WO2020234809A1 - Cannabinoid nanocapsules and production process - Google Patents

Cannabinoid nanocapsules and production process Download PDF

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Publication number
WO2020234809A1
WO2020234809A1 PCT/IB2020/054800 IB2020054800W WO2020234809A1 WO 2020234809 A1 WO2020234809 A1 WO 2020234809A1 IB 2020054800 W IB2020054800 W IB 2020054800W WO 2020234809 A1 WO2020234809 A1 WO 2020234809A1
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WIPO (PCT)
Prior art keywords
cannabinoids
nanoencapsulation
nanoemulsion
cannabis
encapsulating matrix
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PCT/IB2020/054800
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Spanish (es)
French (fr)
Inventor
Alejandro Mauricio Vargas Upegui
Gustavo Rafael Hernandez Sandoval
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Alsec Alimentos Secos S.A.S.
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Publication of WO2020234809A1 publication Critical patent/WO2020234809A1/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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/02—Sprayers or atomisers specially adapted for therapeutic purposes operated by air or other gas pressure applied to the liquid or other product to be sprayed or atomised

Definitions

  • the present invention is framed in the field of chemistry, particularly encapsulated oily cannabis nanoparticles, useful for applications in the pharmaceutical, food and cosmetic industries.
  • Cannabinoids refer to chemical substances, which bind to specific receptor proteins, known as CB1, CB2 and others, these substances can have a diverse origin or structure.
  • cannabinoids or phytocannabinoids that come from the plants Cannabis sativa, C. indica and C. ruderalis, mainly, although they can be isolated from other species of the genus Cannabis sp. (Pascual and Fernández, 2017).
  • D9-THC delta-9-trans-tetrahydrocannabinol
  • D8-THC delta-8-tetrahydrocannabinol
  • CBD cannabidiol
  • CBG cannabigerol
  • CBN cannabinol
  • CBT cannabitriol
  • CBD is the non-psychotropic substance that is used the most for these purposes, and it is having an extensive development of products, especially facial oil or CBD facial masks, it is attributed anti-inflammatory, antioxidant and skin conditioner (Barr, 2018).
  • Formulations are being developed that contain extracts of this plant, isolated cannabinoids or mixtures of these as active principle, among which the following stand out:
  • Patent US6383513 teaches a composition for the nasal delivery of a cannabinoid in a biphasic delivery system, of the oil-in-water emulsion type, or a cannabinoid in a microsphere delivery system, where these are made from albumin.
  • Patent application US20170232210 also prepares an emulsion, using a method for manufacturing a fluid and dispersible powder that includes solubilizing a lipophilic substance in a terpene to form a mixture and treating the mixture to form a nanoemulsion dispersed in an aqueous solution.
  • the aqueous solution includes at least one functional excipient.
  • the nanoemulsion is then spray dried, thus first evaporating the aqueous portion and then the terpene to form a dry powder formed from solid particles comprising the lipophilic substance.
  • Patent application US20160279073 discloses fast-acting stable liposome and micellar formulations of terpenes, hemp oil, cannabinoids or mixtures of a cannabinoid and terpenes or hemp oil and cannabinoids that are suitable for pharmaceutical and nutraceutical applications.
  • WO2001003668 teaches a liposomal composition containing a cannabinoid or a cannabimimetic agent and methods of systemic administration by contacting the lung tissue of a mammal with the liposomal composition to achieve a prolonged psychoactive effect.
  • the 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 oily 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 application WO2016144376 teaches cannabinoid phospholipid nanoparticle compositions formed from phospholipids and 20 simpler lipids in a sequential 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; where the dynamic structure of the nanoparticles reduces the adverse effects of cannabinoids; and allows a more effective and safe cannabinoid therapy.
  • Document WO2018204326 discloses a formulation for creating an encapsulated cannabis-based one-component powder integrated into a polymer matrix and its method of preparation.
  • the method includes the introduction of a component that includes at least one of: (i) a cannabinoid, and (ii) a terpene, to a polymer to produce a polymeric mixture.
  • the component is dispersed in the polymer mixture, which is then dehydrated to encapsulate the component within a polymeric material derived from the polymer.
  • the polymeric material is soluble in water.
  • the dehydrated polymer blend is processed to form particles comprising the encapsulated component within shells formed from the polymeric material.
  • patent US5989583 reports that lipophilic substances with low oral bioavailability are mixed with at least one solid fat and phospholipid to obtain a dry solid composition suitable 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 improved drug release in vitro and improved oral bioavailability in vivo compared to a commercial formulation of CoQ10.
  • the dexanabinol dry lipid blend similarly shows improved oral bioavailability compared to known formulations.
  • patent EP2444071 teaches a formulation that comprises a plurality of seamless mini-capsules, the mini-capsules having a diameter of 0.5 mm to 5 mm, and wherein the mini-capsules have a core that contains 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 delivery system, a self-emulsifying delivery system, a biostable perfluorocarbon formulation, a complex with cyclodextin (and the like), liposomes, hydrogel, directed lymphatic delivery system, liquid bi-layers, an aqueous system, wax, emzaloid, and natural plant extract
  • the present invention solves this problem by providing a new matrix of nanoencapsulated and then dehydrated oily cannabis nanoparticles, which can be made by combining nanoencapsulation and dehydration.
  • the method used and the product thus obtained allows a better bioavailability in the gastrointestinal or epidermal tract of cannabinoids, optimizing the dosage in the products, minimizing risks in final consumers and enhancing health benefits.
  • FIG. 1 Microencapsulated and then dehydrated oily cannabis nanoparticles according to the invention, where their homogeneous shape is observed.
  • the present invention is directed to a product that is nanoencapsulated and then dehydrated cannabis oil nanoparticles. Likewise, the process of making said nanoparticles is taught.
  • Process for obtaining cannabis nanoparticles comprises the elaboration of a nanoemulsion and its subsequent nanoencapsulation by means of the electrospray technique.
  • the active principle corresponds to cannabis extract, which can comprise extracts of any type or category of cannabis plants, mainly of the sativa and indica species and their crosses.
  • Cannabis oil is an oil that results from any extract that contains substances identified as cannabionoids (medicinal compounds).
  • cannabis extracts that can be used in the present invention, are the oils obtained from the extract of the Cannabis plant, CBD oil, THC, CBN, CBG, CBT, a mixture of cannabinoids, cannabinoids and terpenes derived or not derived from the Cannabis plant, cannabinoids and flavonoids derived or not from the Cannabis plant, and / or a mixture of all the above.
  • any type of solvent or mixtures of solvents can be used.
  • solvents in the extracts of the present invention are food grade and pharmaceutically acceptable organic solvents, for example aqueous, alcoholic and mixtures of these. You can also use lyophilized extracts that are reconstituted in water or any other pharmaceutically acceptable solvent.
  • the oily nanoencapsulated cannabis nanoparticles of the present invention are obtained by a process that combines the steps of: 1) nanoemulsion formation; 2) nanoencapsulation; and 3) tray or fluidized bed drying.
  • the process for nanoencapsulation of cannabinoids comprises:
  • step b) Carry out the nanoencapsulation by electrospray of the nanoemulsion obtained in step a), using 0.1 -30 kV; then dehydrate by trays or fluidized bed with hot air; c) Cool the nanocapsules obtained
  • This stage comprises the following steps:
  • the lipophilic phase is understood as any molecule or mixture of them that have affinity for fats and great solubility in lipids, among other compounds fatty acids, vitamins, waxes, fat-soluble extracts or essential oils can be mentioned.
  • the mixture in preferred modalities contains cannabis oil with its active principles as an oily agent.
  • a mixture of cannabis oil is made, with the emulsifier (a and mono glycerides of fatty acids) and the phospholipids (Lecithin). (See ranges in table 1).
  • Emulsifiers 0.1% - 5%, Phospholipids 0.1% - 5%
  • hydrophilic phase is understood that phase that has an affinity for water. In a solution or colloid, the hydrophilic particles tend to approach and maintain contact with water. Hydrophilic molecules are in turn lipophobic, that is, they have no affinity for lipids or fats and do not mix with them.
  • a hydrophilic phase mixer which is used at a temperature in a range between 10 ° C and 100 ° C, preferably 40 ° C.
  • a non-ionic hydrophilic surfactant is slowly added with an HBL greater than 13.
