Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/40—Cyclodextrins; Derivatives thereof
• • 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
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

• lipid formulations are a strategy for formulating the active principles of Classes II and IV.
• emulsions and microemulsions oil in water (O / W) encapsulating and solubilizing insoluble active ingredients, were developed.
• lipid systems as a pharmaceutical form comes from observations made on patients taking their treatment accompanied by high-fat meals. It has actually been reported that the oral bioavailability of lipophilic active ingredients, for example danazol, is increased when the administration of the latter is accompanied by fatty foods. These lipid systems enable among others to extend the gastric emptying time and so promote solubilization and absorption of the active substance in the gastro intestinal ⁇ (Sunesen et al, Journal of Pharmaceutical Sciences .2005;. 24 (4 ): 297-303). Thus, the lipid-based pharmaceutical forms have made it possible very quickly to formulate lipophilic active substances. These forms have particular properties.
• liquid lipid systems in the design of drug formulations for oral administration has become widespread. These formulations are preferred to solid forms such as powders and tablets because they improve the bioavailability of many lipophilic or weakly absorbed active ingredients orally.
• emulsions are more or less viscous liquid forms posing different problems and many studies are moving towards the development of new semi-solid and even solid forms, allowing the use of dry-form technologies (capsules, granules, tablets).
• a dry emulsion is a form of solid (powdery or non-pulverulent), lipid-based, from which an aqueous continuous phase emulsion can be easily reconstituted in contact with water or when administered orally in vivo. It therefore corresponds to a so-called "no water” emulsion obtained either after removal of the free water from a conventional primary emulsion, or by directly mixing a lipid phase and surfactants.
• the dry emulsions represent a smaller volume of administration and allow easier unitary shaping (capsules, tablets) favorable to a better therapeutic observance.
• Dry emulsions improve the well - known instability problems by phase separation: flocculation, coalescence, creaming, sedimentation. They also cause a decrease in lipid oxidation phenomena during manufacture and storage by the elimination of water and a decrease. risks of microbiological contamination.
• NSAIDs nonsteroidal anti-inflammatory drugs
• self-emulsifiable systems improve their gastric tolerance.
• taking oral therapy can improve patient compliance.
• oily continuous phase emulsions each phase of which is adsorbed on a powdered support, of suitable polarity, in order to obtain a free-flowing powder.
• hydrophilic silica is added to adsorb the aqueous phase
• a porous support such as colloidal silica (Aerosil), calcium silicate (Hubersorb) or magnesium aluminometasilicate (Neusilin).
• dry emulsions can be obtained by lyophilization or spray-drying.
• the operating conditions are particularly important (temperature, freezing and sublimation rates, choice of cryoprotectant, etc.).
• nebulization developments are much more numerous. They consist in the manufacture of an aqueous continuous phase emulsion, of low viscosity to facilitate the passage in the nebulization nozzle.
• This emulsion contains one or more powdery carriers which can be either soluble in water (lactose, maltodextrins, mannitol, cellulose esters, etc.) or insoluble (magnesium aluminum silicate, silicas, etc.).
• This emulsion is then divided into fine droplets in a nebulization tower to be dried instantly when passing through the hot air stream.
• the aqueous phase is then evaporated and the solid supports encapsulate the dispersed lipid phase to give an easily redispersible powder in water thanks to its large surface area.
• the solid supports encapsulate the dispersed lipid phase to give an easily redispersible powder in water thanks to its large surface area.
• self-emulsifiable systems By mixing a lipid phase, one or more nonionic surfactants and a lipophilic active substance, self-emulsifiable systems can be obtained. These systems have the particularity of forming spontaneously in situ, in contact with gastro-digestive fluids, a fine aqueous continuous phase emulsion allowing the solubilization of the insoluble active substance within lipid droplets. These self-emulsifiable systems have the advantage, compared to other lipid systems, of being thermodynamically stable with a droplet size of 10 to 2000 nm after dispersion in water.
