NEW SELF-EMULSIFYING INSTANT SOLID SYSTEM BASED ON CYCLODEXTRINS AND OIL FOR ORAL ADMINISTRATION

Abstract

The subject of the invention is a new system in the form of an instant self-emulsifying powder, their preparation process as well as the application of this oily system associated with one or a mixture of cyclodextrins for the instant formation of a solid spherical system of effervescent or non-self-emulsifying granule or pellet types (Spontaneous Powder Self Emulsifying Drug Delivery Systems (SP-SEDDS®)). And for the encapsulation of a substance of therapeutic interest. Applications to the encapsulation of one or more substances of interest, in particular therapeutic or preventive, nutritional, and usable in pharmacy, veterinary, nutrition or agri-food by oral route.

Description

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 very simple and low-cost means for manufacturing new solid self-emulsifiable lipid systems. snapshots (SP-SEDDS®) usable in many sectors of 1 industry. The invention is aimed in particular at therapeutic applications where these new systems make it possible in particular to encapsulate active medicinal ingredients and constitute new galenic forms or any intermediate forms usable in the production of other forms of administration (capsules, granules, tablets, etc.) for oral administration. Another application of interest concerns the field of food supplements. Instant solid self-emulsifying lipid systems (SP-SEDDS®) can be used as is, when the oil used is rich in omega 3, omega 6, omega 9 (ALA, EPA, DHA, SDA, GLA or / and CLA) of animal, vegetable, marine or synthetic origin. New formulations of dietary products, foods or functional foods can be prepared. It should be noted that in these applications, the systems have the advantage of masking unpleasant odors and / or tastes and, on the other hand, allow the bioavailability of active ingredients to be improved by cyclodextrins. Other characteristics and advantages of the invention will be given in the examples which follow and which relate to embodiments of the invention using, by way of illustration, cyclodextrins and oils of vegetable, animal, plant or marine origin, as substances oily. Example 1: Preparation of nalbuphine granules in the form of SP-SEDDS® In the 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 α-cyclodextrins solubilized in the oily phase are added under stirring (variator No. 1) and at room temperature (25°C), then 5 ml of water is added under stirring (variator No. 2) and at room temperature (25°C), until the instant formation of granules in the form of wet powder. The wet granules are then calibrated (1 μm mesh) in an oscillating granulator, then dried in an oven at 45°C for 15 minutes to a moisture content of 5 to 6%. We obtain granules of average size of 800 pim loaded with 2% nabulphine (Photo 1) Example 2: Preparation of acetate granules Medroxyprogesterone (MPA) in the form of SP-SEDDS® 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 α-cyclodextrins. A powder (SP-SEDDS®) is obtained after adding 10 ml of water. Medroxyprogesterone acetate-loaded granules of average size 800 pm are obtained. Example 3: Preparation of fenofibrate granules in the form of SP-SEDDS® 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 α-cyclodextrins. A powder (SP-SEDDS®) is obtained after adding 10 ml of water. We obtain granules of average size of 800 pm loaded with fenofibrate and omega 3 (ALA, EPA and DHA). Example 4: Preparation of effervescent granules of fenofibrate in the form of SP-SEDDS® The granules obtained in Example 3 are mixed with an acid / base pair (effervescent excipient), sorbitol, a perfume and aspartame (Table 2), and are granulated by the