  • the mixture that is formed is subjected to a stirring process by means of a stirrer programmed with a rotation frequency between 100 rpm and 1000 rpm, preferably 500 rpm controlling the generation of foam and the temperature previously reached.
  • an encapsulating matrix selected from the group consisting of carbohydrates such as sodium or calcium alginate is added, native and chemically or physically modified starches, maltodextrins, corn syrups, cyclodextrins, carboxymethylcellulose and derivatives; gums such as arabic, xanthan, guar, gellan, tara, cellulosic, garrafin, tragacanth, karaya, mesquite, sodium alginate, carrageenan and mixtures of these.
  • hydrophilic surfactant can be selected from the group consisting of polysorbates, ethoxylated linear alcohols, ethoxylated alkyl phenols, fatty acid esters, derivatives of amines and amides, ethylene oxide copolymers, propylene oxide, ethoxylated polyalcohols of polyalcohols, ethoxylated thiols (mercaptans) and mixtures of these.
  • the hydrophilic phase is mixed with the lipophilic phase in the hydrophilic phase mixer.
  • the lipophilic phase is prepared by adding a lipophilic agent or nucleus selected from the group consisting of lipids, phospholipids, silicones, paraffins, waxes, among others, in a lipophilic phase mixer between 4000 and 9000 rpm, preferably 5000 rpm generating a pressure emulsion.
  • the previously obtained pre-emulsion is subjected to the application of a high mechanical stress, which can be carried out through a stirring and / or high pressure process.
  • a high mechanical stress which can be carried out through a stirring and / or high pressure process.
  • the temperature of the mixture should not exceed 100 ° C, preferably 40 ° C.
  • the minimum frequency of said agitation is between 10000-50000 rpm and 1000-20000 PSI (6.89 MPa to 130.89 MPa), so that the shear force carried out on the mixture is high enough to decrease the droplet size of the emulsion formed on a nano-scale, particularly, average droplet sizes between 1-500 nm.
  • the minimum pressure must not be less than 700 bar (70 MPa), so that the force exerted on the mixture is high enough to reduce the size. from droplet of the emulsion formed on a nano scale, particularly average droplet sizes between 1-500 nm.
  • the nanoemulsion is generated, it is subjected to a stabilization process through a decrease in temperature, which can occur quickly or slowly, starting at a temperature of 40 ° C until reaching a value of 20 ° C.
  • the nanoencapsulation of said nanoemulsion is carried out.
  • the nanoemulsion is collected in a tank with constant stirring with temperature control.
  • the agitation carried out between 35 and 45 ° C in said tank should be maintained between 10,000 - 20,000 rpm and 10,000 - 20000 PSI (68-138 MPa), preferably between 500 and 1000 rpm, and more preferably 800 rpm.
  • the temperature of the product subsequently stabilizes at a constant value between 15 and 25 ° C, preferably 20 ° C.
  • the product stored in the homogenizing tank is subsequently taken to an electro spray equipment (for example, 150 L of water / h), through a positive pressure pump that allows feeding said equipment with a flow greater than 2 liters per minute, preferably 2 to 4 l / min, in order to carry out an encapsulation process.
  • an electro spray equipment for example, 150 L of water / h
  • a positive pressure pump that allows feeding said equipment with a flow greater than 2 liters per minute, preferably 2 to 4 l / min, in order to carry out an encapsulation process.
  • the sprinkling process is nozzle type, a pressure system is incorporated that allows controlling the flow pressure at the entrance of the equipment.
  • Said inlet pressure to the drying equipment will be 50 to 600 psi (2.07 MPa to 4.14 MPa) and the voltage that surrounds the nozzle will be 190 - 5000 KV, one of the electrodes is located in this nozzle.
  • the liquid spray product will fall on a collecting plate, which connects the other electrode, and which contains an aqueous solution of calcium chloride in a range of 1 -50% by weight which will react with the wall material of the nanoemulsion, for example with sodium alginate.
  • This plate is coupled to a device that removes the nanocapsules that contains the oily nanoparticles of cannabis that will then be subjected to a drying process by trays or fluidized bed and hot air is passed at a temperature of 190- -200 ° C inlet and 90-100 ° C output for a time of 10-20 minutes then it will be sieved, cooled and packed.
  • a granulometric classification of the nanoencapsulated product is carried out, in order to obtain particles with average sizes lower than 500 nm, preferably 100 nm. Additionally, when carrying out this process of sieving the capsules, it is sought to separate impurities and control the quality of the product obtained.
  • a stabilization stage of the nanocapsules is developed, which seeks to gradually reduce the temperature of the product to a maximum value of 10 ° C. This process is preferably done in a room with thermal control.
  • the product obtained through this new process is a nanocapsule that contains cannabis extract or cannabis oil in nanometric size, covered by an encapsulating material, where the concentration of the cannabis extract can be between 10% and 90% based on the weight of the material. encapsulant, as seen in figure 1.
  • the product obtained is a nanoencapsulate that has more flexible physical presentation characteristics and adaptable to applications other than current ones. Furthermore, the product has been found to have improved bioavailability of the active compound, generating curative effects with lower amounts.
  • the nanoparticles have a size between 1 and 500 nm and these nanoparticles are comprised of cannabis oil and a material pharmaceutically acceptable encapsulant or carrier and GRAS (Generally recognized as safe) in the case of food and which may comprise antioxidants, emulsifiers, proteins, pH regulators; colorants, stabilizers, starches, carbohydrates, phospholipids, sweeteners, and anti-compactants among other pharmaceutical, food or cosmetically acceptable components.
  • a material pharmaceutically acceptable encapsulant or carrier and GRAS Generally recognized as safe
  • the preferred particle size for capsules is from 1 nm to 200 nm, even more preferred is from 1 to 100 nm.
  • the main ingredient or active ingredient is cannabis oil that is found in a proportion of from 5% to 95% based on the weight of the encapsulating matrix.
  • the cannabinoids named as THC, CBD, CBN, CBC, CBG, with percentages between 0.1% of the extract up to 80% of it.
  • encapsulating materials are the components that, with the help of other excipients, encapsulate the active ingredient of cannabis.
  • encapsulating materials that can be used in the present invention are: emulsifiers, carbohydrates, proteins, alginates and starches, where stabilizers from 0.01% to 5% by weight, starches from 1% to 30%, alginates 1% to 30% by weight and calcium chloride from 1% to 50%.
  • Another of the components that can participate in the encapsulated nanoparticles of the present invention are materials that can be selected from a group of natural or synthetic antioxidants such as carotenoids, polyphenols, tocopherols, antiocyanins or BHTs and mixtures of these.
  • Emulsifiers such as a and fatty acid mono glycerides, monoleates, TWIN 80, SPAN 80, lecithin, and mixtures thereof.
  • PH regulators such as sodium and calcium tripol phosphate, sodium, calcium and potassium diphosphates, acid salts (sodium lactate, sodium citrate) and mixtures thereof, calcium chloride.
  • Stabilizers such as carrageenan (K, a, l, I), CMC, xanthan, arabic, guar and carob gums and mixtures thereof, sodium alginate.
  • Phospholipids such as lecithin and other phospholipids of plant origin and mixtures thereof.
  • Sweeteners and / or lipophilic potentiators such as sorbitol, mannitol, xylitol, isomalt, hydrogenated starch hydrolysates and others such as, acesulfame k, alitame, aspartame, cyclamate, neohesperidin, saccharin, sucralose, stevioside, thaumatin and mixtures thereof.
  • Example 1 Process for making cannabis nanoparticles
  • a mixture of the cannabis oil is made, with the proteins, the emulsifier (a and mono glycerides of fatty acids) and the phospholipids (Lecithin), according to the ranges given in the table.
  • hydrophilic phase water is added to the previous mixture, in a hydrophilic phase mixer, to which it is necessary to increase its temperature to 40 ° C. Subsequently, a non-ionic hydrophilic surfactant with an HBL greater than 13 is slowly added.
  • the mixture that is formed is subjected to a stirring process by means of a stirrer programmed 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 carbohydrates is added.
  • the two phases are subsequently mixed, controlling the temperature at 40 ° C
  • the mixture that is formed is subjected to a stirring process by means of a stirrer programmed with a rotation frequency of 700 rpm, controlling the foam generation. Subsequently, a non-ionic lipophilic surfactant with an HBL lower than 9 is added slowly.