• self-emulsifiable systems are classified as SEDDS (Self-Emulsifying Drug Delivery Systems), SMEDDS® (Self-Micro-Emulsifying Drug Delivery Systems) and even SNEDDS (Self Nano-Emulsifying Drug Delivery Systems). They occur either in semi-solid forms with waxy appearance hot cast in soft-shell or even hard capsules, or in pulverulent forms.
• the first limit of SEDDS, SMEDDS ® and SNEDDS is their ability to solubilize the active principle of pharmaceutical interest knowing that its solubility in the various excipients and the mixture of excipients is limited to a thermodynamic point of view; which leads to a rate of encapsulation of limited active ingredient.
• the active principle is solubilized in the droplets of the emulsion, microemulsion or nano-emulsion obtained.
• some lipids used in these systems are rapidly metabolized, in particular by pancreatic lipase, which causes destruction of the dispersed system and precipitation of the active ingredient.
• French Patent Application No. 2850040 describes the formation of systems that can be used for trapping substances of interest by external orbital stirring, at room temperature, from two separate phases, an aqueous phase composed of a solution of cyclodextrins and of an oily phase.
• the disadvantage of this system is that the orbital stirring process of the emulsion lasts 4 to 6 days, that the beads are not formed instantly, and that a lyophilization step is necessary to recover the beads in powder form .
• encapsulation ⁇ drug molecules there may be a competition between the active principle and triglycerides at the cavity of the cyclodextrin at the risk of blocking the formation of the beads, as demonstrated when oleic acid is added with soybean oil (M. Hamoudi et al Annales Pharmaceutiques civile Vol 60-Issue 6 Pages 391-398 (2009)).
• a formulation without or with a very small amount of surfactant to reduce mucosal toxicity is provided.
• a solid self-emulsifiable system without organic solvents to be packaged in hard capsules or converted into tablets. Stability during the water removal stage (use of an oven or air bed dryer: LAF).
• a rheological quality of the dry form absence of caking, good flowability, absence of fines, compressible without granulation steps (by direct compression).
• SP-SEDDS Emulsifymg Drug Delivery Systems
• the new SP-SEDDS instantaneous system is attractive because it is physically and microbiologically very stable and it is easy to administer it as powders in capsules or in the form of tablets made by compression.
• the new SP-SEDDS® system has all the advantages of liquid auto-emulsifiable systems and the advantages of a dry form.
• the new SP-SEDDS® system represents a potential oral delivery system for BCS class II, III and IV substances, and for active ingredients to be protected from light, enzymatic degradation or oxidation.
• the subject of the invention is the preparation and the use of a new SP-SEDDS® instantaneous solid self-emulsifiable system in the form of pellets or effervescent or non-effervescent granules for the encapsulation of substances of interest and their applications for the oral route.
• SP-SEDDS® solid self-emulsifiable system
• the invention also relates to the applications of these self-emulsifiable instant solid lipid systems (SP-SEDDS®), in particular in therapeutics, cosmetics, dietary supplements, in the veterinary and agri-food fields.
• SP-SEDDS® self-emulsifiable instant solid lipid systems
• the SP-SEDDS® systems according to the invention are characterized in that they are prepared from oily and / or oleaginous substances and cyclodextrins or their mixture, and form an essentially solid group in which the oily phase is transformed into a solid phase. (powder) instantaneously after addition of a certain amount of water, solid self-emulsifiable lipid system from which an aqueous continuous phase emulsion can be easily reconstituted in contact with water or when administered orally .
• the process of the present invention is preferably applied to oily and / or oleaginous substances, chosen in particular from oils of animal, vegetable, marine or synthetic origin, and to cyclodextrins chosen from ⁇ -cyclodextrin, ⁇ - cyclodextrin and ⁇ -cyclodextrin and hydroxypropyl, methyl, ethyl, sulfobutylether or acetyl derivatives of ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin and mixtures formed from said cyclodextrins and said cyclodextrin derivatives.
