Composition comprising at least one natural or synthetic non-euphoric cannabinoid and its method of manufacture

Abstract

The present invention relates to a composition in the form of a friable/brittle thermoformed extrudate comprising at least one natural or synthetic non-euphoric cannabinoid and at least one natural or synthetic carrier chosen from the group consisting of amino acids, natural or synthetic peptides and polypeptides, natural or synthetic proteins, natural or synthetic saccharides, natural or synthetic lipids, urea, the derivatives thereof and the mixtures thereof.

Claims

1-16. (canceled)

17. A composition in the form of a friable/brittle thermoformed extrudate, packaged in at least one of a pellet, a flake, a granule, a powder, an effervescent tablet, a non-effervescent tablet, an injectable solution, a non-injectable solution, a suspension, a gel, or an ointment for allowing administration to an animal or to a human being, the composition comprising: at least one natural or synthetic non-euphoric cannabinoid; and at least one natural or synthetic carrier chosen from the group consisting of: amino acids, natural or synthetic peptides and polypeptides, natural or synthetic proteins selected from glycoproteins, collagens, collagen hydrolysates, gelatins, pea proteins, soybean proteins, wheat proteins, pumpkin proteins, nut proteins, rice proteins, hazelnut proteins, milk proteins, green pea proteins, lentil proteins, almond proteins, pistachio proteins, chia proteins, hemp proteins, flax proteins, butternut proteins, sesame proteins, poppy proteins, lupine proteins, sunflower proteins, oat proteins, millet proteins, barley proteins, rye proteins, the derivatives thereof and the mixtures thereof, natural or synthetic saccharides selected from calcium alginate, sodium alginate, ammonium alginate, propylene glycol alginate, starches, pregelatinized starches, modified starches, soluble or insoluble fibers, carrageenans, pectin, hydroxypropyl cellulose (HPC), glycogen, β-glucan, amylopectin, amylose, dextrins, cyclodextrins, maltodextrin, isomaltose, isomalt, xylan, pullulan, agar-agar, mannans, fucoidan, xanthan gum, guar gum, mastic gum, gum arabic, acacia gum, gum tragacanth, gum ghatti, karaya gum, Konjac gum, fenugreek gum, cashew or cashew nut gum, tara gum, carob bean gum, cassia gum, benzoin gum, gum cassia, guaiac gum, chitosan, chitin, levan, neoserine, hyaluronic acid, hyaluronates, chondroitin sulfate, dermatan sulfate, keratan sulfate, raffinose, rhamminose, mannose, glucose, rhamnose, sucrose, stachyose, verbascose, trehalose, lactose, lactulose, maltose, erythritol, mannitol, sorbitol, xylitol, the derivatives thereof and the mixtures thereof, natural or synthetic lipids selected from beeswax, candelilla wax, rice bran wax, carnauba wax, microcrystalline waxes, animal or vegetable oils, hydrogenated animal or vegetable oils, phospholipids, ceramides, fatty acid esters, the derivatives thereof and the mixtures thereof, and urea, the derivatives thereof and the mixtures thereof.

18. The composition according to claim 17, where the friable/brittle thermoformed extrudate includes a thermoformed mixture of: at least one natural or synthetic non-euphoric cannabinoid, and of at least one natural or synthetic carrier chosen from the group consisting of: amino acids, natural or synthetic peptides and polypeptides, natural or synthetic proteins selected from glycoproteins, collagens, collagen hydrolysates, gelatins, pea proteins, soybean proteins, wheat proteins, pumpkin proteins, nut proteins, rice proteins, hazelnut proteins, milk proteins, green pea proteins, lentil proteins, almond proteins, pistachio proteins, chia proteins, hemp proteins, flax proteins, butternut proteins, sesame proteins, poppy proteins, lupine proteins, sunflower proteins, oat proteins, millet proteins, barley proteins, rye proteins, the derivatives thereof and the mixtures thereof, natural or synthetic saccharides selected from calcium alginate, sodium alginate, ammonium alginate, propylene glycol alginate, starches, pregelatinized starches, modified starches, soluble or insoluble fibers, carrageenans, pectin, hydroxypropyl cellulose (HPC), glycogen, β-glucan, amylopectin, amylose, dextrins, cyclodextrins, maltodextrin, isomaltose, isomalt, xylan, pullulan, agar-agar, mannans, fucoidan, xanthan gum, guar gum, mastic gum, gum arabic, acacia gum, gum tragacanth, gum ghatti, karaya gum, Konjac gum, fenugreek gum, cashew or cashew nut gum, tara gum, carob bean gum, cassia gum, benzoin gum, gum cassia, guaiac gum, chitosan, chitin, levan, neoserine, hyaluronic acid, hyaluronates, chondroitin sulfate, dermatan sulfate, keratan sulfate, raffinose, rhamminose, mannose, glucose, rhamnose, sucrose, stachyose, verbascose, trehalose, lactose, lactulose, maltose, erythritol, mannitol, sorbitol, xylitol, the derivatives thereof and the mixtures thereof, natural or synthetic lipids selected from beeswax, candelilla wax, rice bran wax, carnauba wax, microcrystalline waxes, animal or vegetable oils, hydrogenated animal or vegetable oils, phospholipids, ceramides, fatty acid esters, the derivatives thereof and the mixtures thereof, and urea, the derivatives thereof and the mixtures thereof.