  • Said mixture is passed through a phase mixer and said mixture is subjected to a stirring process of 5000 rpm, controlling the generation of foam and the temperature previously reached, generating a pre-emulsion
  • the pre-emulsion obtained previously is subjected to the application of a high mechanical stress and the temperature of the mixture is adjusted between a range of 35 to 55 ° C, preferably 40 ° C.
  • the temperature of the mixture is adjusted between a range of 35 to 55 ° C, preferably 40 ° C.
  • this nanoemulsion is stabilized with a change in temperature up to 20 ° C.
  • the nanoemulsion is fed by a pressure system that allows the flow pressure to be controlled at the entrance of the equipment.
  • Said inlet pressure to the electrospry equipment will be 50 to 600 psi (2.07 MPa to 4.14 MPa) and the voltage that surrounds the nozzle will be 190 - 5000 KV, one of the electrodes is located in this nozzle.
  • the liquid spray product will fall on a collecting plate, which connects the other electrode, and which contains an aqueous solution of calcium chloride in a range of 1 -50% by weight which will react with the wall material of the nanoemulsion, for example with sodium alginate causing the generation of the nanocapsule which contains lipid nanoparticles of cannabis oil, then they are collected and hot air is passed at a temperature of 190-200 ° C inlet and 90-100 ° C outlet for a time 10-20 minutes then it will be sieved, cooled and packed.
  • a stabilization stage of the nanocapsules is developed, which seeks to gradually decrease the temperature of the product to a maximum value of 10 ° C.

Abstract

The present invention relates to a process for obtaining cannabinoid nanocapsules using electrospraying, and to the product obtained using the process. The process comprises the steps of: forming a nanoemulsion with an oily phase containing the active ingredient cannabis oil, a hydrophilic phase and an encapsulating matrix; obtaining the nanoemulsion and nanoencapsulating by means of electrospraying at 190-5000 kV; drying by means of trays or a fluidised bed with hot air; and subsequently cooling, sieving and packing. The obtained product is a nanocapsule containing 5-95% cannabis oil by weight of the encapsulating matrix. The nanoparticles have a size of 1-200 nm. The invention belongs to the technical field of chemical processes.

Description

NANOENCAPSULADOS DE CANNABINOIDES Y PROCESO PARA SU CANNABINOID NANOENCAPSULATES AND PROCESS FOR THEIR
ELABORACIÓN ELABORATION
CAMPO DE LA INVENCIÓN FIELD OF THE INVENTION
La presente invención se enmarca en el campo de la química, particularmente a nanopartículas oleosas de cannabis encapsuladas, útiles para aplicaciones en la industria farmacéutica, alimenticia y cosmética. The present invention is framed in the field of chemistry, particularly encapsulated oily cannabis nanoparticles, useful for applications in the pharmaceutical, food and cosmetic industries.
ANTECEDENTES DE LA INVENCIÓN BACKGROUND OF THE INVENTION
Los cannabinoides se refieren a las sustancias químicas, que se enlazan con proteínas receptoras específicas, conocidas como CB1 , CB2 y otras, estas sustancias pueden tener un origen o estructura diversa. Cannabinoids refer to chemical substances, which bind to specific receptor proteins, known as CB1, CB2 and others, these substances can have a diverse origin or structure.
En este grupo de sustancias, están los cannabinoides naturales, o fitocannabinoides que provienen de las plantas Cannabis sativa, C. indica y C. ruderalis, principalmente, aunque pueden ser aislados de otras especies del género Cannabis sp. (Pascual y Fernández, 2017). In this group of substances, there are the natural cannabinoids, or phytocannabinoids that come from the plants Cannabis sativa, C. indica and C. ruderalis, mainly, although they can be isolated from other species of the genus Cannabis sp. (Pascual and Fernández, 2017).
Se han identificado 60 principios activos que pertenecen al grupo de los cannabinoides, entre los cuales sobresalen: delta-9-trans-tetrahidrocannabinol (D9- THC), que es el principal psicoactivo de la planta, delta-8- tetrahidrocannabinol (D8- THC), cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN) y cannabitriol (CBT) (Avello, et.al, 2017). 60 active principles have been identified that belong to the group of cannabinoids, among which stand out: delta-9-trans-tetrahydrocannabinol (D9-THC), which is the main psychoactive of the plant, delta-8-tetrahydrocannabinol (D8-THC ), cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN) and cannabitriol (CBT) (Avello, et.al, 2017).
Son vahas las aplicaciones médicas que se le reconocen a los cannabinoides, entre las principales están la disminución de síntomas asociados con: náuseas y vómitos debido a la quimioterapia, estimulación del apetito en el VIH/SIDA, dolor crónico, espasticidad debida a esclerosis múltiple o paraplejia, depresión, trastorno de ansiedad, trastorno del sueño, psicosis, glaucoma o síndrome de Tourette (Whiting, et.al., 2015). En cuanto a sus aplicaciones en productos cosméticos, el CBD es la sustancia no- psicotrópica que más emplea para estos fines, y está teniendo un amplio desarrollo de productos, especialmente aceite facial o máscaras faciales de CBD, se le atribuyen propiedades antinflamatorias, antioxidantes y acondicionador de la piel (Barr, 2018). There are several medical applications that are recognized for cannabinoids, among the main ones are the reduction of symptoms associated with: nausea and vomiting due to chemotherapy, appetite stimulation in HIV / AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome (Whiting, et.al., 2015). Regarding its applications in cosmetic products, CBD is the non-psychotropic substance that is used the most for these purposes, and it is having an extensive development of products, especially facial oil or CBD facial masks, it is attributed anti-inflammatory, antioxidant and skin conditioner (Barr, 2018).
Se están desarrollando formulaciones que contengan como principio activo extractos de esta planta, cannabinoides aislados o mezclas de éstos, entre las que se destacan: Formulations are being developed that contain extracts of this plant, isolated cannabinoids or mixtures of these as active principle, among which the following stand out:
La patente US6383513 enseña una composición para el suministro nasal de un cannabinoide en un sistema de suministro bifásico, de tipo emulsión aceite en agua, o un cannabinoide en un sistema de suministro de microesferas, donde éstas son elaboradas de albúmina. Patent US6383513 teaches a composition for the nasal delivery of a cannabinoid in a biphasic delivery system, of the oil-in-water emulsion type, or a cannabinoid in a microsphere delivery system, where these are made from albumin.
La solicitud de patente US20170232210 también prepara una emulsión, usando un método para fabricar un polvo fluido y dispersable que incluye solubilizar una sustancia lipófila en un terpeno para formar una mezcla y tratar la mezcla para formar una nanoemulsión dispersada en una solución acuosa. La solución acuosa incluye al menos un excipiente funcional. La nanoemulsión se seca luego por pulverización, evaporando así primero la porción acuosa y luego el terpeno para formar un polvo seco formado a partir de partículas sólidas que comprenden la sustancia lipófila. Patent application US20170232210 also prepares an emulsion, using a method for manufacturing a fluid and dispersible powder that includes solubilizing a lipophilic substance in a terpene to form a mixture and treating the mixture to form a nanoemulsion dispersed in an aqueous solution. The aqueous solution includes at least one functional excipient. The nanoemulsion is then spray dried, thus first evaporating the aqueous portion and then the terpene to form a dry powder formed from solid particles comprising the lipophilic substance.
La solicitud de patente US20160279073 divulga formulaciones de liposomas y m ¡celas estables de acción rápida de terpenos, aceite de cáñamo, cannabinoides o mezclas de un cannabinoide y terpenos o aceite de cáñamo y cannabinoides que son adecuados para aplicaciones farmacéuticas y nutracéuticas. Patent application US20160279073 discloses fast-acting stable liposome and micellar formulations of terpenes, hemp oil, cannabinoids or mixtures of a cannabinoid and terpenes or hemp oil and cannabinoids that are suitable for pharmaceutical and nutraceutical applications.
Otros documentos enseñan formulaciones de liposomas, que incluyen fosfolípidos, entre estos documentos están: Other documents teach liposome formulations, which include phospholipids, among these documents are:
El documento WO2001003668 muestra una composición liposomal que contiene un cannabinoide o un agente cannabimimético y métodos de administración sistémica al poner en contacto el tejido pulmonar de un mamífero con la composición liposomal para lograr un efecto psicoactivo prolongado. Es así 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. WO2001003668 teaches a liposomal composition containing a cannabinoid or a cannabimimetic agent and methods of systemic administration by contacting the lung tissue of a mammal with the liposomal composition to achieve a prolonged psychoactive effect. Thus, the 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 oily 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.
