WO2019025880A1 - Cannabis oil nanoparticles micro-encapsulated in powder - Google Patents

Cannabis oil nanoparticles micro-encapsulated in powder Download PDF

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Publication number
WO2019025880A1
WO2019025880A1 PCT/IB2018/054559 IB2018054559W WO2019025880A1 WO 2019025880 A1 WO2019025880 A1 WO 2019025880A1 IB 2018054559 W IB2018054559 W IB 2018054559W WO 2019025880 A1 WO2019025880 A1 WO 2019025880A1
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Prior art keywords
cannabis
nanoparticles
mixtures
pharmaceutically acceptable
group
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PCT/IB2018/054559
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Spanish (es)
French (fr)
Inventor
Zahara Dolid Colorado Arango
Alejandro Mauricio Vargas Upegui
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Alsec Alimentos Secos S.A.S.
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Publication of WO2019025880A1 publication Critical patent/WO2019025880A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • 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

Definitions

  • the present invention relates to oily micro-encapsulated cannabis nanoparticles in powder form for applications in the pharmaceutical, food and cosmetic fields.
  • the present invention relates to powdered microencapsulated oily cannabis nanoparticles, characterized in comprising a cannabis extract and pharmaceutically acceptable carriers, wherein the nanoparticles have a particle size between 1 and 500 nm with applications in the pharmacy, food industry and cosmetics.
  • cannabis contains some 60 phytocannabinoids, among which the best known for medicinal use are tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) and its attention is focused on the Therapeutic use of the active principles of the plant.
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • CBN cannabinol
  • CBN is another important cannabinoid.
  • CBN has only a slight psychotropic effect and presumably acts as a weak receptor agonist CB1 and CB2 in the endocannabinoid system.
  • it is known for its multiple applications at the medical level, for example, as an anticonvulsant and as an antiemetic.
  • the CBN may be responsible, in part, for the calming effect of some types of cannabis
  • patent WO2016147186 describes a cannabis-based emulsion formulation for use in various medical conditions and optionally with various pharmaceutical or nutraceutical compositions, in which the oil fraction used contains approximately 50% cannabinoids.
  • the present invention further describes manufacturing methods and uses of the aforementioned composition.
  • patent WO2016094810 refers to cannabinoid compositions, wherein said compositions can be encapsulated (for example, microencapsulated).
  • these compositions can be administered to a subject, such as by oral consumption or topical treatment.
  • patent WO2016144376 teaches compositions of cannabinoid phospholipid nanoparticles formed from phospholipids and simpler lipids in a sequence process! and creates standardized dosage forms with precise amounts of cannabinoids; producing an increase in the transport of cannabinoids through the hydrophobic mucosa; increase the bioavailability of the cannabinoid from 2 to 8 times, decrease the dose of cannabinoids from 2 to 8 times less than the amount of cannabinoids needed to cause the same therapeutic effect compared to raw and non-encapsulated cannabinoids; where the dynamic structure of nanoparticles reduces the adverse effects of cannabinoids; and allows a more effective and safe cannabinoid therapy.
  • patent US5989583 reports that lipoflix substances of low oral bioavailability are mixed with at least one solid fat and phospholipid to obtain a suitable dry solid composition as an oral dosage form.
  • Solid lipid compositions are exemplified for food additives or dietary supplements such as coenzyme Q10 and for drugs such as dexanabinol.
  • Coenzyme Q10 dry lipid mixtures show enhanced drug release in vitro and improved oral bioavailability in vivo compared to a commercial CoQ10 formulation.
  • the dry lipid mixture of dexanabinol similarly shows an improved oral bioavailability compared to known formulations.
  • patent EP2444071 teaches a formulation comprising a plurality of mini-cups without cracks, the mini-cups having a diameter of 0.5 mm to 5 mm, and wherein the mini-cups have a core containing an active entity and an encapsulating body.
  • the active entity being in the form of one or more of: a microemulsion, a nanoemulsion, a self-emulsifying release system, an auto-emulsifier delivery system, a biostable perfluorocarbon formulation, a complex with cyclodextrin (and the like), liposomes, hydrogel, targeted lymphatic delivery system, bi liquid layers, an aqueous system, wax, emzaloide, and natural vegetal extract
  • Figure 1 shows a microphotograph showing oily nanoparticles of powdered microencapsulated cannabis according to the invention, where it is observed that they have a homogeneous shape.
  • Figure 2 shows the final appearance and appearance of the powder of the product according to the invention, which comprises the microencapsulated oily cannabis nanoparticles in which a fine powder is observed.
  • the present invention is directed to a product that is micro-encapsulated powdered oily nanoparticles of cannabis.
  • the nanoparticles have a size between 1 and 500 nm and these nanoparticles are comprised of cannabis oil and a pharmaceutically acceptable encapsulating or carrier material and GRAS (Generally recognized as safe) in the case of foods and which may comprise antioxidants , emulsifiers, proteins, pH regulators; dyes, stabilizers, starches, carbohydrates, phospholipids, sweeteners, and anti-compactants among other pharmaceutical, food or cosmetically acceptable components.
  • GRAS Generally recognized as safe
  • Cannabis oil is an oil that results from any type of extract that contains substances identified as cannabionoids (medicinal compounds).
  • the cannabis extracts that can be used in the present invention there are extracts of any type or category of cannabis plants, mainly of the sativa and indica varieties and the crosses of these. Additionally, it is possible to use any solvent variety or solvent mixtures.
  • the most known and used solvents in the extracts of the present invention are the food grade organic solvents and pharmaceutically acceptable, for example, aqueous, alcoholic and mixtures thereof. It is also possible to use freeze-dried extracts which are reconstituted in water or in any other pharmaceutically acceptable solvent.
  • the main ingredient or active ingredient is cannabis oil which is in a proportion of from 5% to 95% by total weight of the composition:
  • the cannabinoids in the cannabis extract is a main compound, the cannabinoids named THC, CBD, CBN, CBC, CBG, with percentages between 0.1% of the extract up to 60% of it.
  • these are the components that, with the help of other excipients, encapsulate the active ingredient of cannabis within the encapsulating materials that can be used in the present invention are: stabilizers, carbohydrates, proteins, carbohydrates and starches, wherein the proteins may be present from 0.1 to 20% by weight, stabilizers from 0.01% to 5% by weight, starches from 1% to 30% and carbohydrates from 1 % up to 30% by weight.
  • Another component that can participate in the microencapsulated nanoparticles in the present invention are materials that can be selected from a group of natural or synthetic Antioxidants such as carotenoids, polHenoles, tocofsroles, antiocian ⁇ nas or BHT and mixtures of the same; Emulsifiers such as ⁇ and mono glycerides of fatty acids, monoleates, TWIN 80, SPAN 80, lecithin and mixtures thereof; PH regulators such as sodium and calcium tripolyrbhosphate, sodium, calcium and potassium diphosphates, acid salts (sodium lactate, sodium crtrate) and mixtures thereof; Stabilizers such as canagenins (K, ⁇ , ⁇ , I), CMC, xanthan gums, arabic, guar and carob and mixtures thereof; Phospholipids such as Lecithin and other phospholipids of vegetable origin and mixtures thereof; Lipophilic sweeteners and / or potentifiers such as
  • the antioxidants can be in a proportion of from 0.001% to 0.1%; the emulsifiers from 0.1% to 5%; the pH regulator from 0.1 to 5%; the stabilizers from 0.01% to 5%, the phospholipids from 0.1% to 5%, and the anticompactants from 0.1 to 5%.
  • microencapsulated cannabis oily nanoparticles of the present invention are obtained by a process that combines the steps of nanotechnology (nanoemulsion formation), microencapsulation and spray drying wherein the nanotechnology comprises: PREPARATION LIPOPHYL PHASE It is understood as any molecule or mixture of them that have affinity for fats and great solubility in lipids, among other compounds can be mentioned fatty acids, vitamins, waxes, liposolubies extracts or essential oils, for this case is the mixture of:
  • hydrophilic phase is meant that phase that has an affinity for water.
  • the hydrophilic particles tend to approach and maintain contact with water.
  • the hydrophilic molecules are in turn lipophobic, ie they have no affinity for lipids or fats and do not mix with them.
  • water is added in a hydrolytic phase mixer, to which it is necessary to increase its temperature in a range between 30 ° C and 100 ° C, preferably 70 ° C.
  • a hydrophilic surfactant of a non-ionic character is added slowly with an HBL higher than 13.
  • the mixture that is formed is subjected to a stirring process by means of a programmed stirrer with a rotation frequency between 100 rpm and 1000 rpm, preferably 500 rpm controlling the generation of foam and the previously reached temperature.
  • an encapsulating matrix selected from the group consisting of carbohydrates such as starch and derivatives, maltodextrins, maize syrups, cyclodextrins, carboxymethylcellulose and derivatives is added; gums such as arabic, xanfhan, guar, gellan, tara, cellulose, garrafin, tragacanth, karaya, mesquite, sodium alginate, carrageenan; lipids such as waxes, paraffins, fats, phospholipids, glycerides and fatty acids; proteins like gelatin, soy protein or isolates of soy, caseinates, whey proteins, whey, casein and mixtures thereof.
  • the hydrophilic surfactant can be selected from the group formed by those of the ethoxylated linear alcohol type, ethoxylated alkyl phenols, fatty acid esters, amine and amide derivatives, ethylene oxide-propylene oxide copolymers, ethoxylated polyalcohol polyalcohols, phyllos ( mercaptans) ethoxylates and mixtures of these.
  • a hydrophilic masking agent can be added, which, due to its interaction with the surfactant, reduces the generation of foam. The generation of foam in the agitation process prevents the correct homogenization of the hydrophilic phase due to the fact that air particles are incorporated into said phase.