alcoholic wet method. Effervescent granules of average size 890 pm loaded with fenofibrate are obtained. Composition Formulation Quantity (gram) Fenofibrate SP-SEDDS® 46 Sodium bicarbonate 8 Sodium citrate 12 Sorbitol 1.2 Perfume 0.3 Aspartame 0.1 Table 2: Formula of effervescent granules Example 5: Preparation and evaluation of nimesulide dissolution in the form of SP-SEDDS® 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 α-cyclodextrins. A powder (SP-SEDDS®) is obtained after adding 125 ml of water. Granules with an average size of 800 μm loaded with 10% nimesulide are obtained. Operating conditions for dissolution tests Dissolution medium: Buffer at pH 7.4 Volume: 500 ml Temperature: 37°C ± 0.5°C Rotation speed: 100 rpm Sample: 33 mg of nimesulide Volume collected: 5.0 ml with compensation Sampling time: 5, 10, 15, 20, 30, 40 minutes. Analytical method: HPLC Column: Cl 8 at 5pm Kromasil Mobile phase: KH2P04 0.01M / CAN (40 / 60%), pH 1.5 Detection: UV at 260 nm; Retention time 10 minutes. Results: The release rate is 100% from 120 min (Figure 1) Example 6: Preparation of nimesulide pellets in the form of SP-SEDD^1 by extrusion-spheronization a) Preparation of SP-SEDDS® granules The procedure is as described in Example 1, but using 40 grams of olive oil loaded with 20 grams of nimesulide and 40 grams of α-cyclodextrins. A powder (SP-SEDDS®) is obtained after adding 125 ml of water, which will be extruded and spheronized. b) Preparation of SP-SEDDS® pellets by extrusion-spheronization a) The mixture: 100 g of SP-SEDDS® granules and 100 g of microcrystalline cellulose are mixed in a planetary mixer for 10 minutes, then 150 ml of water is added. a) Extrusion The mass is extruded through the perforated drum (diameter: 1 mm) at a speed of 20 rpm (Caleva model 30). b) Spheronization The extrudates are spheronized for 30 seconds at a speed of 800 rpm (Caleva model 250). c) Drying This step was carried out in an oven at 50°C for 12 hours. SP-SEDDS® pellets loaded with 10% nimesulide were obtained (Photo 2). Example 7: Film coating of nimesulide pellets in the form of SP-SEDDS® for enteral release The pellets obtained in Example 6 are film-coated in a LAF (PROCEPT 4M8). 100 grams of pellets are heated to a temperature of 35°C. The 15% (m / v) polymer film-coating solution composed of Aquacoat ECD, 15% Triethylcitrate and a colorant is sprayed at 2 ml / min for 15 minutes, in Top spray mode (1 bar). After film-coating, the pellets are dried at a temperature of 50°C (Photo 2). Example 8: Preparation and evaluation of the dissolution of Ketoprofen pellets in the form of SP-SEDDiP or not a) Preparation of ketoprofen pellets in the form of SP-SEDDS® The procedure is as described in Example 6, but using 80 grams of corn oil loaded with 40 grams of Ketoprofen and 80 grams of α-cyclodextrins. A powder (SP-SEDDS®) is obtained after adding 100 ml of water, which will be extruded and spheronized. We obtain SP-SEDDS® pellets loaded with 10% Ketoprofen. b) Preparation of ketoprofen pellets a) The mixture: In a planetary mixer, 20 grams of Ketoprofen and 180 grams of microcrystalline cellulose are mixed for 10 minutes, then a volume of 230 ml of water is added. a) Extrusion The mass is extruded through the perforated drum (diameter: 1 mm) at a speed of 20 rpm (Caleva model 30). b) Spheronization The extrudates are spheronized for 30 seconds at a speed of 800 rpm (Caleva model 250). c) Drying This step is carried out in an oven at 50°C for 12 hours. SP-SEDDS® pellets loaded with 10% nimesulide are obtained. Operating conditions for dissolution tests Dissolution medium: Buffer at pH 7.4 Volume: 500 ml Temperature: 37°C ± 0.5°C Rotation speed: 100 rpm Sample: 30 mg of Ketoprofen Volume