La solicitud de patente WO2016144376 enseña composiciones de nanopartículas de fosfolípidos de cannabinoides formadas a partir de fosfolípidos y 20 lípidos más simples en un proceso secuencial 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; donde la estructura dinámica de las nanopartículas reduce los efectos adversos de los cannabinoides; y permite una terapia de cannabinoides más eficaz y segura. Patent application WO2016144376 teaches cannabinoid phospholipid nanoparticle compositions formed from phospholipids and 20 simpler lipids in a sequential 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; where the dynamic structure of the nanoparticles reduces the adverse effects of cannabinoids; and allows a more effective and safe cannabinoid therapy.
Otras aproximaciones han sido encapsular los cannabinoides con polímeros. El documento WO2018204326 divulga una formulación para crear un polvo de un componente a base de cannabis encapsulado integrado en una matriz de polímero y su método de preparación. El método incluye la introducción de un componente que incluye al menos uno de: (i) un cannabinoide, y (¡i) un terpeno, a un polímero para producir una mezcla polimérica. El componente se dispersa en la mezcla polimérica, que luego se deshidrata para encapsular el componente dentro de un material polimérico derivado del polímero. El material polimérico es soluble en agua. La mezcla polimérica deshidratada se procesa para formar partículas que comprenden el componente encapsulado dentro de las cubiertas formadas a partir del material polimérico. Adicionalmente, la patente US5989583 reporta que sustancias lipofílicas de baja biodisponibilidad oral, se mezclan con al menos una grasa sólida y fosfolípido 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 vitro 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. Other approaches have been to encapsulate cannabinoids with polymers. Document WO2018204326 discloses a formulation for creating an encapsulated cannabis-based one-component powder integrated into a polymer matrix and its method of preparation. The method includes the introduction of a component that includes at least one of: (i) a cannabinoid, and (ii) a terpene, to a polymer to produce a polymeric mixture. The component is dispersed in the polymer mixture, which is then dehydrated to encapsulate the component within a polymeric material derived from the polymer. The polymeric material is soluble in water. The dehydrated polymer blend is processed to form particles comprising the encapsulated component within shells formed from the polymeric material. Additionally, patent US5989583 reports that lipophilic substances with low oral bioavailability are mixed with at least one solid fat and phospholipid to obtain a dry solid composition suitable 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 improved drug release in vitro and improved oral bioavailability in vivo compared to a commercial formulation of CoQ10. The dexanabinol dry lipid blend similarly shows improved oral bioavailability compared to known formulations.
Por su parte, la patente EP2444071 enseña 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 nanoemulsión, un sistema de liberación autoemulsionante, un sistema de administración automicroemulsionante, una formulación de perfluorocarbono bioestable, un complejo con ciclodextñna (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 that comprises a plurality of seamless mini-capsules, the mini-capsules having a diameter of 0.5 mm to 5 mm, and wherein the mini-capsules have a core that contains 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 delivery system, a self-emulsifying delivery system, a biostable perfluorocarbon formulation, a complex with cyclodextin (and the like), liposomes, hydrogel, directed lymphatic delivery system, liquid bi-layers, an aqueous system, wax, emzaloid, and natural plant extract
En el estado de la técnica evidencia que el problema técnico más significativo es, que la mayoría de los aceites que contienen cannabinoides son químicamente inestables y susceptibles al deterioro oxidativo, especialmente cuando son expuestos a oxígeno, luz, humedad y cambios de temperatura, por esto existe la necesidad de proveer cannabis empleando técnicas de encapsulación que permitan la protección del compuesto de esos factores, para facilitar la estabilidad y la incorporación en diferentes matrices nutracéuticas o alimenticias. Así mismo, se requiere 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, y puedan ser aplicados a cualquier producto o matriz con gran mejoría en sus condiciones organolépticas In the state of the art it shows that the most significant technical problem is that most of the oils that contain cannabinoids are chemically unstable and susceptible to oxidative deterioration, especially when exposed to oxygen, light, humidity and changes in temperature, for this reason There is a need to provide cannabis using encapsulation techniques that allow the protection of the compound from these factors, to facilitate stability and incorporation into different nutraceutical or food matrices. Likewise, it is required to regulate the concentrations of cannabinoids, optimizing the dosage in the products, minimizing risks in the end consumers and enhancing the health benefits, and where the particle size helps to a greater bioavailability, and can be applied to any product or matrix with great improvement in its organoleptic conditions
BREVE DESCRIPCIÓN DE LA INVENCIÓN BRIEF DESCRIPTION OF THE INVENTION
La presente invención soluciona este problema al proveer una nueva matriz de nanopartículas oleosas de cannabis nanoencapsuladas y luego deshidratadas, que se puedan hacer mediante la combinación de nanoencapsulación y deshidratación. The present invention solves this problem by providing a new matrix of nanoencapsulated and then dehydrated oily cannabis nanoparticles, which can be made by combining nanoencapsulation and dehydration.
También se describe el proceso para la nanoencapsulación de cannabinoides que emplea metodología electrospray, lo que implica que no se debe someter el principio activo a ninguna condición severa de temperatura, o humedad, entre otros. The process for the nanoencapsulation of cannabinoids using electrospray methodology is also described, which implies that the active principle should not be subjected to any severe temperature or humidity conditions, among others.
El método empleado y el producto así obtenido permite una mejor biodisponibilidad en el tracto gastrointestinal o epidérmico de los cannabinoides, optimizando la dosificación en los productos, minimizando riesgos en los consumidores finales y potenciando los beneficios para la salud. The method used and the product thus obtained allows a better bioavailability in the gastrointestinal or epidermal tract of cannabinoids, optimizing the dosage in the products, minimizing risks in final consumers and enhancing health benefits.
LISTADO DE FIGURAS LIST OF FIGURES
Figura 1. Microfotografía de nanopartículas oleosas de cannabis microencapsuladas y luego deshidratadas de acuerdo con la invención, en donde se observa su forma homogénea. Figure 1. Microencapsulated and then dehydrated oily cannabis nanoparticles according to the invention, where their homogeneous shape is observed.
DESCRIPCIÓN DETALLADA DE LA INVENCIÓN DETAILED DESCRIPTION OF THE INVENTION
La presente invención está dirigida a un producto que es nanopartículas oleosas de cannabis nanoencapsuladas y luego deshidratadas. Así mismo, se enseña el proceso de elaboración de dichas nanopartículas. The present invention is directed to a product that is nanoencapsulated and then dehydrated cannabis oil nanoparticles. Likewise, the process of making said nanoparticles is taught.
Proceso de obtención de nanopartículas de cannabis El proceso de obtención de nanopartículas de la presente invención comprende la elaboración de una nanoemulsión y su posterior nanoencapsulación mediante la técnica de electrospray. Process for obtaining cannabis nanoparticles The process for obtaining nanoparticles of the present invention comprises the elaboration of a nanoemulsion and its subsequent nanoencapsulation by means of the electrospray technique.
Para efectos de la presente invención, el principio activo corresponde a extracto de cannabis, el cual puede comprender extractos de cualquier tipo o categoría de plantas de cannabis, principalmente, de las especies sativa e indica y los cruces de estas. For the purposes of the present invention, the active principle corresponds to cannabis extract, which can comprise extracts of any type or category of cannabis plants, mainly of the sativa and indica species and their crosses.
El aceite de cannabis es un aceite que resulta de cualquier 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 aceites obtenidos del extracto de la planta de Cannabis, aceite de CBD, THC, CBN, CBG, CBT, mezcla de cannabinoides, cannabinoides y terpenos derivados o no de la planta de Cannabis, cannabinoides y flavonoides derivados o no de la planta de Cannabis, y/o mezcla de todos los anteriores. Cannabis oil is an oil that results from any extract that contains substances identified as cannabionoids (medicinal compounds). Among the cannabis extracts that can be used in the present invention, are the oils obtained from the extract of the Cannabis plant, CBD oil, THC, CBN, CBG, CBT, a mixture of cannabinoids, cannabinoids and terpenes derived or not derived from the Cannabis plant, cannabinoids and flavonoids derived or not from the Cannabis plant, and / or a mixture of all the above.
