms and liquid injectable forms.
Les formes injectables solides sont des suspensions de microbilles ou de nanobilles, dont le diamètre moyen est compris entre 0,01 μm et 100 μm, dans une solution aqueuse isotonique. De telles suspensions ont souvent tendance à sédimenter et sont donc peu stables au stockage et l'homogénéité du médicament n'est pas toujours garantie, ce qui peut poser des problèmes pour assurer l'administration d'une dose précise de principe actif au patient. Les microbilles ou les nanobilles de ces suspensions sont généralement constituées de polymères biodégradables comme les copolymères d'acide lactique et/ou d'acide glycolique, tels que décrits dans la demande de brevet américain publiée sous le numéro 2005/048115 Al. Des inconvénients majeurs dans la mise en œuvre de ces microbilles ou de ces nanobilles sont l'utilisation de solvants organiques volatiles dangereux pour la santé humaine pour les préparer ainsi que la présence résiduelle de monomères toxiques dans la formulation finale. D'autres auteurs ont décrit des microbilles de corps gras, solides à température ambiante comme vecteurs de principe actif injectable, comme celles décrites la demande internationale publiée sous le numéro WO 94/26252. Dans ce cas, les inconvénients résident dans le fait que les suspensions ne peuvent être que faiblement chargées en microbilles, donc en principe actif, pour rester fluides et injectables. De plus des modifications de la forme cristalline des corps gras au cours du temps, ou pendant le stockage à froid, ont été observées, ce qui entraîne des profils de libération insatisfaisants des principes actifs également décrits. Enfin, de telles microbilles ne peuvent être mises en œuvre qu'avec des principes actifs lipophiles. Les formes injectables liquides, stables, homogènes et fluides, sont préférées pour une administration par voie injectable. Une forme particulièrement utile est l'émulsion, qui est un mélange d'une phase aqueuse et d'une phase lipidique liquide, stabilisé par des agents tensioactifs. Lorsque la phase lipidique est dispersée dans la phase aqueuse, on obtient une émulsion de type «huile - dans-eau », notée H/E. De telles émulsions sont utilisées depuis longtemps pour l'alimentation parentérale et ont été aussi proposées pour l'injection de principes actifs lipophiles pour en assurer une libération prolongée dans le corps humain. Cependant de telles émulsions mettent en œuvre des phases grasses telles que les huiles végétales, les triglycérides à chaînes moyennes qui ont un pouvoir solvant faible et ne permettent de solubiliser que de faibles quantités de médicaments bien choisis.Solid injectable forms are suspensions of microbeads or nanobeads, the average diameter of which is between 0.01 μm and 100 μm, in an isotonic aqueous solution. Such suspensions often tend to sediment and are therefore not very stable storage and homogeneity of the drug is not always guaranteed, which can cause problems to ensure the administration of a specific dose of active ingredient to the patient. The microbeads or nanobeads of these suspensions generally consist of biodegradable polymers such as copolymers of lactic acid and / or glycolic acid, as described in the United States patent application published under the number 2005/048115 A1. Major drawbacks in the implementation of these microbeads or nanobeads are the use of volatile organic solvents dangerous to human health to prepare them and the residual presence of toxic monomers in the final formulation. Other authors have described microbeads of fatty substances, solid at room temperature as injectable active agent vectors, such as those described in the international application published under the number WO 94/26252. In this case, the disadvantages lie in the fact that the suspensions can only be weakly loaded with microbeads, so active ingredient, to remain fluid and injectable. In addition, modifications of the crystalline form of the fatty substances over time, or during cold storage, have been observed, which results in unsatisfactory release profiles of the active principles also described. Finally, such microbeads can only be used with lipophilic active principles. Liquid injectable forms, stable, homogeneous and fluid, are preferred for administration by injection. A particularly useful form is the emulsion, which is a mixture of an aqueous phase and a liquid lipid phase, stabilized with surfactants. When the lipid phase is dispersed in the aqueous phase, an "oil-in-water" emulsion, denoted H / E, is obtained. Such emulsions have long been used for parenteral nutrition and have also been proposed for the injection of lipophilic active principles to ensure prolonged release into the human body. However, such emulsions use fatty phases such as vegetable oils, medium chain triglycerides which have a low solvent power and solubilize only small amounts of well-chosen drugs.
La majorité des principes actifs étant soluble dans l'eau, on a essayé d'utiliser des émulsions de type « eau dans huile », notées E/H, pour lesquelles la phase aqueuse est dispersée dans une phase lipidique qui joue le rôle de barrière ou de membrane, isolant le médicament des fluides biologiques du corps humain et permettant sa libération progressivement dans le temps. Cependant les émulsions de type « eau dans huile » sont souvent trop visqueuses et sont donc difficiles à injecter par seringues ; lorsqu'elles sont injectées, elles provoquent des réactions locales au site d'injection, dues à la fois à la viscosité et à la nature huileuse de la phase continue ; enfin elles sont peu stables dans le temps.The majority of the active ingredients being soluble in water, it was tried to use emulsions of "water-in-oil" type, denoted E / H, for which the aqueous phase is dispersed in a lipid phase which acts as a barrier or membrane, isolating the drug from biological fluids of the human body and allowing its release gradually over time. However, "water-in-oil" type emulsions are often too viscous and are therefore difficult to inject by syringes; when injected, they cause local reactions at the injection site, due to both the viscosity and the oily nature of the continuous phase; finally they are not stable in time.