collected: 5.0 ml with compensation Sampling time: 5, 10, 15, 20, 30, 40 minutes. Analytical method: HPLC Column: Cl 8 at 5pm Kromasil Mobile phase: KH2PO4 0.01M / CAN (40 / 60%) pH 1.5 Detection: UV at 260 nm; Retention time 10 minutes Results: The release rate is 100% for ketoprofen in the form of SP-SEDD^ (1) and 20% for the control (2). (Figure 2) Example 9: Preparation and evaluation of the dissolution of Cholecalciferol (Vit D3) in the form of SP-SEDD^ 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 α-cyclodextrins. A powder (SP-SEDDS®) is obtained after adding 60 ml of water. Granules with an average size of 800 μm loaded with 1.1% cholecalciferol are obtained. Operating conditions for dissolution tests Dissolution medium: water at 4% (m / V) sodium dodecyl sulfate Volume: 500 ml Temperature: 37°C ± 0.5°C Rotation speed: 100 rpm Sample: 200 mg of cholecalciferol Volume collected: 5.0 ml with compensation Sampling times: 5, 10, 15, 20, 30, 40, 60, 90, 120, 150 and 180 minutes. Analytical method: HPLC Column: Cl 8 at 3pm Kromasil Mobile phase: acetonitrile / methanol (95 / 5%) Flow rate 1.5 ml / min - Injection volume: 25 pl Detection: UV at 254 nm; Retention time 6 minutes Conclusion Vitamin D3 release is not complete. However, approximately 70% release is achieved within 180 minutes. Encapsulation of vitamin D3 appears to result in a delayed release (Figure 3). Example 10: Preparation and biopharmaceutical evaluation of SP- SEDDS^ from oil encapsulating Cyclosporine A 1- Preparation of SP-SEDD^ of cyclosporine without cremophore EL® (Formula 1) 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 α-cyclodextrins. A powder (SP-SEDDS®) is obtained after adding 60 ml of water. Minigranules of average size of 800 |im loaded with cyclosporine are obtained. 2- Preparation of SP-SEDD^ of cyclosporine with cremophore EL® (Formula 2) The procedure is as described in Example 1, but using 6 grams of oleic acid loaded with 500 milligrams of cyclosporine, 1 ml of Cremophore EL® and 6 grams of α-cyclodextrins. A powder (SP-SEDDS®) is obtained after adding 60 ml of water. Granules of average size of 800 pm loaded with cyclosporine are obtained. PRECLINICAL STUDY The oral administration of cyclosporine in the form of SP-SEDDS® (Formulas 1 and 2) was evaluated in six rats (Charles River®) with an average 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 cyclosporine dosage is performed by HPLC. Chromatographic conditions of the HPLC assay method Column: SUPELCOSIL™ LC-18, 120 x 4.6 mm, C18 pm Column temperature: 70°C Flow rate: 1.0 ml / min Detection: 210 nm Injection volume: 50 pl Mobile phase: 85% acetonitrile + 15% water (v / v) Analysis time: 10 minutes Retention time: approximately 6 minutes Plasma concentrations of cyclosporine in formulas 1 and 2, compared with those of the reference product Neoral®, are shown in Figure 4 and Table 3. Cmax (ng / ml) Tmax (H) AUMC (nghr*hr / ml) Neoral® 756.4 2 8022.1 SP-SEDDS® without cremophore 667.3 2 9163 SP-SEDDS® with cremophore 822.9 3 16113.2 Table 3: Pharmacokinetic parameters Example 11: Formation of SP-SEDDS® from 50% (m / m) α-cyclodextrins and 50% (m / m) Linseed oil. The procedure is as described in Example 1, but using 200 grams of linseed oil, 200 grams of α-cyclodextrins and 40 ml of water. Granules with an average size of 800 μm are obtained (Photo 2). Example 12: Formation of SP-SEDD^ from 35% (m / m) α-cyclodextrins and 65% (m / m) sunflower oils stabilized by an antioxidant (Herbalox XT-O). The procedure is as described in Example 1, but using 260 grams of sunflower oil loaded with 100 mg of oleoresin rosemary herbalox XT-O, 140 grams of α-cyclodextrins and 10 ml of water. Granules with an average size of 