Adicionalmente, se puede emplear cualquier tipo de 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 estos. También se puede emplear extractos liofilizados que son reconstituidos en agua o en cualquier otro solvente farmacéuticamente aceptable. Additionally, any type of solvent or mixtures of solvents can be used. Among the best known and used solvents in the extracts of the present invention are food grade and pharmaceutically acceptable organic solvents, for example aqueous, alcoholic and mixtures of these. You can also use lyophilized extracts that are reconstituted in water or any other pharmaceutically acceptable solvent.
Las nanopartículas oleosas de cannabis nanoencapsuladas de la presente invención se obtienen mediante un proceso que combina las etapas de: 1 ) formación de nanoemulsión; 2) nanoencapsulación; y 3) secado por bandejas o lecho fluidizado. The oily nanoencapsulated cannabis nanoparticles of the present invention are obtained by a process that combines the steps of: 1) nanoemulsion formation; 2) nanoencapsulation; and 3) tray or fluidized bed drying.
El proceso para la nanoencapsulación de cannabinoides comprende: The process for nanoencapsulation of cannabinoids comprises:
a) Formar una nanoemulsión con una fase oleosa que comprende aceite de cannabis, una fase hidrofílica y una matriz encapsulante; a) Forming a nanoemulsion with an oily phase comprising cannabis oil, a hydrophilic phase and an encapsulating matrix;
b) Realizar la nanoencapsulación por electrospray de la nanoemulsión obtenida en la etapa a), usando de 0, 1 -30 kV; luego deshidratar por bandejas o lecho fluidizado con aire caliente; c) Enfriar las nanocápsulas obtenidas b) Carry out the nanoencapsulation by electrospray of the nanoemulsion obtained in step a), using 0.1 -30 kV; then dehydrate by trays or fluidized bed with hot air; c) Cool the nanocapsules obtained
Se describe a continuación el detalle de cada una de estas etapas: The details of each of these stages are described below:
Etapa a) Formación de nanoemulsión Stage a) Formation of nanoemulsion
Esta etapa comprende los siguientes pasos: This stage comprises the following steps:
1 . Preparación de fase lipofílica 1 . Preparation of lipophilic phase
La 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 liposolubles o aceites esenciales. Para este caso la mezcla en modalidades preferidas contiene como agente oleoso el aceite de cannabis con sus principios activos. The lipophilic phase is understood as any molecule or mixture of them that have affinity for fats and great solubility in lipids, among other compounds fatty acids, vitamins, waxes, fat-soluble extracts or essential oils can be mentioned. For this case, the mixture in preferred modalities contains cannabis oil with its active principles as an oily agent.
Se realiza una mezcla del aceite de cannabis, con el emulsificante (a y mono glicéridos de ácidos grasos,) y los fosfolípidos (Lecitina). (Ver rangos en la tabla 1 ). Emulsificantes 0.1 % - 5 %, Fosfolípidos 0.1 % - 5 % A mixture of cannabis oil is made, with the emulsifier (a and mono glycerides of fatty acids) and the phospholipids (Lecithin). (See ranges in table 1). Emulsifiers 0.1% - 5%, Phospholipids 0.1% - 5%
2. Preparación de fase hidrofílica 2. Preparation of hydrophilic phase
Por fase hidrofílica se entiende aquella fase que tiene afinidad por el agua. En una disolución o coloide, las partículas hidrófilas tienden a acercarse y mantener contacto con el agua. Las moléculas hidrófilas son a su vez lipófobas, es decir, no tienen afinidad por los lípidos o grasas y no se mezclan con ellas. Durante la preparación de la fase hidrofílica, se adiciona agua en un mezclador de fase hidrofílica, que se emplea a temperatura en un rango entre 10°C y 100°C, preferiblemente 40°C. Posteriormente, se adiciona lentamente un surfactante hidrofílico 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. By hydrophilic phase is understood that phase that has an affinity for water. In a solution or colloid, the hydrophilic particles tend to approach and maintain contact with water. Hydrophilic molecules are in turn lipophobic, that is, 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 hydrophilic phase mixer, which is used at a temperature in a range between 10 ° C and 100 ° C, preferably 40 ° C. Subsequently, a non-ionic hydrophilic surfactant is slowly added with an HBL greater than 13. The mixture that is formed is subjected to a stirring process by means of a stirrer programmed with a rotation frequency between 100 rpm and 1000 rpm, preferably 500 rpm controlling the generation of foam and the temperature previously reached.
Durante dicho proceso de agitación, se adiciona una matriz encapsulante seleccionada del grupo conformado por carbohidratos como alginato de sodio o calcio, almidón nativos y modificados química o físicamente, maltodextrinas, jarabes de maíz, ciclodextrinas, carboximetilcelulosa y derivados; gomas como arábiga, xanthan, guar, gellan, tara, celulósicas, garrafin, tragacanto, karaya, mezquite, alginato de sodio, carragenina y mezclas de éstos. During said stirring process, an encapsulating matrix selected from the group consisting of carbohydrates such as sodium or calcium alginate is added, native and chemically or physically modified starches, maltodextrins, corn syrups, cyclodextrins, carboxymethylcellulose and derivatives; gums such as arabic, xanthan, guar, gellan, tara, cellulosic, garrafin, tragacanth, karaya, mesquite, sodium alginate, carrageenan and mixtures of these.
Adicionalmente, el surfactante hidrofílico puede ser seleccionado del grupo que forman aquellos de tipo polisorbatos, alcoholes lineales etoxilados, alquil fenoles etoxilados, esteres de ácidos grasos, derivados de aminas y amidas, copolímeros óxidos de etileno, óxido de propileno, polialcoholes de polialcoholes etoxilados, tioles (mercaptanos) etoxilados y mezclas de estos. Additionally, the hydrophilic surfactant can be selected from the group consisting of polysorbates, ethoxylated linear alcohols, ethoxylated alkyl phenols, fatty acid esters, derivatives of amines and amides, ethylene oxide copolymers, propylene oxide, ethoxylated polyalcohols of polyalcohols, ethoxylated thiols (mercaptans) and mixtures of these.
Posteriormente, la fase hidrofílica es mezclada con la fase lipofílica en el mezclador de fase hidrofílica. La fase lipofílica es preparada mediante la adición de un agente lipofílico o núcleo seleccionado del grupo constituido por lípidos, fosfolípidos, siliconas, parafinas, ceras entre otras, en un mezclador de fase lipofílica entre 4000 y 9000 rpm, preferiblemente 5000 rpm generando una pre-emulsión. Subsequently, the hydrophilic phase is mixed with the lipophilic phase in the hydrophilic phase mixer. The lipophilic phase is prepared by adding a lipophilic agent or nucleus selected from the group consisting of lipids, phospholipids, silicones, paraffins, waxes, among others, in a lipophilic phase mixer between 4000 and 9000 rpm, preferably 5000 rpm generating a pressure emulsion.
3. Elaboración de nanoemulsión 3. Manufacture of nanoemulsion
Con el fin de generar una nanoemulsión, la pre-emulsión 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 alta presión. Durante la aplicación de dicho esfuerzo mecánico, la temperatura de la mezcla no debe superar los 100°C, preferiblemente 40°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 stirring and / or high pressure process. During the application of said mechanical stress, the temperature of the mixture should not exceed 100 ° C, preferably 40 ° C.
Si la aplicación del esfuerzo mecánico es realizada a través de agitación, la frecuencia mínima de dicha agitación es entre 10000-50000 rpm y 1000-20000 PSI (6,89 MPa a 130.89 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. If the application of mechanical stress is carried out through agitation, the minimum frequency of said agitation is between 10000-50000 rpm and 1000-20000 PSI (6.89 MPa to 130.89 MPa), so that the shear force carried out on the mixture is high enough to decrease the droplet size of the emulsion formed on a nano-scale, particularly, average droplet sizes between 1-500 nm.
Si la aplicación de un alto esfuerzo mecánico es realizada a través de alta 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 alta para disminuir el tamaño de gota de la emulsión formada a escala nanométrica, particularmente tamaños medios de gota entre 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), so that the force exerted on the mixture is high enough to reduce the size. from droplet of the emulsion formed on a nano 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 descenso de temperatura, el cual puede darse de forma rápida o lenta, partiendo de una temperatura de 40°C hasta llegar a un valor de 20°C. Once the nanoemulsion is generated, it is subjected to a stabilization process through a decrease in temperature, which can occur quickly or slowly, starting at a temperature of 40 ° C until reaching a value of 20 ° C.