  • Said hydrophilic masking agent can be selected from the group consisting of the statistical mixtures of one or several sweeteners and of one or more hydrophilic potentiators, such as: refined sugars, high fructose corn syrup, crystalline fructose, glucose, dextrose , sweeteners from corn, honey, lactose, maltose, various syrups, inverted sugars or concentrated fruit juice, sorbitol, mannitol, xylitol, isomaft, hydrogenated starch hydrolysates and others such as, acesulfame k, alitamo , aspartame, cyclamate, neohesperidin, saccharin, sucralose, stevioside, thaumatin.
  • hydrophilic potentiators such as: refined sugars, high fructose corn syrup, crystalline fructose, glucose, dextrose , sweeteners from corn, honey, lactose, maltose, various
  • the hydrophilic phase is mixed with a lipophilic phase in the hydrophilic phase mixer.
  • the lipoflicic phase is prepared by the addition of a lipophilic agent or nucleus selected from the group consisting of lipids, phospholipids, silicones, paraffins, waxes among others, in a lipoflex phase mixer. Then a first temperature increase is made until reaching a temperature value in a range between 30 ° C and 45 ° C, preferably 40 ° C.
  • a preserving agent which may be an antioxidant of natural or synthetic origin, capable of retarding or preventing the oxidation of the lipoflic phase.
  • antioxidants that can be used are vitamins A, E, C, oligoelements, polyphenols or mixtures of these.
  • the mixture that is formed is subjected to a stirring process by means of a programmed agitator with a rotation frequency between 500 and 1500 rpm, preferably 800 rpm, controlling the generation of foam.
  • a second temperature rise is made until reaching a value between 45 ° C and 80 ° C, preferably 70 ° C.
  • a non-ionic lipophilic surfactant with a HBL of less than 9 is added slowly.
  • a lipophilic masking agent and / or any lipoflicic source can be added which, by its interaction with said lipophilic surfactant, allows improving the organoleptic properties of the lipophilic surfactant. nucleus.
  • Said lipophilic masking agent can be selected from the group consisting of statistical mixtures of one or more sweeteners and of one or more ionophilic enhancers, such as: refined sugars, high fructose corn syrup, crystalline fructose, glucose, dextrose , sweeteners from maize, honey, lactose, maltose, various syrups, inverted sugars or concentrated fruit juice, sorbitol, mannitol, xylitol, isomalt, hydrogenated starch hydroisases and others such as, acesulfarno k, alitame, aspartame, cyclamate, neohesperidin , saccharin, lucid, stevioside, thaumatin and equivalents known to the skilled artisan.
  • ionophilic enhancers such as: refined sugars, high fructose corn syrup, crystalline fructose, glucose, dextrose , sweeteners from maize, honey, lac
  • both the hydrophilic phase and the lipofiic phase are prepared, they are combined in a phase mixer and said mixture is subjected to a stirring process between 4000 and 9000 rpm, preferably 5000 rpm, controlling the generation of foam and the temperature previously reached, generating a pre-emulsion.
  • the previously obtained pre-emulsion is subjected to the application of a high mechanical stress, which can be carried out through a process of agitation and / or high pressure.
  • a high mechanical stress which can be carried out through a process of agitation and / or high pressure.
  • the temperature of the mixture should not exceed 100 ° C, preferably 80 ° C.
  • the minimum frequency of said agitation between 10000-60000 rpm and 1000-3000 PSI (6.89 MPa at 20.68 MPa), in order that the shear force carried out on the mixture is high enough to decrease the droplet size of the emulsion formed at the nanometer scale, particularly average droplet sizes between 1- 500 nm.
  • the minimum pressure must not be less than 700 bar (70 MPa), in order that the force made on the mixture is enough to reduce the size of droplet of the emulsion formed at nanometric scale, particularly average droplet sizes between 1- 500 nm.
  • the nanoemulsion is generated, it is subjected to a stabilization process through a temperature change, which can occur quickly or slowly, starting at a temperature of 1 ° C until reaching a value of 25 ° C.
  • the protein is added to the nanoemulsion and then subjected to a high mechanical stress, which can be effected through a process of agitation and / or high pressure.
  • a high mechanical stress which can be effected through a process of agitation and / or high pressure.
  • the temperature of the mixture should not exceed 100 ° C, preferably 95 ° C, pH between 3.5 and 5.2, preferably 4.1.
  • the protein dimer polymerizes in an octamer of 100-180 kd.
  • the content of cysteine and cystine residues facilitates the polymerization of the protein by formation of intermolecular disulfide bridges during processing at high temperature.
  • the microencapsulation of said nanoemulsion is proceeded.
  • the microencapsulation starts with a filtering process of the generated nanoemulsion.
  • the product of the nanoemulsion is passed through a filtration medium, which allows to remove impurities.
  • the filtration medium used in this step is characterized in that the particle size that passes through it is less than 75 micrometers.
  • the product of this process is collected in a tank with constant stirring and temperature control.
  • the stirring effected in said tank should be maintained between 500 and 1000 rom, preferably 800 rpm, and the temperature of the product at a constant value between 40 and 70 ° C, preferably 65 ° C.
  • the filtration medium can be selected from the group formed by the open filters, the slow filters, the gravity filters, the fast filters, the pressure filters and the filters. closed filters.
  • Impurity means any component that consists of foreign material that is not part of raw materials, lumps or solid particles that are not disowned.
  • the product stored in the homogenizer tank is then taken to a spray drying equipment (150 L of water / h), through a positive pressure pump that allows to feed said drying equipment with a flow higher than 2.3 liters per minute, in order to carry out a microencapsulation process.
  • Spray drying equipment may employ nozzle or disc type spray media. If the drying process is carried out with a device that uses a spray nozzle type, a pressure system must be incorporated to control the flow pressure at the equipment entrance. Said inlet pressure to the drying equipment will be 300 to 600 psi (2.07 MPa to 4.14 MPa). The inlet temperature to the dryer must be between 120 - 270 ° C, in order to decrease the humidity of the emulsion.
  • the residence time of the particle inside the equipment should be between 15 and 30 seconds and the minimum temperature of the exhaust air between 75 to 95 ° C.
  • the microencapsulated product that contains the oily nanoparticles of cannabis through said drying process is collected in a collecting medium for later to be taken to a sieving process.
  • a granulometric classification of the microencapsulated product is carried out, in order to obtain particles with average temperatures below 1000 microns, preferably 400 microns. Additionally, in carrying out said sieving process of the microcapsules, it is sought to separate impurities and control the quality of the product obtained. After the sieving process, a stage of stabilization of the microcapsules is developed, where it is sought to gradually reduce the temperature of the product up to a maximum value of 10 ° C. This process is preferably carried out in a room with thermal control.
  • an anticompacting agent is added, which reduces the tendency of the microcapsules to cohere, adhere, aggregate or. clumping together due to their hygroscopic characteristics.
  • Said anticompacting agent is constituted by substances able to avoid the formation of aggregate structures or lumps by agglutination of particles, and can be selected from the group consisting of dicalcium diphosphate, calcium and sodium polyphosphates, calcium polyphosphates, silicon oxide, calcium silicate. , potassium aluminum silicate, zinc silicate, sodium aluminum silicate, calcium aluminum silicate, stearic acid, aluminum stearate, magnesium stearate, oleic acid salt with calcium, potassium and sodium, and all possible combinations.
  • the anticompacting agent For the addition of the anticompacting agent, first weigh the amount of microencapsulated product to which said agent will be added, to later determine the amount of agent that will be added.
  • the amount of anti-compactant agent in the mixture is in a range between 0.1 and 3%; preferably 2%.
  • the powder product together with the anti-compacting agent are added to a finished product mixer for complete homogenization of the microencapsulated product.
  • the lipophilic active compounds or emulsifiers include cosmetic oils, edible oils, essential oils, as well as any of their combinations.
  • Example 1 To obtain the micro-encapsulated powdered cannabis nanoparticles, a process is carried out that combines the steps of nanotechnology, microencapsulation and spray drying where nanotechnology includes:
  • a mixture of the cannabis oil is made with the proteins, the emulsifier (a and mono glycerides of fatty acids) and the phospholipids (Lecithin). (See ranges in table N 1).
  • the water is added to the previous mixture, in a hydrophilic phase mixer, at which it is necessary to increase its temperature in a range at 70 ° C.
  • a non-ionic hydrophilic surfactant is added slowly with an HBL higher than 13.
  • the mixture that is formed is subjected to a stirring process by means of a programmed agitator with a rotation frequency of 550 rpm controlling the generation of foam and the temperature previously reached.
  • an encapsulating matrix selected from the group consisting of maftodextrins is added.
  • a hydrophilic masking agent is added, which, due to its interaction with the surfactant, reduces foam generation. Subsequently the two phases are mixed, then a first temperature increase is made up to 40 ° C.
  • an antioxidant agent is added.
  • the mixture that is formed is subjected to a stirring process by means of a programmed agitator with a rotation frequency of 700 rpm, controlling the generation of foam.
  • a second temperature rise is made until reaching a value of 75 ° C.
  • a non-ionic lipofunctional surfactant with an HBL of less than 9 is added slowly.
  • Said mixture is passed through a phase mixer and said mixture is subjected to a 5000 rpm stirring process, controlling the generation of foam and the previously reached temperature, generating a pre-emulsion
  • the previously obtained pre-emulsion is subjected to the application of a high mechanical stress and the temperature of the mixture is adjusted between a range of 70 to 100 ° C, preferably at 80 ° C.
  • the temperature of the mixture is adjusted between a range of 70 to 100 ° C, preferably at 80 ° C.
  • this nanoemulsion is stabilized with a temperature change up to 20 ° C.
  • DRYING BY ATOMIZATION Microencapsulation is performed with a filtering process of the generated nanoemulsion.