La demande internationale publiée sous le numéro WO 02/067899 divulgue des compositions sous forme d'émulsions eau dans huile (E/H) pour vaccins, ayant une viscosité de préférence inférieure à 100 mPas, dans lesquelles l'agent émulsionnant est par exemple l'ARCACEL™ P135 [émulsionnant polyesters de type poly(acide 12- hydroxystéarique)] dans lesquelles les la phase aqueuse comprend au moins un principe actif hydrosoluble.The international application published under the number WO 02/067899 discloses compositions in the form of water-in-oil (W / O) emulsions for vaccines, having a viscosity of preferably less than 100 mPas, in which the emulsifying agent is, for example, ARCACEL ™ P135 [poly (12-hydroxystearic acid)] polyester-type emulsifiers in which the aqueous phase comprises at least one water-soluble active principle.
La demande internationale publiée sous le numéro WO 96/40057 divulgue un médicament sous forme d'une émulsion inverse de type eau dans huile, de faible viscosité, la phase grasse comprenant une huile fluorocarbonée, et la phase aqueuse au moins un principe actif.The international application published under the number WO 96/40057 discloses a drug in the form of a water-in-oil inverse emulsion of low viscosity, the fatty phase comprising a fluorocarbon oil, and the aqueous phase at least one active ingredient.
C'est pourquoi les inventeurs se sont attachés à mettre au point une émulsion eau dans huile de principes actifs qui n'aient pas les inconvénients exposés ci-dessus.This is why the inventors have endeavored to develop a water-in-oil emulsion of active ingredients that do not have the disadvantages described above.
Selon un premier aspect, l'invention a pour objet une Composition pour la mise en œuvre d'une méthode thérapeutique du corps humain ou animal, comprenant une phase grasse (H) et une phase aqueuse (E), sous forme d'une émulsion de type eau - dans - huile (E/H) injectable dans ledit corps humain ou animal, dans laquelle ladite phase aqueuse (E) comprend au moins un principe actif hydrosoluble pharmaceutique ou vétérinaire, caractérisée en ce que ladite phase grasse (H) comprend un ou plusieurs agents tensioactifs ayant un nombre HLB global compris entre 3 et 8, choisis parmi les esters d'acides gras avec le sorbitol ou le mannitol ou les esters d'acides gras avec le sorbitane ou le mannitane, les triglycérides d'acides gras (poly)alcoxylés, les esters (poly)alcoxylés de polyglycérol d'acides gras et ladite composition a une viscosité mesurée à 25°C dans un bêcher de 250 cm3 ayant un diamètre de 7 cm environ, au moyen d'un viscosimètre Brookfield LVT équipé d'un mobile N°2 tournant à la vitesse de 30 ou de 60 tours par minute, inférieure ou égale à 200 mPas.According to a first aspect, the subject of the invention is a composition for the implementation of a therapeutic method of the human or animal body, comprising a fat phase (H) and an aqueous phase (E), in the form of a water - in - oil (W / O) type emulsion injectable in said human or animal body, wherein said aqueous phase (E) comprises at least a water-soluble pharmaceutical or veterinary active ingredient, characterized in that said fatty phase (H) comprises one or more surfactants having an overall HLB number of between 3 and 8, chosen from fatty acid esters with sorbitol or mannitol or esters of fatty acids with sorbitan or mannitane, triglycerides of (poly) alkoxylated fatty acids, (poly) alkoxylated polyglycerol esters of fatty acids and said composition has a viscosity measured at 25 ° C. in a beaker of 250 cm 3 having a diameter of about 7 cm, using a Brookfield LVT viscometer equipped with a mobile No. 2 rotating at a speed of 30 or 60 revolutions per minute, less than or equal to 200 mPas.
Au sens de la présente invention, le nombre HLB d'un tensioactif de la famille des esters d'acide gras est calculé par la formule HLB = 20 (1-I/Ia), dans laquelle Is représente l'indice de saponification et Ia, l'indice d'acide dudit tensioactif. Ces deux indices, de saponification et d'acide, sont déterminés par des méthodes décrites dans la Pharmacopée européenne. Le nombre HLB des tensioactifs faisant partie d'une autre famille chimique est calculé par la formule générale HLB= 5E/M où E représente la masse molaire de la partie hydrophile du tensioactif et M la masse molaire totale dudit tensioactif. Dans le cas d'un mélange de tensioactifs, le HLB global du mélange est la somme pondérée des HLB de chaque tensioactif.For the purpose of the present invention, the HLB number of a surfactant of the family of fatty acid esters is calculated by the formula HLB = 20 (1-I / Ia), in which I s represents the saponification number and I a , the acid number of said surfactant. These two indices, saponification and acid, are determined by methods described in the European Pharmacopoeia. The HLB number of the surfactants belonging to another chemical family is calculated by the general formula HLB = 5E / M where E represents the molar mass of the hydrophilic part of the surfactant and M the total molar mass of said surfactant. In the case of a mixture of surfactants, the overall HLB of the mixture is the weighted sum of the HLBs of each surfactant.
La phase grasse constitutive de la composition objet de la présente invention, qui doit être liquide à 4°C, comprend généralement un ou plusieurs composés choisis parmi les huiles d'origine minérale, végétale ou animale, les esters alkyliques desdites huiles, les esters alkyliques d'acides gras ou les éthers alkyliques d'alcools gras, les esters d'acides gras et de polyols ou les éthers d'alcools gras et de polyols.The constituent fatty phase of the composition which is the subject of the present invention, which must be liquid at 4 ° C., generally comprises one or more compounds chosen from oils of mineral, vegetable or animal origin, the alkyl esters of the said oils and the alkyl esters. of fatty acids or alkyl ethers of fatty alcohols, esters of fatty acids and polyols or ethers of fatty alcohols and polyols.