19. The composition according to claim 17, wherein the at least one natural or synthetic non-euphoric cannabinoid is chosen from the group consisting of cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabidivarin (CBDV), cannabidiolic acid (CBDA), cannabigerovarin (CBGV), cannabichromenic acid (CBCA), cannabiorcichromenic acid, 8-chloro-cannabiorcichromenic acid, cannachromevarinic acid (CBCVA), lacannabielsoin (CBE), cannabicyclol (CBL), perrottetinene, perrottittenic acid, lunularic acid, vittatin, helichrysum CBG, amorfrutins (A, B, C and D), machaeridiols (A, B, C), daurichromenic acid, anthopogocyclolic acid, anthopogochromenic acid, geranyl-orsellinic acid, confluentine, griffolic acid, rubiginosin A, the derivatives thereof and the mixtures thereof.

20. The composition according to claim 17, wherein at least one of the collagens, the collagen hydrolysates, or the gelatins have a molecular weight between 50 Da and 300000 Da.

21. The composition according to claim 20, wherein the molecular weight is between 1200 and 1000 Da.

22. The composition according to claim 17, further including at least one plasticizer.

23. The composition according to claim 17, further including at least one additive chosen from the group consisting of lubricants, surfactants, antioxidants, chelants, the derivatives thereof and the mixtures thereof.

24. The composition according to claim 17, further including at least one polyphenol type compound chosen from the group consisting of phenolic acids, stilbenes, phenolic alcohols, lignans, flavonoids, the derivatives thereof and the mixtures thereof.

25. A method of treating one or more pathologies related to at least one of a cardiovascular system, a gastrointestinal system, a premature aging of cells, an endocrine system, an immune system, a central nervous system, a sleep disorder, a skin disease, a disease due to a presence of a microorganism, a cancer, an eye disease, a disease of a respiratory system, or diabetes, the method comprising administering the composition of claim 17 to a subject.

26. The method according to claim 25, wherein the one or more pathologies including at least one of ischemia, a metabolic disorder, nausea, vomiting, diarrhea, digestive inflammations, hyperglycaemia, an inflammatory disease, rheumatoid arthritis, multiple sclerosis, osteoarthritis, fibromyalgia, pain, migraine, epilepsy, Parkinson's disease, Alzheimer's disease, anxiety, depression, a tumor, glaucoma, or asthma.

27. A thermoforming method for manufacturing a composition in the form of a friable/brittle thermoformed extrudate, the method comprising: a) simultaneous or delayed supplying into an extruder of: at least one natural or synthetic non-euphoric cannabinoid, and at least one natural or synthetic carrier chosen from the group consisting of: amino acids, natural or synthetic peptides and polypeptides, natural or synthetic proteins selected from glycoproteins, collagens, collagen hydrolysates, gelatins, pea proteins, soybean proteins, wheat proteins, pumpkin proteins, nut proteins, rice proteins, hazelnut proteins, milk proteins, green pea proteins, lentil proteins, almond proteins, pistachio proteins, chia proteins, hemp proteins, flax proteins, butternut proteins, sesame proteins, poppy proteins, lupine proteins, sunflower proteins, oat proteins, millet proteins, barley proteins, rye proteins, the derivatives thereof and the mixtures thereof, natural or synthetic saccharides selected from calcium alginate, sodium alginate, ammonium alginate, propylene glycol alginate, starches, pregelatinized starches, modified starches, soluble or insoluble fibres, carrageenans, pectin, hydroxypropyl cellulose (HPC), glycogen, β-glucan, amylopectin, amylose, dextrins, cyclodextrins, maltodextrin, isomaltose, isomalt, xylan, pullulan, agar-agar, mannans, fucoidan, xanthan gum, guar gum, mastic gum, gum arabic, acacia gum, gum tragacanth, gum ghatti, karaya gum, Konjac gum, fenugreek gum, cashew or cashew nut gum, tara gum, carob bean gum, cassia gum, benzoin gum, gum cassia, guaiac gum, chitosan, chitin, levan, neoserine, hyaluronic acid, hyaluronates, chondroitin sulfate, dermatan sulfate, keratan sulfate, raffinose, rhamminose, mannose, glucose, rhamnose, sucrose, stachyose, verbascose, trehalose, lactose, lactulose, maltose, erythritol, mannitol, sorbitol, xylitol, the derivatives thereof and the mixtures thereof, natural or synthetic lipids selected from beeswax, candelilla wax, rice bran wax, carnauba wax, microcrystalline waxes, animal or vegetable oils, hydrogenated animal or vegetable oils, phospholipids, ceramides, fatty acid esters, the derivatives thereof and the mixtures thereof, and urea, the derivatives thereof and the mixtures thereof; b) mixing, in the extruder, the at least one natural or synthetic non-euphoric cannabinoid and the at least one natural or synthetic carrier to form a mixture; and c) hot melt extruding the mixture in the extruder to obtain the friable/brittle thermoformed extrudate.

