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EP-4734961-A1 - NEW METHOD OF PRODUCING AN AQUEOUS MESOPARTICLE COMPOSITION COMPRISING A LIPOPHILIC COMPOUND

EP4734961A1EP 4734961 A1EP4734961 A1EP 4734961A1EP-4734961-A1

Abstract

Described is a method for the preparation of an aqueous mesoparticle composition comprising a lipophilic compound, comprising the steps of: a. Providing an emulsifier or a blend of emulsifiers in powder form; b. Mixing one or more oils at a temperature above 40°C where all oils have become liquid, wherein said oils differ in melting temperature and which mixture comprises at least a sufficient amount of medium chain triglycerides to enable the composition formed in step g have a partly liquid oil phase at temperatures around about 4°C; c. Adding the hydrophobic or amphiphilic compound in any hydrophobic solvent to the oil mixture; d. Optionally letting the mixture cool down to room temperature; e. Adding the emulsifier powder and water to the oil mixture and letting the mixture emulsify, under optional agitation and heating to 30-40°C; f. Subjecting the emulsified mixture to a sonication and optionally mixing or fluidisation treatment until the average particle size of the mixture remains stable; g. Cooling down the sonicated mixture allowing sufficient time for crystallisation; and h. Optionally, a second sonication treatment while keeping the mixture cold and compositions produced by the above method.

