WO2019211771A1

WO2019211771A1 - Water soluble and water dispersible formulations of cannabinoids

Info

Publication number: WO2019211771A1
Application number: PCT/IB2019/053569
Authority: WO
Inventors: Tomasz Popek; Steven Splinter; Anna BAKOWSKA-BARCZAK; Harmandeep KAUR
Original assignee: Radient Technologies Inc.
Priority date: 2018-05-03
Filing date: 2019-05-01
Publication date: 2019-11-07

Abstract

A method of preparing a water-soluble or water-dispersible formulation of cannabinoids is disclosed. The formulation may comprise cannabinoids, terpenes, and flavonoids extracted from a raw cannabis biomass. The formulation can be prepared by dispersing a resinous extract containing the cannabinoids in an aqueous solution to form an emulsion. The aqueous solution can contain complexing agents, which form a complex with the cannabinoids. The aqueous solution containing solubilized cannabinoids can be separated from the emulsion by a liquid-liquid separation process. The obtained aqueous solution containing the solubilized cannabinoids can be subjected to a drying process to form a powdered cannabinoid formulation. The solids may be soluble or dispersible in aqueous-based preparations, such as beverages for consumption.

Description

WATER SOLUBLE AND WATER DISPERSIBLE FORMULATIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present patent application claims the priority benefit of U.S. provisional patent application number 62/666,444 filed May 3, 2018; and U.S. provisional patent application number 62/666,527 filed May 3, 2018; the disclosures of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Disclosure

[0002] The present disclosure generally relates to a formulation of cannabinoids. More particularly, the present disclosure relates to a method and system for preparing both water- soluble and water-dispersible formulations of cannabinoids.

2. Description of Related Art

[0003] Cannabis is a genus belonging to the family of cannabaceae. Three common species include Cannabis sativa, Cannabis indica, and Cannabis ruderalis. The genus has been indigenous to Central Asia and the Indian subcontinent. Cannabis has a long history being used for medicinal, therapeutic, and recreational purposes. The importance of cannabis in therapeutics is emphasized by the ever-increasing number of research publications related to the new indications for cannabis. For example, pharmaceutical research companies are presently developing new natural cannabinoid formulations and delivery systems to meet various regulatory requirements. Cannabis is known, for example, to be capable of relieving nausea (such as that accompanying chemotherapy), pain, vomiting, spasticity in multiple sclerosis, and increase hunger in anorexia.

[0004] The term cannabis or "cannabis biomass" encompasses the Cannabis sativa plant and also variants thereof, including subspecies sativa, indica and ruderalis, cannabis cultivars, and cannabis chemovars (varieties characterised by chemical composition), which naturally contain different amounts of the individual cannabinoids, and also plants which are the result of genetic crosses. The term "cannabis biomass" is to be interpreted accordingly as encompassing plant material derived from one or more cannabis plants.

[0005] Cannabis biomass contains a unique class of terpeno-phenolic compounds known as cannabinoids or phytocannabinoids, which have been extensively studied since the discovery of the chemical structure of tetrahydrocannabinol (Delta-9-THC), commonly known as THC. Over 113 phytocannabinoids have been identified. Such cannabinoids are generally produced by glandular trichomes that occur on most aerial surfaces of the plant. The cannabinoids are biosynthesized in the plant in acidic forms known as acidic cannabinoids. The addic cannabinoids may be slowly decarboxylated during drying of harvested plant material. Decarboxylation may be hastened by heating the cannabis biomass, such as when the cannabis biomass is smoked or vaporized.

[0006] The principle cannabinoids present in cannabis are the Delta-9- tetrahydrocannabinolic add (Delta-9-THCA) and cannabidiolic acid (CBDA). The Delta-9- THCA does not have its own psychoactive properties as is, but may be decarboxylated to Delta-9-tetrahydrocannabinol (Delta-9-THC), which is the most potent psychoactive cannabinoid among known cannabinoids. The neutral form of CBDA is cannabidiol (CBD), which is a major cannabinoid substituent in hemp cannabis. CBD is non-psychoactive and is widely known to have therapeutic potential for a variety of medical conditions. The proportion of cannabinoids in the plant may vary from species to species, as well as vary within the same spedes at different times and seasons. Furthermore, the proportion of cannabinoids in a plant may further depend upon soil, climate, and harvesting methods. Thus, based on the proportion of the cannabinoids present in a plant variety, the

psychoactive and medicinal effects obtained from different plant varieties may vary.

[0007] Depending upon the psychoadive and medidnal effects obtained from different varieties of the cannabis plant or the different methods of cultivation for cannabis, a specific variety of cannabis may be considered more effective or potent than others ( e.g ., in providing the desired physiological effect at a desired level in an individual). Similarly, some specific combinations of pharmacologically active compounds in a cannabis variety may be more desirable in comparison to other varieties. When preparing cannabis plant extracts, the retention of the full mix of cannabinoids present in the original plant may be desirable for some varieties, while other varieties may be preferred in altered form due to the variances in the specific cannabinoid composition and concentrations. Such variance is further exacerbated by the presence of certain terpenoid or phenolic compounds, which may have pharmacological activity of their own and which may be desired at different concentrations in different combinations.

[0008] Historical delivery methods have involved smoking ( e.g ., combusting) the dried cannabis plant material. Smoking results, however, in adverse effects on the respiratory system via the production of potentially toxic substances. In addition, smoking is an inefficient mechanism that delivers a variable mixture of active and inactive substances, many of which may be undesirable. Alternative delivery methods such as ingesting typically require extracts of the cannabis biomass (also known as cannabis concentrates or cannabis oils). Often, cannabis extracts are formulated using any convenient pharmacologically acceptable diluents, carriers or excipients to produce a composition. Raw cannabis biomass may also be more susceptible to possible biological contaminants such as fungi and bacteria than extracts.