  • the product of the nanoemulsion is passed through a filtration medium, which allows to remove impurities, then the nanoemulsion is brought to the homogenizer tank, and from there it passes to the spray drying equipment and is Drying with nozzle, with an outlet temperature between 75 and 95 ° C, preferably at 86 ° C.
  • a stabilization stage of the microcapsules is developed, where the product's temperature is gradually reduced to a maximum value of 10 ° C. Then- the anticompactant is added.

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Abstract

The present invention relates to cannabis oil nanoparticles micro-encapsulated in powder, characterised in that they comprise a cannabis extract in a proportion of between 5 and 95% and pharmaceutically acceptable carriers, wherein the nanoparticles have a particle size between 1 and 500 nm and have uses in the fields of pharmacy, food and cosmetics.

Description

NANOPARTICULAS OLEOSAS DE CANNABIS MICROENCAPSULADAS EN  NANOPARTICULAS OLEOUS CANNABIS MICROENCAPSULATED IN
POLVO  POWDER
CAMPO DE LA INVENCIÓN FIELD OF THE INVENTION
La presente invención se refiere a nanopartículas oleosas de cannabis microencapsuladas en polvo para aplicaciones en el campo farmacéutico, alimentos y cosmética. The present invention relates to oily micro-encapsulated cannabis nanoparticles in powder form for applications in the pharmaceutical, food and cosmetic fields.
RESUMEN SUMMARY
La presente invención se refiere a nanopartículas oleosas de cannabis microencapsuladas en polvo, caracterizada al comprender un extracto de cannabis y portadores farmacéuticamente aceptables, en donde las nanopartículas tienen un tamaño de partícula entre 1 y 500 nm con aplicaciones en ia industria de la farmacia, alimentos y cosmética.  The present invention relates to powdered microencapsulated oily cannabis nanoparticles, characterized in comprising a cannabis extract and pharmaceutically acceptable carriers, wherein the nanoparticles have a particle size between 1 and 500 nm with applications in the pharmacy, food industry and cosmetics.
ESTADO DE LA TÉCNICA Se estima que el cannabis contiene unos 60 fitocannabinoides, entre los cuales los más conocidos para el uso- medicinal son el tetrahidrocannabinol (THC), el cannabidiol (CBD) y el cannabinol (CBN) y su atención se centra en el uso terapéutico de los principios activos de la planta. Después del THC y del CBD, el CBN es otro cannabinoide importante. El CBN tiene sólo un ligero efecto psicotrópico y presumiblemente actúa como un agonista débil de los receptores CB1 y CB2 en el sistema de endocannabinoide. Por otra parte, es .conocido por sus múltiples aplicaciones a nivel medico, por ejemplo, como anticonvulsivo y como antiemético. Además, el CBN puede ser responsable, en parte, del efecto calmante de algunos tipos de cannabis
Figure imgf000003_0001
STATE OF THE ART It is estimated that cannabis contains some 60 phytocannabinoids, among which the best known for medicinal use are tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) and its attention is focused on the Therapeutic use of the active principles of the plant. After THC and CBD, CBN is another important cannabinoid. CBN has only a slight psychotropic effect and presumably acts as a weak receptor agonist CB1 and CB2 in the endocannabinoid system. On the other hand, it is known for its multiple applications at the medical level, for example, as an anticonvulsant and as an antiemetic. In addition, the CBN may be responsible, in part, for the calming effect of some types of cannabis
Figure imgf000003_0001
Debido a su interés en la medicina alternativa, se han realizado estudios sobre esta planta con el fin de poder determinar su actividad biológica para enfermedades como el cáncer. Se está desarrollando formulaciones que contengan como principio activo extractos de esta planta. Due to his interest in alternative medicine, studies have been conducted on this plant in order to be able to determine its biological activity for diseases such as cancer. It is developing formulations that contain as an active ingredient extracts of this plant.
Es asi como la patente WO2016147186 describe una formulación de emulsión basada en cannabis para uso en diversas condiciones médicas y opcionalmente con diversas, composiciones farmacéuticas o nutracéuticas, en las que la fracción oleosa utilizada contiene aproximadamente un 50% de cannabinoides. La presente invención describe adicionalmente métodos de fabricación y usos de la composición antes mencionada. This is how patent WO2016147186 describes a cannabis-based emulsion formulation for use in various medical conditions and optionally with various pharmaceutical or nutraceutical compositions, in which the oil fraction used contains approximately 50% cannabinoids. The present invention further describes manufacturing methods and uses of the aforementioned composition.
Por su parte, la patente WO2016094810 se refiere a composiciones de cannabinoides, en donde dichas composiciones pueden ser encapsuladas (por ejemplo, microencapsuladas). En particular, estas composiciones se pueden administrar a un sujeto, tal como mediante consumo oral o tratamiento tópico. For its part, patent WO2016094810 refers to cannabinoid compositions, wherein said compositions can be encapsulated (for example, microencapsulated). In particular, these compositions can be administered to a subject, such as by oral consumption or topical treatment.
De otra parte, la patente WO2016144376 ensena composiciones de nanopartículas de fosfolfpidos de cannabinoides formadas a partir de fosfolípidos y
Figure imgf000003_0002
lípidos más simples en un proceso secuencia! y crea formas de dosificación estandarizadas con cantidades precisas de cannabinoides; produciendo un aumento del transporte de cannabinoides a través de la mucosa hidrofóbica; aumentar la biodisponibilidad del cannabinoide de 2 a 8 veces, disminuir la dosis de cannabinoides de 2 a 8 veces menos que la cantidad de cannabinoides necesaria para provocar el mismo efecto terapéutico en comparación con los cannabinoides crudos y no encapsulados; donde la estructura dinámica de las nanopartlculas reduce los efectos adversos de los cannabinoides; y permite una terapia de cannabinoides más eficaz y segura. On the other hand, patent WO2016144376 teaches compositions of cannabinoid phospholipid nanoparticles formed from phospholipids and
Figure imgf000003_0002
simpler lipids in a sequence process! and creates standardized dosage forms with precise amounts of cannabinoids; producing an increase in the transport of cannabinoids through the hydrophobic mucosa; increase the bioavailability of the cannabinoid from 2 to 8 times, decrease the dose of cannabinoids from 2 to 8 times less than the amount of cannabinoids needed to cause the same therapeutic effect compared to raw and non-encapsulated cannabinoids; where the dynamic structure of nanoparticles reduces the adverse effects of cannabinoids; and allows a more effective and safe cannabinoid therapy.
Adicionalmente, la patente US5989583 reporta que sustancias lipofflicas de baja biodisponibilidad oral, se mezclan con al menos una grasa sólida y fosfolfpido para obtener una composición sólida seca adecuada como forma de dosificación oral. Las composiciones lipídicas sólidos se ejemplifican para aditivos alimentarios o suplementos dietéticos tales como coenzima Q10 y para fármacos tales como dexanabinol. Las mezclas de lípidos secos de Coenzima Q10 muestran una liberación de fármaco mejorada in vrtro y una biodisponibilidad oral mejorada in vivo en comparación con una formulación comercial de CoQ10. La mezcla de lípidos secos de dexanabinol muestra similarmente una biodisponibilidad oral mejorada en comparación con las formulaciones conocidas. Additionally, patent US5989583 reports that lipoflix substances of low oral bioavailability are mixed with at least one solid fat and phospholipid to obtain a suitable dry solid composition as an oral dosage form. Solid lipid compositions are exemplified for food additives or dietary supplements such as coenzyme Q10 and for drugs such as dexanabinol. Coenzyme Q10 dry lipid mixtures show enhanced drug release in vitro and improved oral bioavailability in vivo compared to a commercial CoQ10 formulation. The dry lipid mixture of dexanabinol similarly shows an improved oral bioavailability compared to known formulations.
Por su parte, la patente EP2444071 ensena una formulación que comprende una pluralidad de minicápsulas sin fisuras, teniendo las minicápsulas un diámetro de 0,5 mm a 5 mm, y en donde las minicápsulas tiene un núcleo que contiene una entidad activa y un cuerpo encapsulante, estando la entidad activa en forma de uno o más de: una microemulsión, una nanoemufsión, un sistema de liberación autoemulsionante, un sistema de administración automicroemulsionante, una formulación de perfluorocarbono bioestable, un complejo con ciclodextrína (y similares), liposomas, hidrogel, sistema de suministro linfático dirigido, bi-capas líquidas, un sistema acuoso, cera, emzaloide, y extracto vegetal natural For its part, patent EP2444071 teaches a formulation comprising a plurality of mini-cups without cracks, the mini-cups having a diameter of 0.5 mm to 5 mm, and wherein the mini-cups have a core containing an active entity and an encapsulating body. , the active entity being in the form of one or more of: a microemulsion, a nanoemulsion, a self-emulsifying release system, an auto-emulsifier delivery system, a biostable perfluorocarbon formulation, a complex with cyclodextrin (and the like), liposomes, hydrogel, targeted lymphatic delivery system, bi liquid layers, an aqueous system, wax, emzaloide, and natural vegetal extract
En este sentido, luego de investigación en el estado del arte, se ha encontrado que el problema técnico más significativo es el poder desarrollar una nueva matriz de nanopartlculas oleosas de cannabis microencapsuladas en polvo, que se puedan hacer mediante la combinación de nanctecnologfa, microencapsulacfón y secado por aspersión en un solo proceso, con el fin de permitir regular las concentraciones de cannabinoides, optimizando la dosificación en los productos, minimizando riesgos en los consumidores finales y potenciándose los beneficios para la salud, y en donde el tamaño de partícula ayude a una mayor biodisponibilidad, además que por su presentación en polvo, puedan ser aplicados a cualquier producto o matriz con gran mejoría en sus condiciones organolépticas. In this sense, after research in the state of the art, it has been found that the most significant technical problem is to be able to develop a new matrix of powdered micro-encapsulated cannabis nanoparticles, which can be made by combining nanotechnology, microencapsulation and spray drying in a single process, in order to regulate the concentrations of cannabinoids, optimizing the dosage in the products, minimizing risks in the final consumers and boosting the health benefits, and where the particle size helps a greater bioavailability, in addition to its presentation in powder, can be applied to any product or matrix with great improvement in its organoleptic conditions.
