Microparticles containing cannabidiol and methods for producing the same

Abstract

The present invention relates to microparticles containing cannabidiol, which have a problem that the stability is reduced due to oxidation of the cannabidiol contained in the microparticles, and to a method for producing the microparticles by preventing the oxidation of the cannabidiol in the microparticles and thereby increasing the stability. The present invention also relates to a method for producing microparticles containing cannabidiol and a biodegradable polymer, which have a uniform distribution of cannabidiol within the particles and a uniform particle size.

Description

[Technical Field]

[0001] The present invention relates to microparticles containing cannabidiol and methods for making the same. [Background technology]

[0002] Cannabis, also known as hemp, has the scientific name Cannabis sativa L. Its straight roots grow 30-40cm underground, but lateral roots do not develop vigorously, making it easy to pull out. Cannabis is used for textiles, mosquito nets, ropes, fishing nets, and as a raw material for papermaking. Its fruit is extracted for oil, which is used for food, kerosene, soap, varnish, paint, and more, and its oil cake is used as animal feed and fertilizer.

[0003] In particular, the mucus that comes out of the hairs is called hashish and has hallucinogenic properties. When this is dried, it becomes cannabis. The main physiologically active substances in cannabis are cannabidiol (CBD) and tetrahydrocannabinol (THC).

[0004] Cannabidiol (CBD) is one of the main components of cannabis and is often compared to tetrahydrocannabinol (THC). In Korea, it is designated as a narcotic drug and not much research has been done on it, but in other countries, it is not only used for medical purposes to relieve symptoms such as pain, memory loss, and anxiety, but is also a substance that is actively researched.

[0005] Cannabidiol has been known to have various effects through previous research, and various dosage forms are being developed to improve the convenience of administration.

[0006] For such medical applications, it is necessary to develop a convenient dosage form that can provide a long-term medication effect with a single injection. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] KR10-2107715B1 Summary of the Invention [Problem to be solved by the invention]

[0008] It is an object of the present invention to provide microparticles containing cannabidiol and methods for their production.

[0009] Another object of the present invention is to provide microparticles containing cannabidiol that have improved stability by preventing the oxidation of cannabidiol contained in the microparticles, since oxidation of the cannabidiol contained in the microparticles can cause a problem of reduced stability.

[0010] Another object of the present invention is to provide a method for producing microparticles having a uniform particle size and a uniform cannabidiol content within the particles. [Means for solving the problem]

[0011] To achieve the above object, the present invention relates to cannabidiol-containing microparticles, which may contain cannabidiol (CBD), a release-sustaining agent, and an antioxidant.

[0012] The sustained-release agent may be a biodegradable polymer.

[0013] The biodegradable polymer can be selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof.

[0014] The antioxidant may be selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), vitamin C, vitamin E, propyl gallate, and mixtures thereof.

[0015] The antioxidant may be contained in an amount of 0.11% by weight to 9.9% by weight based on the total weight of cannabidiol and the sustained-release agent.

[0016] Another embodiment of the present invention provides a method for producing microparticles containing cannabidiol, including dissolving cannabidiol (CBD), a release-sustaining agent, and an antioxidant in an organic solvent to prepare an oil phase solution, dissolving a surfactant in water to prepare an aqueous phase solution, and mixing the oil phase solution and the aqueous phase solution to form an emulsion.

[0017] The method may further include the steps of obtaining the prepared emulsion in an aqueous phase solution to remove residual solvent, and washing and freeze-drying the emulsion from which the residual solvent has been removed.

[0018] The antioxidant may be selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), vitamin C, vitamin E, propyl gallate, and mixtures thereof.

[0019] The antioxidant may be contained in an amount of 0.06% by weight to 9.9% by weight based on the total weight of cannabidiol and the sustained-release agent.

[0020] The oil phase solution and the aqueous phase solution are injected into each microchannel and allowed to flow, and an emulsion containing cannabidiol, an antioxidant, and a time-release agent can be formed at the point where the oil phase solution flow and the aqueous phase solution flow intersect with each other. [Effects of the Invention]

[0021] The present invention relates to microparticles containing cannabidiol, and the problem of stability being reduced due to oxidation of the cannabidiol contained in the microparticles can be prevented, thereby increasing stability.