[0009] Previously, compounds may be extracted from cannabis by using conventional methods of extraction, such as maceration, decoction, or solvent extraction. Such conventional methods may suffer from various limitations and disadvantages (e.g., extraction times may be very high so as to be impractical to scale). For example, subjecting the biomass to a prolonged extraction process may risk modification of the plant profile, negative effects on terpenes, or otherwise cause other undesirable effects that lower the quality or purity of the end product. Traditional methods of extraction may therefore hamper quality and purity of the final product. Further, final concentrated or purified active compounds are often diluted or dispersed into an oil, fat or other lipid-based excipient or carrier to a desired concentration for certain uses (e.g., in a pharmaceutical, food, or cosmetic formulation).

[0010] Other methods such as supercritical fluid extraction (SFE) make use of supercritical fluids to selectively remove compounds from solid, semisolid, and liquid matrices in a batch process. SFE is, however, dangerous and requires very high pressures to be employed (> 70 atm). In addition, SFE is also inefficient and therefore not conducive to high throughputs, as well as environmentally damaging (e.g., producing large amounts of the greenhouse gas carbon dioxide as a by-product). Meanwhile, traditional methods of extracting inactive cannabinoids from a raw cannabis biomass typically involve subjecting the raw cannabis biomass to a heating process in order to decarboxylate the cannabinoids prior to extraction.

[0011] Thus, there is a need for improved methods and systems to obtain higher quality and quantity of cannabis extract from a given biomass, as well as a need to provide pharmacological formulations of cannabis that will allow alternative delivery methods besides smoking and that will allow for control and consistency of dosage. The active ingredients present in cannabis, including cannabinoids and terpenes, are generally hydrophobic in nature, and therefore show poor solubility in aqueous solutions. There is significant interest in the development of cannabinoid-infused aqueous-based beverages. Thus, there is also a need for a water-soluble and water dispersible formulations of cannabinoids.

SUMMARY OF THE CLAIMED INVENTION

[0012] Embodiments of the present invention provide methods for producing water- soluble and water-dispersible formulations of active cannabinoids. The processes described herein include the heating of a cannabis biomass to extract pharmaceutically active cannabinoids and the dispersal of said extract in an aqueous solution. Thus, a novel approach is provided for the dispersal of pharmaceutically active cannabinoids in an aqueous solution.

[0013] Exemplary methods for dispersing or dissolving active cannabinoids from a raw cannabis biomass. The method includes preparing a raw cannabis biomass, adding a solvent to form a slurry, extracting and separating out a quantity of pharmaceutically active cannabinoids, and dissolving or dispersing the extract in an aqueous solution.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 is a flowchart illustrating an exemplary method for preparing either a water-soluble or water-dispersible formulation of cannabinoids.

[0015] FIG. 2 is a block diagram representation of an exemplary system for obtaining a water-soluble or water-dispersible cannabis extract.

[0016] FIG. 3 is a block diagram representation of an exemplary system for a downstream process of extracted cannabinoids.

[0017] FIG. 4 is a block diagram representation of an exemplary method for preparing a water soluble formulation of cannabinoids.

[0018] FIG. 5 is a flow chart illustrating an alternative exemplary method for preparing a water soluble or water dispersible formulation of cannabinoids.

DETAILED DESCRIPTION

[0019] In at least one embodiment, the present disclosure provides a system and a method of preparing both water-soluble and water-dispersible formulations of cannabinoids. The water-soluble and water-dispersible formulations described herein can comprise cannabinoids, such as delta-9-tetrahydrocannabinol (A9-THC) or cannabidiol (CBD). The cannabinoids and other compounds present in the water-soluble or water-dispersible formulation, including terpenes and flavonoids, are resinous in nature and referred to herein as active compounds. The cannabinoids can be used for medicinal, therapeutic, and recreational purposes, while terpenes and flavonoids can be used to provide taste and aroma. Additionally, the cannabinoids, terpenes, and flavonoids can be used to create an effect known as the entourage effect, which suggest that many different cannabinoids, terpenes and flavonoids can work in concert to create or enhance the medicinal properties of the cannabis. However, the preferable active compound, according to the present disclosure, may be the neutral form of cannabinoids.

[0020] In the at least one embodiment of the present disclosure, the cannabinoids present in the extract used for the preparation of the water-soluble formulation may be present in their acidic form, their decarboxylated (or neutral) form, or as a mixture of both their acidic and decarboxylated cannabinoid forms. Cannabis can often be decarboxylated either before or after an extraction process is performed to convert any inactive cannabinoid carboxylic adds into their active, neutral cannabinoid forms ( e.g ., the conversion of THCA to THC). In at least some examples, the full conversion of THCA to THC may not be desired; for example, THCA is a compound having its own indications which may be indicated for one or more applications for which THC is not. In some examples, the cannabis biomass may only be partially decarboxylated; e.g., a portion of the THCA may be converted to THC while the remaining portion of THCA remains. A partial decarboxylation may be performed by decarboxylating a portion of the cannabis biomass, or by controlling the conditions of the decarboxylation process. In some embodiments, a cannabinoid decarboxylation before or after extradion may not be required. In these embodiments, the desired final formulation can affect the procedure in that the desired formulation may eliminate the step of

decarboxylation of biomass.. [0021] To prepare the water-soluble or water-dispersible formulations of cannabinoids, a resinous extract containing the active compounds, may be obtained from cannabis biomass using a suitable extraction process. The resinous extract may then be dispersed in an aqueous solution to form an emulsion. In at least some embodiments, the aqueous solution may contain suitable excipients for preparing the emulsion. In addition, the excipients may contain suitable complexing agents which can be used to form a complex with the active compounds present in the resinous extract. In at least one example, the complex formed may be substantially soluble in the aqueous solution. In an additional example, the complex formed may be substantially dispersible in an aqueous solution. Thus, the complexing agent may solubilize or disperse the active compounds within the aqueous solution.

[0022] In other embodiments the suitable excipient may be added to a liquid

cannabinoid extract obtained from the cannabis biomass using a suitable extraction process. The liquid extract may be partially desolventized and mixed with water to prepare a dispersed solution. In at least some embodiments, the suitable excipients can be dissolved in a desired amount of water and added to a liquid extract and the organic solvent can then be evaporated, creating an emulsion.