Etapa b) Generación de nanoencapsulados por electrospray y secado Stage b) Generation of nanoencapsulates by electrospray and drying
Posterior al proceso de estabilización de la nanoemulsión, se procede a la nanoencapsulación de dicha nanoemulsión. After the stabilization process of the nanoemulsion, the nanoencapsulation of said nanoemulsion is carried out.
La nanoemulsión es recolectada en un tanque con agitación constante con control de temperatura. La agitación efectuada entre 35 y 45°C en dicho tanque debe mantenerse entre 10000 - 20000 rpm y 10000 - 20000 PSI (68-138 MPa), preferiblemente entre 500 y 1000 rpm, y más preferiblemente 800 rpm. La temperatura del producto posteriormente se estabiliza en un valor constante entre 15 y 25°C, preferiblemente 20°C. The nanoemulsion is collected in a tank with constant stirring with temperature control. The agitation carried out between 35 and 45 ° C in said tank should be maintained between 10,000 - 20,000 rpm and 10,000 - 20000 PSI (68-138 MPa), preferably between 500 and 1000 rpm, and more preferably 800 rpm. The temperature of the product subsequently stabilizes at a constant value between 15 and 25 ° C, preferably 20 ° C.
El producto almacenado en el tanque homogenizador, posteriormente es llevado a un equipo electro spray (por ejemplo, de 150 L de agua/h), a través de una bomba de presión positiva que permite alimentar dicho equipo con un flujo superior a 2 litros por minuto, preferiblemente de 2 a 4 l/min, con el fin de efectuar un proceso de encapsulación. The product stored in the homogenizing tank is subsequently taken to an electro spray equipment (for example, 150 L of water / h), through a positive pressure pump that allows feeding said equipment with a flow greater than 2 liters per minute, preferably 2 to 4 l / min, in order to carry out an encapsulation process.
El proceso de aspersión es tipo boquilla, se incorpora un sistema de presión que permite controlar la presión de flujo al ingreso del equipo. Dicha presión de entrada al equipo de secado será 50 a 600 psi (2.07 MPa a 4.14 MPa) y el voltaje que rodea la boquilla será de 190 - 5000 KV, en esta boquilla se ubica uno de los electrodos. El producto liquido en aspersión caerá sobre un plato colector, que conecta el otro electrodo, y que contiene solución acuosa de cloruro de calcio en un rango de 1 -50% en peso la cual reaccionara con el material de pared de la nanoemulsión por ejemplo con el alginato de sodio. Este plato está acoplado a un dispositivo que retira las nanocápsulas que contiene las nanopartículas oleosas de cannabis que luego someterá a un proceso de secado por bandejas o de lecho fluidizado y se pasa aire caliente a una temperatura de 190- -200°C de entrada y salida de 90-100°C por un tiempo de 10-20 minutos luego será tamizado, enfriado y empacado. The sprinkling process is nozzle type, a pressure system is incorporated that allows controlling the flow pressure at the entrance of the equipment. Said inlet pressure to the drying equipment will be 50 to 600 psi (2.07 MPa to 4.14 MPa) and the voltage that surrounds the nozzle will be 190 - 5000 KV, one of the electrodes is located in this nozzle. The liquid spray product will fall on a collecting plate, which connects the other electrode, and which contains an aqueous solution of calcium chloride in a range of 1 -50% by weight which will react with the wall material of the nanoemulsion, for example with sodium alginate. This plate is coupled to a device that removes the nanocapsules that contains the oily nanoparticles of cannabis that will then be subjected to a drying process by trays or fluidized bed and hot air is passed at a temperature of 190- -200 ° C inlet and 90-100 ° C output for a time of 10-20 minutes then it will be sieved, cooled and packed.
Etapa c) Enfriamiento de las nanocápsulas obtenidas Stage c) Cooling of the nanocapsules obtained
Durante dicho proceso de tamizado pasado por malla número 35/200 se realiza una clasificación granulométrica del producto nanoencapsulado, con el fin de obtener partículas con tamaños medios inferiores a 500 nm, preferiblemente 100 nm. Adicionalmente al efectuar dicho proceso de tamizado de las cápsulas, se busca separar impurezas y controlar la calidad del producto obtenido. Posterior al proceso de tamizado, se desarrolla una etapa de estabilización de las nanocápsulas, 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. During said sieving process passed through 35/200 mesh, a granulometric classification of the nanoencapsulated product is carried out, in order to obtain particles with average sizes lower than 500 nm, preferably 100 nm. Additionally, when carrying out this process of sieving the capsules, it is sought to separate impurities and control the quality of the product obtained. After the sieving process, a stabilization stage of the nanocapsules is developed, which seeks to gradually reduce the temperature of the product to a maximum value of 10 ° C. This process is preferably done in a room with thermal control.
Nanoencapsulados obtenidos Nanoencapsulates obtained
El producto obtenido mediante este nuevo proceso es una nanocápsula que contiene extracto de cannabis o aceite de cannabis en tamaño nanométñco recubierto por un material encapsulante, en donde la concentración del extracto de cannabis puede estar entre 10% y 90% en base al peso del material encapsulante, tal como se observa en la figura 1 . The product obtained through this new process is a nanocapsule that contains cannabis extract or cannabis oil in nanometric size, covered by an encapsulating material, where the concentration of the cannabis extract can be between 10% and 90% based on the weight of the material. encapsulant, as seen in figure 1.
El producto obtenido es un nanoencapsulado que tiene características físicas de presentación más flexibles y adaptables a aplicaciones diferentes a las actuales. Además, se ha encontrado que el producto tiene una biodisponibilidad del compuesto activo mejorada, generando efectos curativos con menores cantidades. The product obtained is a nanoencapsulate that has more flexible physical presentation characteristics and adaptable to applications other than current ones. Furthermore, the product has been found to have improved bioavailability of the active compound, generating curative effects with lower amounts.
De acuerdo con la invención, las nanopartículas tienen un tamaño entre 1 y 500 nm y estas nanopartículas están comprendidas por aceite cannabis y un material encapsulante o portador farmacéuticamente aceptable y GRAS (Generalmente reconocido corno seguro) en el caso de alimentos y que pueden comprender antioxidantes, emulsificantes, proteínas, reguladores de pH; colorantes, estabilizantes, almidones, carbohidratos, fosfolípidos, edulcorantes, y anticompactantes entre otros componentes farmacéuticos, alimenticios o cosméticamente aceptables. According to the invention, the nanoparticles have a size between 1 and 500 nm and these nanoparticles are comprised of cannabis oil and a material pharmaceutically acceptable encapsulant or carrier and GRAS (Generally recognized as safe) in the case of food and which may comprise antioxidants, emulsifiers, proteins, pH regulators; colorants, stabilizers, starches, carbohydrates, phospholipids, sweeteners, and anti-compactants among other pharmaceutical, food or cosmetically acceptable components.
El tamaño de partícula preferido para las cápsulas es de 1 nm a 200 nm, aún más preferido es de 1 a 100 nm. The preferred particle size for capsules is from 1 nm to 200 nm, even more preferred is from 1 to 100 nm.
De acuerdo con la presente invención, el ingrediente principal o ingrediente activo es aceite de cannabis que se encuentra en una proporción de desde 5% hasta 95% en base al peso de la matriz encapsulante. According to the present invention, the main ingredient or active ingredient is cannabis oil that is found in a proportion of from 5% to 95% based on the weight of the encapsulating matrix.
En el 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 80% del mismo. In the cannabis extract there is a main compound, the cannabinoids named as THC, CBD, CBN, CBC, CBG, with percentages between 0.1% of the extract up to 80% of it.
En relación con los 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: emuísificantes, carbohidratos, proteínas, alginatos y almidones, en donde los estabilizantes desde 0.01 % hasta 5% en peso, los almidones de desde 1 % hasta 30% , los alginatos 1 % hasta 30% en peso y cloruro de calcio desde 1 % hasta 50% . In relation to encapsulating materials, as their name indicates, they are the components that, with the help of other excipients, encapsulate the active ingredient of cannabis. Among the encapsulating materials that can be used in the present invention are: emulsifiers, carbohydrates, proteins, alginates and starches, where stabilizers from 0.01% to 5% by weight, starches from 1% to 30%, alginates 1% to 30% by weight and calcium chloride from 1% to 50%.