[0022] The present invention also provides a method for producing microparticles that contain cannabidiol uniformly and have a uniform particle size. [Brief explanation of the drawings]

[0023] [Figure 1] 1 shows the results of measuring the encapsulation rate of cannabidiol depending on the type of antioxidant in microparticles according to an embodiment of the present invention. [Figure 2] 1 shows the results of measuring the encapsulation rate of cannabidiol depending on the type of antioxidant in microparticles according to an embodiment of the present invention. [Figure 3] 1 shows the results of measuring the encapsulation rate of cannabidiol depending on the range of antioxidant content in microparticles according to an embodiment of the present invention. [Figure 4] 1 shows the results of measuring the encapsulation rate of cannabidiol depending on the range of antioxidant content in microparticles according to an embodiment of the present invention. [Figure 5] 1 shows the results of measuring the encapsulation rate of cannabidiol depending on the range of antioxidant content in microparticles according to an embodiment of the present invention. [Figure 6] 1 shows the results of measuring the encapsulation rate of cannabidiol depending on the range of antioxidant content in microparticles according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0024] Although the present invention may be embodied in various different forms, it is not intended to be limited to the embodiments set forth herein, and the present invention is not limited to the embodiments set forth herein.

[0025] The cannabidiol of the present invention is a physiologically active substance isolated from cannabis, and can be extracted directly from cannabis, extracted cannabidiol can be used, or can be produced by chemical synthesis, but is not limited to these.

[0026] Cannabis, also known as hemp, has traditionally been used for fabrics: its fibers are used for textiles, mosquito nets, ropes, fishing nets, and papermaking, its seeds are extracted to produce oil for food, kerosene, soap, varnish, and paint, and its oil cake is used as animal feed and fertilizer.

[0027] In countries where cannabis is designated as an illegal drug, storing and handling it without special permission is illegal. Cannabis designated as an illegal drug is called cannabis or marijuana and has been classified as the most dangerous and controlled.

[0028] The World Health Organization (WHO) has released a report stating that cannabidiol (CBD) oil, made from cannabis extract, is effective in treating epilepsy, Alzheimer's disease, and other conditions.

[0029] The World Anti-Doping Agency (WADA) has published the 2018 International Standard Prohibited List, which removes cannabidiol from the list of banned substances starting this year. Cannabidiol is a drug widely used by athletes to treat pain. While it bans hashish, marijuana, and other substances derived from the cannabis plant, it allows cannabidiol oil for medical purposes.

[0030] As such, the current situation is that the use of cannabidiol for medical purposes is permitted in many countries.

[0031] It has also been scientifically proven to be effective in treating a variety of illnesses, including epilepsy, Alzheimer's disease, allergic asthma, anxiety and sleep disorders, blood pressure improvement, diabetes, inflammation, irritable bowel disease, and multiple convulsions.

[0032] Based on these therapeutic effects, various dosage forms containing cannabidiol have been developed.

[0033] Specifically, the present invention relates to microparticles comprising cannabidiol (CBD), a time-release agent, and an antioxidant.

[0034] In this way, microparticles containing a sustained-release agent can be injected into the body and, as the sustained-release agent decomposes, cannabidiol can be released over a long period of time.

[0035] In the case of cannabidiol, as mentioned above, although its use for medical purposes has been approved, considering that strict control is required for administration, etc., the microparticles of the present invention are intended to be used as an injectable dosage form and can be said to be suitable for administering cannabidiol for medical purposes.

[0036] Furthermore, the microparticles can exhibit a long-term sustained release effect with a single administration, thereby eliminating the inconvenience of repeated administration and improving the convenience of administration.

[0037] Previously, for diseases for which cannabidiol is known to have an improving effect, it was difficult to demonstrate a disease treatment or disease improving effect with a single administration when using conventional pharmaceutical dosage forms.

[0038] In other words, it can be said that this corresponds to a disease for which continuous repeated administration can improve symptoms or produce a therapeutic effect.