[0023] After preparing the emulsion, the aqueous solution may be separated from the emulsion using a liquid-liquid separation process or a centrifugation process, wherein the aqueous solution contains the solubilized active compounds. The aqueous solution may be subjected to a spray -drying process or a similar process to produce a powder. The powder may then be reconstituted to form an aqueous-based preparation; for example, the powder may be dissolved, dispersed, or dispensed in a beverage or added to an aqueous-based food item.

[0024] An exemplary method of preparing both a water-soluble or a water-dispersible formulation of cannabinoids is described with specific reference to FIG. 1 and FIG. 2.

Specifically, FIG. 1 is a flowchart illustrating an exemplary method 100 for preparing the water-soluble or water-dispersible formulation of cannabinoids. FIG. 2 illustrates a block diagram of an exemplary solvent extraction system which can be used in the disclosed methods.

[0025] At step 102, a raw biomass can be provided to a raw biomass holding chamber 202. The raw cannabis biomass can be obtained from cannabis plants. Such raw biomass may be present in the form of dried, ground, non-decarboxylated flowers (such as buds) of the cannabis plant In one embodiment, the method of preparing a water-soluble formulation containing both acidic (non- decarboxylated) and decarboxylated cannabinoids. The raw biomass can be any part of the cannabis plant which may contain cannabinoids including, but not limited to, leaves, stems, roots, and the like. In some embodiment, average particle size of the raw biomass may lie between approximately 0.5 mm and approximately 10 mm. The raw biomass may contain target compounds that need to be extracted. In one embodiment, the raw biomass may be heated to approximately 125° C for approximately 45 minutes to decarboxylate the cannabinoid carboxylic acids into neutral cannabinoid forms. The mass of decarboxylated cannabis following such treatment may get reduced ( e.g ., 11.7% weight loss). In an embodiment, the raw biomass may be dried, non-decarboxylated cannabis biomass. In another embodiment, the raw biomass may be fresh, non-dried, non- decarboxylated cannabis biomass. Said cannabis biomass can be provided into the raw biomass holding chamber 202.

[0026] Successively, in step 104, the raw biomass material can be sampled and analyzed in sampling chamber 204. The raw biomass may be sampled and analyzed using several methods. In a preferred embodiment, the raw biomass may be analyzed to determine the cannabinoid content and provide a cannabinoid profile (providing specific cannabinoids present in the sample and concentrations thereof) of the sampled raw biomass. Such analysis may be performed using an Ultra High Performance Liquid Chromatography coupled with Mass Spectrometry (UPLC-MS) detection technique. Furthermore, a terpene profile of the raw biomass may be created using a Gas Chromatography-Mass Spectrometry (GC-MS) detection technique. The sampling and analytical techniques may help in determining the cannabinoid content and cannabinoid profile of the raw biomass. The cannabinoid profile can include the total cannabinoids content (wt%), concentration of individual cannabinoids (wt%), THCA+THC (wt%), CBD+CBDA (wt%), total THC equivalents (determined using the formula THC+THCA x 0.877 (wt%)), and total CBD equivalents (determined using the formula CBD+CBDA x 0.877 (wt%)). The cannabinoid profile created can be used to determine the amount of acidic and neutral cannabinoids which may be extracted.

[0027] In one exemplary embodiment, details of the analysis of five samples of cannabis biomass obtained from different cannabis cultivars were analyzed and the results are presented in Table 1, provided below. Specifically, Table 1 illustrates test data related to various cannabis biomass samples collected from different cannabis cultivars (strains), locations, and in one case, on different dates. In one case, five cultivars (cultivars A to D) from Location 1 were analyzed by UHPLC and found to have wide variability in cannabinoid profiles (e.g., THCA, THC, CBDA, CBD, and total cannabinoids content). In other cases, different cultivars from different locations also were found to have variability in cannabinoid profile. In one case, cultivar G taken from Location 4 was determined to have very low concentrations of cannabinoids. In another case, identical cultivars I from Location 4 were analyzed by UHPLC and found to have variability in cannabinoid profile based on the date of harvest. In a preferred embodiment the conditions used for the method of extracting pharmacologically active compounds from cannabis biomass as described herein may be adjusted and controlled based on the results of the raw biomass sampling and analysis so as to increase purity and yield of cannabis extract.

Table 1

[0028] Next, in step 106, the raw cannabis biomass may be ground into small particles in biomass preparation chamber 206 to obtain a prepared biomass. The size of the particles of the ground biomass may range between about 0.5 mm to about 10 mm. The biomass preparation process may be performed utilizing one or more of a grinding machine, a shredding machine, a biomass pulverizing machine, and the like. The prepared biomass may then be provided from biomass preparation chamber 206 to a prepared biomass holding chamber 208.

[0029] The prepared biomass may be used in the formation of a slurry in step 108. For example, the slurry may be formed in slurry formation chamber 210, where one or more solvents from a solvent holding chamber 212 and the prepared biomass from the prepared biomass chamber 208 are combined. The solvent added to the prepared biomass may be selected with different dielectric and solvent parameter properties. The solvent may be, for example, an edible or food-grade solvent or emulsifier used to standardize active compounds in pharmaceutical, nutraceutical, functional, food, or cosmetic formulations. Further, the solvent may be a water, an alcohol group, an alkane group, a ketone group, a polyunsaturated fatty acid (PUFA), corn oil, safflower oil, borage oil, flax oil, canola oil, cottonseed oil, soybean oil, olive oil, sunflower oil, coconut oil, palm oil, avocado oil, monoglycerides, diglycerides, triglycerides, medium chain triglycerides (MCT), long chain tryglycerides, lecithin, limonene, essential oils of spices, herbs, or other plants, fish oil, glycerol, glycols, or mixtures thereof. In a preferred embodiment, ethanol may be used as the solvent. It should be understood that certain solvents may be preferable from a marketing standpoint and/or cost standpoint. Furthermore, the choice of the solvent and maintaining a suitable ratio of solvent to biomass is important for optimum extraction of pharmacologically active compounds. The solvent-to-biomass ratio may be maintained at approximately 5 1/kg to approximately 10 1/kg to ease the pumping operation of the slurry. In an embodiment, the solvent-to-biomass ratio may be maintained as low as possible. The cannabinoid profile created using the raw biomass material can be used in determining the desired solvent-to- biomass ratio of the slurry.