• Cyclodextrins are cyclic oligomers composed of 6, 7 or 8 glucose units, which are respectively called alpha
• cyclodextrins refers to cyclic oligosaccharides, and / or their derivatives.
• said cyclodextrins are oligosaccharides and, in particular, natural cyclodextrins, modified cyclodextrins and their derivatives and / or their mixture.
• the subject of the invention is an SP-SEDDS® system comprising, or consisting of: at least one oily and / or oleaginous substance, chosen in particular from oils of animal, vegetable, marine and synthetic origin, and
• At least one cyclodextrin chosen from alpha-, beta- and gamma-cyclodextrin and / or their derivatives, in particular their modified derivatives on the primary and / or secondary hydroxyl groups.
• the cyclodextrin mixture comprises at least two different cyclodextrins, in particular an alpha-cyclodextrin / beta-cyclodextrin, alpha-cyclodextrin / gamma-cyclodextrin, beta-cyclodextrin / gamma-cyclodextrin mixture.
• the cyclodextrin mixture comprises three cyclodextrins, in particular an alpha-cyclodextrin / beta-cyclodextrin / gamma-cyclodextrin mixture.
• the cyclodextrins may be in the dispersed state and / or soluble in the oily phase, for example natural cyclodextrins and, in particular, 1'-cyclodextrin.
• the SP-SEDDS® system according to the invention may comprise an oily substance content greater than or equal to 10% by weight, in particular greater than or equal to 30% by weight, in particular greater than or equal to 40% by weight, or even greater or equal to 55% by weight relative to the total weight of the SP-SEDDS ® system .
• the oily or oleaginous substance may especially comprise or consist of at least one fatty acid, especially saturated and / or unsaturated fatty acid, a corresponding ester or triglyceride, in particular a mono- or polyunsaturated fatty acid.
• fatty acids is intended to mean carboxylic acids comprising from 6 to 50 carbon atoms, in particular from 10 to 30 carbon atoms, and in particular from 12 to 22 carbon atoms.
• fatty substances which are esters of long-chain carboxylic acids, in particular fats of animal, marine or vegetable origin which can be triesters of glycerol.
• unsaturated fatty acids within the meaning of the present invention, monounsaturated and / or polyunsaturated fatty acids.
• the unsaturated fatty acids can come from: of a vegetable oil and are advantageously chosen for example from camelina oil, soybean oil, wheat germ oil, avocado oil or sweet almond oil, oil rapeseed oil, walnut oil, linseed oil, Inca inchi oil, Chia oil, Echium oil, Buglossoides arvensis oil (Ahiflower TM), sunflower oil, walnut oil coconut, grape seed, peanut, cotton, sesame, olive, corn, wheat germ, safflower, lupine, walnut, hazelnut or mixtures thereof, or essential oils or their mixtures.
• camelina oil soybean oil, wheat germ oil, avocado oil or sweet almond oil, oil rapeseed oil, walnut oil, linseed oil, Inca inchi oil, Chia oil, Echium oil, Buglossoides arvensis oil (Ahiflower TM), sunflower oil, walnut oil coconut, grape seed, peanut, cotton, sesame, olive, corn, wheat germ, safflower, lupine, walnut
• Animal oil are advantageously chosen for example from fish oil, Krill oil or their mixtures
• Marine oil and are advantageously chosen, for example, from microalgae oil
• the oily or oleaginous substance comprises a content of omega fatty acid (s), in particular omega-3, omega-6 and / or omega-9, greater than or equal to 5% by weight, in particular greater than or equal to 55% by weight, in particular greater than or equal to 80% by weight, or even greater than or equal to 99% by weight relative to the total weight of oily substance.
• omega fatty acid s
• omega-3, omega-6 and / or omega-9 greater than or equal to 5% by weight, in particular greater than or equal to 55% by weight, in particular greater than or equal to 80% by weight, or even greater than or equal to 99% by weight relative to the total weight of oily substance.
• the oily and / or oleaginous substances used in the composition of the systems of the invention are liquid and are capable of reacting with the cyclodextrins to transform into powder after adding a certain amount of water with stirring.