[0039] Therefore, when the microparticles of the present invention are used as an injection, a single administration can provide a sustained cannabidiol administration effect. Specifically, a single administration can maintain the blood cannabidiol concentration at or above the effective concentration for one day, a single administration can maintain the blood cannabidiol concentration at or above the effective concentration for several days, a single administration can maintain the blood cannabidiol concentration at or above the effective concentration for one week, a single administration can maintain the blood cannabidiol concentration at or above the effective concentration for several weeks, a single administration can maintain the blood cannabidiol concentration at or above the effective concentration for one month, a single administration can maintain the blood cannabidiol concentration at or above the effective concentration for several months, a single administration can maintain the blood cannabidiol concentration at or above the effective concentration for three months, a single administration can maintain the blood cannabidiol concentration at or above the effective concentration for six months, and a single administration can maintain the blood cannabidiol concentration at or above the effective concentration for 12 months.

[0040] That is, the cannabidiol release effect can be sustained for one day or more, one week or more, one month or more, three months or more, six months or more, or twelve months or more.

[0041] The sustained release of cannabidiol can be affected by the decomposition rate of the release-sustaining agent, which will be described in detail later.

[0042] However, the microparticles containing cannabidiol and a sustained-release agent have the problem of oxidation of cannabidiol. As will be described later, after cannabidiol is prepared into microparticles, it can be confirmed that the cannabidiol in the microparticles is oxidized and turns yellow.

[0043] Cannabidiol may be a compound represented by the following chemical formula: [ka]

[0044] Cannabidiol, a compound represented by the above chemical formula, is a stable compound that does not oxidize when exposed to oxygen in the air.

[0045] However, when formulated into microparticles containing a sustained-release agent, as in the present invention, cannabidiol may be oxidized.

[0046] When cannabidiol is oxidized in this way, as mentioned above, it turns yellow, and the structure of the compound changes due to oxidation, which can lead to a decrease in efficacy.

[0047] Therefore, the present invention is characterized in that it contains an antioxidant to prevent oxidation of cannabidiol in the microparticles.

[0048] The antioxidant is selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), vitamin C, vitamin E, propyl gallate, and mixtures thereof, and may be selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), and mixtures thereof, and may be butylhydroxytoluene (BHT) or butylhydroxyanisole (BHA).

[0049] The antioxidant can be contained in the microparticles to prevent oxidation of cannabidiol. That is, an antioxidant generally refers to a substance that prevents oxidation. The antioxidant oxidizes instead of cannabidiol within the microparticles, thereby preventing the oxidation of cannabidiol.

[0050] However, the oxidation of cannabidiol cannot be prevented by including all antioxidants in the microparticles, and the antioxidant effect of cannabidiol can only be exhibited when the aforementioned antioxidants are included.

[0051] That is, an antioxidant is generally a substance that prevents oxidation, and as described above, it can prevent the oxidation of a target substance by oxidizing it before the target substance.

[0052] As will be described later, the microparticles of the present invention are spherical microparticles, and when the solvent is completely removed during the manufacturing process, cannabidiol, a sustained-release agent, and an antioxidant can be uniformly distributed.

[0053] At this time, when the microparticles come into contact with oxygen, an oxidation reaction of cannabidiol occurs, but the oxidation reaction of the antioxidant occurs preferentially compared to the cannabidiol, thereby preventing the oxidation reaction of cannabidiol.

[0054] Although this action can prevent the oxidation reaction of cannabidiol, not all antioxidants exhibit this antioxidant effect, but only the antioxidants of the present invention can exhibit the antioxidant effect of cannabidiol by oxidizing the antioxidant before cannabidiol. In other words, in the case of microparticles containing antioxidants other than the antioxidants of the present invention, cannabidiol may oxidize before the antioxidant.

[0055] More specifically, among the antioxidants of the present invention, only antioxidants selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), and mixtures thereof are able to oxidize before cannabidiol and exhibit antioxidant effects. Other antioxidants are unable to exhibit antioxidant effects because cannabidiol is preferentially oxidized.

[0056] The antioxidant may be present in an amount of 0.11 to 9.9 wt %, 0.2 to 9 wt %, 0.3 to 8 wt %, or 0.5 to 5 wt % based on the total weight of cannabidiol and sustained-release agent, and can be manufactured into spherical microparticles within the above ranges, maintaining an appropriate cannabidiol content range and allowing use in a sustained-release dosage form, and the antioxidant's effect of preventing the oxidation of cannabidiol can increase stability.

[0057] The biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof, and preferably polylactide-co-glycolide (PLGA) or polylactide (PLA), but is not limited to these examples.