[0030] Thereafter, at step 110, the slurry may be transferred from the slurry formation chamber 210 to an extraction chamber 214. In at least one example, the slurry may be transported to the extraction chamber 214 using a set of mechanical conveyors ( e.g ., a slurry pump, a screw conveyor, or a worm gear). In the extraction chamber 214, the slurry may be subjected to a thermal process, such as that provided by a microwave generator 216. In at least one example, the slurry may be transported into an extractor chamber 214 through a tube. In a preferred example, the extraction chamber 214 is a continuous flow extractor. At least one portion of the extraction chamber 214, or the entire extraction chamber 214, can be microwave transparent. The microwave transparent portion of the extraction chamber 214 may allow microwaves (e.g., microwaves generated using a magnetron of microwave generator 216) to pass through the extraction chamber 214 and heat the slurry inside. The slurry may be heated within the extraction chamber 214 to a certain temperature by exposing the slurry to the microwave for a predefined time with a predefined, and controlled, microwave energy density range. In a preferred embodiment, the slurry may be heated to a temperature range of approximately 20° C to approximately 75° C with a contact time of approximately 1 minute to approximately30 minutes, and a microwave energy density range of approximately O.lkW per 1kg of biomass (0.1 kW/kg) to approximately 10 kW/kg. The methods described herein can be conducted on an industrial scale. In at least one example, the methods can be performed on samples of over 1,000 kg to over 10,000 kg of biomass per extraction. The microwave energy, contact time and temperature range can be selected specifically to avoid decarboxylation of the cannabinoids. The heating process described herein can, in at least some examples, facilitate the extraction of various (pharmacologically active) compounds from the prepared biomass into the solvent. Thus, the slurry residence time in the extractor 214 is a function of both slurry flow rate and length of chamber through which the slurry travels. It should be noted that adjustment of the microwave parameters, the flow rate, or the length of chamber may be utilized to permit maximal extraction of the active compounds, while limiting extraction of less desirable compounds and minimizing run time. Due care may be taken to keep the operating temperatures in the thermal process low, to avoid decarboxylation of the acidic cannabinoids, if desired, and to avoid possible thermal degradation of sensitive molecules. Moreover, the residence time of the slurry in the extractor 214 may be optimized for optimum extraction of the active compounds while avoiding extraction of undesired compounds, such as chlorophyll or waxes.

[0031] For controlling the operational parameters of the extractor 214, suitable sensors may be deployed at various points within the process (i.e., between an input and an output). The suitable sensors may monitor the temperature, the flow rate, and/or the residence time. The residence time may indicate a total amount of time for which a specific volume of the slurry is exposed to the microwave extraction process. In some embodiments, residence time may indicate a total amount of time for which the biomass and solvent are in contact (e.g. the time between the slurry formation at step 102 and separation of extract and spent biomass at step 106). It should be noted that the presence of the sensors may ensure that the residence time is optimized for both high levels of extraction and obtaining maximum throughput without affecting the active compounds. In an exemplary embodiment effect of temperature and the residence time of the slurry on recovery percentage of THC can be experimentally determined and the results are presented in Tables 2 and 3, provided below. Table 2 illustrates test data of concentrations of THCA or CBDA obtained at different temperatures related to the processing, according to an embodiment. Table 3 illustrates test data of concentrations of THCA or CBDA obtained at different extractor residence time values related to the processing. Sensors may monitor temperature, flow rate, or residence time. Extractor residence time may indicate a total amount of time for which a specific volume of slurry is exposed to the microwave extraction process. The presence of the extractor residence time monitoring sensors may ensure residence time is optimized for both high levels of extraction and maximum throughput without damage to any target compounds.

[0032] In an exemplary embodiment, Table 2 illustrates % cannabinoid recovery at various input slurry temperatures and extractor output temperatures. For sample Run 06, at an input slurry temperature of 23°C and an extractor output temperature of 23°C, 86% of THCA recovery was determined. For sample Run 03 at an input slurry temperature of 23°C and an extractor output temperature of 27°C, 93% of THCA recovery was determined. For sample Run 07 at an input slurry temperature of 23°C and an extractor output temperature of 40°C, 85% of CBDA recovery was determined. In one case, for sample Run 08 an input slurry temperature of 22°C and an extractor output temperature of 60°C, 91% of THC recovery was determined.

[0033] In an exemplary embodiment, Table 3 illustrates CBDA% recovery at different extractor residence times. For sample Run 09 with an extractor residence time of 5 min, 83% CBDA recovery was determined. In another case, sample Run 010 with an extractor residence time of 10 min, 90% CBDA recovery was determined. Further, in one case sample RunOll with an extractor residence time of 20 min, 83% THC recovery was determined.

Table 2

Table 3

[0034] As shown in Table 2, at an extractor output temperature of 27°C, the THC recovery can be maximized (i.e., 93%) for a particular raw biomass input. The THC recovery was decreased when the extractor output temperature corresponds to 50°C. Further, as shown in Table 3, the CBDA recovery percentage is a function of residence time of the slurry. It should be noted that during a residence time of 10 min, maximum CBDA recovery may be obtained for a particular raw biomass input. By increasing the residence time from 10 min to 20 min, a drop in CBDA recovery may be observed. In an exemplary embodiment, the residence time of the slurry may be less than 5 min. The slurry may then be subjected to a downstream process for obtaining resinous extract from the slurry.