Comme exemples d'huile d'origine minérale, il y a les huiles d'origine pétrolière, comme les huiles blanches minérales, telles que le MARCOL™ 52, le MARCOL™ 82 ou le DRAKEOL™ 6 VR. Comme exemples d'huiles d'origine végétale, il y a l'huile d'arachide, l'huile d'olive l'huile de sésame, l'huile de soja, l'huile de germes de blé, l'huile de pépins de raisin, l'huile de tournesol, l'huile de ricin, l'huile de lin, l'huile de soja, l'huile de maïs, l'huile de coprah, l'huile de palme, l'huile de noix, l'huile de noisette, l'huile de colza ou encore le squalane ou le squalène d'olive. Comme exemples d'huiles d'origine animale, il y a l'huile de spermaceti, l'huile de suif, le squalane ou le squalène extraits des foies de requins ou les huiles de poissons. Comme exemples d'esters alkyliques d'huiles, il y a les esters méthyliques éthyliques, propyliques linéaires ou ramifiés ou butyliques, linéaires ou ramifiés, desdites huiles.Examples of oil of mineral origin are petroleum oils, such as mineral white oils, such as MARCOL ™ 52, MARCOL ™ 82 or DRAKEOL ™ 6 VR. Examples of vegetable oils include peanut oil, olive oil sesame oil, soybean oil, wheat germ oil, coconut oil, grape seed, sunflower oil, castor oil, linseed oil, soybean oil, corn oil, coconut oil, palm oil, nuts, hazelnut oil, rapeseed oil or squalane or olive squalene. Examples of oils of animal origin are spermaceti oil, tallow oil, squalane or squalene extracted from shark livers or fish oils. As examples of alkyl esters of oils, there are linear or branched or linear butyl, linear or branched methyl, propyl esters of said oils.
Comme acides gras appropriés à la préparation des esters cités ci-dessus, il y a plus particulièrement, ceux comportant de 12 à 22 atomes de carbone, tels que par exemple, l'acide myristique, l'acide palmitique, l'acide oléique, l'acide ricinoléique ou l'acide isostéarique et avantageusement un acide gras liquide à 200C.As fatty acids suitable for the preparation of the esters mentioned above, there are more particularly those having from 12 to 22 carbon atoms, such as, for example, myristic acid, palmitic acid, oleic acid, ricinoleic acid or isostearic acid and preferably a fatty acid liquid at 20 ° C.
Comme exemples d'esters d'acides gras ou d'éthers d'alcools gras, il y a les esters alkyliques d'acides gras, tels que, l'oléate d'éthyle, l'oléate de méthyle, le myristate d'isopropyle ou le palmitate d'octyle, les esters d'acides gras et de polyols ou les éthers d'alcools gras et de polyols, tels que les monoglycérides d'acides gras, les diglycérides d'acides gras, les triglycérides d'acides gras, les esters d'acides gras avec un polyglycérol ou les esters d'acides gras et de propylèneglycol, et plus particulièrement les esters d'acides gras avec un hexol, tel que par exemple le sorbitol ou le mannitol, les esters d'acides gras avec un anhydride d'hexol, comme le sorbitan ou le mannitan.Examples of fatty acid esters or fatty alcohol ethers are alkyl esters of fatty acids, such as ethyl oleate, methyl oleate, isopropyl myristate, and the like. or octyl palmitate, esters of fatty acids and polyols or ethers of fatty alcohols and polyols, such as monoglycerides of fatty acids, diglycerides of fatty acids, triglycerides of fatty acids, fatty acid esters with a polyglycerol or esters of fatty acids and of propylene glycol, and more particularly esters of fatty acids with a hexol, such as for example sorbitol or mannitol, esters of fatty acids with a hexol anhydride, such as sorbitan or mannitan.
Dans le cadre de la présente invention, la phase grasse peut comprendre un seul des composés cités ci-dessus ou bien un mélange de plusieurs des composés cités ci- dessus.In the context of the present invention, the fatty phase may comprise only one of the compounds mentioned above or a mixture of several of the compounds mentioned above.
Selon un premier aspect particulier de la présente invention, la phase grasse (H) constitutive de la composition pharmaceutique est choisie parmi les huiles blanches minérales, les huiles de paraffine fluides, le squalane, le squalène, l'oléate d'éthyle ou un mélange de ces huiles.According to a first particular aspect of the present invention, the fatty phase (H) constituting the pharmaceutical composition is chosen from mineral white oils, liquid paraffin oils, squalane, squalene, ethyl oleate or a mixture of these oils.
La phase grasse comprend pour 100% de sa masse, environ entre 1% et 15% massique, de préférence entre 3% et 10% massique d'agents tensioactifs. L'invention a plus particulièrement pour objet, une composition telle que définie précédemment dans laquelle l'agent tensioactif ou le mélange d'agents tensioactifs a un nombre HLB global est supérieur ou égal à 5 et inférieur à 8.The fatty phase comprises, for 100% of its mass, approximately between 1% and 15% by weight, preferably between 3% and 10% by weight of surfactants. The invention more particularly relates to a composition as defined above in which the surfactant or the mixture of surfactants has an overall HLB number greater than or equal to 5 and less than 8.