[0058] As an example, the molar ratio of glycolide to lactide in polylactide-co-glycolide may be about 60:40 to about 90:10, about 60:40 to about 85:15, about 60:40 to about 80:20, about 60:40 to about 75:25, about 65:35 to about 90:10, about 70:30 to about 90:10, about 75:25 to about 90:10, about 65:35 to about 85:15, or about 70:30 to about 80:20. The molar ratio is not limited to the above examples, but preferably, the molar ratio of glycolide to lactide in polylactide-co-glycolide may be about 75:25.

[0059] The biodegradable polymer may include one or more polylactides and one or more polylactide-co-glycolides. In the present invention, the biodegradable polymer may include, for example, a combination of two polylactides, one polylactide and one polylactide-co-glycolide, two polylactide-co-glycolides, three polylactides, two polylactides and one polylactide-co-glycolide, or one polylactide and two polylactide-co-glycolides, and particularly, but is not limited to, one polylactide and one polylactide-co-glycolide, or two polylactide-co-glycolides.

[0060] The biodegradable polymer can include two or more types of polylactide-co-glycolide.

[0061] The microparticles may contain cannabidiol and biodegradable polymer in a weight ratio of 1:1 to 1:10, a weight ratio of 1:2 to 1:8, a weight ratio of 1:2 to 1:6, or a weight ratio of 1:4. Microparticles containing cannabidiol within these ranges can be used as sustained-release injections that continuously release cannabidiol within an injectable dose range when used as an injectable composition. That is, if the cannabidiol content relative to the biodegradable polymer is below this range, the amount of the injectable composition increases to achieve the total dose of cannabidiol required for injection, which can result in an insufficient amount for a single injection. Furthermore, if the cannabidiol content relative to the biodegradable polymer exceeds this range, it is difficult to produce microparticles in which cannabidiol is uniformly distributed.

[0062] A sustained-release injectable composition containing cannabidiol according to another embodiment of the present invention may include microparticles containing the cannabidiol and a suspension solvent.

[0063] The injectable composition may contain a suspension medium, which contains an isotonic agent, a suspending agent, and a solvent.

[0064] More specifically, the tonicity agent can be selected from the group consisting of D-mannitol, maltitol, sorbitol, lactitol, xylitol, sodium chloride, and mixtures thereof, preferably D-mannitol, but is not limited to these examples.

[0065] The suspending agent may be sodium carboxymethylcellulose, polysorbate 80, starch, starch derivatives, polyhydric alcohols, chitosan, chitosan derivatives, cellulose, cellulose derivatives, collagen, gelatin, hyaluronic acid (HA), alginic acid, algin, pectin, carrageenan, chondroitin, chondroitin sulfate, dextran, dextran sulfate, polylysine, titin, fibrin, agarose, fluran, xanthan gum, etc. gum), and mixtures thereof, preferably sodium carboxymethylcellulose and polysorbate 80, but not limited to the above examples.

[0066] The solvent may be water for injection, and any solvent that can be used as water for injection may be used without limitation.

[0067] Another embodiment of the present invention provides a method for producing microparticles containing cannabidiol, including dissolving cannabidiol (CBD), a release-sustaining agent, and an antioxidant in an organic solvent to prepare an oil phase solution, dissolving a surfactant in water to prepare an aqueous phase solution, and mixing the oil phase solution and the aqueous phase solution to form an emulsion.

[0068] In the production method, an emulsion can be formed using an oil phase solution prepared by dissolving cannabidiol, a sustained-release agent, and an antioxidant in an organic solvent, and an aqueous phase solution containing a surfactant.

[0069] As will be described later, although the present invention produces the emulsion by a microfluidic method using a microchannel, the production method is not limited to this, and all microparticle production methods such as a solvent evaporation method and a membrane method can be applied.

[0070] The organic solvent can be one that can completely dissolve the cannabidiol, the release-sustaining agent, and the antioxidant. Specifically, it can be any one or more selected from the group consisting of chloroform, chloroethane, dichloroethane, dichloromethane, trichloroethane, methylene chloride, methanol, and mixtures thereof, preferably methylene chloride, methanol, and mixtures thereof. The organic solvent can be any one that can completely dissolve the cannabidiol, the release-sustaining agent, and the antioxidant, and is not limited to the above examples, and any organic solvent that can be easily selected by a person skilled in the art can be used.