[0035] In at least some embodiments, the extraction chamber 214 may be filled completely with solvent prior to the extraction process in order to remove air and other gases from the extraction chamber 214. In alternative embodiments, the extraction chamber 214 may be purged with an inert gas such as nitrogen prior to the extraction process in order to remove air and other oxidizing gases from the extraction chamber 214. In at least one embodiment, the cannabis biomass may be subjected to heat for effecting decarboxylation of addic cannabinoids. Cannabis is often decarboxylated before extraction to convert inactive cannabinoid carboxylic adds into neutral cannabinoids by removing a carboxyl group from cannabinoid acid molecules. In some cases, the conversion of the acidic forms of the cannabinoid to the neutral forms of the cannabinoid may not be desired, for example, the addic forms may have therapeutic value as well. In other cases, the cannabis biomass may only be partially decarboxylated; for example, a portion of the acidic form of the cannabinoid may be converted to the neutral form. Such methods may be done by decarboxylating a portion of the cannabis biomass, or controlling conditions of decarboxylation. In some embodiments, the decarboxylation before or after the extraction process may not be required. In such embodiments, a formulation process can be performed which may eliminate the step of decarboxylation of the biomass, or extract. [0036] Post heating, the slurry and compounds extracted from the biomass (the now- spent biomass) and solvent(s) may be transferred to separation chamber. The method of preparing either a water soluble or water-dispersible formulation of cannabinoids in the extracted form will now be explained with reference to FIG. 1 and FIG. 3. The downstream process for extracting a water-soluble or water-dispersible cannabinoid is illustrated in FIG. 3. For example, the material is transferred from the extraction chamber 214 to the separation chamber 302, as illustrated in FIG. 3.

[0037] Once in the separation chamber 302, the slurry is subject to filtration and separation at step 112. Such separation can be performed within a separation chamber 302 and may result in the isolation of the slurry components from each other: the spent biomass and the solvent(s) containing the extracted compounds. The separation process may be performed using filtration, centrifugation, and other similar processes. Once isolated, the spent biomass and the solvent(s) containing the extracted compounds may be transferred into a spent biomass holding chamber 304 and solvent recovery chamber 306, respectively. The solvent provided to the solvent recovery chamber 306 can have the active compounds dissolved therein.

[0038] In at least one embodiment, the spent biomass from spent biomass holding chamber 304 may be sampled and analyzed at step 114. The sampling of the spent biomass may be performed in a sampling chamber. In at least one example, the spent biomass may be sampled and analyzed to determine the remaining cannabinoid content of the spent biomass and create a cannabinoid profile. Such analyses can be performed using several methods. For example, the analysis may be performed using an Ultra High Performance Liquid

Chromatography coupled with Mass Spectrometry detection (UPLC-MS). Furthermore, the terpene profile of the spent biomass may be determined using a Gas Chromatography-Mass Spectrometry Detection (GC-MS). The cannabinoid profile of the spent biomass can be used to determine the effectiveness of the extraction process as illustrated in Tables 2 and 3, above. In at least one embodiment, the procedure ( e.g ., time, temperature, or energy range) used in the extraction process can be adjusted based on the cannabinoid profile of the spent biomass in order to achieve a desired formulated extract.

[0039] Post-treatment of the slurry in the extractor 214, the slurry may be transported to a filtration and separation chamber 302. The filtration and separation chamber 302 may be equipped with suitable equipment(s) to isolate the solvent extract mixture (the "miscella") from the solids content of the slurry. Separation may be by filtration, centrifugation or other suitable methods known in the art. Furthermore, spent (extracted) biomass left behind in the slurry may be filtered out or separated and cannabinoid-containing extract may be collected, at step 106. The spent biomass may be stored in a spent biomass storage holding chamber 304. The spent biomass storage holding chamber 304 may be connected to a sampling chamber 320 to permit sampling and analysis of the spent biomass.

[0040] The solvent may be separated from the resinous extract (filtrate) to obtain a resinous extract. In at least one example, the solvent may be removed from the liquid extract, filtrate, by suitable separation methods known in the art including, but not limited to, basification, vacuum distillation, vacuum evaporation, and combinations thereof. In at least one embodiment, the basification process may depend upon usage of an ion-exchange process. The basification process may include increasing pH value of the solution by adding a base, and thereafter crystallization to provide substantially pure crystals of cannabinoids.

[0041] In another embodiment, a vacuum distillation may be used for separation of the solvent. During vacuum distillation, the solvent may be evaporated out of the solvent extract mixture (miscella) by distillation under reduced pressure. The solution may be subjected to vacuum, which may enable distillation process to occur at a lower temperature. It should be noted that under vacuum, the boiling point of the solvent is lowered. Such low temperatures may also be advantageous to temperature sensitive components present in the miscella. The vacuum distillation method can be further used to minimize the decarboxylation of the addic cannabinoids due to the exposure to high temperatures. In at least one embodiment, separation may preferably be effected by thin film evaporation such as wiped film evaporation or by short-path distillation.

[0042] The product of the extraction process described above may be a resinous extract mixture (miscella). The miscella may still contain small amount of the solvent. The miscella obtained from the separation chamber 302 may be transported to a solvent removal and recovery chamber 306, for the removal of remaining solvent. In the solvent removal and recovery chamber 306, the remaining amount of solvent in the miscella may be evaporated out, either partially or completely, using a distillation or evaporation process. The removed solvent may be then recovered and used in a subsequent extraction process. The resinous extract may undergo a physical separation process (e.g., evaporation or stripping) where the solvent (e.g., ethanol) can be removed partially or completely, from the resin and recovered. In at least some examples, the solvent removal can use mass transfer to transfer a component of interest (e.g., ethanol) from the liquid resin to a vapor phase.

[0043] After extraction, the desolventized resinous extract may be dispersed in an aqueous solution to form an emulsion, at step 116. To prepare the emulsion, the resinous extract may be transferred from the solvent removal and recovery chamber 306 to an emulsification chamber 308. The emulsification chamber 308 may be equipped with suitable apparatuses used for emulsification, such as a homogenizer. For preparing the emulsion, the resinous extract may be dispersed in the aqueous solution containing either water-soluble or water-dispersible excipients provided by excipient storage chamber 310. The water-soluble or water-dispersible excipients may correspond to inactive substances that may serve as a medium for an active substance (e.g., THC). For example, cyclodextrins may correspond to drug carrier molecules known for enhancing the solubility of a drug or the ability of a drug to disperse in water and can stabilize the emulsion due to the complexation ability. Different formulations of cyclodextrins (e.g. alpha-cyclodextrins, beta-cyclodextrins, and gamma- cyclodextrins, or their hydroxypropyl, sulfobutyl ether, or other derivatives) in an aqueous solution may be considered appropriate excipients for this invention.