Les agents tensioactifs mis en œuvre sont généralement choisis parmi les corps gras modifiés. Les corps gras modifiés utilisés dans le cadre de la présente invention, peuvent être d'origine minérale végétale ou animale. Comme corps gras modifiés d'origine minérale, il y a les huiles d'origine pétrolière. Comme corps gras modifiés d'origine végétale, il y a les huiles végétales modifiées, par exemple, les huiles modifiées d'arachide, d'olive, de sésame, de soja, de germes de blé, de pépins de raisin de tournesol, de ricin, de lin, de soja, de maïs, de coprah, de palme, de noix, de noisettes ou de colza. Comme corps gras modifiés d'origine animale, il y a par exemple le squalane modifié, le squalène modifié, l'huile modifiée de spermaceti ou l'huile modifiée de suif. Par corps gras modifiés, on désigne notamment les dérivés carboxylés, sulfatés, phosphatés ou alcoxylés de corps gras et plus particulièrement les dérivés (poly)alcoxylés d'huiles ou les dérivés (poly)alcoxylés d'esters alkyliques d'huiles et plus particulièrement, les dérivés (poly)éthoxylés et/ou (poly)propoxylés d'huiles ou les dérivés (poly)éthoxylés et/ou (poly)propoxylés des esters méthyliques, éthyliques, propyliques linéaires ou ramifiés ou butyliques, linéaires ou ramifiés, desdites huiles.The surfactants used are generally chosen from modified fatty substances. The modified fatty substances used in the context of the present invention may be of plant or animal mineral origin. As mineral modified fatty substances, there are oils of petroleum origin. Vegetable modified modified fats include modified vegetable oils, for example modified peanut, olive, sesame, soy, wheat germ, sunflower seed castor, linseed, soybean, corn, copra, palm, walnuts, hazelnuts or rapeseed. Modified fatty substances of animal origin include, for example, modified squalane, modified squalene, modified spermaceti oil or modified tallow oil. The term "modified fatty substances" denotes, in particular, carboxylated, sulphated, phosphated or alkoxylated derivatives of fatty substances and more particularly (poly) alkoxylated derivatives of oils or (poly) alkoxylated derivatives of alkyl esters of oils and more particularly, (poly) ethoxylated and / or (poly) propoxylated derivatives of oils or (poly) ethoxylated and / or (poly) propoxylated derivatives of linear or branched, linear or branched or linear butyl, methyl, ethyl, propyl esters of said oils.
L'invention a plus spécifiquement pour objet une composition telle que définie précédemment, dans laquelle le corps gras modifié est choisi parmi les dérivés éthoxylés d'huiles ayant un degré moyen d'éthoxylation compris entre 1 et 10 (désigné aussi par indice d'OE compris entre 1 et 10). Par corps gras modifiés on désigne aussi, les esters d'acides gras et de polyols ou les éthers d'alcools gras et de polyols, et plus particulièrement, les esters d'acides gras avec un hexol, tel que par exemple le sorbitol ou le mannitol ou les esters d'acides gras avec un anhydride d'hexol, comme le sorbitan ou le mannitan, les dérivés (poly)alcoxylés d'esters d'acides gras et de polyols ou les dérivés (poly)alcoxylés d'éthers d'alcools gras et de polyols, comme les triglycérides d'acides gras (poly)alcoxylés, les esters (poly)alcoxylés de polyglycérol d'acides gras, et plus particulièrement les esters (poly)alcoxylés d'acides gras avec un hexol, tel que par exemple le sorbitol ou le mannitol ou les esters (poly)alcoxylés d'acides gras avec un anhydride d'hexol, comme le sorbitan ou le mannitan ayant un degré moyen d'éthoxylation compris entre 1 et 40 (désigné aussi par indice d'OE compris entre 1 et 40), de préférence entre 5 et 20.The invention more specifically relates to a composition as defined above, in which the modified fatty substance is chosen from ethoxylated derivatives of oils having an average degree of ethoxylation of between 1 and 10 (also referred to as the EO between 1 and 10). Modified fatty substances also denote esters of fatty acids and polyols or ethers of fatty alcohols and polyols, and more particularly esters of fatty acids with a hexol, such as, for example, sorbitol or mannitol or esters of fatty acids with a hexol anhydride, such as sorbitan or mannitan, (poly) alkoxylated derivatives of fatty acid esters and polyols or (poly) alkoxylated derivatives of ethers of fatty alcohols and polyols, such as triglycerides of (poly) alkoxylated fatty acids, (poly) alkoxylated polyglycerol esters of fatty acids, and more particularly (poly) alkoxylated esters of fatty acids with a hexol, such as for example, sorbitol or mannitol or (poly) alkoxylated esters of fatty acids with a hexol anhydride, such as sorbitan or mannitan having an average degree of ethoxylation of from 1 to 40 (also referred to as OE between 1 and 40), preferably between 5 and 20.
Par esters d'acides gras et de polyols, on désigne dans le cadre de la présente invention, les monoesters d'acides gras et de polyols ou les polyesters d'acides gras et de polyol tels que par exemple les diesters d'acides gras et de polyols ou les triesters d'acides gras et de polyols. Il en est de même pour les dérivés (poly)alcoxylés desdits esters.For the purposes of the present invention, the term "fatty acid and polyol esters" denotes monoesters of fatty acids and of polyols or polyesters of fatty acids and of polyol, such as for example diesters of fatty acids and of polyols or triesters of fatty acids and polyols. It is the same for (poly) alkoxylated derivatives of said esters.