[0071] The cannabidiol and sustained-release agent in the organic solvent may be contained in a weight ratio of 1:1 to 1:10, a weight ratio of 1:2 to 1:8, a weight ratio of 1:2 to 1:6, or a weight ratio of 1:4.

[0072] The sustained-release agent content in the oil phase solution is 10 to 20 wt %, preferably 12 to 18 wt %, and more preferably 15 wt %, but is not limited to these examples. If the content is less than this range, it is impossible to prepare an emulsion, and if the content is more than this range, the viscosity of the oil phase solution becomes too high, making it difficult to prepare an emulsion.

[0073] The biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof, and preferably polylactide-co-glycolide (PLGA) or polylactide (PLA), but is not limited to these examples.

[0074] The surfactant contained in the aqueous phase solution is 0.1 to 1.0% by weight, 0.2 to 0.5% by weight, or may be 0.25% by weight, with the remainder being water.

[0075] The surfactants include methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol, sorbitan monooleate (e.g., Span 80), and the like. TM 80), polyoxyethylene sorbitan fatty acid esters (e.g., Tween 80), TM 80), polyoxyethylene castor oil derivatives, sodium lauryl sulfate, sodium stearate, esteramine, linear diamine, pattyamine, and mixtures thereof, and preferably polyvinyl alcohol. However, the surfactant is not limited to the above examples, and any surfactant that can be used to produce a perfectly spherical emulsion can be used.

[0076] As described above, after the oil phase solution and the aqueous phase solution are prepared, there is no limitation on the method for preparing an emulsion using them.

[0077] However, in this invention, a method for producing microparticles by microfluidic methods will be described.

[0078] The microchip for use in the microfluidic method may be formed on a wafer or glass substrate. The microchip has microchannels formed thereon, more specifically, the microchannels include a channel through which an oil phase solution flows, a channel through which an aqueous phase solution flows, and a transfer channel, the channel through which the oil phase solution flows and the channel through which the aqueous phase solution flows being formed to meet at one point, and one end of the transfer channel being connectable to the junction of the two channels.

[0079] The channel through which the oil phase solution flows and the channel through which the aqueous phase solution flows may be connected to injection sections for injecting the oil phase solution and the aqueous phase solution, respectively, and a recovery section for recovering the solution containing the emulsion may be connected to one end of the transfer channel.

[0080] The microchannel may be formed in a material selected from the group consisting of a glass substrate, a silicon wafer, or a polymer film, but examples of the material are not limited to these examples, and any material capable of forming a microchannel can be used.

[0081] The polymer film may be selected from the group consisting of polyimide, polyethylene, fluorinated ethylene propylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polysulfone, and mixtures thereof, but is not limited to these examples.

[0082] For example, aluminum is deposited on a silicon wafer using an e-beam evaporator, and photoresist is patterned on the aluminum using photolithography. The aluminum is then etched using the photoresist as a mask. After the photoresist is removed, the silicon is etched using deep ion reactive etching (DRIE) using the aluminum as a mask. After removing the aluminum, glass is anodically bonded onto the wafer and sealed to form the microchannel.

[0083] The microchannels have an average diameter of 60 to 150 μm, preferably 80 to 100 μm, but are not limited to this example. If microchannels having an average diameter below this range are used, the emulsion may have an excessively small diameter, which may affect effective drug release and in vivo absorption.

[0084] Furthermore, if the average diameter of the microchannel exceeds the above range, the average size of the produced microparticles will exceed 120 μm, which may increase the foreign body sensation and pain when administered as an injection. Furthermore, the larger the diameter of the microchannel, the larger the particle size distribution of the produced particles, making it difficult to produce microparticles of uniform particle size.

[0085] Furthermore, the average diameter of the microchannel is closely related to the average diameter of the particles, and also to the flow rate ratio (μl / min) of the oil phase solution and the aqueous phase solution.

[0086] The cross-sectional width (w) and cross-sectional height (d) of the microchannel are closely related to the average diameter (d') of the produced microparticles. The ratio of the cross-sectional width (w) of the microchannel to the average diameter (d') of the microparticles is in the range of 0.7 to 1.3, and the cross-sectional height (d) of the microchannel to the average diameter (d') of the microparticles is in the range of 0.7 to 1.3.