• the invention therefore relates to SP-SEDDS ® systems containing, in addition, one or more substances of pharmacological interest or nutraceutical.
• These Substances are amphiphilic substances, hydrophilic o u liposoluble substances.
• the invention advantageously makes it possible to formulate fragile molecules that are sensitive to oxidation, enzymes and / or light, or that can be denatured by conventional encapsulation methods.
• compositions of the present invention may also include absorption promoters, co-solvents, surfactants, co-surfactants to enhance the solubility of drug molecules and antioxidants to improve the stability of oils, such as glyceryl caprylate / caprate, Cremophor EL ® , polyoxyethylene sorbitan oleate, diethylene glycol monoethyl ether, propylene glycol monocaprylate, ethanol, macrogol 800 to 30, vitamin C, polyphenols, Quercetin and Herbalox ® .
• Antioxidants which are selected from the following compounds: vitamin C, vitamin A, vitamin E, rosemary extract, curcumin, green tea extract, flavonoids, polyphenols, lycopenes, anthocyanins and / or essential oils.
• the systems of the invention are in particular in the form of solid solid structure pellets, prepared by extrusion-spheronization.
• Such pellets generally have a particle size of the order of one micron to several millimeters, in particular from 0.1 to 5 mm, in particular from 0.5 to 3 mm.
• pellets of the invention can be introduced into capsules or transformed into tablets, for their uses as pharmaceutical compositions, cosmetic, veterinary, dietary supplement or nutraceutically ad reatible by the oral route.
• the systems of the invention are in particular in the form of effervescent pellets or granules prepared by wet alcoholic granulation after addition of excipient excipients.
• the invention also relates to a process for preparing the systems defined above.
• the first step is to prepare a dispersion or solubilization in an oily phase from at least one cyclodextrin
• the second step consists of stirring, in particular under an inert atmosphere and / or absence of light, at a temperature of 15 to 40.degree. C., preferably of 18 to 37.degree. C., more particularly of 20 to 25.degree. is carried out under conditions of speed and duration for obtaining a suspension or solution of cyclodextrins in the oil.
• lipophilic or amphiphilic molecules of interest in the oily phase and to improve the solubility of the molecules of interest, provision may be made to use a co-solvent, surfactant, and can improve the chemical stability of the solid self-emulsifiable lipid system by adding antioxidant (s).
• the third step is to add an aqueous phase with stirring until the conversion of the oily phase into solid granules.
• this aqueous phase may contain hydrophilic molecules of interest to be encapsulated.
• the fourth step is to calibrate wet granules through an oscillating granulator.
• the powder mixture can also be extruded and spheronized after adding Avicel PH 102 to obtain calibrated pellets.
• the powder mixture can be granulated by alcoholic wet process after adding effervescent excipients, for obtaining effervescent granules.
• the fifth step is to dry either in a fluidized air bed (LAF) or in a ventilated oven.
• LAF fluidized air bed
• the granules or pellets may be film coated or coated to control the release of the molecules of interest.
• this method of manufacturing SP-SEDDS® systems does not require special equipment for manufacturing, that the manufacturing process does not involve organic solvents, which represents an advantage in terms of safety and environmental protection, and that the solid self-emulsifiable system is formed instantly respecting the ratio between the amount of oil, cyclodextrins and water.
• SP-SEDDS ® The excipients used for the formation of SP-SEDDS ® systems are non-toxic and biodegradable (oily or oleaginous substances and cyclodextrins).
• the invention thus provides means of great simplicity and low cost for manufacturing new solid self-emulsifiable lipid systems. Snapshots (SP-SEDDS ®) used in many sectors From 1 1 industry.
• the invention is aimed in particular at therapeutic applications where these novel systems make it possible in particular to encapsulate medicinal active principles and constitute new galenic forms or any intermediate forms that can be used in the production of other forms of administration (capsules, granules, tablets). ..) for the oral route.