DESCRIPCIÓN DETALLADA DE LAS FIGURAS DETAILED DESCRIPTION OF THE FIGURES
La figura 1 muestra una microfotografía que ensena nanopartlculas oleosas de cannabis microencapsuladas en polvo de acuerdo con la invención, en donde se observa que tienen una forma homogénea. La figura 2 muestra la presentación y apariencia final del polvo del producto de acuerdo con la invención, que comprende las nanopartfculas oleosas de cannabis microencapsuladas en donde se observa un polvo fino. Figure 1 shows a microphotograph showing oily nanoparticles of powdered microencapsulated cannabis according to the invention, where it is observed that they have a homogeneous shape. Figure 2 shows the final appearance and appearance of the powder of the product according to the invention, which comprises the microencapsulated oily cannabis nanoparticles in which a fine powder is observed.
DESCRIPCIÓN DE TALLADA DE LA INVENCIÓN DETAILED DESCRIPTION OF THE INVENTION
La presente invención está dirigida a un producto que es nanopartfculas oleosas de cannabis microencapsuladas en polvo. De acuerdo con la invención, las nanopartfculas tienen un tamaño entre 1 y 500 nm y estas nanopartfculas están comprendidas por aceite cannabis y un material encapsulante o portador farmacéuticamente aceptable y GRAS (Generalmente reconocido como seguro) en el caso de alimentos y que pueden comprender antioxidantes, emulsifícantes, proteínas, reguladores de pH; colorantes, estabilizantes, almidones, carbohidratos, fosfolípidos, edulcorantes, y anticompactantes entre otros componentes farmacéuticos, alimenticios o cosméticamente aceptables. The present invention is directed to a product that is micro-encapsulated powdered oily nanoparticles of cannabis. According to the invention, the nanoparticles have a size between 1 and 500 nm and these nanoparticles are comprised of cannabis oil and a pharmaceutically acceptable encapsulating or carrier material and GRAS (Generally recognized as safe) in the case of foods and which may comprise antioxidants , emulsifiers, proteins, pH regulators; dyes, stabilizers, starches, carbohydrates, phospholipids, sweeteners, and anti-compactants among other pharmaceutical, food or cosmetically acceptable components.
El aceite de cannabis es un aceite que resulta de cualquier tipo de extracto que contiene sustancias identificadas como.cannabionoides (compuestos medicinales). Entre los extractos de cannabis que se pueden emplear en la presente invención, se encuentran los extractos de cualquier tipo o categoría de plantas de cannabis, principalmente, de las variedades sativa e indica y los cruces de estas. Adicionalmente, se puede, emplear cualquier variedad solvente o mezclas de solventes. Entre los solventes más conocidos y usados en los extractos de la presente invención se tienen los solventes orgánicos grado alimenticio y farmacéuticamente aceptable, por ejemplo, acuoso, alcohólico y mezclas de los mismos. También se puede emplear extractos llofilizados que son reconstituidos en agua o en cualquier otro solvente farmacéuticamente aceptable. De acuerdo con ia presente invención, el ingrediente principal o ingrediente activo es aceite de cannabis que se encuentra en una proporción de desde 5% hasta 95% en peso total de la composición: Cannabis oil is an oil that results from any type of extract that contains substances identified as cannabionoids (medicinal compounds). Among the cannabis extracts that can be used in the present invention, there are extracts of any type or category of cannabis plants, mainly of the sativa and indica varieties and the crosses of these. Additionally, it is possible to use any solvent variety or solvent mixtures. Among the most known and used solvents in the extracts of the present invention are the food grade organic solvents and pharmaceutically acceptable, for example, aqueous, alcoholic and mixtures thereof. It is also possible to use freeze-dried extracts which are reconstituted in water or in any other pharmaceutically acceptable solvent. According to the present invention, the main ingredient or active ingredient is cannabis oil which is in a proportion of from 5% to 95% by total weight of the composition:
En ei extracto de cannabis se encuentra un compuesto principal, los cannabinoides nombrados como THC, CBD, CBN, CBC, CBG, con porcentajes entre 0.1 % del extracto hasta un 60% del mismo. In the cannabis extract is a main compound, the cannabinoids named THC, CBD, CBN, CBC, CBG, with percentages between 0.1% of the extract up to 60% of it.
En relación con (os materiales encapsulantes, como su nombre lo indica, son los componentes que, con ayuda de otros excipientes, encapsulan el ingrediente activo de cannabis. Dentro de los materiales encapsulantes que se pueden usar en la presente invención se tienen: estabilizantes, carbohidratos, proteínas, carbohidratos y almidones, en donde las proteínas pueden estar presentes de desde 0.1 a 20% en peso, estabilizantes de desde 0.01% hasta 5% en peso, los almidones de desde 1% hasta 30% y los carbohidratos de desde 1% hasta 30% en peso. In relation to the encapsulating materials, as the name implies, these are the components that, with the help of other excipients, encapsulate the active ingredient of cannabis Within the encapsulating materials that can be used in the present invention are: stabilizers, carbohydrates, proteins, carbohydrates and starches, wherein the proteins may be present from 0.1 to 20% by weight, stabilizers from 0.01% to 5% by weight, starches from 1% to 30% and carbohydrates from 1 % up to 30% by weight.
Otro de los componentes que pueden participar en las nanoparticulas microencapsuladas en la presente invención, son materiales que pueden ser seleccionados de un grupo de Antioxidantes naturales o sintéticos tales como carotenoides, polHenoles, tocofsroles, antiocianínas o BHT y mezclas de los mismos; Emulsificantes tales como α y mono glicéridos de ácidos grasos, monoleatos, TWIN 80, SPAN 80, lecitina y mezclas de los mismos; Reguladores de pH tales como Tripolrrbsfato de sodio y calcio, difosfatos sodio, calcio y potasio, sales de ácidos (lactato de sodio, crtrato de sodio) y mezclas de los mismos; Estabilizantes tales como canageninas (K, α, λ, I), CMC, gomas xantan, arábiga, guar y algarrobo y mezclas de los mismos; Fosfolfpidos tales como Lecitina y otros fosfólfpidos de origen vegetal y mezclas de los mismos; Edulcorantes y/o potenctaiizadores lipofílicos tales como sorbitol, manitol, xylitol, isomalt, los hidrolisados de almidón hidrogenados y otros como, acesurfamo k, alitamo, aspartamo, ciclamato, neohesperidina de, sacarina, sucraíosa, steviosida, taumatina y mezclas de los mismos; Anticompactantes tales como silicas, fosfato tricalcico, carbonato de calcio y mezclas de los mismos, y agua. Another component that can participate in the microencapsulated nanoparticles in the present invention are materials that can be selected from a group of natural or synthetic Antioxidants such as carotenoids, polHenoles, tocofsroles, antiocianínas or BHT and mixtures of the same; Emulsifiers such as α and mono glycerides of fatty acids, monoleates, TWIN 80, SPAN 80, lecithin and mixtures thereof; PH regulators such as sodium and calcium tripolyrbhosphate, sodium, calcium and potassium diphosphates, acid salts (sodium lactate, sodium crtrate) and mixtures thereof; Stabilizers such as canagenins (K, α, λ, I), CMC, xanthan gums, arabic, guar and carob and mixtures thereof; Phospholipids such as Lecithin and other phospholipids of vegetable origin and mixtures thereof; Lipophilic sweeteners and / or potentifiers such as sorbitol, mannitol, xylitol, isomalt, hydrogenated starch hydrolysates and others such as, acesurfam k, alitame, aspartame, cyclamate, neohesperidin, saccharin, sucralose, stevioside, thaumatin and mixtures thereof; Anticompactants such as silicas, tricalcium phosphate, calcium carbonate and mixtures thereof, and water.