28. The method according to claim 27, wherein the friable/brittle thermoformed extrudate includes a solid dispersion.

29. The method according to claim 27, wherein the friable/brittle thermoformed extrudate includes a glassy structure including a molecular mixture of the at least one non-euphoric cannabinoid and of the at least one carrier.

30. The method according to claim 27, further including premixing the at least one natural or synthetic non-euphoric cannabinoid and the at least one natural or synthetic carrier to form a premixture prior to supplying the premixture into the extruder.

31. The method according to claim 27, wherein the hot melt extruding includes an extrusion temperature between 20 and 180° C.

32. The method according to claim 31, wherein the extrusion temperature is about 80° C.

33. The method according to claim 27, wherein the hot melt extruding includes a rotation speed of an extrusion screw between 20 and 900 rpm.

34. The method according to claim 33, wherein the rotation speed is 200 rpm.

35. The method according to claim 27, further including cooling at an outlet of the extruder.

36. The method according to claim 27, further including treating the friable/brittle thermoformed extrudate at an outlet of the extruder by at least one of cutting the extrudate at a pelletizer, grinding the extrudate, crushing the extrudate, or powdering the extrudate.

37. A composition in the form of a friable/brittle thermoformed extrudate packaged in at least one of a pellet, a flake, a granule, a powder, an effervescent table, a non-effervescent tablet, an injectable solution, a non-injectable solution, a suspension, a gel, or an ointment for administration to an animal or to a human being, obtained according to the method of claim 27.

Description

[0172] Other characteristics, details and advantages of the invention will emerge from the examples given below, not by way of limitation and with reference to the appended figures.

[0173] FIGS. 1 to 3 are graphs illustrating the rate of dispersion and solubilization of a non-euphoric cannabinoid, in this case the rate of dispersion and solubilization of cannabidiol over time, starting from examples of compositions according to the invention.

EXAMPLES

Example 1: Method for Manufacturing by Thermoforming Compositions According to the Invention in the Form of Friable/Brittle Thermoformed Extrudates