[0087] In other words, once the average diameter (d') of the microparticles to be produced is determined, the width (w) and height (d) of the cross section of the microchannel must be set within the ratio range of 0.7 to 1.3 of d' to produce microparticles of the desired size.

[0088] To produce microparticles using the microchip, an oil phase solution can be injected into the channel through which the oil phase solution flows, and an aqueous phase solution can be injected into the channel through which the aqueous phase solution flows, to form an emulsion at the junction of the two channels.

[0089] When the oil phase solution and the aqueous phase solution are injected into the microchannel, the flow rate ratio of the oil phase solution to the aqueous phase solution may be 1:10 to 1:50, 1:15 to 1:40, 1:15 to 1:30, or 1:15 to 1:25. By adjusting the flow rate ratio of the oil phase solution to the aqueous phase solution in this manner, microparticles with a uniform diameter can be produced.

[0090] The emulsion formed at the interface can be obtained using the prepared aqueous phase solution, i.e., a mixture of surfactant and water, which can be injected into a microchannel to form an emulsion and can also be used to prevent the collected emulsion from clumping by filling a water tank.

[0091] The emulsion collected in the water tank can have residual organic solvents removed. The residual organic solvent removal step can involve stirring at a constant temperature and stirring speed to evaporate and remove the residual organic solvent present inside the emulsion. The stirring conditions are a primary stirring step at 15-20°C for 50-70 minutes, a secondary stirring step at 20-40°C for 50-70 minutes, and a tertiary stirring step at 40-60°C for 1-3 hours.

[0092] The stirring speed is the same for the first to third stirring steps, and is 300 to 500 rpm, and may be 400 rpm.

[0093] As described above, the temperature condition is gradually increased as the stirring process progresses, and the temperature is gradually increased to adjust the evaporation rate of the organic solvent present in the emulsion.

[0094] The temperature of the oil phase solution and the aqueous phase solution when they flow through the microchannel is also 5 to 20°C, preferably 10°C. That is, after they flow through the microchannel and form an intersection to produce an emulsion, the collected emulsion is maintained at a constant low temperature of 5 to 20°C until it is subjected to primary stirring. Maintaining a low temperature during the emulsion production process is essential to produce and maintain spherical particles. In other words, if the temperature is not low, it becomes difficult to produce uniform spherical particles.

[0095] In the subsequent secondary stirring process, the temperature is gradually increased and the stirring time is increased, so that the organic solvent present in the interior of the emulsion gradually migrates to the surface, where it evaporates, thereby minimizing the effect on the emulsion properties. That is, if the organic solvent evaporates too quickly, the surface of the final microparticles may become uneven and pores may form. To prevent this problem, the temperature condition is gradually increased and the stirring time is also increased, as described above, to adjust the evaporation rate of the organic solvent, and the surface properties of the produced microparticles can be controlled by adjusting the evaporation rate of the organic solvent.

[0096] In the tertiary stirring step, after the organic solvent in the emulsion is extracted as an external aqueous phase, the external aqueous phase is heated to a temperature close to the boiling point of the organic solvent and stirred, thereby removing the saturated organic solvent from the aqueous phase and facilitating the removal of the residual organic solvent in the emulsion.

[0097] Finally, in the step of washing and drying the microparticles from which the residual organic solvent has been removed, the microparticles from which all the organic solvent on the surface has been removed by stirring are washed several times with sterilized and filtered purified water to remove any surfactant remaining on the microparticles, and then freeze-dried.

[0098] The final microparticles are spherical microparticles made of biodegradable polymers in which cannabidiol is uniformly distributed, and can contain cannabidiol and biodegradable polymer in a weight ratio of 1:1 to 1:10.

[0099] Furthermore, as mentioned above, the final microparticles contain cannabidiol and an antioxidant uniformly distributed therein, and when they come into contact with oxygen in the air, the antioxidant is preferentially oxidized, preventing the oxidation of cannabidiol.