800 μm are obtained. Example 13: Preparation of SP-SEDD^ from a mixture of three cyclodextrins and linseed oil The procedure is as described in Example 1, but using a mixture of three cyclodextrins (a, p and y) in a ratio 1 / 1 / 1 which represents 50% of the total mass and 200 g of linseed oil. We obtain granules with an average size of 800 pm. Example 14: Preparation of SP-SEDD^® from a mixture of two cyclodextrins (a and P) and linseed oil The procedure is as described in Example 1, but using a mixture of two cyclodextrins (a and P) in a 1 / 1 ratio representing 50% of the total mass and 200 g of linseed oil. Granules with an average size of 800 μm are obtained. Example 15: Preparation of SP-SEDD^ from a mixture vegetable oil and fish oil The procedure is as described in Example 1, but using a mixture of oils (camelina oil and Denomega® fish oil) in a 1 / 1 ratio which represents 50% of the total mass and 200 g of α-cyclodextrins. Granules with an average size of 800 μm are obtained. Example 16: Preparation and evaluation of stability of Inca inchi oil in the form of SP-SEDD^ The procedure is as described in Example 1, but using Inca inchi oil representing 50% of the total mass and 200 g of α-cyclodextrins. Granules with an average size of 800 μm are obtained. The stability of the granules is evaluated by the Rancimat Test (ISO 6886), the Rancimat Induction Time (IRT) (expressed in hours). The Rancimat test allows the stability of different fatty substances to be compared by determining their oxidation resistance time. The SP-SEDDS® system acts by delaying the initiation of oxidation. Comparing the induction times of a standard oil and an oil formulated in SP-SEDDS® form demonstrates the improved stability of SP-SEDDS® oils against oxidation. This evaluation using the Rancimat method shows that oils in SP-SEDDS® form have a stability factor 13 times greater than standard oils (Figure 5). Example 17 preparation and evaluation of the acid stability conjugated linoleic acid (CLA) at 37% and 50% (m / m) oil in the form of SP-SEDD^. The procedure is as described in Example 1, but using CLA, which represents 37 or 50% of the total mass, with the addition of 200 grams of α-cyclodextrins. Granules with an average size of 800 μm are obtained. The stability of the granules is assessed by the Rancimat Test (ISO 6886) This evaluation using the Rancimat method shows that oils in SP-SEDDS® form have a stability factor 3 times greater than standard oils at 37% for Polaris original oil and 2.8 times for Cognis original oil (Figure 6). Example 18: preparation of a mixture of vegetable and marine oils and animal products rich in omega 3 in the form of SP-SEDD^1 The procedure is as described in Example 1, but using a mixture of oils (camelina oil and different fish and algae oils) (Table 3). Granules of average size of 800 pm. Composition of the powder a-cyclodextin (%) Oil (%) w3 (%) Camelina Fish 100% camelina 63 63 - 11 Camelina + Fish oils 17% EPA 8% DHA (Daudruy) 55.4 31.8 12.8 13.4 Camelina + fish oils 13% EPA 13% DHA (Denomega) 57.5 33.1 9.4 13.7 Camelina + algae oil 40% DHA (Lonza) 58.4 33.5 8.1 13.3 Table 4: Composition of formulations Example 19: Production of an industrial batch of SP-SEDDS^ to manufacture tablets with a 20% camelina oil content The procedure is as described in example 1, for a batch of 105 kg, i.e. 20 kg of camelina oil, 80 kg of α-cyclodextrins and 20 liters of water to prepare the SP-SEDD^® system, then 5 kg of Croscarmellose sodium (disintegrant) are added. Compression: to obtain tablets with a hardness of 60N and a diameter of 12mm (Photo 3) Composition of a tablet Camelina oil 2.00 mg cc-cyclodextrin 8.00 mg Croscarmellose 63 mg Total mass 1063 mg