Otro de los componentes que pueden participar en las nanopartículas encapsuladas de la presente invención, son materiales que pueden ser seleccionados de un grupo de antioxidantes naturales o sintéticos tales como carotenoides, polifenoles, tocoferoles, antiocianinas o BHT y mezclas de estos. Emuísificantes tales como a y mono glicéridos de ácidos grasos, monoleatos, TWIN 80, SPAN 80, lecitina y mezclas de los mismos. Reguladores de pH tales como Tripol ¡fosfato de sodio y calcio, difosfatos sodio, calcio y potasio, sales de ácidos (lactato de sodio, citrato de sodio) y mezclas de los mismos, cloruro de calcio. Estabilizantes tales como carrageninas (K, a, l, I), CMC, gomas xantan, arábiga, guar y algarrobo y mezclas de los mismos, alginato de sodio. Fosfolípidos tales como lecitina y otros fosfolípidos de origen vegetal y mezclas de los mismos. Edulcorantes y/o potencializadores lipofílicos tales como sorbitol, manitol, xylitol, isomalt, los hidrolisados de almidón hidrogenados y otros como, acesulfamo k, alitamo, aspartamo, ciclamato, neohesperidina de, sacarina, sucralosa, steviosida, taumatina y mezclas de los mismos. Another of the components that can participate in the encapsulated nanoparticles of the present invention are materials that can be selected from a group of natural or synthetic antioxidants such as carotenoids, polyphenols, tocopherols, antiocyanins or BHTs and mixtures of these. Emulsifiers such as a and fatty acid mono glycerides, monoleates, TWIN 80, SPAN 80, lecithin, and mixtures thereof. PH regulators such as sodium and calcium tripol phosphate, sodium, calcium and potassium diphosphates, acid salts (sodium lactate, sodium citrate) and mixtures thereof, calcium chloride. Stabilizers such as carrageenan (K, a, l, I), CMC, xanthan, arabic, guar and carob gums and mixtures thereof, sodium alginate. Phospholipids such as lecithin and other phospholipids of plant origin and mixtures thereof. Sweeteners and / or lipophilic potentiators such as sorbitol, mannitol, xylitol, isomalt, hydrogenated starch hydrolysates and others such as, acesulfame k, alitame, aspartame, cyclamate, neohesperidin, saccharin, sucralose, stevioside, thaumatin and mixtures thereof.
EJEMPLOS EXAMPLES
Ejemplo 1. Proceso de elaboración de nanopartículas de cannabis Example 1. Process for making cannabis nanoparticles
Para la obtención de las nanopartículas oleosas de cannabis nanoencapsuladas y luego deshidratadas, se realiza un proceso que combina las etapas de preparación de nanoemulsión, nanoencapsulación por electrospray y secado por bandejas o lecho fluidizado con aire caliente: To obtain the oily nanoencapsulated and then dehydrated cannabis nanoparticles, a process is carried out that combines the steps of preparing nanoemulsion, nanoencapsulation by electrospray and drying by trays or fluidized bed with hot air:
Para la preparación de la fase lipofílica se realiza una mezcla del aceite de cannabis, con las proteínas, el emulsificante (a y mono glicéridos de ácidos grasos,) y los fosfolípidos (Lecitina), según los rangos dados en la tablal . For the preparation of the lipophilic phase, a mixture of the cannabis oil is made, with the proteins, the emulsifier (a and mono glycerides of fatty acids) and the phospholipids (Lecithin), according to the ranges given in the table.
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 a 40°C. Posteriormente, se adiciona lentamente un surfactante hidrofílico 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 carbohidratos. During the preparation of the hydrophilic phase, water is added to the previous mixture, in a hydrophilic phase mixer, to which it is necessary to increase its temperature to 40 ° C. Subsequently, a non-ionic hydrophilic surfactant with an HBL greater than 13 is slowly added. The mixture that is formed is subjected to a stirring process by means of a stirrer programmed 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 carbohydrates is added.
Posteriormente se mezclan las dos fases, controlando la temperatura a 40°C The two phases are subsequently mixed, controlling the temperature at 40 ° C
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. Posteriormente, se adiciona de manera lenta un surfactante lipofílico de carácter no iónico con un HBL inferior a 9. The mixture that is formed is subjected to a stirring process by means of a stirrer programmed with a rotation frequency of 700 rpm, controlling the foam generation. Subsequently, a non-ionic lipophilic surfactant with an HBL lower 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 stirring process of 5000 rpm, controlling the generation of foam and the temperature previously reached, generating a pre-emulsion
Para generar la nanoemulsión, la pre-emulsión obtenida previamente es sometida a la aplicación de un alto esfuerzo mecánico y la temperatura de la mezcla se ajusta entre un rango de 35 a 55°C, preferiblemente a 40°C. A una agitación de 10000 rpm y 10000 PSI (6.89 MPa), luego esta nanoemulsión se estabiliza con un cambio de temperatura hasta 20°C. To generate the nanoemulsion, the pre-emulsion obtained previously is subjected to the application of a high mechanical stress and the temperature of the mixture is adjusted between a range of 35 to 55 ° C, preferably 40 ° C. At an agitation of 10,000 rpm and 10,000 PSI (6.89 MPa), then this nanoemulsion is stabilized with a change in temperature up to 20 ° C.
Para la generación de nanocápsulas por electro spray se alimenta la nanoemulsión por un sistema de presión que permite controlar la presión de flujo al ingreso del equipo. Dicha presión de entrada al equipo de electrospry será 50 a 600 psi (2.07 MPa a 4.14 MPa) y el voltaje que rodea la boquilla será de 190 - 5000 KV, en esta boquilla se ubica uno de los electrodos. El producto liquido en aspersión caerá sobre un plato colector, que conecta el otro electrodo, y que contiene solución acuosa de cloruro de calcio en un rango de 1 -50% en peso la cual reaccionara con el material de pared de la nanoemulsión por ejemplo con el alginato de sodio provocando la generación de la nanocápsula la cual contiene nanopartículas lipídicas de aceite de cannabis, luego son recolectadas y se pasa aire caliente a una temperatura de 190- 200°C de entrada y salida de 90-100°C por un tiempo de 10-20 minutos luego será tamizado, enfriado y empacado. For the generation of nanocapsules by electro spray, the nanoemulsion is fed by a pressure system that allows the flow pressure to be controlled at the entrance of the equipment. Said inlet pressure to the electrospry equipment will be 50 to 600 psi (2.07 MPa to 4.14 MPa) and the voltage that surrounds the nozzle will be 190 - 5000 KV, one of the electrodes is located in this nozzle. The liquid spray product will fall on a collecting plate, which connects the other electrode, and which contains an aqueous solution of calcium chloride in a range of 1 -50% by weight which will react with the wall material of the nanoemulsion, for example with sodium alginate causing the generation of the nanocapsule which contains lipid nanoparticles of cannabis oil, then they are collected and hot air is passed at a temperature of 190-200 ° C inlet and 90-100 ° C outlet for a time 10-20 minutes then it will be sieved, cooled and packed.
Posterior al proceso de tamizado se desarrolla una etapa de estabilización de las nanocápsulas, donde se busca disminuir gradualmente la temperatura del producto hasta un valor máximo de 10°C. After the sieving process, a stabilization stage of the nanocapsules is developed, which seeks to gradually decrease the temperature of the product to a maximum value of 10 ° C.
Tabla 1. Formulación de las nanopartículas obtenidas por el proceso de la invención. Table 1. Formulation of the nanoparticles obtained by the process of the invention.
Figure imgf000015_0001
Figure imgf000015_0001
REFERENCIAS BIBLIOGRÁFICAS BIBLIOGRAPHIC REFERENCES
• Avello M, Pastene E, Fernández P, Córdova P. (2017) Potencial uso terapéutico de cannabis. Rev. Med. Chile, 145: 360-367. • Avello M, Pastene E, Fernández P, Córdova P. (2017) Potential therapeutic use of cannabis. Rev. Med. Chile, 145: 360-367.
• Barr S. (2018) Cannabis being used in makeup producís is on the rise. • Barr S. (2018) Cannabis being used in makeup producís is on the rise.
Independen†, 9 november, 2018. Disponible en: Independen †, 9 November 2018.Available at:
https://www.independent.co.uk/life~style/cannabis~marijuana~cbd-oil-makeup~ cannabidiol-sephora~beautv-a8625571.html https://www.independent.co.uk/life~style/cannabis~marijuana~cbd-oil-makeup~ cannabidiol-sephora ~ beautv-a8625571.html
• Pascual J.R, Fernández B.L. (2017) Breve reseña sobre la farmacología de los cannabinoides. Medisan, 21 (3):351 - 362. • Pascual J.R, Fernández B.L. (2017) Brief review on the pharmacology of cannabinoids. Medisan, 21 (3): 351-362.