Inventors

  • BEINTEMA, Rients Pieter
  • JOUBERT, George Peter

Assignees

  • BIOGNTX R&D B.V.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1 . Method for the preparation of an aqueous mesoparticle composition comprising a lipophilic compound, comprising the steps of: a. Providing an emulsifier or a blend of emulsifiers in powder form; b. Mixing one or more oils at a temperature above 40°C where all oils have become liquid, wherein said oils differ in melting temperature and which mixture comprises at least a sufficient amount of medium chain triglycerides to enable the composition formed in step g to have a partly liquid oil phase at temperatures around about 4°C; c. Adding the hydrophobic or amphiphilic compound in any hydrophobic solvent to the oil mixture; d. Optionally letting the mixture cool down to room temperature; e. Adding the emulsifier powder and water to the oil mixture and letting the mixture emulsify, under optional agitation and heating to 30-40°C; f. Subjecting the emulsified mixture to a sonication and optionally mixing or fluidisation treatment until the average particle size of the mixture remains stable; g. Cooling down the sonicated mixture allowing sufficient time for crystallisation; and h. Optionally, a second sonication treatment while keeping the mixture cold.
  2. 2. Method according to claim 1 , wherein the emulsifier is a blend of emulsifiers, preferably wherein said emulsifiers are non-toxic emulsifiers, more preferably wherein said blend comprises lecithin and sugar-based emulsifiers, such as sucrose ester and/or cyclodextrin.
  3. 3. Method according to claim 2, wherein the emulsifier is a blend comprising sucrose ester, cyclodextrin and lecithin, preferably sunflower lecithin.
  4. 4. Method according to claim 3, wherein the amount of lecithin is such, that in the final sonified mixture from step g. the concentration of lecithin is less than 5%, preferably less than 2%, more preferably less than 1 %.
  5. 5. Method according to claim 3 or 4, wherein the amount of sugar-based emulsifiers is at least two times the amount of lecithin, preferably at least four times.
  6. 6. Method according to any of claims 3-6, wherein the ratio between sucrose ester, cyclodextrin and lecithin is 2 : 2 : 1.
  7. 7. Method according to any of the previous claims, wherein the oil mixture comprises oils or fats that are non toxic.
  8. 8. Method according to any of the previous claims, wherein the oil mixture comprises at least one oil with a melting point above 50°C, preferably above 60°C.
  9. 9. Method according to any of the previous claims, wherein the oil mixture comprises an oil with a melting point in between room temperature and body temperature .
  10. 10. Method according to any of the previous claims, wherein the oil mixture comprises stearic acid, coconut oil and medium chain triglycerides.
  11. 11. Method according to any of the previous claims, wherein the oil mixture, when mixed with the lipophilic compound comprises the components in a ratio of stearic acid : coconut oil : medium chain triglycerides : solvent with lipophilic compound of 1 : 2 : 3 : 5.
  12. 12. Method according to any of the previous claims, wherein a non-toxic antioxidant is added to the oil mixture, preferably wherein said antioxidant is a blend of antioxidants, more preferably wherein said antioxidant or blend of antioxidants in total does not exceed the amount of 10% of the oil mixture, preferably does not exceed the amount of 5% of the oil mixture.
  13. 13. Method according to claim 12, wherein said blend of antioxidants comprises linseed oil, hempseed oil, tocopherol and/or rosemary extract; preferably where it comprises linseed oil, hempseed oil, tocopherol and rosemary extract, preferably in a ratio of 2 : 2 : 2 : 1 .
  14. 14. Method according to any of the previous claims, wherein the ratio of oil to emulsifiers is from 3.0 to 5.0, more preferable from 3.2 to 4.0, more preferably about 3.5
  15. 15. Method according to any of the previous claims, wherein the water is food-grade water.
  16. 16. Method to any of the previous claims, wherein the mesoparticles in the sonicated mixture will have a mean particle size of 10 - 600 nm, preferably of 50 - 150 nm and more preferably of 80 - 130 nm, most preferably about 110 nm.
  17. 17. Method according to any of the previous claims, wherein glycerol is added to the sonicated mixture, more preferably wherein the concentration of glycerol is more than 20%, preferably more than 25%.
  18. 18. Method according to any of the previous claims, wherein the lipophilic compound is a plant-based extract in oil.
  19. 19. Method according to claim 18, wherein the plant-based extract is an extract of Cannabis sativa, preferably, wherein said extract comprises a cannabinoid, more preferably, wherein said extract comprises a cannabinoid chosen from the group consisting of A9-tetrahydrocannabinol (THC), A9-tetrahydrocannabinolic acid (A9- THCA or THCA), A9-tetrahydrocannabiorolic acid (A9-THCA-C1 or THCA-C1), A9-tetra-hydrocannabiorcol (A9-THCO-C1 or THCO-C1), A9-tetrahydrocanna- biorcolic acid (A9-THCOA or THCOA), A9-tetra-hydrocannabivarin (A9-THCV or THCV), A9-tetrahydrocannabivarinic acid (A9-THCVA or THCVA), trihydroxy-A9- tetrahydro-cannabinol (TRIOH-THC), A10-tetrahydro-cannabinol (A10-THC), tetrahydro-cannabiphorol (THCP), THC-0 acetate (THCO), hexa-hydrocannabinol (HHC), 10-oxo- A6a-tetrahydrocannabinol (OTHC), A8-tetra-hydrocannabinol (A8- THC), A8-tetrahydrocannabinolic acid (A8-THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidiorcol (CBDC1), cannabidiol-C4 (CBDC4), cannabidiol dimethyl ether (CBDD), cannabidiol monomethyl ether (CBDM), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), nabilone, nabiximol, anandamide, cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerolic acid A monomethykether (CBGAM), canna-bigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabigerol mono-methylether (CBGM), cannabinol (CBN), cannabinolic acid (CBNA), cannabdiorcol (CBN-C1), cannabinol-C2 (CBN-C2), cannabivarin (CBN-C3), cannabinol-C4 (CBN-C4), cannabinodivarin (CBNDC3), cannabinol methylether (CBNM-C5), cannabichromene (CBC), cannabichromenc acid (CBCA), cannabichromanon (CBCN-C5), cannabicoumaronone (CBCON-C5), cannabi-chromanone-C3 (CBCN-C3), cannabichromevarin (CBCV), cannabichromevarinic acid (CBCVA), cannabielsoin (CBE-C5), cannabigelndol-C3 (OH-iso-HHCVC3), C3-canna- bielsoicacid B (CBEA-C3 B), cannabifuran (CBF), dehydrocannabifuran (DCBF- C5), cannabifuran (CBF-C5), dehydrocannabifuran (DCBF or CBFD), cannabicyclol (CBL-C5), cannabicyclovarin (CBLV-C3), cannabitriol (CBT), cannabitriolvarin (CBTV), cannabiripsol (CBR), cannabinodivarin (CBV or CBVD), 2-arachidonoylglycerol (2-AG), 2-arachidonoylglycerol ether (2-AGE), isotetrahydrocannabinol, isotetrahydrocannabivarin, palmitoylethanolamide, epigallo- catechin (EGC), (-)-epicatechin gallate (ECG) and (-)-epigallocatechin gallate (EGCG).
  20. 20. Method according to any of the previous claims, wherein said extract comprises THC or a blend with THC.