De acuerdo con la presente invención, los antioxidantes pueden estar en una proporción de desde 0.001% hasta 0.1%; los emulsificantes de desde 0.1% hasta 5%; el regulador de pH de desde 0.1 hasta 5%; los estabilizantes de desde 0.01% hasta 5%, los fosfolfpidos de desde 0.1% hasta 5%, y los anticompactantes de desde 0.1 hasta 5%. Las nanopartículas oleosas de cannabis microencapsuladas de la presente invención se obtienen mediante un proceso que combina las etapas de nanotecnologfa (formación de nanoemulsón), microencapsulación y secado por aspersión en donde la nanotecnologfa comprende: PREPARACIÓN FASE LIPOFÍLICA Se entiende como toda molécula o mezcla de ellas que tienen afinidad por las grasas y gran solubilidad en los lípidos, entre otros compuestos se pueden mencionar los ácidos grasos, las vitaminas, las ceras, extractos liposolubies o aceites esenciales, para este caso es la mezcla de: According to the present invention, the antioxidants can be in a proportion of from 0.001% to 0.1%; the emulsifiers from 0.1% to 5%; the pH regulator from 0.1 to 5%; the stabilizers from 0.01% to 5%, the phospholipids from 0.1% to 5%, and the anticompactants from 0.1 to 5%. The microencapsulated cannabis oily nanoparticles of the present invention are obtained by a process that combines the steps of nanotechnology (nanoemulsion formation), microencapsulation and spray drying wherein the nanotechnology comprises: PREPARATION LIPOPHYL PHASE It is understood as any molecule or mixture of them that have affinity for fats and great solubility in lipids, among other compounds can be mentioned fatty acids, vitamins, waxes, liposolubies extracts or essential oils, for this case is the mixture of:
Sistema proteico  Protein system
Emulsrficantes  Emulsifiers
Fosfolípidos  Phospholipids
PREPARACIÓN FASE HIDROFÍLICA  HYDROPHILIC PHASE PREPARATION
Por fase hidrofflica se entiende aquella fase que tiene afinidad por el agua. En una disolución o coloide, las partículas hidrófitas tienden a acercarse y mantener contacto con el agua. Las moléculas hidrófitas son a su vez lipófobas, es decir no tienen afinidad por los lipidos o grasas y no se mezclan con ellas. Durante la preparación de la fase hidrofflica, se adiciona agua en un mezclador de fase hidrofflica, a la cual es necesario incrementarle su temperatura en un rango entre 30°C y 100°C, preferiblemente 70°C. Posteriormente, se adiciona lentamente un suriactante hidrofllico de carácter no iónico con un HBL superior a 13. La mezcla que se forma es sometida a un proceso de agitación por medio de un agitador programado con una frecuencia de giro entre 100 rpm y 1000 rpm, preferiblemente 500 rpm controlando la generación de espuma y la temperatura previamente alcanzada. Durante dicho proceso de agitación, se adiciona una matriz encapsulante seleccionada del grupo conformado por carbohidratos como almidón y derivados, maltodextrinas, jarabes de mafz, ciclodextrinas,.carboximefilcelulosa y derivados; gomas como arábiga, xanfhan, guar, gellan, tara, celulósicas, garrafin, tragacanto, karaya, mezquite, alginato de sodio, carragenina; lípidos como ceras, parafinas, grasas, fosfolípidos, glicéridos y ácidos grasos; proteínas como gelatina, proteína de soya o aislados de soya, caseinatos, proteínas de suero, suero de leche, caseína y mezclas de éstos. By hydrophilic phase is meant that phase that has an affinity for water. In a solution or colloid, the hydrophilic particles tend to approach and maintain contact with water. The hydrophilic molecules are in turn lipophobic, ie they have no affinity for lipids or fats and do not mix with them. During the preparation of the hydrophilic phase, water is added in a hydrolytic phase mixer, to which it is necessary to increase its temperature in a range between 30 ° C and 100 ° C, preferably 70 ° C. Subsequently, a hydrophilic surfactant of a non-ionic character is added slowly with an HBL higher than 13. The mixture that is formed is subjected to a stirring process by means of a programmed stirrer with a rotation frequency between 100 rpm and 1000 rpm, preferably 500 rpm controlling the generation of foam and the previously reached temperature. During said stirring process, an encapsulating matrix selected from the group consisting of carbohydrates such as starch and derivatives, maltodextrins, maize syrups, cyclodextrins, carboxymethylcellulose and derivatives is added; gums such as arabic, xanfhan, guar, gellan, tara, cellulose, garrafin, tragacanth, karaya, mesquite, sodium alginate, carrageenan; lipids such as waxes, paraffins, fats, phospholipids, glycerides and fatty acids; proteins like gelatin, soy protein or isolates of soy, caseinates, whey proteins, whey, casein and mixtures thereof.
Adicionalmente, el surfactante hidrofílico puede ser seleccionado del grupo que forman aquellos de tipo alcoholes lineales etoxilados, alquil fenoles etoxilados, esteres de ácidos grasos, derivados de aminas y amidas, copolfmeros óxidos de etileno-óxido de propileno, polialcoholes de polialcholes etoxilados, fióles (mercaptanos) etoxilados y mezclas de estos. Además, puede agregarse un enmascarante hidrofílico, el cual permite por su interacción con el suriactante disminuir la generación de espuma. La generación de espuma en el proceso de agitación, evita que se presente una correcta homogenizacíón de la tase hidrofilica debido a que partículas de aire se incorporan a dichafase. Additionally, the hydrophilic surfactant can be selected from the group formed by those of the ethoxylated linear alcohol type, ethoxylated alkyl phenols, fatty acid esters, amine and amide derivatives, ethylene oxide-propylene oxide copolymers, ethoxylated polyalcohol polyalcohols, phyllos ( mercaptans) ethoxylates and mixtures of these. In addition, a hydrophilic masking agent can be added, which, due to its interaction with the surfactant, reduces the generation of foam. The generation of foam in the agitation process prevents the correct homogenization of the hydrophilic phase due to the fact that air particles are incorporated into said phase.
Dicho enmascarante hidrofílico puede ser seleccionado del grupo que forman las mezclas estadísticas de uno o varios edulcorantes y de uno o varios potenciadores hidrofflicos, tales como: los azúcares refinados, el jarabe de maíz de alta fructosa, la fructosa cristalina, la glucosa, la dextrosa, los edulcorantes provenientes del maíz, la miel, la lactosa, la maltosa, varios jarabes, los azúcares invertidos o el jugo concentrado de frutas, sorbitol, manitol, xylitol, isomaft, los hidrolisatos de almidón hidrogenados y otros como, acesulfamo k, alitamo, aspartamo, ciclamato, neohesperidina de, sacarina, sucraiosa, steviosida, taumatína. Posteriormente, la fase hidrofftica es mezclada con una fase lipofllica en el mezclador de fase hidrofílica. La fase lipofflica es preparada mediante la adición de un agente lipofílico o núcleo seleccionado del grupo constituido por Ifpidos, fosfolípidos, siliconas, parafinas, ceras entre otras, en un mezcfador de fase lipofflica. Luego se realiza un primer aumento de temperatura hasta alcanzar un valor de temperatura en un rango entre 30°C y 45°C, preferiblemente de 40°C. Said hydrophilic masking agent can be selected from the group consisting of the statistical mixtures of one or several sweeteners and of one or more hydrophilic potentiators, such as: refined sugars, high fructose corn syrup, crystalline fructose, glucose, dextrose , sweeteners from corn, honey, lactose, maltose, various syrups, inverted sugars or concentrated fruit juice, sorbitol, mannitol, xylitol, isomaft, hydrogenated starch hydrolysates and others such as, acesulfame k, alitamo , aspartame, cyclamate, neohesperidin, saccharin, sucralose, stevioside, thaumatin. Subsequently, the hydrophilic phase is mixed with a lipophilic phase in the hydrophilic phase mixer. The lipoflicic phase is prepared by the addition of a lipophilic agent or nucleus selected from the group consisting of lipids, phospholipids, silicones, paraffins, waxes among others, in a lipoflex phase mixer. Then a first temperature increase is made until reaching a temperature value in a range between 30 ° C and 45 ° C, preferably 40 ° C.
Una vez alcanzada a dicha temperatura, se adiciona un agente preservante, el cual puede ser un antioxidante de origen natural o sintético, capaz de retardar o prevenir la oxidación de la fase lipofflica. Dentro de los antioxidantes que se pueden emplear se encuentra vitaminas A, E, C, oligoelementos, polifenoles o mezclas de estos. La mezcla que se forma es sometida a un proceso de agitación por medio de un agitador programado con una frecuencia de giro entre 500 y 1500 rpm, preferiblemente 800 rpm, controlando la generación de espuma. Durante el proceso de agitación se realiza un segundo aumento de temperatura hasta alcanzar un valor entre 45°C y 80°C, preferiblemente 70°C. Posteriormente, se adiciona de manera lenta un surfactante lipofílico de carácter no iónico con un HBL inferior a 9. Adicionalmente, puede adicionarse un enmascarante lipofílico y/o cualquier fuente lipofflica que permita, por su interacción con dicho surfactante lipofílico, mejorar las propiedades organolépticas del núcleo. Once reached at said temperature, a preserving agent is added, which may be an antioxidant of natural or synthetic origin, capable of retarding or preventing the oxidation of the lipoflic phase. Among the antioxidants that can be used are vitamins A, E, C, oligoelements, polyphenols or mixtures of these. The mixture that is formed is subjected to a stirring process by means of a programmed agitator with a rotation frequency between 500 and 1500 rpm, preferably 800 rpm, controlling the generation of foam. During the stirring process a second temperature rise is made until reaching a value between 45 ° C and 80 ° C, preferably 70 ° C. Subsequently, a non-ionic lipophilic surfactant with a HBL of less than 9 is added slowly. Additionally, a lipophilic masking agent and / or any lipoflicic source can be added which, by its interaction with said lipophilic surfactant, allows improving the organoleptic properties of the lipophilic surfactant. nucleus.
Dicho enmascarante lipofílico puede ser seleccionado del grupo que forman las mezclas estadísticas de uno o varios edulcorantes y de uno o varios potenciadores Ijpofííicos, tales como: los azúcares refinados, el jarabe de maíz de alta fructosa, la fructosa cristalina, la glucosa, la dextrosa, los edulcorantes provenientes del mafz, la miel, la lactosa, la maltosa, varios jarabes, los azúcares invertidos o el jugo concentrado de frutas, sorbitol, manitol, xylitol, isomalt, los hidroiisatos de almidón hidrogenados y otros como, acesulfarno k, alitamo, aspartamo, ciclamato, neohesperidina de, sacarina, lúcralos, steviosida, taumatina y equivalentes conocidos por el técnico versado en la materia. Said lipophilic masking agent can be selected from the group consisting of statistical mixtures of one or more sweeteners and of one or more ionophilic enhancers, such as: refined sugars, high fructose corn syrup, crystalline fructose, glucose, dextrose , sweeteners from maize, honey, lactose, maltose, various syrups, inverted sugars or concentrated fruit juice, sorbitol, mannitol, xylitol, isomalt, hydrogenated starch hydroisases and others such as, acesulfarno k, alitame, aspartame, cyclamate, neohesperidin , saccharin, lucid, stevioside, thaumatin and equivalents known to the skilled artisan.