[0044] In some embodiments, the formulations may require the presence of an emulsifying agent to stabilize the emulsion. Emulsifying agents may include gums, polysorbates or others known in the art. The emulsifiers may be utilized with a co-emulsifier. Depending on the specific formulation chosen, suitable co-emulsifiers may be chosen from any co-emulsifier or emulsifier. As described above, the water-soluble and water-dispersible excipients may be obtained from a water-soluble/water-dispersible excipients storage chamber 310 connected to the emulsification chamber 308. The water-soluble and water- dispersible excipients may include complexing agents, such as beta-cyclodextrin. The complexing agents may form a complex with the active compounds present in the resinous extract, for example, A9-TlTC/beta-cyclodextrin complex. The complex formed may be substantially soluble or dispersible in the aqueous solution. Thus, upon forming the emulsion, the active compounds may become solubilized or dispersed and move into an aqueous phase of the emulsion. The extract and the water-soluble or water-dispersible excipients may be combined according to a predetermined stoichiometry. In some embodiments, the emulsifying or complexing agent may be completely soluble in water or ethanol/water solution at a temperature between approximately 0°C and approximately 100°C to obtain an emulsifying solution. The excipient solution and extracted resin may be combined using a mechanical stirrer at a temperature between approximately 0°C and approximately 100°C.

[0045] Post emulsification, the emulsion may be transported to a final separation chamber 312. In the final separation chamber 312, the aqueous solution may be obtained from the emulsion, at step 118. The emulsion, being thermodynamically unstable, can undergo liquid-liquid separation resulting into an organic phase and an aqueous phase. The aqueous phase may be an aqueous solution. The active compounds present in complexed form may go into the aqueous phase ( e.g ., aqueous solution). The organic phase may be recycled or disposed off. In order to recover the organic phase from the final separation chamber 312, a recycling/disposal of the organic compounds 314 may be coupled to the final separation chamber 312.

[0046] Finally, the aqueous solution obtained from the emulsion, containing the active compounds may be subjected to drying (e.g., spray drying) in drying chamber 316 to form a powder, at step 120. The drying method may define the composition of the final dry product. The powder formed may be suitable for dispersion in an aqueous solution. For example, a mean particle size of the obtained powder may be less than approximately 2 pm to approximately 5 pm. It should be noted that drying process may be performed in a drying chamber 316. The drying chamber 316 may be equipped with any suitable drying apparatus, for example a spray dryer. Additionally, the drying chamber 316 may be coupled with a formulated extract storage chamber 318. The solvent (e.g., water, ethanol) may be eliminated from the aqueous solution upon drying (e.g. spray drying). The aqueous solution can be mixed with a suitable excipient (e.g., maltodextrin) and a drying carrier and dried for example with hot gas to produce a powder, which may be soluble or dispersible in water. As such, a final form of product derived upon drying may be a dry powder that can be reconstituted by mixing with water. The formulated extract may be in the form of a powder and may be stored in a formulated extract storage chamber 318. The formulated extract storage chamber 318 may be coupled with a sampling chamber 320 to perform analysis on the formulated extract at step 220. The samples may be analyzed using suitable analytical methods known in the art for sampling and analyzing natural products. For example, analysis of cannabinoids amount, and cannabinoids profiling may be performed using a Ultra High-Performance Liquid Chromatography coupled with Mass Spectrometry (UPLC- MS) detection technique. In addition, the samples may be analyzed for terpene profile using a Gas Chromatography coupled with Mass Spectrometry (GC-MS) detection technique.

[0047] In at least one embodiment, the method of preparing a water-soluble or water- dispersible formulation of cannabinoids can be further explained with reference to a block diagram as shown in FIG. 4. In one embodiment, the method of preparing a water-soluble formulation containing both acidic (non- decarboxylated) and decarboxylated cannabinoids. For example, water-soluble or water-dispersible excipients can be received from excipient storage chamber at step 402 and a solvent can be received from a solvent holding chamber at step 404. The water-soluble or water-dispersible excipients and solvent may be combined, to form a mixture of excipient and solvent at step 406. Thereafter, an extract that has either had the residual solvent fully or partially removed may be received from the removal process described above and combined with the mixture of exdpient and solvent at step 408. In at least one example, the fully or partially solvent removed extract may be derived from a stripping process. Successively, a mixture of the extract, excipients, and solvent may be formed. In at least one example, the mixture may be present in the form of an emulsion. The emulsion may thereafter be subjected to liquid-liquid separation, at step 410, resulting into an aqueous solution and an organic phase. The aqueous solution containing cannabinoids and other active compounds in solubilized form may be dried using any suitable method in drying chamber, at step 412. In at least one example, an aqueous solution containing both addic and decarboxylated cannabinoids and other adive compounds in solubilized form may be dried using a drying method that protects acidic cannabinoids from decarboxylation, e.g. freeze drying or vacuum drying. The drying process can result in the production of a powdered form of cannabinoids. The powdered form of cannabinoids may be collected and stored, at step 414.

[0048] A method 500 for preparing a water-soluble or water-dispersible formulation of cannabinoids is illustrated in FIG. 5. [0049] At step 502, a resinous extract may be obtained from cannabis biomass as described in detail above. In at least some embodiments, the resinous extract may contain cannabinoids and other active compounds, such as terpenes and flavonoids.

[0050] At step 504, the resinous extract may be dispersed in an aqueous solution. The aqueous solution may contain suitable water-soluble or water-dispersible excipients to form an emulsion comprising the resinous extract and the excipients. In at least some

embodiments, the water-soluble or water-dispersible excipients may contain complexing agents, which may form a complex with the active compounds. The complex may be substantially soluble or dispersible in the aqueous solution.

[0051] At step 506, the aqueous solution containing the solubilized or dispersed active compounds, including cannabinoids may be obtained from the emulsion as described above. In one case, the aqueous solution may be obtained from the emulsion by liquid-liquid separation technique.