• Whiting P.F, et.al. (2015) Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA, June 23/30, 313 (24): 2456-2473. • Whiting P.F, et.al. (2015) Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA, June 23/30, 313 (24): 2456-2473.

Claims

REIVINDICACIONES
1. Proceso para la nanoencapsulación de cannabinoides caracterizado por: 1. Process for nanoencapsulation of cannabinoids characterized by:
d) Formar una nanoemulsión con una fase oleosa que comprende aceite de cannabis, una fase hidrofílica y una matriz encapsulante; d) Forming a nanoemulsion with an oil phase comprising cannabis oil, a hydrophilic phase and an encapsulating matrix;
e) Realizar la nanoencapsulación por electrospray de la nanoemulsión obtenida en la etapa a), usando de 30-5000 KV; luego deshidratar por bandejas o lecho fluidizado con aire caliente; e) Carry out the nanoencapsulation by electrospray of the nanoemulsion obtained in step a), using 30-5000 KV; then dehydrate by trays or fluidized bed with hot air;
f) Enfriar las nanocápsulas obtenidas. f) Cool the nanocapsules obtained.
2. Proceso para la nanoencapsulación de cannabinoides de acuerdo con la reivindicación 1 caracterizado porque el aceite de cannabis es seleccionado de extracto de la planta de Cannabis, CBD, THC, CBN, CBG, CBT, mezcla de cannabinoides, cannabinoides y terpenos derivados o no de la planta de Cannabis, cannabinoides y flavonoides derivados o no de la planta de Cannabis, o mezclas de éstos. 2. Process for the nanoencapsulation of cannabinoids according to claim 1 characterized in that the cannabis oil is selected from an extract of the Cannabis plant, CBD, THC, CBN, CBG, CBT, a mixture of cannabinoids, cannabinoids and terpenes derived or not from the Cannabis plant, cannabinoids and flavonoids derived or not from the Cannabis plant, or mixtures of these.
3. Proceso para la nanoencapsulación de cannabinoides de acuerdo con la reivindicación 1 caracterizado porque la fase hidrofílica es seleccionada de agua, alcoholes, polialcoholes o mezclas de éstos. 3. Process for the nanoencapsulation of cannabinoids according to claim 1 characterized in that the hydrophilic phase is selected from water, alcohols, polyalcohols or mixtures of these.
4. Proceso para la nanoencapsulación de cannabinoides de acuerdo con la reivindicación 1 caracterizado porque la nanoemulsión además comprende surfactante hidrofílico y lipofílico 4. Process for the nanoencapsulation of cannabinoids according to claim 1 characterized in that the nanoemulsion also comprises hydrophilic and lipophilic surfactant
5. Proceso para la nanoencapsulación de cannabinoides de acuerdo con la reivindicación 1 caracterizado porque la matriz encapsulante de la nanoemulsión es seleccionada de carbohidratos como alginatos o alginato de sodio , almidón y derivados, maltodextrinas, jarabes de maíz, ciclodextrinas, carboximetilcelulosa y derivados; gomas como arábiga, xanthan, guar, gellan, tara, celulósicas, garrafin, tragacanto, karaya, mezquite, alginato de sodio, carragenina; lípidos como ceras, parafinas, grasas, fosfolípidos, mono y diglicéridos de ácidos grasos; 5. Process for the nanoencapsulation of cannabinoids according to claim 1 characterized in that the encapsulating matrix of the nanoemulsion is selected from carbohydrates such as alginates or sodium alginate, starch and derivatives, maltodextrins, corn syrups, cyclodextrins, carboxymethylcellulose and derivatives; gums such as arabic, xanthan, guar, gellan, tara, cellulosic, garrafin, tragacanth, karaya, mesquite, sodium alginate, carrageenan; lipids such as waxes, paraffins, fats, phospholipids, mono- and diglycerides of fatty acids;
6. Proceso para la nanoencapsulación de cannabinoides de acuerdo con la reivindicación 1 caracterizado porque la nanoemulsión de la etapa a) tiene partículas entre 1 y 500 nm. 6. Process for the nanoencapsulation of cannabinoids according to claim 1 characterized in that the nanoemulsion of step a) has particles between 1 and 500 nm.
7. Proceso para la nanoencapsulación de cannabinoides de acuerdo con la reivindicación 1 caracterizado porque la etapa b) de nanoencapsulación por electrospray tiene las siguientes etapas: 7. Process for the nanoencapsulation of cannabinoids according to claim 1 characterized in that step b) of nanoencapsulation by electrospray has the following steps:
i. Agitación entre 35 y 45°C, a 10000 - 20000 rpm y 10000 -20000 PSI, luego esta nanoemulsión se estabiliza entre 15 y 25°C; i. Stirring between 35 and 45 ° C, at 10,000 - 20000 rpm and 10,000 -20000 PSI, then this nanoemulsion is stabilized between 15 and 25 ° C;
¡i. Realizar nanoencapsulación por electrospray usando una presión de flujo de 50 a 600 psi; el voltaje que rodea la boquilla será de 30 - 5000 KV; MI. Secar las partículas a una temperatura de aire de 190-200°C de entrada y salida de 90-100°C por 10-20 minutos. I. Perform nanoencapsulation by electrospray using a flow pressure of 50 to 600 psi; the voltage surrounding the nozzle will be 30 - 5000 KV; ME. Dry the particles at an air temperature of 190-200 ° C inlet and 90-100 ° C outlet for 10-20 minutes.
8. Nanoencapsulados de cannabinoides caracterizados porque el interior posee una nanoemulsión con aceite de cannabis con un tamaño entre 1 y 100 qm y el exterior una matriz encapsulante de 1 y 200 qm, donde la concentración del aceite de cannabis puede estar entre 5% hasta 95% en base al peso de la matriz encapsulante. 8. Nanoencapsulates of cannabinoids characterized in that the interior has a nanoemulsion with cannabis oil with a size between 1 and 100 qm and the exterior an encapsulating matrix of 1 and 200 qm, where the concentration of the cannabis oil can be between 5% up to 95% % based on the weight of the encapsulating matrix.
9. Nanoencapsulados de cannabinoides de acuerdo con la reivindicación 8 caracterizados porque la matriz encapsulante es seleccionada de: emulsificantes, carbohidratos, almidones, alginato de sodio y cloruro de calcio y mezclas de éstos. 9. Nanoencapsulates of cannabinoids according to claim 8 characterized in that the encapsulating matrix is selected from: emulsifiers, carbohydrates, starches, sodium alginate and calcium chloride and mixtures of these.
10. Uso del nanoencapsulado de cannabinoides para producir un medicamento, alimento o cosmético. 10. Use of nanoencapsulated cannabinoids to produce a medicine, food or cosmetic.
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Citations (3)

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ES2582287A2 (en) * 2015-02-09 2016-09-12 Universidad De Sevilla Method of obtaining and pharmaceutical composition of polymeric nanoparticles for the treatment of neuropathic pain produced by peripheral nervous compression (Machine-translation by Google Translate, not legally binding)
WO2016144376A1 (en) * 2015-03-10 2016-09-15 Nanosphere Health Sciences, Llc Lipid nanoparticle compositions and methods as carriers of cannabinoids in standardized precision-metered dosage forms
WO2019025880A1 (en) * 2017-08-04 2019-02-07 Alsec Alimentos Secos S.A.S. Cannabis oil nanoparticles micro-encapsulated in powder

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2582287A2 (en) * 2015-02-09 2016-09-12 Universidad De Sevilla Method of obtaining and pharmaceutical composition of polymeric nanoparticles for the treatment of neuropathic pain produced by peripheral nervous compression (Machine-translation by Google Translate, not legally binding)
WO2016144376A1 (en) * 2015-03-10 2016-09-15 Nanosphere Health Sciences, Llc Lipid nanoparticle compositions and methods as carriers of cannabinoids in standardized precision-metered dosage forms
WO2019025880A1 (en) * 2017-08-04 2019-02-07 Alsec Alimentos Secos S.A.S. Cannabis oil nanoparticles micro-encapsulated in powder

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