Una vez preparadas tanto la fase hidrofílica como la fase lipoffiica, se combinan, en un mezclador de fases y dicha mezcla es sometida a proceso de agitación entre 4000 y 9000 rpm, preferiblemente 5000 rpm, controlando la generación de espuma y la temperatura previamente alcanzada, generando una pre-emulsión. Once both the hydrophilic phase and the lipofiic phase are prepared, they are combined in a phase mixer and said mixture is subjected to a stirring process between 4000 and 9000 rpm, preferably 5000 rpm, controlling the generation of foam and the temperature previously reached, generating a pre-emulsion.
ELABORACIÓN DE NANOEMULSIÓN ELABORATION OF NANOEMULSION
Con el fin de generar una nanoemulsión, la preemulsión previamente obtenida es sometida a la aplicación de un alto esfuerzo mecánico, el cual puede efectuarse a través de un proceso de agitación y/o arta presión. Durante la aplicación de dicho esfuerzo mecánico, la temperatura de la mezcla no debe superar los 100°C, preferiblemente 80°C.  In order to generate a nanoemulsion, the previously obtained pre-emulsion is subjected to the application of a high mechanical stress, which can be carried out through a process of agitation and / or high pressure. During the application of said mechanical stress, the temperature of the mixture should not exceed 100 ° C, preferably 80 ° C.
Si la aplicación del esfuerzo mecánico es realizada a través de agitación, ia frecuencia mínima de dicha agitación entre 10000-60000 rpm y 1000-3000 PSI (6,89 MPa a 20.68 MPa), con el fin de que la fuerza de cizalla efectuada sobre la mezcla sea lo suficientemente alta para disminuir el tamaño de gota de la emulsión formada a escala nanométrica, particularmente tamaños medios de gota entre 1- 500 nm. Si la aplicación de un alto esfuerzo mecánico es realizada a través de afta presión, la presión mínima no debe ser inferior a 700 bar (70 MPa), con el fin de que la fuerza efectuada sobre la mezcla sea lo suficientemente arta para disminuir el tamaño de gota de la emulsión formada a escala nanométrfca, particularmente tamaños medios de gota entre 1- 500 nm. If the application of the mechanical stress is carried out through agitation, the minimum frequency of said agitation between 10000-60000 rpm and 1000-3000 PSI (6.89 MPa at 20.68 MPa), in order that the shear force carried out on the mixture is high enough to decrease the droplet size of the emulsion formed at the nanometer scale, particularly average droplet sizes between 1- 500 nm. If the application of a high mechanical stress is carried out through high pressure, the minimum pressure must not be less than 700 bar (70 MPa), in order that the force made on the mixture is enough to reduce the size of droplet of the emulsion formed at nanometric scale, particularly average droplet sizes between 1- 500 nm.
Una vez generada la nanoemulsión, esta es sometida a un proceso de estabilización a través de un cambio de temperatura, el cuai puede darse de forma rápida o lenta, partiendo de una temperatura de 1°C hasta llegar a un valor de 25ºC. Once the nanoemulsion is generated, it is subjected to a stabilization process through a temperature change, which can occur quickly or slowly, starting at a temperature of 1 ° C until reaching a value of 25 ° C.
ELABORACIÓN DE AGREGADOS DE PROTEINAS ELABORATION OF PROTEIN AGGREGATES
Con el fin de generar agregados de protefna como polímero tipo octámero, a la nanoemulsión se le agrega la protefna y luego se somete a un alto esfuerzo mecánico, el cual puede efectuarse a través de un proceso de agitación y/o alta presión. Durante la aplicación de dicho esfuerzo mecánico, la temperatura de la mezcla no debe superar los 100°C, preferiblemente 95°C, pH entre 3,5 y 5,2 preferiblemente 4,1. De esta forma el dfmero proteico se polimeriza en un octámero de 100-180 kd. liste contenido de residuos de cisteina y cistina facilita la polimerización de la proteína por formación de puentes disulfuro intermoleculares durante el procesamiento a arta temperatura. SECADO POR ATOMIZACIÓN In order to generate protein aggregates as an octamer-type polymer, the protein is added to the nanoemulsion and then subjected to a high mechanical stress, which can be effected through a process of agitation and / or high pressure. During the application of said mechanical stress, the temperature of the mixture should not exceed 100 ° C, preferably 95 ° C, pH between 3.5 and 5.2, preferably 4.1. In this way, the protein dimer polymerizes in an octamer of 100-180 kd. The content of cysteine and cystine residues facilitates the polymerization of the protein by formation of intermolecular disulfide bridges during processing at high temperature. DRYING BY ATOMIZATION
Posterior al proceso de estabilización de la nanoemulsión y generación de agregados de proteína se procede a la microencapsulación de dicha nanoemulsión. La microencapsulación inicia con un proceso de filtración de la nanoemulsión generada. En dicho proceso de filtración se hace pasar el producto de la nanoemulsión a través de un medio de filtración, el cual permite separar impurezas. El medio de filtración empleado en esta etapa se caracteriza porque el tamaño de partícula que lo atraviesa es inferior a 75 micrómetros. El producto de este proceso es recolectado en un tanque con agitación contante y control de temperatura. La agitación efectuada en dicho tanque debe mantenerse entre 500 y 1000 rom, preferiblemente 800 rpm, y la temperatura del producto en un valor constante entre 40 y 70°C, preferiblemente 65°C. El medio de filtración puede ser seleccionado del grupo que forman los filtros abiertos, los filtros lentos, los filtros de gravedad, los filtros rápidos, los filtros de presión y los. filtros cerrados. After the process of stabilization of the nanoemulsion and generation of protein aggregates, the microencapsulation of said nanoemulsion is proceeded. The microencapsulation starts with a filtering process of the generated nanoemulsion. In said filtration process the product of the nanoemulsion is passed through a filtration medium, which allows to remove impurities. The filtration medium used in this step is characterized in that the particle size that passes through it is less than 75 micrometers. The product of this process is collected in a tank with constant stirring and temperature control. The stirring effected in said tank should be maintained between 500 and 1000 rom, preferably 800 rpm, and the temperature of the product at a constant value between 40 and 70 ° C, preferably 65 ° C. The filtration medium can be selected from the group formed by the open filters, the slow filters, the gravity filters, the fast filters, the pressure filters and the filters. closed filters.
Por impureza se entiende todo aquel componente constituido por material extraño que no hace parte de materias primas, grumos o partículas sólidas que no se encuentran disuettas. Impurity means any component that consists of foreign material that is not part of raw materials, lumps or solid particles that are not disowned.
El producto almacenado en el tanque homogenizador, posteriormente es llevado a un equipo de secado por aspersión (150 L de agua/h), a través de una bomba de presión positiva que permite alimentar dicho equipo de secado con un flujo superior a 2,3 litros por minuto, con el fin de efectuar un proceso de microencapsulación. El equipo de secado por aspersión puede emplear un medio de aspersión tipo boquilla o disco. En caso de efectuarse el proceso de secado con un equipo que emplea un medio de aspersión tipo boquilla, debe incorporarse un sistema de presión que permite controlar la presión de flujo al ingreso del equipo. Dicha presión de entrada al equipo de secado será 300 a 600 psi (2.07 MPa a 4.14 MPa). La temperatura de entrada al secador debe ser estar entre 120 - 270°C, con el fin de disminuir la humedad de la emulsión. El tiempo de residencia de la partícula dentro del equipo debe ser entre 15 y 30 segundos y la temperatura mínima del aire de salida entre 75 a 95 °C. El producto microencapsulado que contiene las nanopartfculas oleosas de cannabis a través de dicho proceso de secado es recogido en un medio recolector para posteriormente ser llevado a un proceso de tamizado. ENFRIAMIENTO The product stored in the homogenizer tank, is then taken to a spray drying equipment (150 L of water / h), through a positive pressure pump that allows to feed said drying equipment with a flow higher than 2.3 liters per minute, in order to carry out a microencapsulation process. Spray drying equipment may employ nozzle or disc type spray media. If the drying process is carried out with a device that uses a spray nozzle type, a pressure system must be incorporated to control the flow pressure at the equipment entrance. Said inlet pressure to the drying equipment will be 300 to 600 psi (2.07 MPa to 4.14 MPa). The inlet temperature to the dryer must be between 120 - 270 ° C, in order to decrease the humidity of the emulsion. The residence time of the particle inside the equipment should be between 15 and 30 seconds and the minimum temperature of the exhaust air between 75 to 95 ° C. The microencapsulated product that contains the oily nanoparticles of cannabis through said drying process is collected in a collecting medium for later to be taken to a sieving process. COOLING
Durante dicho proceso de tamizado pasado por malla número 10780 se realiza una clasificación granulométrica del producto microencapsulado, con el fin de obtener partículas con temarlos medios inferiores a 1000 micrómetros, preferiblemente 400 micrómetros. Adicíonalmente ai efectuar dicho proceso de tamizado de las microcápsulas, se busca separar impurezas y controlar la calidad del producto obtenido. Posterior al proceso de tamizado, se desarrolla una etapa de estabilización de las microcápsulas, donde se busca disminuir gradualmente la temperatura del producto hasta un valor máximo de 10°C. Este proceso se realiza preferiblemente en un cuarto con control térmico. Una vez el producto microencapsulado alcanza la temperatura deseada, este es sometido a un proceso de mezclado donde se agrega un agente anticompactante, el cual reduce la tendencia de las microcápsulas a cohesionarse, adherirse, agregarse o. apelmazarse unas a otras debido a sus características higroscópicas. Dicho agente anticompactante está constituido por sustancias capaces de evitar la formación de estructuras agregadas o de grumos por aglutinación de partículas, y puede ser seleccionado del grupo compuesto por difosfato dicálcico, polifosfatos de calcio y sodio, polifosfatos de calcio, oxido de silicio, silicato calcico, silicato de potasio y aluminio, silicato de zinc, silicato de sodio y aluminio, silicato de calcio y aluminio, acido esteárico, estearato de aluminio, estearato magnésico, sal de ácido oleico con calcio, potasio y sodio, y todas sus posibles combinaciones. During said sieving process passed by mesh number 10780, a granulometric classification of the microencapsulated product is carried out, in order to obtain particles with average temperatures below 1000 microns, preferably 400 microns. Additionally, in carrying out said sieving process of the microcapsules, it is sought to separate impurities and control the quality of the product obtained. After the sieving process, a stage of stabilization of the microcapsules is developed, where it is sought to gradually reduce the temperature of the product up to a maximum value of 10 ° C. This process is preferably carried out in a room with thermal control. Once the microencapsulated product reaches the desired temperature, it is subjected to a mixing process where an anticompacting agent is added, which reduces the tendency of the microcapsules to cohere, adhere, aggregate or. clumping together due to their hygroscopic characteristics. Said anticompacting agent is constituted by substances able to avoid the formation of aggregate structures or lumps by agglutination of particles, and can be selected from the group consisting of dicalcium diphosphate, calcium and sodium polyphosphates, calcium polyphosphates, silicon oxide, calcium silicate. , potassium aluminum silicate, zinc silicate, sodium aluminum silicate, calcium aluminum silicate, stearic acid, aluminum stearate, magnesium stearate, oleic acid salt with calcium, potassium and sodium, and all possible combinations.