[0052] At step 508, the aqueous solution may be spray-dried to obtain a water-soluble or water-dispersible formulation of pharmaceutically active cannabinoids. In at least one example, the water-soluble or water-dispersible cannabinoids may be derived in the form of a powdered formulation. The powdered formulation may be reconstituted by dissolving in an aqueous based preparation.

[0053] In at least one example, the resinous extract may be dispersed in an aqueous solution containing 2% of gamma-cyclodextrin (g-CD) as a complexation agent using a homogenizer as described in step 504. The g-CD forms inclusion complex with insoluble cannabinoid compounds: the complexes are soluble but are prone to sedimentation at a certain concentration. The solubility of the complexes is mainly dictated by the type of drug and the nature of cyclodextrin. The mixing of the emulsion may be performed for 3 hours at 750rpm. Thereafter, the ethanol may be evaporated from the emulsion by vacuum evaporation. Next, the aqueous solution may be separated from the emulsion by

centrifugation (10,000 rpm for 5 min), as described in step 506. The supernatant containing soluble g-CD-cannabinoid complex may be stored in the dark before sampling and analysis. The precipitate containing the insoluble complex may be solubilized by diluting it with water and sonication. The concentration of THC in the supernatant and precipitate, and the complexation of THC may be confirmed by Liquid Chromotography analysis. Soluble complexes may be diluted in water and in methanol separately before analysis. THC was not found in the sample diluted water, which can be explained by the fact that THC was trapped in the g-CD cavity. A release of THC from the cavity of g-CD-THC complexes in non-polar solvent was confirmed by HPLC analysis. The aqueous solution containing g-CD-THC complexes in solubilized form may be dried by e.g. spray drying to form a powder form or utilized as such in formulation of water-soluble products containing THC, as described in step 508.

[0054] In another exemplary embodiment, a liquid form of water soluble cannabinoids formulation that may contain full-spectrum cannabis extract was developed. Recent data suggest that full-spectrum extract may be a more effective medication than isolated cannabinoids. The additional compounds may lead to a longer-lasting as well as more therapeutic form of treatment. Polysorbates (e.g., 20, 60, 65, 80, and other esters) may be selected to solubilize every compound extracted from cannabis plants by solvent extraction, e.g., ethanol extraction. Polysorbates may be added to ethanol extract and ethanol may be removed from the mixture by e.g. vacuum distillation. Polysorbates, (e.g., 80), may be able to completely dissolve full-spectrum extract since no precipitation was observed in the final formulation. The full-spectrum extract dissolved in polysorbate 80 was transferred to formulated extract storage chamber, sampled and analyzed using Liquid Chromatography. The prepared full-spectrum formulation may be dissolved in water to a desired

concentration giving a clear solution. The HPLC analysis of aqueous sample confirmed the effectiveness of polysorbates in solubilizing cannabinoids in water.

[0055] In an exemplary embodiment, a water dispersible formulation of cannabinoids may be prepared. An emulsion of cannabis extract with appropriate surfactants and polymer molecules was developed. The ethanol present in a pre-concentrated cannabis extract (which may contain 29.3 mg THC/mL) may be fully separated from the extract for the formation of emulsions. Ethanol may be removed by evaporation under vacuum at 40°C. The resin obtained may be diluted with MCT oil. The THC dissolved in MCT oil may be homogenized with a 0.5% w/v aqueous solution of lecithin at 20,000 rpm. To further stabilize the created single emulsion a chitosan solution (1.5% w/v) may be homogenized with the single emulsion to create a stable double emulsion. In such a prepared emulsion the amphiphilic molecules may surround the cannabis - MCT droplets at the oil-water interface. The prepared stable double emulsion may be subsequently solidified using for example spray drying with maltodextrin as a carrier at 150°C. The obtained powder may easily be re dispersible in water providing a stable suspension possible for use in preparation of food drinks such as protein shakes or smoothies.

[0056] Thereafter, the final formulation may be dispersed in water. The final formulation may be a formulation of the cannabinoids in water dispersion, for example, in a specified concentration of milligrams of cannabinoids per gram of water (e.g., 30 mg/g). The dispersion in water may be performed using one or more methods such as, but not limited to, nano-emulsions, nanoparticles, and liposomes. In one case, the nano-emulsions may be a colloidal particulate system in submicron size range acting as carriers of drug molecules (for example, the cannabinoids). The size range may vary from approximately 10 nm to approximately 1,000 nm. Further the carriers having solid spheres and surface of the carriers may be amorphous and lipophilic with a negative charge. Further, the term "nano-emulsion" may refer to a mini-emulsion which may be fine oil/water or water/oil dispersion stabilized by an interfacial film of surfactant molecule having droplet size range of approximately 20 nm to approximately 600 nm. It should be noted that due to small size, the nano-emulsions may be transparent. Further, the nano-emulsions may be of three types such as oil in water nano-emulsion in which oil may be dispersed in the continuous aqueous phase, water in oil nano-emulsion in which water droplets may be dispersed in continuous oil phase, andbi- continuous nano-emulsions.

[0057] Further, magnetic nanoparticles may be used to enhance site specificity. As a drug delivery system, the magnetic nanoparticles may enhance therapeutic efficacy of the drug and may result in reducing adverse effect and toxic reactions. On the other hand, an emulsion may be a biphasic system in which one phase may be intimately dispersed in other phase in a form of minute droplets ranging in diameter from approximately 0.1 pm to approximately 100 pm. Further, the emulsion may be a thermodynamically unstable system, which may be stabilized by a presence of an emulsifying agent ( e.g ., an emulgent or an emulsifier). The emulsifying agent may be called as intermediate or interphase. The dispersed phase may be called as internal phase or discontinuous phase while the outer phase may be called as dispersion medium, external phase or continuous phase. [0058] In another example, the final formulation may be dispersed in water using a method such as the nanoparticles. The nanoparticles may correspond to particles of size ranging between approximately 1 nm and approximately 100 nm, with surrounding interfacial layer. The interfacial layer may be an integral part of nano-scale matter, fundamentally affecting properties. Typically, the interfacial layer may include ions, inorganic, and organic molecules. The organic molecules coating inorganic nanoparticles may be called as stabilizers, capping and surface ligands, or passivating agents. In one case, cross-linked polymeric nanoparticles may contain one or more bioactive agents such as poorly water-soluble medicines, and may be suitable for oral delivery, and other applications, including injectable or topical formulations. The preparation of polymeric nanoparticles may entrap poorly water-soluble drugs, alone or in combination with other bioactive agents, to the maximum extent. The polymeric nanoparticles may entrap one or more types of medicament (for example, cannabinoids). Further, the polymeric nanoparticles having an average diameter of less than or equal to approximately 50 nm to