Par éthers d'alcools gras et de polyols, on désigne dans le cadre de la présente invention, les monoéthers d'alcools gras et de polyols ou les polyéthers d'alcools gras et de polyol tels que par exemple les diéthers d'alcools gras et de polyols ou les triéthers d'acides gras et de polyols. Il en est de même pour les dérivés (poly)alcoxylés desdits éthers. L'invention a plus particulièrement pour objet une composition telle que définie précédemment, dans laquelle les corps gras modifiés sont choisis parmi les dérivés (poly)éthoxylés d'esters d'acides gras et de polyols ou les dérivés (poly)éthoxylés d'éthers d'alcools gras et de polyols, et plus particulièrement, les esters (poly)éthoxylés d'acides gras avec le glycérol avec un hexol, tel que par exemple le sorbitol ou le mannitol ou les esters (poly)éthoxylés d'acides gras avec un anhydride d'hexol, comme le sorbitan ou le mannitan ayant un degré moyen d'éthoxylation compris entre 5 et 10 (désigné aussi par indice d'OE compris entre 5 et 10).By ethers of fatty alcohols and of polyols, the term "monoethers of fatty alcohols and polyols or polyethers of fatty alcohols and of polyols such as, for example, the diethers of fatty alcohols, is meant in the context of the present invention. polyols or triethers of fatty acids and polyols. It is the same for (poly) alkoxylated derivatives of said ethers. The subject of the invention is more particularly a composition as defined above, in which the modified fatty substances are chosen from (poly) ethoxylated derivatives of fatty acid esters and of polyols or (poly) ethoxylated derivatives of ethers. fatty alcohols and polyols, and more particularly, the (poly) ethoxylated esters of fatty acids with glycerol with a hexol, such as for example sorbitol or mannitol or (poly) ethoxylated esters of fatty acids with a hexol anhydride, such as sorbitan or mannitan having an average degree of ethoxylation of between 5 and 10 (also referred to as an EO value between 5 and 10).
Comme acides gras appropriés à la préparation des corps gras modifiés décrits ci-dessus, il y a ceux comportant en moyenne de 12 à 22 atomes de carbone, tels que par exemple, ceux comportant de 16 à 18 atomes de carbone, comme l'acide oléique, l'acide ricinoléique, l'acide hydroxy stéarique ou l'acide isostéarique et avantageusement les acides gras liquides à 20 0C. La composition, telle que définie ci-dessus, contient plus particulièrement un ou plusieurs corps gras modifiés tels que décrits ci-dessus, dérivés de l'acide oléique.Suitable fatty acids for the preparation of the modified fatty substances described above are those containing on average from 12 to 22 carbon atoms, for example those containing from 16 to 18 carbon atoms, such as oleic acid, ricinoleic acid, hydroxy stearic acid or isostearic acid and advantageously fatty acids that are liquid at 20 ° C. The composition, as defined above, more particularly contains one or more modified fatty substances as described above, derivatives of oleic acid.
Selon un autre aspect particulier de la présente invention, l'agent tensioactif ou le mélange d'agents tensioactifs présents dans la phase grasse, consiste essentiellement en un ou plusieurs esters choisis parmi les esters de mannitan, les esters de sorbitan, les esters de mannitan (poly)alcoxylés ou les esters de sorbitan (poly)alcoxylés. De façon toute particulière, l'agent tensioactif présent dans la phase grasse consiste en un mélange d'oléate de mannitan et d'oléate de mannitan (poly)éthoxylé, un mélange d'oléate de sorbitan et d'oléate de sorbitan (poly)éthoxylé, un mélange d'oléate de sorbitan et d'oléate de mannitan (poly)éthoxylé ou un mélange d'oléate de mannitan et d'oléate de sorbitan (poly)éthoxylé, lesdits mélanges ayant un nombre HLB global est supérieur ou égal à 3 et inférieur à 8.According to another particular aspect of the present invention, the surfactant or the mixture of surfactants present in the fatty phase essentially consists of one or more esters chosen from the mannitan esters, the sorbitan esters, the mannitan esters. (poly) alkoxylated or (poly) alkoxylated sorbitan esters. More particularly, the surfactant present in the fatty phase consists of a mixture of mannitan oleate and (poly) ethoxylated mannitan oleate, a mixture of sorbitan oleate and sorbitan oleate (poly) ethoxylated, a mixture of sorbitan oleate and (poly) ethoxylated mannitan oleate or a mixture of mannitan oleate and (poly) ethoxylated sorbitan oleate, said mixtures having an overall HLB number is greater than or equal to 3 and less than 8.