Description

NEW METHOD OF PRODUCING AN AQUEOUS MESOPARTICLE COMPOSITION COMPRISING A LIPOPHILIC COMPOUND BACKGROUND Mesoparticles comprise particles having an average size of 80 - 300 nm and are sometimes indicated in the scientific literature as nanoparticles (NPs) and nanocarriers (NC). However, for the present invention nanoparticles are meant to be particles with an average size of 100 nm or less, while mesoparticles are particles having a size that is larger than this common nanoscale. Mesoparticle formulations of highly lipophilic drugs enable the delivery of compounds that previously could not be administered at therapeutic levels by conventional formulations. Complex NC constructs, such as liposomes, nanocapsules, polymeric NPs, micelles and polymersomes can improve the observed therapeutic effect of drug compounds by increasing solubility, improving pharmacokinetics or altering biodistribution. Metallic, organic, inorganic and polymeric structures, including dendrimers, micelles, and liposomes are frequently considered in designing the target-specific drug delivery systems. In particular, those drugs having poor solubility with less absorption ability are tagged with these mesoparticles. However, the efficacy of these mesostructures as drug delivery vehicles varies depending on the size, shape, and other inherent biophysical/chemical characteristics. For these reasons, there is still need for a new, stable mesoparticle composition comprising a lipophilic compound enabling longterm storage and easy application for producing a pharmaceutical composition comprising the lipophilic compound. Many drugs are lipophilic and thus would require a different carrier system to reach their target than drugs that are hydrophilic. A non-exhaustive list of such compounds includes the well known drugs imipramine, verapamil, vortiotoxetine, lurasidone, posaconazole, diazepam (and various other benzodiazeptines like midazolam and oxazepam), propranolol, trazodone, phenytoin, various statins such as atorvastatin, simvastatin and lovastatin, bifonazole, ciprofloxacin, clarithromycin, tigecyclin and clindamycin. Outside the pharmaceutical compounds also many other compounds have a hydrophobic or amphiphilic character, such as the plant-derived cannabinoids and auxins. In practice, (oral) compositions with lipophilic substances, such as cannabinoid compositions are usually provided in the form of a solution in an oily solvent wherein, in the example of cannabinoids, compounds such as cannabidiol (CBD) and tetrahydrocannabinol (THC) dissolve, allowing a rather concentrated cannabinoid content. Most of the known compositions are oil-based, i.e. an oily solution wherein the cannabinoids are dissolved, or a water-in oil dispersion, wherein the cannabinoids are in the oily phase. For oral administration, the oily solvent needs to be food grade and acceptable for oral administration. The composition is defined as oily or oil-based when more than half of the volume of the composition is an oil, and in case of a dispersion, the oily phase should be the continuous phase. Ingestion of oil is however cumbersome and since the ingestion volume is limited, the cannabinoid compositions known in the art are highly concentrated, e.g. in concentrations of 5 w/w% to 60 w/w%. Such high concentrated composition are however difficult to dose properly and often, undesired side effects are observed. Furthermore, the bioavailability of lipophilic compounds from oily preparations is low, which means that much of the ingested active compound is not utilized. In more recent times many approaches have been published to provide waterbased compositions comprising lipophilic substances, such as cannabinoids. The present invention, which provides an aqueous mesoparticle composition, is advantageously suited for comprising such a lipophilic substance, in particular a plant extract, such as a cannabinoid composition, and thereby overcomes many of the disadvantages of the presently available aqueous dosage forms of lipophilic substances, such as cannabinoids. Mesoparticles have been a big step forward in getting lipophilic drugs, like some components of cannabis, into the body. They have helped drugs work better by making them dissolve more easily, getting them to the right places in the body, and changing how they spread out once they are there. However, there are still some problems to solve. One big issue is finding a way to create mesoparticles that are stable for a long time and are easy to apply, especially for drugs that do not like water. Therefore in the present invention water soluble mesocarriers have been developed in which the oil phase still is partly liquid. Further, such mesoparticles may not only be used in pharmaceutics, but they can also be used in cosmetics and even in uses not intended for humans (but e.g. for plant nutrition and protection). Right now, most methods for delivering lipophilic substances, such as cannabis components, use an oil