Claims

CLAIMS 1. Systems for microencapsulation in powder form, characterized in that it is obtained from at least one oily and / or oleaginous substance, chosen from oils of animal, vegetable, marine and synthetic origin or their mixture, and from at least one cyclodextrin chosen from alpha-, beta- and gamma-cyclodextrin and / or their derivatives chosen from hydroxypropylated, methylated, ethylated, sulfobutylated ether or acetylated derivatives of α-cyclodextrin, β-cyclodextrin, or mixture of cyclodextrins, and water, in which said at least one oily and / or oleaginous substance is present at a content greater than 8% by weight, said at least one cyclodextrin is present at a content greater than 8% by weight and the water is present at a content greater than 3% by weight relative to the total weight.

2. Systems according to any one of the preceding claims, such that the oily substances are vegetable oils chosen from camelina oil, soybean oil, wheat germ oil, avocado oil or sweet almond oil, rapeseed oil, linseed oil, Inca inchi oil, Chia oil, Echium oil, Buglossoides arvensis (Ahiflower™) oil, sunflower oil, coconut oil, grape seed oil, peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, wheat germ oil, safflower oil, lupin oil, walnut oil, hazelnut oil or mixtures thereof, or essential oils or mixtures thereof, animal oils chosen from fish oil, Krill oil or mixtures thereof, and / or marine oils chosen from microalgae oil.

3. Systems according to any one of the preceding claims, such that the oily or oleaginous substance comprises a content of omega, omega-3, omega-6 and / or omega-9 fatty acid(s) greater than or equal to 5% by weight, in particular greater than or equal to at 55% by weight relative to the total weight of oily substance.

4. Systems according to any one of the preceding claims, such that the cyclodextrin is chosen from α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin and in that the cyclodextrin derivatives are chosen from hydroxypropylated, methylated, ethylated, sulfobutylated ether or acetylated derivatives of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin and binary or ternary mixtures of said cyclodextrins and said cyclodextrin derivatives.

5. Systems according to any one of the preceding claims, such that they comprise at least two cyclodextrins, in particular: - an alpha-cyclodextrin / beta-cyclodextrin mixture, - an alpha-cyclodextrin / gamma-cyclodextrin mixture, - a beta-cyclodextrin / gamma-cyclodextrin mixture, - an alpha-cyclodextrin / beta-cyclodextrin / gamma-cyclodextrin mixture.

6. A five-step process for preparing a dry self-emulsifiable instant system according to any preceding claim, such that it comprises the following steps: 1) the first step consists of preparing a dispersion or a solution from at least one cyclodextrin and an oily phase, 2) the second step consists of stirring, in particular under an inert atmosphere and / or in the absence of light, at a temperature from 15 to 40° C. 3) the third step consists of adding an aqueous phase in fractions and with stirring until the transformation of the oily phase into solid granules or pellets. 4) The fourth step is to calibrate wet granules through an oscillating granulator. 5) the fifth step consists of drying the granules or pellets either in a fluidized air bed (LAF) or in a ventilated oven.

7. Method for preparing a dry self-emulsifiable instant system according to claim 6, such that the quantity of water added makes it possible to instantly obtain a powder.

8. Systems according to one of claims 1 to 5, such that they comprise surfactants / co-surfactants which are chosen from the following compounds: glyceryl caprylate / caprate, Cremophor EL® and polyoxyethylene sorbitan oleate, diethylene glycol monoethyl ether, propylene glycol monocaprylate, absolute ethanol, and macrogol 800 to 300.

9. Systems according to one of claims 1 to 5, such that they comprise antioxidants which are chosen from the following compounds: vitamin C, vitamin A, vitamin E, rosemary extract, curcumin, green tea extract, flavonoids, polyphenols, lycopenes, anthocyanins and / or essential oils.

10. Systems according to one of claims 1 to 5, such that they comprise one or more liposoluble or water-soluble substances of pharmaceutical, nutraceutical, cosmetic or veterinary interest.

11. Systems according to one of claims 1 to 5, such that they are in the form of a powder, tablets, mini tablets, capsules, pellets, granules, microgranules, film-coated or not or in effervescent form.

12. Systems according to one of claims 1 to 5, for their use as pharmaceutical, cosmetic, veterinary, food supplement or nutraceutical compositions which can be administered orally.

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