Selon un autre aspect particulier de la présente invention, l'agent tensioactif ou le mélange d'agents tensioactifs présent dans la phase grasse, consiste essentiellement en un ou plusieurs composés choisis parmi les lécithines, comme les lécithines de soja ou d'œuf, les lécithines hydrogénées, les phospho lipides ou les sphingolipides. La composition telle que définie précédemment comprend pour 100% de sa masse généralement jusqu'à 50% massique de phase aqueuse, la phase aqueuse consistant en de l'eau ou tout solvant aqueux bio-disponible, tel que l'eau tamponnée au tampon phosphate additionnée du ou des principes actifs hydrophiles à injecter; De préférence la composition telle que définie précédemment est mise en œuvre dans une méthode de traitement thérapeutique curative. Comme principes actifs hydrophiles appropriés à une telle formulation injectable, il y a par exemple les principes actifs anticancéreux hydrosolubles, les hormones, les antibiotiques, les antiviraux, les actifs analgésiques, les vasodilatateurs, les actifs antidiabétiques, les anesthésiques, les sédatifs, les agents de contraste, les immunomodulateurs, les facteurs anti-hémophiliques, les neuroleptiques, les actifs de nutrition, les stéroïdes, les thrombolytiques ou les actifs biopharmaceutiques comme les protéines recombinantes.According to another particular aspect of the present invention, the surfactant or the mixture of surfactants present in the fatty phase consists essentially of one or more compounds selected from lecithins, such as soy or egg lecithins, hydrogenated lecithins, phospholipids or sphingolipids. The composition as defined above comprises, for 100% of its mass, generally up to 50% by weight of aqueous phase, the aqueous phase consisting of water or any bioavailable aqueous solvent, such as water buffered with phosphate buffer added to the hydrophilic active ingredient (s) to be injected; Preferably the composition as defined above is implemented in a curative therapeutic treatment method. Suitable hydrophilic active ingredients for such an injectable formulation are, for example, water-soluble anti-cancer active ingredients, hormones, antibiotics, antivirals, analgesic agents, vasodilators, antidiabetic agents, anesthetics, sedatives, agents and the like. immunomodulators, anti-hemophilic factors, neuroleptics, nutritional agents, steroids, thrombolytics or biopharmaceuticals such as recombinant proteins.
Selon un autre aspect, l'invention a pour objet un procédé de préparation d'une composition telle que définie précédemment, caractérisé en ce qu'il comprend les étapes successives suivantes :According to another aspect, the subject of the invention is a method for preparing a composition as defined above, characterized in that it comprises the following successive stages:
Une étape (a) de dissolution du principe hydrophile dans l'eau ou le solvant aqueux pharmacologiquement acceptable ;A step (a) of dissolving the hydrophilic principle in water or the pharmacologically acceptable aqueous solvent;
Une étape b) de mélange de la phase aqueuse préparée à l'étape (a) avec une phase grasse contenant un tensioactif ou un mélange de tensioactifs.A step b) of mixing the aqueous phase prepared in step (a) with a fatty phase containing a surfactant or a mixture of surfactants.
Selon un dernier aspect, l'invention a pour objet un procédé pour permettre la libération prolongée dans le corps humain ou animal d'un principe actif caractérisé en ce que ledit principe actif est administré par injection sous forme d'une émulsion eau dans huile telle que définie précédemment. Les exemples suivants illustrent l'invention sans toutefois la limiter.According to a last aspect, the subject of the invention is a method for allowing the prolonged release into the human or animal body of an active ingredient characterized in that said active ingredient is administered by injection in the form of a water-in-oil emulsion such as than previously defined. The following examples illustrate the invention without limiting it.
1 - Préparation d'émulsions E / H de caféine1 - Preparation of caffeine W / O emulsions
La caféine est préalablement dissoute à la concentration souhaitée, en particulier de 1 mg/mL, mais plus généralement de 0,1 à 10 mg/mL, dans l'eau physiologique, les quantités nécessaires d'huile et de tensioactifs nécessaires sont mises sous agitation jusqu'à obtenir un mélange homogène. Dans tous les exemples décrits, les proportions de phase grasse (huile plus tensioactifs) et de solution aqueuse de caféine sont maintenues égales à 70% de phase grasse et 30% massique de phase aqueuse. Pour réaliser l'émulsion, on verse la phase aqueuse sur la phase huileuse et l'agitation maintenu pendant 3 minutes au moyen d'un agitateur rotor stator de laboratoire de typeThe caffeine is dissolved beforehand at the desired concentration, in particular of 1 mg / ml, but more generally from 0.1 to 10 mg / ml, in physiological saline, the necessary quantities of oil and the necessary surfactants are put under stirring until a homogeneous mixture. In all the examples described, the proportions of fatty phase (oil plus surfactants) and of aqueous caffeine solution are maintained equal to 70% of fatty phase and 30% by weight of aqueous phase. To carry out the emulsion, the aqueous phase is poured onto the oily phase and the stirring is maintained for 3 minutes by means of a stator rotor stator of the laboratory type.
Silverson™ L4R. On a préparé six échantillons d'émulsions E/H avec de la caféine comme principe actif hydrophile et les ingrédients indiqués dans les tableaux suivants : Les mélanges de tensioactifs utilisés, sont caractérisés par leurs spécifications physicochimiques comme indiqué dans le tableau ci dessous. Silverson ™ L4R. Six samples of W / O emulsions were prepared with caffeine as the hydrophilic active principle and the ingredients indicated in the following tables: The surfactant mixtures used are characterized by their physicochemical specifications as indicated in the table below.