• Lipid systems self emulsifiable instant solid may be used such that when the used oil is rich in omega 3, omega 6, omega 9 (ALA, EPA, DHA, SDA, GLA and / or CLA ) of animal, vegetable, marine or synthetic origin.
• SP-® SEDDS may be used such that when the used oil is rich in omega 3, omega 6, omega 9 (ALA, EPA, DHA, SDA, GLA and / or CLA ) of animal, vegetable, marine or synthetic origin.
• New formulations of dietary products, foods or nutraceuticals can be prepared.
• the systems have the advantage of masking odors and / or unpleasant tastes and, on the other hand, they make it possible to improve the bioavailability of the active ingredients by the cyclodextrins.
• a first step 18.5 grams of soybean oil mixture are introduced into a planetary mixer (Hobart type). and sesame oil (50/50%) loaded with 1 gram of nalbuphine. 31.5 grams of ⁇ -cyclodextrins solubilized in the oily phase are added with stirring (variator No. 1) and at room temperature (25 ° C.), then 5 ml of water are added with stirring (variator No. 2). and at room temperature (25 ° C), until the instant formation of granules as a wet powder. The wet granules are then calibrated (1 ⁇ mesh) in an oscillating granulator and then dried in an oven at 45 ° C for 15 minutes to a moisture content of 5 to 6%.
• Example 2 Preparation of granules of medroxyprogesterone acetate (MPA) as SP-SEDDS ®
• Example 2 The procedure is as described in Example 1, but using 18.5 grams of a mixture of camelina oil and oleic acid (50/50%) loaded with 50 milligrams of AMP and 31.5 grams of a-cyclodextrins. A powder is obtained (SP-SEDDS ®) after adding 10 ml of water.
• Example 3 Preparation of granules of fenofibrate in the form of SP-SEDDS ®
• Example 2 The procedure is as described in Example 1, but using 18.5 grams of a mixture of linseed oil and fish oil (50/50%) loaded with 1 gram of fenofibrate and 31.5 grams of ⁇ -cyclodextrins. A powder is obtained (SP-SEDDS ®) after adding 10 ml of water.
• Example 4 Preparation of effervescent granules of fenofibrate in the form of SP-SEDDS ®
• Example 3 The granules obtained in Example 3 are mixed with an acid / base pair (effervescent excipient), sorbitol, a perfume and aspartame (Table 2), and are wet-alcohol granulated.
• an acid / base pair effervescent excipient
• sorbitol sorbitol
• perfume and aspartame Table 2
• Example 2 The procedure is as described in Example 1, but using 40 grams of olive oil loaded with 10 grams of nimesulide and 40 grams of ⁇ -cyclodextrin. A powder is obtained (SEDDS ® SP) after addition of 125 ml of water. We obtain pellets of average size of 800 ⁇ loaded with 10% nimesulide.
• Example 6 Preparation of pellets of nimesulide in the form of SP-SEDDtf by extrusion-spheronization a) Preparation of SP-SEDDS ® granules
• the mass is extruded through the perforated drum (diameter: 1 mm) at a speed of 20 rpm (Caleva model 30).
• the extrudas are spheronized for 30 sec at a speed of 800rpm (Caleva model 250).
• Example 6 The pellets obtained in Example 6 are film-coated in an LAF (PROCEPT 4M8). 100 grams of pellets are heated to a temperature of 35 ° C. The 15% (w / v) film coating solution of Aquacoat ECD, 15% Triethylcitrate and a dye is sprayed at 2 ml / min for 15 minutes in Top spray mode (1 bar) . After pelleting, the pellets are dried at a temperature of 50 ° C (Photo 2).
• Example 8 Preparation and evaluation of the dissolution of ketoprofen pellet form or not SP-SEDD a) Preparation of ketoprofen pellets as SP- SEDDS ®
• ketoprofen pellets a) The mixture:
• Ketoprofen 20 grams of Ketoprofen and 180 grams of microcrystalline cellulose are mixed in a planetary mixer for 10 minutes and then 230 ml of water is added.