Para la adición del agente anticompactante, primero se pesa la cantidad de producto microencapsulado al cual se le adicionará dicho agente, para posteriormente determinar la cantidad de agente que será agregado. La cantidad de agente anticompactante en la mezcla está en un rango entre 0,1 y 3%; preferiblemente 2%. El producto en polvo junto con el agente anticompactante son adicionados a un mezclador de producto terminado para la completa homogenización del producto microencapsulado. For the addition of the anticompacting agent, first weigh the amount of microencapsulated product to which said agent will be added, to later determine the amount of agent that will be added. The amount of anti-compactant agent in the mixture is in a range between 0.1 and 3%; preferably 2%. The powder product together with the anti-compacting agent are added to a finished product mixer for complete homogenization of the microencapsulated product.
Entre los compuestos activos lipofllicos o emulsificantes se incluyen los aceites cosméticos, aceites alimentarios, aceites esenciales, asi como cualquiera de sus combinaciones. Los compuestos formados por grupos de flavonol, antocianina, fítoalexina, hidroxitirosol, ácido retínoico, retinal, retino!, calcíferol, alfa-toco feral, tocotrienol, fitomenadiona, alfa-caroteno, beta- caroteno, lioopeno, capsantina, lutelna, zeaxantina, xantofila, EPA, DHA, ácido linoleico, campesterol, estigmasterol, sltosterol, sus derivados, esteres 6 sales farmacéuticamente o cosméticamente aceptables, o de grado alimentario, y sus mezclas. Ácidos grasos saturados e insatu nados presentes en aceites de pescado, algas, oliva, linaza, cañóla, girasol, soya, chía, palma, maíz, aguacate, cacahuate, cártamo, mil pesos, coco, algodón sésamo, arroz, semillas de uva- o combinaciones de los mismos, vitaminas de la familia de vitaminas A, D, E o K; un fosfolípido; un carotenoide; un ácido graso; poiifenoles tales como, por ejemplo, un flavonol (e.g., una catequina, una epicatequina, isoramnetina, kaempferol, miricetina, quercetina, etc.); una antocianina (e.g., cianidina, delfinidina, malvidina, peonidina, petunidlna, etc.); una fitoalexína (e.g., resveratrol, etc.); hidroxitirosol, etc.; una vitamina liposoluble tal como, por ejemplo, vitamina A y sus derivadas (e.g., ácido retinóico, retinal, retino 1, etc.); vitamina E y sus derivados (e.g., un tocoferol, por ejemplo, alfa-toco feral, etc., un tocotrienol, etc.); vitamina D y sus derivados (e.g., vitamina Di, vitamina D2 (ergo calciferol), vitamina D3 (colecalciferol), vitamina D4 (22- dihidroergocalctferol), vitamina D5 (sito calciferol), etc.); vitamina K o fitomenadiona y sus derivados (e.g., vitamina Kl (filoquinona), vitamina K2 (menaquinona), menadinona, etc.); un carotenoide tal como, por ejemplo, un caroteno (e.g., arfa-caroteno, beta-caroteno , criptoxantina, licopeno , etc.); una xantofila (e.g., astaxantina, cantaxantina, capsantina, criptoxantina, flavoxantina, lutelna, rodoxantina. The lipophilic active compounds or emulsifiers include cosmetic oils, edible oils, essential oils, as well as any of their combinations. The compounds formed by flavonol, anthocyanin, phytoalexin, hydroxytyrosol, retinoic acid, retinal, retinal, calcineuric, alpha-toco feral, tocotrienol, phytomedione, alpha-carotene, beta-carotene, lyo-opene, capsanthin, lutein, zeaxanthin, xanthophyll, EPA, DHA, linoleic acid, campesterol, stigmasterol, sltosterol, its derivatives, esters 6 pharmaceutically or cosmetically acceptable salts, or food grade , and their mixtures. Saturated and unsaturated fatty acids present in fish oils, seaweed, olive, linseed, cañola, sunflower, soybean, chia, palm, corn, avocado, peanut, safflower, thousand pesos, coconut, sesame cotton, rice, grape seeds- or combinations thereof, vitamins of the family of vitamins A, D, E or K; a phospholipid; a carotenoid; a fatty acid; poiiphenols such as, for example, a flavonol (eg, a catechin, an epicatechin, isoramnetin, kaempferol, myricetin, quercetin, etc.); an anthocyanin (eg, cyanidin, delphinidin, malvidin, peonidin, petunidin, etc.); a phytoalexin (eg, resveratrol, etc.); hydroxytyrosol, etc .; a fat-soluble vitamin such as, for example, vitamin A and its derivatives (eg, retinoic acid, retinal, retino 1, etc.); vitamin E and its derivatives (eg, a tocopherol, for example, alpha-toco feral, etc., a tocotrienol, etc.); vitamin D and its derivatives (eg, vitamin Di, vitamin D2 (ergo calciferol), vitamin D3 (cholecalciferol), vitamin D4 (22- dihydroergocalctoferol), vitamin D5 (calciferol site), etc.); vitamin K or fitomenadione and its derivatives (eg, vitamin Kl (phylloquinone), vitamin K2 (menaquinone), menadinone, etc.); a carotenoid such as, for example, a carotene (eg, arfa-carotene, beta-carotene, cryptoxanthin, lycopene, etc.); a xanthophyll (eg, astaxanthin, canthaxanthin, capsanthin, cryptoxanthin, flavoxanthin, lutein, rodoxanthin.
Ejemplo Para la obtención de las nanopartículas oleosas de cannabis microencapsuladas en polvo, se realiza un proceso que combina las etapas de nanotecnología, microencapsulación y secado por aspersión en donde la nanotecnología comprende: Example To obtain the micro-encapsulated powdered cannabis nanoparticles, a process is carried out that combines the steps of nanotechnology, microencapsulation and spray drying where nanotechnology includes:
PREPARACIÓN FASE UPOFÍLICA PREPARATION OF UPHOLIC PHASE
Se realiza una mezcla del aceite de cannabis, con las proteínas, el emulsificante (a y mono glicéridos de ácidos grasos,) y ios fosfolípidos (Lecitina). (Ver rangos en la tabla N 1).  A mixture of the cannabis oil is made with the proteins, the emulsifier (a and mono glycerides of fatty acids) and the phospholipids (Lecithin). (See ranges in table N 1).
PREPARACIÓN FASE HIDROFÍLICA HYDROPHILIC PHASE PREPARATION
Durante la preparación de la fase hidrofílica, se adiciona el agua a la anterior mezcla, en mezclador de fase hidrofílica, a la cual es necesario incrementarle su temperatura en un rango a 70°C. Posteriormente, se adiciona lentamente un suríactante hidrofítico de carácter no iónico con un HBL superior a 13. La mezcla que se forma es sometida a un proceso de agitación por medio de un agitador programado con una frecuencia de giro de 550 rpm controlando la generación de espuma y la temperatura previamente alcanzada. Durante dicho proceso de agitación es adicionada una matriz encapsulante seleccionada del grupo conformado por maftodextrinas. During the preparation of the hydrophilic phase, the water is added to the previous mixture, in a hydrophilic phase mixer, at which it is necessary to increase its temperature in a range at 70 ° C. Subsequently, a non-ionic hydrophilic surfactant is added slowly with an HBL higher than 13. The mixture that is formed is subjected to a stirring process by means of a programmed agitator with a rotation frequency of 550 rpm controlling the generation of foam and the temperature previously reached. During said stirring process, an encapsulating matrix selected from the group consisting of maftodextrins is added.
Adicionalmente, se agrega un enmascarante hidrofílico, el cual permite por su interacción con el surfactartte disminuir la generación de espuma. Posteriormente se mezclan las dos fases, luego se realiza un primer aumento de temperatura hasta de 40°C. Additionally, a hydrophilic masking agent is added, which, due to its interaction with the surfactant, reduces foam generation. Subsequently the two phases are mixed, then a first temperature increase is made up to 40 ° C.