Les émulsions de caféine obtenues présentent les caractéristiques suivantes : 2 - Evaluation in vitro des émulsions dans leur aptitude à la libération prolongée de principes actifsThe caffeine emulsions obtained have the following characteristics: 2 - In vitro evaluation of emulsions in their ability to prolonged release of active principles
L'échantillon de l'émulsion à évaluer est déposé sur une phase aqueuse dite réceptrice, contenue dans le récipient de l'appareil de dissolution Erweka™ DT 600 ; le tout est mélangé et un échantillon de cette phase est prélevé régulièrement (t = 0, 24 h, 48 h 72 h 96 h), afin d'en doser l'actif libéré dans la phase réceptrice. Les résultats obtenus sont consignés dans le tableau suivant en termes de pourcentage de caféine libérée :The sample of the emulsion to be evaluated is deposited on a so-called aqueous receptor phase, contained in the container of the Erweka ™ DT 600 dissolution apparatus; the whole is mixed and a sample of this phase is taken regularly (t = 0, 24 h, 48 h 72 h 96 h), in order to assay the released active in the receiving phase. The results obtained are recorded in the following table in terms of percentage of caffeine released:
3 - Evaluation in vivo des émulsions selon l'invention, dans leur aptitude à la libération prolongée de principes actifs3 - In vivo evaluation of the emulsions according to the invention, in their ability to prolong the release of active principles
La pharmacocinétique de la caféine a été évaluée sur quatre groupes de 4 animaux par injection sous - cutanée des émulsions N° 1 et 2, d'une solution physiologique de caféine (solution SC) et d'une solution physiologique de caféine par intraveineuse (Solution IV). Pour ces quatre groupes, la dose de caféine injectée est deThe pharmacokinetics of caffeine were evaluated in four groups of 4 animals by subcutaneous injection of emulsions No. 1 and 2, a physiological solution of caffeine (SC solution) and a physiological solution of intravenous caffeine (Solution IV). For these four groups, the dose of caffeine injected is
40 mg/ kg de rat.40 mg / kg of rat.
On détermine périodiquement la concentration en caféine dans le sang (en μg / ml de sang) et l'on obtient les résultats suivants : The concentration of caffeine in the blood is periodically determined (in μg / ml of blood) and the following results are obtained:
Ces résultats conduisent aux données pharmacocinétiques suivantesThese results lead to the following pharmacokinetic data
A.U.C. : Aire sous la courbe (Area Under the Curve en langue anglaise), c'est à dire la mesure de l'aire sous la courbe tracée en plaçant en abscisse la durée (en heure, h) et en ordonnée la concentration en μg/mL de sang.A.U.C. : Area Under the Curve, that is the measurement of the area under the curve plotted by placing the abscissa duration (in hours, h) and the ordinate the concentration in μg / mL of blood.
Les résultats font apparaître que la caféine passe plus lentement dans le sang lorsqu'elle est injectée sous forme d'une emulsion sous-cutanée, par rapport à une solution aqueuse injectée de la même manière, tout en conservant des aires sous courbes équivalentes à celle correspondant à une injection intraveineuse.The results show that caffeine passes more slowly in the blood when injected as a subcutaneous emulsion, compared to an aqueous solution injected in the same way, while maintaining areas under curves equivalent to that corresponding to an intravenous injection.
La phase d'absorption de la caféine en emulsion est trois fois plus lente et le temps pour atteindre la concentration maximale plasmatique est retardé d'une heure. Les concentrations plasmatiques maximales obtenues avec les émulsions selon l'invention, sont diminuées de 20% à 35% de celles obtenues avec la solution de caféine. The absorption phase of the caffeine emulsion is three times slower and the time to reach the maximum plasma concentration is delayed by one hour. The maximum plasma concentrations obtained with the emulsions according to the invention are reduced by 20% to 35% of those obtained with the caffeine solution.

Claims

REVENDICATIONS
1. Composition pour la mise en œuvre d'une méthode thérapeutique du corps humain ou animal, comprenant une phase grasse (H) et une phase aqueuse (E), sous forme d'une émulsion de type eau - dans - huile (E/H) injectable dans ledit corps humain ou animal, dans laquelle ladite phase aqueuse (E) comprend au moins un principe actif hydrosoluble pharmaceutique ou vétérinaire, caractérisée en ce que ladite phase grasse (H) comprend un ou plusieurs agents tensioactifs ayant un nombre HLB global compris entre 3 et 8, choisis parmi les esters d'acides gras avec le sorbitol ou le mannitol ou les esters d'acides gras avec le sorbitane ou le mannitane, les triglycérides d'acides gras (poly)alcoxylés, les esters (poly)alcoxylés de polyglycérol d'acides gras et ladite composition a une viscosité mesurée à 25°C dans un bêcher de 250 cm3 ayant un diamètre de 7 cm environ, au moyen d'un viscosimètre Brookfield LVT équipé d'un mobile N°2 tournant à la vitesse de 30 ou de 60 tours par minute, inférieure ou égale à 200 mPas.1. Composition for the implementation of a therapeutic method of the human or animal body, comprising a fatty phase (H) and an aqueous phase (E), in the form of a water-in-oil emulsion (E / H) injectable in said human or animal body, wherein said aqueous phase (E) comprises at least one water-soluble pharmaceutical or veterinary active ingredient, characterized in that said fatty phase (H) comprises one or more surfactants having a global HLB number between 3 and 8, selected from fatty acid esters with sorbitol or mannitol or esters of fatty acids with sorbitan or mannitane, triglycerides of (poly) alkoxylated fatty acids, esters (poly) alkoxylated polyglycerol fatty acid and said composition has a viscosity measured at 25 ° C in a beaker of 250 cm 3 having a diameter of about 7 cm, using a Brookfield LVT viscometer equipped with a rotating mobile No. 2 at the speed of 30 or 60 rounds per minute, less than or equal to 200 mPas.