• the mass is extruded through the perforated drum (diameter: 1 mm) at a speed of 20 rpm (Caleva model 30).
• This step is carried out in an oven at 50 ° C. for 12 hours.
• SP-SEDDS ® pellets charged 10% of nimesulide.
• Example 2 The procedure is as described in Example 1, but using 37 grams of sunflower oil loaded with 1.1 grams of cholecalciferol and 63 grams of ⁇ -cyclodextrins. A powder (SP-SEDDS ® ) is obtained after adding 60 ml of water.
• Dissolution medium 4% (m / V) sodium dodecyl sulfate water
• Sampling time 5, 10, 15, 20, 30, 40, 60, 90, 120, 150 and 180 minutes.
• Example 2 The procedure is as described in Example 1, but using 6 grams of oleic acid loaded with 500 milligrams of cyclosporine and 6 grams of -cyclodextrins. A powder (SP-SEDDS ® ) is obtained after adding 60 ml of water.
• Example 2 The procedure described in Example 1, but using 6 grams of oleic acid charge of 500 milligrams of cyclosporin, of 1 ml of Cremophor EL ® and 6 grams of ⁇ -cyclodextrins. A powder (SP-SEDDS ® ) is obtained after adding 60 ml of water.
• the passage oral cyclosporin as SEDDS SP ® was evaluated in six rats (Charles River ®) with a mean weight of 250 g.
• the oral dosage is 10 mg / kg for Formulas 1, 2 and Neoral ® (marketed reference drug). Samples were taken at regular times: 0, 60, 120, 180, 240, 300 and 360 minutes. Plasma determination of cyclosporine is performed by HPLC.
• Example 12 Formation of SP-SEDD® from 35% (w / w) cc-cyclodextrins and 65% (w / w) of antioxidant stabilized sunflower oils (Herbalox XT-O).
• Example 2 The procedure is as described in Example 1, but using 260 grams of sunflower oil loaded with 100 mg oleoresin rosemary herbalox XT-0, 140 grams of ⁇ -cyclodextrins and 10 ml of water. Granules of average size of 800 ⁇ are obtained.
• Example 13 Preparation of SP-SEDD 2 from a mixture of three cyclodextrins and linseed oil
• Example 14 Preparation of SP-SEDD 2 from a mixture of two cyclodextrins (aet ⁇ ) and linseed oil
• Example 16 Preparation and evaluation of the stability of Inca inchi oil in the form of SP-SEDD ⁇
• Example 2 The procedure is as described in Example 1, but using Inca inchi oil representing 50% of the total mass and 200 g of ⁇ -cyclodextrins. Granules having a mean size of 800 ⁇ m are obtained. The stability of the granules is evaluated by the Rancimat Test (ISO 6886), the Rancimat Induction Time (TIR) (expressed in hours).
• Rancimat Test ISO 6886
• TIR Rancimat Induction Time
• the Rancimat test makes it possible to compare the stability of different fatty substances by determining their resistance time to oxidation.
• the SP-SEDDS ® system works by delaying the initiation of oxidation. Comparing the induction time of a standard oil and an oil formulated as SP-SEDDS ® can prove the improved stability of oils under ® SP-SEDDS shape face 1 oxidation.
• Example 17 Preparation and evaluation of the stability of conjugated linoleic acid (CLA) at 37% and 50% (m / m) of oil as SP-SEDD.
• CLA conjugated linoleic acid
• the stability of the granules is evaluated by the Rancimat Test (ISO 6886)
• Example 18 preparation of a mixture of vegetable oils, animal and marine rich in omega 3 as SP-5 EU SDS ®! The procedure is as described in Example 1, but using a mixture of oils (camelina oil and various fish and algae oils) (Table 3). Granules of average size of 800 ⁇ are obtained.
• Example 19 Manufacture of an industrial batch
• Example 2 The procedure is as described in Example 1, for a batch of 105 kg, that is to say 20 kg of camelina oil, 80 kg of cyclodextrins and 20 liters of water to develop the SP-SEDD system.

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