approximatelylOO nm, and less than 5% in excess of 200 nm in diameter. The preparation of the nano particles having inter-crosslinked polymeric chains that may allow release of the entrapped medidne(s) encapsulated in the nanoparticles. The preparation of the nanoparticles incorporating single or combinations of the medicines, with an option of chemically conjugated polyethylene glycol (PEG) chains of varying chain length at an outer surface of the nanoparticles to reactive moieties on the surface of formed nanoparticles. The PEG chains may help the nanoparticles to circulate in the blood for a relatively long time, following systemic administration.

[0059] In another case, the final formulation may be dispersed in water using a method such as the liposomes. The liposomes may be a spherical vesicle having at least one lipid bilayer. The liposomes may be used for administration of nutrients and pharmaceutical drugs. Further, the liposomes may be prepared by disrupting biological membranes (for example, by sonication). The liposomes may be composed of phosphatidylethanolamine, especially phosphatidylcholine, and may further include other lipids, such as

phosphatidylethanolamine. It should be noted that a design of the liposomes may employ surface ligands for attaching to unhealthy tissue. [0060] Further, the liposomes may be used as a carrier of dietary and nutritional supplements and targeted drug delivery. The liposomes may further be implemented for a specific oral delivery of certain dietary and nutritional supplements. It should be noted that new direction and employment of liposome science may be a part due to the low absorption and bio-availability rates of traditional oral dietary and nutritional tablets and capsules. The low oral bioavailability and absorption of nutrients may be clinically well documented. Therefore, the natural encapsulation of lipophilic and hydrophilic nutrients within the liposomes may be made for a very effective method of bypassing destructive elements of gastric system and aiding the encapsulated nutrient to be delivered to the cells and tissues.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method for preparing a water-soluble or water dispersible formulation of cannabinoids, the method comprising:

preparing a resinous extract from cannabis biomass, wherein the resinous extract comprises a plurality of compounds;

dispersing the resinous extract in an aqueous solution containing a water-soluble excipient to form an emulsion, wherein the water-soluble excipients comprise a complexing agent, and wherein the plurality of compounds are solubilized in the aqueous solution by complexation;

performing liquid-liquid separation on the aqueous solution; and

drying the aqueous solution to obtain a powder formulation of a cannabinoid.

2. The method of claim 1, wherein the plurality of compounds are selected from the group consisting of active compounds, inactive compounds, and combinations thereof.

3. The method of claim 2, wherein the plurality of compounds are active compounds comprising a combination of cannabinoids, terpenes, and flavonoids.

4. The method of claim 2, wherein the inactive compounds are associated with non- decarboxylated cannabis plant matter.

5. The method of claim 1, wherein preparing the resinous extract further comprises:

preparing a slurry by mixing the cannabis biomass with a solvent to achieve a predefined solvent-to-biomass ratio;

subjecting the slurry to a continuous flow extractor to extract the resinous extract, wherein a residence time of the slurry in the continuous flow extractor is less than a predefined time;

collecting a filtrate by performing a separation process on the slurry; and removing, via a drying process, the solvent from the filtrate to obtain the resinous extract.

6. The method of claim 1, wherein the powder formulation of the cannabinoids is soluble in an aqueous solution.

7. The method of claim 6, wherein the aqueous solution is water.

8. The method of claim 1, wherein the powder formulation of the cannabinoids is dispersible in an aqueous solution.

9. The method of claim 8, wherein the aqueous solution is water.

10. The method of claim 1, wherein the drying process includes at least one of spray drying, freeze drying, vacuum drying, or combinations thereof.

11. The method of claim 1, wherein preparing the resinous extract further comprises applying heat to the slurry in the continuous flow extractor.

12. A method for preparing a water-soluble or water-dispersible formulation of cannabinoids, the method comprising:

preparing a solvent extract from a non-decarboxylated cannabis biomass, wherein the solvent extract comprises a plurality of active compounds;

removing an alcohol from the solvent extract without causing a decarboxylation of the cannabis biomass to produce an emulsion;

extracting an aqueous solution from the emulsion via a liquid-liquid separation process; and

drying the aqueous solution to obtain a powder formulation of a cannabinoid.

13. The method of claim 12, wherein the powder formulation of the cannabinoids is soluble in an aqueous solution.

14. The method of claim 13, wherein the aqueous solution is water.

15. The method of claim 12, wherein the powder formulation of the cannabinoids is dispersible in an aqueous solution.

16. The method of claim 15, wherein the aqueous solution is water.

17. The method of claim 12, wherein the drying process includes at least one of comprising spray drying, freeze drying, vacuum drying, or combinations thereof.

18. A system for producing a water-soluble or water-dispersible cannabinoids comprising: a biomass preparation chamber for preparing a raw cannabis biomass comprising a plurality of plant matter particles;

a slurry formation chamber coupled with each of the biomass preparation chamber and a solvent holding chamber, the slurry formation chamber operable to receive the prepared biomass and a solvent from the solvent holding chamber and form a slurry having a predetermined solvent-to-biomass ratio;

an extraction chamber configured to receive the slurry from the slurry formation chamber and coupled with a heating apparatus to produce a formulated extract comprising a plurality of acidic and neutral cannabinoids;

a separation chamber coupled with the extraction chamber and operable to separate a spent biomass from a solvent having therapeutically active compounds therein; and

a drying chamber coupled with the emulsification chamber and operable to remove the solvent from the therapeutically active compounds producing a powder.

19. The system of claim 18, further comprising an emulsification chamber coupled with the separation chamber and operable to create an emulsification of the therapeutically active compounds comprising one or more excipients.