[0174] Thermoformed compositions according to the invention comprising at least one non-euphoric cannabinoid, such as those forming the subject of Example 2 below, were obtained according to the following method also forming the subject of the present invention: [0175] a) a step of premixing at least one non-euphoric cannabinoid in the crystalline state in powder form and at least one carrier chosen from the group consisting of amino acids, natural or synthetic peptides and polypeptides, natural or synthetic proteins selected from glycoproteins, collagens, collagen hydrolysates, gelatins, pea proteins, soybean proteins, wheat proteins, pumpkin proteins, nut proteins, rice proteins, hazelnut proteins, milk proteins, green pea proteins, lentil proteins, almond proteins, pistachio proteins, chia proteins, hemp proteins, flax proteins, butternut proteins, sesame proteins, poppy proteins, lupine proteins, sunflower proteins, oat proteins, millet proteins, barley proteins, rye proteins, the derivatives thereof and the mixtures thereof, natural or synthetic saccharides selected from calcium alginate, sodium alginate, ammonium alginate, propylene glycol alginate, starches, pregelatinized starches, modified starches, soluble or insoluble fibers, carrageenans, pectin, hydroxypropyl cellulose (HPC), glycogen, β-glucan, amylopectin, amylose, dextrins, cyclodextrins, maltodextrin, isomaltose, isomalt, xylan, pullulan, agar-agar, mannans, fucoidan, xanthan gum, guar gum, mastic gum, gum arabic, acacia gum, gum tragacanth, gum ghatti, karaya gum, Konjac gum, fenugreek gum, cashew or cashew nut gum, tara gum, carob bean gum, cassia gum, benzoin gum, gum cassia, guaiac gum, chitosan, chitin, levan, neoserine, hyaluronic acid, hyaluronates, chondroitin sulfate, dermatan sulfate, keratan sulfate, raffinose, rhamminose, mannose, glucose, rhamnose, sucrose, stachyose, verbascose, trehalose, lactose, lactulose, maltose, erythritol, mannitol, sorbitol, xylitol, the derivatives thereof and the mixtures thereof, natural or synthetic lipids selected from beeswax, candelilla wax, rice bran wax, carnauba wax, microcrystalline waxes, animal or vegetable oils, hydrogenated animal or vegetable oils, phospholipids, ceramides, fatty acid esters, the derivatives thereof and the mixtures thereof, urea, the derivatives thereof and the mixtures thereof; [0176] b) a step of supplying said premixture formed in step a) to be fed into a Process 11 Hygienic type extruder of Thermo-Fischer®; [0177] c) a step of mixing, in said extruder, said premixture to obtain a mixture; [0178] d) a step of hot melt extrusion thermoforming said mixture obtained in step c) in said extruder to obtain a friable/brittle thermoformed extrudate, the hot melt extrusion step being carried out at a rotation speed of an extrusion screw of 200 rpm and at a temperature comprised between 20 and 80° C., [0179] e) a step of cooling at the outlet of the extruder said friable/brittle thermoformed extrudate obtained in step d); and [0180] f) a step of cutting/grinding, at a grinder, the cooled friable/brittle thermoformed extrudate obtained in step e) in such a way to to obtain a homogeneous powder, that is to say a thermoformed extrudate packaged in powder (in powder form).

[0181] The thermoforming temperature at which the hot melt extrusion step is carried out is determined by the type of constituents used, in particular according to the type of carrier and/or plasticizer used, which the person skilled in the art is able to determine. Moreover, a person skilled in the art, in particular according to the type of extruder employed and in accordance with the general principle of the hot melt extrusion (HME), is able to define possible temperature stages in different zones along the extrusion screw(s) so that there is a gradual increase in the temperature within the material transported by the extrusion screw(s), this in a advancing direction of the material within the extruder. Typically, between zones defined along the extrusion screw(s), temperature differences in the range of 0 to 40° C. are observed. For example, in the context of the present invention, the compositions tested below were obtained in a Process 11 Hygienic type extruder of Thermo-Fischer® having 8 temperature zones which are as follows in a advancing direction of the material moving at a speed of 200 rpm: 20° C.-40° C.-60° C.-60° C.-80° C.-80° C.-80° C. and 80° C.

Example 2: Dispersion and Solubility Test of Thermoformed Compositions According to the Invention

[0182] Thermoformed compositions, obtained according to the manufacturing method described in example 1, were tested in terms of dispersion and solubility of cannabidiol. This dispersion and this solubility were measured over time starting from thermoformed extrudates obtained according to the invention. As indicated above, the thermoformed extrudates are in the form of a homogeneous powder (ground material) in which cannabidiol (a non-euphoric cannabinoid) preferentially comprises at least one amorphous phase.

[0183] The dispersion and solubility test was carried out with a vane dissolution apparatus starting with approximately 360 mg of thermoformed extrudate, at a temperature of 37° C. under stirring at 50 rpm in 900 ml of a 0.1N HCl dissolution medium. This dispersion and solubility test was carried out according to the recommendations of the pharmacopoeia Ph.Eur.9.0 (Recommendations on Dissolution Testing). At determined times (after 15 min, after 30 min, after 1 h and after 2 h), a sample of 1 ml is taken to carry out the dispersion and solubility test.

[0184] In order to perform the dispersion and solubility test, the sample is diluted in an appropriate solvent (methanol) then filtered through a filter (PET, pore size of 0.45 μm, Macherey Nagel) before HPLC analysis (Nucleodur 100-5 EC C18 125/4 column (Macherey-Nagel): mobile phase: 85%—A (Methanol) and 15% B (Water); flow rate: 1 ml/min, loop: 10 μl, t°=25° C.; 220 nm).

[0185] The thermoformed compositions according to the invention listed in Table 1 were formulated according to the method of the invention and tested in terms of dispersion and solubility over time according to the principle indicated above. Cannabidiol (CBD) in native crystalline form and in powder form (native CBD) was used as a control. The amounts mentioned in Table 1 are percentages by weight of the compounds used (subjected to the method according to the invention) based on the total weight of the composition.

