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)
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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Dispersion Chemistry (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2006
  • 2006-07-12 FR FR0652929A patent/FR2903602B1/fr not_active Expired - Fee Related
• 2007
  • 2007-07-03 EP EP07823540A patent/EP2043605A1/de not_active Withdrawn
  • 2007-07-03 WO PCT/FR2007/051584 patent/WO2008007001A1/fr active Application Filing
  • 2007-07-03 JP JP2009518930A patent/JP2009542782A/ja not_active Withdrawn
  • 2007-07-03 US US12/307,849 patent/US20100048452A1/en not_active Abandoned

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