2. Composition telle que définie à la revendication 1, dans laquelle ladite phase grasse (H) est choisie parmi les huiles blanches minérales, les huiles de paraffine fluides, le squalane, le squalène, l'oléate d'éthyle ou un mélange de ces huiles.2. The composition as defined in claim 1, wherein said fatty phase (H) is chosen from mineral white oils, liquid paraffin oils, squalane, squalene, ethyl oleate or a mixture thereof. oils.
3. Composition telle que définie à l'une des revendications précédentes, dans laquelle ladite phase grasse (H) comprend pour 100% de sa masse, entre 1 % et 15 % massique et de préférence entre 3 % et 10% massique d'agents tensioactifs.3. Composition as defined in one of the preceding claims, wherein said fatty phase (H) comprises for 100% of its mass, between 1% and 15% by mass and preferably between 3% and 10% by mass of agents. surfactants.
4. Composition telle que définie à la revendication 3, dans laquelle les agents tensioactifs sont choisis parmi les esters d'acide gras et de polyols, en particulier parmi les esters (poly)alcoxylés d'acides gras et de glycérol, de sorbitol ou de mannitol ou les esters (poly)alcoxylés d'acides gras et de sorbitan ou de mannitan ayant un degré moyen d'éthoxylation, compris entre 1 et 40 et de préférence entre 5 et 10.4. The composition as defined in claim 3, wherein the surfactants are chosen from fatty acid esters and polyols, in particular from (poly) alkoxylated esters of fatty acids and of glycerol, of sorbitol or of mannitol or (poly) alkoxylated esters of fatty acids and of sorbitan or mannitan having an average degree of ethoxylation of between 1 and 40 and preferably between 5 and 10.
5. Composition telle que définie à la revendication 4, dans laquelle les agents tensioactifs sont choisis parmi des mélanges d'oléate de mannitane et d'oléate de mannitane (poly)éthoxylé, des mélanges d'oléate de sorbitan et d'oléate de sorbitan (poly)éthoxylé, des mélanges d'oléate de sorbitan et d'oléate de mannitan (poly)éthoxylé ou des mélanges d'oléate de mannitan et d'oléate de sorbitan (poly)éthoxylé, lesdits mélanges ayant un nombre HLB global est supérieur ou égal à 3 et inférieur à 8.5. The composition as defined in claim 4, wherein the surfactants are selected from mixtures of mannitane oleate and (poly) ethoxylated mannitane oleate, mixtures of sorbitan oleate and sorbitan oleate. (poly) ethoxylated, mixtures of sorbitan oleate and (poly) ethoxylated mannitan oleate or mixtures of mannitan oleate and (poly) ethoxylated sorbitan oleate, said mixtures having an overall HLB number of greater than or equal to 3 and less than 8.
6. Composition telle que définie à la revendication 3, dans laquelle les agents tensioactifs sont choisis parmi les lécithines, comme les lécithines de soja ou d'œuf, les lécithines hydrogénées, les phospho lipides ou les sphingolipides.6. The composition as defined in claim 3, wherein the surfactants are chosen from lecithins, such as soy or egg lecithins, hydrogenated lecithins, phospholipids or sphingolipids.
7. Composition telle que définie à l'une quelconque des revendications 1 à 6, caractérisée en ce qu'elle comprend pour 100% de sa masse, au moins 30% massique de phase aqueuse.7. Composition as defined in any one of claims 1 to 6, characterized in that it comprises for 100% of its mass, at least 30% by weight of aqueous phase.
8. Composition telle que définie à l'une quelconque des revendications 1 à 7, caractérisée en ce que le principe actif hydrosoluble est choisi parmi les principes actifs anti - cancéreux, les hormones, les immunomodulateurs, les facteurs anti- hémophiliques, les neuroleptiques, les actifs de nutrition, les stéroïdes, les thrombolytiques ou les actifs pharmaceutiques comme les protéines recombinantes.8. Composition as defined in any one of claims 1 to 7, characterized in that the water-soluble active ingredient is chosen from anti-cancer active ingredients, hormones, immunomodulators, anti-hemophilic factors, neuroleptics, nutrition assets, steroids, thrombolytics or pharmaceutical active ingredients such as recombinant proteins.
9. Procédé de préparation d'une composition telle que définie à l'une quelconque des revendications 1 à 8, caractérisé en ce qu'il comprend les étapes successives suivantes :9. Process for the preparation of a composition as defined in any one of Claims 1 to 8, characterized in that it comprises the following successive stages:
Une étape (a) de dissolution du principe hydrophile dans l'eau ou le solvant aqueux pharmacologiquement acceptable ;A step (a) of dissolving the hydrophilic principle in water or the pharmacologically acceptable aqueous solvent;
Une étape b) de mélange de la phase aqueuse préparée à l'étape (a), avec une phase grasse contenant un tensioactif ou un mélange de tensioactifs. A step b) of mixing the aqueous phase prepared in step (a), with a fatty phase containing a surfactant or a mixture of surfactants.
EP07823540A 2006-07-12 2007-07-03 Injectable slow-release formulation of active ingredients, method for the preparation thereof Withdrawn EP2043605A1 (en)

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FR0652929A FR2903602B1 (en) 2006-07-12 2006-07-12 INJECTABLE FORMULATION WITH PROLONGED RELEASE OF ACTIVE INGREDIENTS, PROCESS FOR PREPARING THE SAME
PCT/FR2007/051584 WO2008007001A1 (en) 2006-07-12 2007-07-03 Injectable slow-release formulation of active ingredients, method for the preparation thereof

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