TABLE-US-00001 TABLE 1 Cannabidiol (CBD) (1) Protein (2) Saccharide (3) Glycerol (4) Compo 1 20 70 0 10 Compo 2 20 0 70 10 (1) Cannabidiol (Shanghai Freemen) (2) Bovine collagen 5000 Da (Rousselot) (3) Modified Starch Cleargum ®CO01 (Roquette) (4) Glycerol (Brenntag)

[0186] The results of the dispersion and solubility tests obtained are shown in FIG. 1. As can be seen, the dispersion+the solubility measured for the CBD starting from compositions in the form of thermoformed extrudates according to the invention (Compo 1 and Compo 2) is clearly higher relative to the control (native CBD).

Example 3: Dispersion and Solubility Test of Thermoformed Compositions According to the Invention

[0187] Thermoformed compositions, obtained according to the manufacturing method described in Example 1, were tested in terms of dispersion and solubility of cannabidiol. This dispersion and this solubility were measured over time starting from thermoformed extrudates obtained according to the invention. As indicated above, the thermoformed extrudates are in the form of a homogeneous powder (ground material) in which cannabidiol (a non-euphoric cannabinoid) preferentially comprises at least one amorphous phase.

[0188] The dispersion and solubility test was carried out as indicated in Example 2.

[0189] The thermoformed compositions according to the invention listed in Table 2 were formulated according to the method of the invention and tested in terms of dispersion and solubility over time according to the principle indicated above. Cannabidiol (CBD) in native crystalline form and in powder form (native CBD) was used as a control. The amounts mentioned in Table 2 are percentages by weight of the compounds used (subjected to the method according to the invention) based on the total weight of the composition.

TABLE-US-00002 TABLE 2 Cannabidiol (CBD) (1) Protein (2) Glycerol (3) Compo 1 20 70 10 Compo 2 25 70 5 Compo 3 30 70 0 (1) Cannabidiol (Shanghai Freemen) (2) Collagen Peptan B 5000 HD (Ingrizo) (3) Glycerol (Brenntag)

[0190] The results of the dispersion and solubility tests obtained are shown in FIG. 2. As can be seen, the dispersion+the solubility measured for the CBD starting from compositions in the form of thermoformed extrudates according to the invention (Compo 1, Compo 2 and Compo 3) is significantly higher relative to the control (native CBD).

Example 4: Dispersion and Solubility Test of Thermoformed Compositions According to the Invention

[0191] Thermoformed compositions, obtained according to the manufacturing method described in Example 1, were tested in terms of dispersion and solubility of cannabidiol. This dispersion and this solubility were measured over time starting from thermoformed extrudates obtained according to the invention. As indicated above, the thermoformed extrudates are in the form of a homogeneous powder (ground material) in which cannabidiol (a non-euphoric cannabinoid) preferentially comprises at least one amorphous phase.

[0192] The dispersion and solubility test was carried out as indicated in Example 2.

[0193] The thermoformed compositions according to the invention listed in Table 3 were formulated according to the method of the invention and tested in terms of dispersion and solubility over time according to the principle indicated above. Cannabidiol (CBD) in native crystalline form and in powder form (native CBD) was used as a control. The amounts mentioned in Table 3 are percentages by weight of the compounds used (subjected to the method according to the invention) based on the total weight of the composition.

TABLE-US-00003 TABLE 3 Cannabidiol (CBD) (1) Saccharide Glycerol (6) Compo 1 20 70 (2) 10 Compo 2 20 70 (3) 10 Compo 3 20 70 (4) 10 Compo 4 20 70 (5) 10 (1) Cannabidiol (Shanghai Freemen) (2) Dextrin Tackidex ® C760 (Roquette) (3) Modified Starch Cleargum ® CB95 (Roquette) (4) Modified Starch Cleargum ® MG85 (Roquette) (5) Modified Starch Cleargum ® LG7015 (Roquette) (6) Glycerol (Brenntag)

[0194] The results of the dispersion and solubility tests obtained are shown in FIG. 3. As can be seen, the dispersion+the solubility measured for the CBD starting from compositions in the form of thermoformed extrudates according to the invention (Compo 1, Compo 2, Compo 3 and Compo 4) is always higher relative to the control (native CBD).

[0195] The present invention has been described in relation to the specific embodiments, which have a purely illustrative value and should not be considered as limitative. In general, it will appear obvious to the person skilled in the art that the present invention is not limited to the examples illustrated and/or described above.

[0196] The use of the verbs “comprise”, “include”, or any other variant, as well as the conjugations thereof, can in no way exclude the presence of elements other than those mentioned.

[0197] The use of the indefinite article “a”, “an”, or of the definite article “the”, to introduce an element does not exclude the presence of a plurality of these elements.