[0100] The weight ratio of cannabidiol and biodegradable polymer contained in the microparticles is the same as the weight ratio in the oil phase solution when the emulsion is produced. By passing the emulsion through a microchannel and removing all of the organic solvent in the emulsion, microparticles containing cannabidiol and biodegradable polymer in the same weight ratio as in the oil phase solution can be produced.

[0101] The microparticles may have an average diameter of 30 to 70 μm, 30 to 65 μm, or 30 to 60 μm. The standard deviation of the average diameter may be 1 to 30 μm, 1 to 20 μm, 1 to 10 μm, or 1 to 7 μm. It has been confirmed that uniform particles can be produced within this diameter range. When used as a sustained-release injection, the uniform particles can reduce the sensation of foreign matter, improve the convenience of administration, and prevent initial over-release upon infusion, thereby providing a sustained cannabidiol-releasing effect.

[0102] Manufacturing Example 1 Microparticle production Microspheres were produced using the ingredients and amounts shown in Table 1 by the method described below.

[0103] 1) Preparation of oil phase solution An oil phase solution was prepared by dissolving lactide-glycolide copolymer (75:25) and cannabidiol or lactide-glycolide copolymer (75:25), cannabidiol, and an antioxidant in methylene chloride or a mixture of methylene chloride and methanol. The polymer in the oil phase solution was contained at a ratio of 15 wt% and the weight ratio of polymer to cannabidiol was 4:1.

[0104] 2) Preparation of aqueous solution Polyvinyl alcohol was dissolved in water to prepare an aqueous phase solution, and the aqueous phase solution contained 0.25% by weight of polyvinyl alcohol.

[0105] 3) Microparticle production The oil-phase solution and aqueous solution were injected into a microchannel formed on a silicon wafer to produce microparticles. The oil-to-aqueous flow ratio was 1:20, and the temperature was maintained at 10.0°C. The produced microparticles were collected in a water bath containing the aqueous solution and stirred at 400 rpm at 10.0°C for 1 hour, 30.0°C for 1 hour, and 45.0°C for 2 hours.

[0106] 4) Cleaning and harvesting After stirring, the microparticles were washed with sterilized and filtered purified water, and then freeze-dried to obtain a powder.

[0107] [Table 1]

[0108] Manufacturing Example 2 Microparticle production Microspheres were produced using the ingredients and amounts shown in Table 2 by the method described below.

[0109] 1) Preparation of oil phase solution An oil phase solution was prepared by dissolving lactide-glycolide copolymer (75:25), cannabidiol, and butylhydroxytoluene in methylene chloride. The polymer in the oil phase solution was contained at a ratio of 15 wt% and the weight ratio of polymer to cannabidiol was 4:1.

[0110] 2) Preparation of aqueous solution Polyvinyl alcohol was dissolved in water to prepare an aqueous phase solution, and the aqueous phase solution contained 0.25% by weight of polyvinyl alcohol.

[0111] 3) Microparticle production The oil-phase solution and aqueous solution were injected into a microchannel formed on a silicon wafer to produce microparticles. The oil-to-aqueous flow ratio was 1:20, and the temperature was maintained at 10.0°C. The produced microparticles were collected in a water bath containing the aqueous solution and stirred at 400 rpm at 10.0°C for 1 hour, 30.0°C for 1 hour, and 45.0°C for 2 hours.

[0112] 4) Cleaning and harvesting After stirring, the microparticles were washed with sterilized and filtered purified water, and then freeze-dried to obtain a powder.

[0113] [Table 2]

[0114] Manufacturing Example 3 Microparticle production Microspheres were produced using the ingredients and amounts shown in Table 3 by the method described below.

[0115] 1) Preparation of oil phase solution An oil phase solution was prepared by dissolving lactide-glycolide copolymer (75:25), cannabidiol, and butylhydroxyanisole in methylene chloride. The polymer in the oil phase solution was contained at a ratio of 15 wt% and the weight ratio of polymer to cannabidiol was 4:1.

[0116] 2) Preparation of aqueous solution Polyvinyl alcohol was dissolved in water to prepare an aqueous phase solution, and the aqueous phase solution contained 0.25% by weight of polyvinyl alcohol.

[0117] 3) Microparticle production The oily and aqueous solutions were injected into a microchannel formed on a silicon wafer to produce microparticles, with the oil-to-aqueous flow ratio of 1:20 and the temperature maintained at 10.0°C.