Una vez alcanzada dicha temperatura se adiciona un agente antioxidante. La mezcla que se forma es sometida a un proceso de agitación por medio de un agitador programado con una frecuencia de giro de 700 rpm, controlando la generación de espuma. Durante el proceso de agitación se realiza un segundo aumento de temperatura hasta alcanzar un valor de 75°C. Posteriormente, se adiciona de manera lenta un surfactante lipoffiico de carácter no iónico con un HBL inferior a 9. Once this temperature is reached, an antioxidant agent is added. The mixture that is formed is subjected to a stirring process by means of a programmed agitator with a rotation frequency of 700 rpm, controlling the generation of foam. During the stirring process a second temperature rise is made until reaching a value of 75 ° C. Subsequently, a non-ionic lipofunctional surfactant with an HBL of less than 9 is added slowly.
Dicha mezcla se pasa por un mezclador de fases y dicha mezcla es sometida a proceso de agitación de 5000 rpm, controlando la generación de espuma y la temperatura previamente alcanzada, generando una pre-emulsión Said mixture is passed through a phase mixer and said mixture is subjected to a 5000 rpm stirring process, controlling the generation of foam and the previously reached temperature, generating a pre-emulsion
ELABORACIÓN DE NANOEMULSIÓN ELABORATION OF NANOEMULSION
Para generar la nanoemulsion, la preemulsión obtenida previamente es sometida a la aplicación de un alto esfuerzo mecánico y la temperatura de la mezcla se ajusta entre un rango de 70 a 100°C, preferiblemente a 80°C. A una agitación de 10000 rpm y 1000 PSI (6.89 MPa), luego esta nanoemulsión se estabiliza con un cambio de temperatura hasta 20°C. To generate the nanoemulsion, the previously obtained pre-emulsion is subjected to the application of a high mechanical stress and the temperature of the mixture is adjusted between a range of 70 to 100 ° C, preferably at 80 ° C. At an agitation of 10000 rpm and 1000 PSI (6.89 MPa), then this nanoemulsion is stabilized with a temperature change up to 20 ° C.
SECADO POR ATOMIZACIÓN Se realiza la microencapsulación con un proceso de filtración de la nanoemulsión generada. En dicho proceso de filtración, se hace pasar el producto de la nanoemulsión a través de un medio de filtración, el cual permite separar impurezas, luego se lleva la nanoemulsión al tanque del homogeneizador, y de allí pasa al equipo de secado por aspersión y es secado con boquilla, con una temperatura de salida entre 75 y 95°C, preferiblemente a 86°C. DRYING BY ATOMIZATION Microencapsulation is performed with a filtering process of the generated nanoemulsion. In this filtration process, the product of the nanoemulsion is passed through a filtration medium, which allows to remove impurities, then the nanoemulsion is brought to the homogenizer tank, and from there it passes to the spray drying equipment and is Drying with nozzle, with an outlet temperature between 75 and 95 ° C, preferably at 86 ° C.
ENFRIAMIENTO COOLING
Posterior al proceso de tamizado se desarrolla una etapa de estabilización de las mícrocápsulas, donde se busca disminuir gradualmente la temperatura del producto hasta un valor máximo de 10°C. Luego- se agrega el anticompactante.  After the sieving process, a stabilization stage of the microcapsules is developed, where the product's temperature is gradually reduced to a maximum value of 10 ° C. Then- the anticompactant is added.
Tabla N 1 Table N 1
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000020_0001
Figure imgf000021_0001

Claims

REIVINDICACIONES 1. Nanopartfculas oleosas de cannabís microencapsuladas en polvo, caracterizadas porque comprenden un extracto de cannabis en una proporción de desde 5% hasta 95% y portadores farmacéuticamente aceptables, en donde las nanopartfculas tienen un tamaño entre 1 nm y 500 nm. CLAIMS 1. Oil micro-encapsulated powdered cannabis nanoparticles, characterized in that they comprise a cannabis extract in a proportion of from 5% to 95% and pharmaceutically acceptable carriers, wherein the nanoparticles have a size between 1 nm and 500 nm.
2. Las nanopartfculas oleosas de cannabis microencapsuladas en polvo de acuerdo con la reivindicación 1, caracterizadas porque el extracto de cannabis se selecciona de plantas de las variedades sativa e indica y sus cruces. The oily micro-encapsulated powder cannabis nanoparticles according to claim 1, characterized in that the cannabis extract is selected from plants of the sativa and indica varieties and their crosses.
3. Las nanopartfculas oleosas de cannabis microencapsuladas en polvo de acuerdo con la reivindicación 1 ó 2 caracterizada porque los portadores farmacéuticamente aceptables se seleccionan del grupo que consiste de materiales encapsulantes carbohidratos, proteínas, almidones y mezclas de los mismos. 3. The powdered microencapsulated oily cannabis nanoparticles according to claim 1 or 2 characterized in that the pharmaceutically acceptable carriers are selected from the group consisting of encapsulating materials carbohydrates, proteins, starches and mixtures thereof.
4. Las nanopartfculas oleosas de cannabis microencapsuladas en polvo con cualquiera de las reivindicaciones anteriores, caracterizada porque los portadores farmacéuticamente aceptables además se seleccionan del grupo de antioxidantes naturales o sintéticos como carotenoides, politenoles, tocoferoles, antiocianinas, BHT y mezclas de los mismos. 4. The oily nanoparticles of microencapsulated powdered cannabis with any of the preceding claims, characterized in that the pharmaceutically acceptable carriers are further selected from the group of natural or synthetic antioxidants such as carotenoids, polyethenols, tocopherols, antiocyanins, BHT and mixtures thereof.
5. Las nanopartículas oleosas de cannabis microencapsuladas en polvo con cualquiera de las reivindicaciones anteriores, caracterizada porque los portadores farmacéuticamente aceptables además se seleccionan del grupo que consiste de materiales emulstficantes del grupo que consiste de o y mono glicéridos de ácidos grasos, monoleatos, TWIN 80, SPAN 80, lecrüna y mezclas de los mismos. 5. The oily nanoparticles of microencapsulated powdered cannabis with any of the preceding claims, characterized in that the pharmaceutically acceptable carriers are furthermore selected from the group consisting of emulsifying materials of the group consisting of mono and glycerides of fatty acids, monoleates, TWIN 80, SPAN 80, lecrüna and mixtures thereof.
6. Las nanopartículas oleosas de cannabis microencapsuladas en polvo con cualquiera de las reivindicaciones anteriores, caracterizada porque los portadores farmacéuticamente aceptables se seleccionan del grupo que consiste de materiales reguladores de pH que consiste de tripolifosfato de sodio y calcio, difosfatos sodio, calcio y potasio, sales de ácidos (lactato de sodio, citrato de sodio) y mezclas de los mismos. 6. The powdered micro-encapsulated cannabis nanoparticles with any of the preceding claims, characterized in that the pharmaceutically acceptable carriers are selected from the group consisting of pH-regulating materials consisting of sodium and calcium tripolyphosphate, sodium, calcium and potassium diphosphates, salts of acids (sodium lactate, sodium citrate) and mixtures thereof.
7. Las nanopartículas oleosas de cannabis microencapsuladas en polvo con cualquiera de las reivindicaciones anteriores, caracterizada porque además los portadores farmacéuticamente aceptables se seleccionan del grupo que consiste de materiales estabilizantes: carrageninas (K, α, λ, I), CMC, gomas xantan, arábiga, guar y algarrobo y mezclas de los mismos.. 7. The oily nanoparticles of microcapsulated powdered cannabis with any of the preceding claims, characterized in that in addition the pharmaceutically acceptable carriers are selected from the group consisting of stabilizing materials: carrageenans (K, α, λ, I), CMC, xanthan gums, Arabic, guar and carob and mixtures thereof ..
8. Las nanopartículas oleosas de cannabis microencapsuladas en polvo con cualquiera de las reivindicaciones anteriores, caracterizada porque los portadores farmacéuticamente aceptables además se seleccionan del grupo que consiste de materiales fosfollpidos seleccionados de lecitina y otros fosfollpidos de origen vegetal y mezclas de los mismos. 8. The oily nanoparticles of microencapsulated powdered cannabis with any of the preceding claims, characterized in that the pharmaceutically acceptable carriers are further selected from the group consisting of phospholipid materials selected from lecithin and other phospholpides of vegetable origin and mixtures thereof.
9. Las nanopartículas oleosas de cannabis microencapsuladas en polvo con cualquiera de las reivindicaciones anteriores, caracterizada porque además los portadores farmacéuticamente aceptables se seleccionan del grupo que consiste materiales edulcorantes/potencializadores lipofflicos seleccionados de sorbitol, manitol, xylitol, isomalt, los hidrolisatos de almidón hidrogenados, acesulfamo k, alitamo, aspartamo, ciclamato, neohesperidina de, sacarina, sucralosa, steviosida, taumatina y mezclas de los mismos. 9. The powdered micro-encapsulated cannabis nanoparticles in powder with any of the preceding claims, characterized in that in addition the pharmaceutically acceptable carriers are selected from the group consisting of lipophilic sweetening / potentiating materials selected from sorbitol, mannitol, xylitol, isomalt, the hydrogenated starch hydrolysates , acesulfame k, alitame, aspartame, cyclamate, neohesperidin, saccharin, sucralose, stevioside, thaumatin and mixtures thereof.
10. Las. nanopartículas oleosas de cannabis microencapsuladas en polvo con cualquiera de las reivindicaciones anteriores, caracterizada porque los portadores farmacéuticamente aceptables se seleccionan del grupo que consiste de materiales anti compactantes seleccionado de silicas, fosfato tricalcico, carbonato de calcio y mezclas de los mismos. 10. The. Powdered micro-encapsulated cannabis nanoparticles with any of the preceding claims, characterized in that the pharmaceutically acceptable carriers are selected from the group consisting of anti-compactant materials selected from silicas, tricalcium phosphate, calcium carbonate and mixtures thereof.
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