[0118] The produced microparticles were collected in a water bath containing the aqueous phase solution and stirred at 400 rpm at 10.0°C for 1 hour, 30.0°C for 1 hour, and 45.0°C for 2 hours.

[0119] 4) Cleaning and harvesting After stirring, the microparticles were washed with sterilized and filtered purified water, and then freeze-dried to obtain a powder.

[0120] [Table 3]

[0121] Experimental Method Experimental Example 1 Stability testing 1) Sample preparation Approximately 100 mg of microspheres were weighed into a 5 mL glass vial and placed in a capped or uncapped (closed / open) stability chamber.

[0122] 2) Stable stocking The stability test was carried out under long-term conditions (temperature: 25±2°C, relative humidity 60±5%), and the presence or absence of yellowing was confirmed by observing daily changes in properties. Meanwhile, the initial samples and samples on the sixth day of storage were subjected to an encapsulation rate test to confirm the presence or absence of changes in content.

[0123] Experimental Example 2 Encapsulation rate test HPLC (liquid chromatography) was carried out to measure the encapsulation rate (EE%), and standard and test solutions for analysis were prepared as follows.

[0124] 1) Standard solution production Take approximately 10 mg of the active ingredient, cannabidiol, and place it in a 100 mL volumetric flask. Add approximately 50 mL of diluent (acetonitrile) and sonicate for 10 minutes. After cooling thoroughly, align the mark with the diluent, filter through a 0.45 μm filter (water-soluble PTFE), and use as the standard solution. (Concentration: 0.1 mg / mL)

[0125] 2)Test solution production Take approximately 50 mg of microspheres (10.0 mg of the main component) and place it in a 100 mL volumetric flask. Add approximately 50 mL of diluent (acetonitrile) and sonicate for 10 minutes. After cooling sufficiently, align the mark with the diluent, filter through a 0.45 μm filter (water-soluble PTFE), and use as the test solution. (Concentration: 0.1 mg / mL)

[0126] 3) HPLC conditions Detector: UV (220 nm) Column: ODS column (4.6*150mm, 5μm) Flow rate: 1.0mL / min Mobile phase: methanol: purified water = 85:15 (Isocratic method)

[0127] 4) Formula for calculating encapsulation rate (EE%) Encapsulation rate (EE%) = At / As*Cs / CtxP At:Area response of Cannabidiol in test solution As:Area response of Cannabidiol in standard solution Cs:Concentration of Cannabidiol in stabdard solution Ct:Concentration of Cannabidiol in test solution P: Purity of Cannabidiol

[0128] Experimental result 1 Preparation Example 1 is an experiment to confirm the antioxidant effect of each antioxidant.

[0129] The experimental results are shown in Figures 7, 1 and 2 below.

[0130] The experimental results showed that in the group without added antioxidants, the glass vials turned yellow whether they were completely closed or opened, confirming that the cannabidiol in the microparticles was oxidized without the addition of antioxidants.

[0131] The above experimental results can be clearly confirmed by the encapsulation rate experiment and the difference in values ​​between the initial and 6-day intervals.

[0132] Furthermore, the results of confirming whether or not the type of antioxidant has an antioxidant effect can be observed with the naked eye, and can also be numerically confirmed in encapsulation rate tests, showing that the antioxidant effect of cannabidiol is only apparent when BHT and BHA are included.

[0133] Preparation Example 2 was conducted to confirm the antioxidant effect depending on the content of the antioxidant when BHT was used as an antioxidant. The experimental results are shown in Figures 8, 3 and 4 below: According to the above experimental results, it can be confirmed that when BHT is contained in an amount of 0.05% by weight based on the total weight of cannabidiol and biodegradable polymer, the antioxidant effect is slight.

[0134] Furthermore, when the content is 0.1% by weight relative to the total weight of cannabidiol and biodegradable polymer, the color changes to yellow when observed with the naked eye, and the encapsulation rate measurement results confirm that the oxidation inhibitory effect of cannabidiol is apparent.

[0135] Furthermore, when BHT was contained in an amount of 10% by weight based on the total weight of cannabidiol and biodegradable polymer, it was confirmed that the problem of microsphere aggregation occurred, resulting in the problem of unsuitable quality.

[0136] Preparation Example 3 was conducted to confirm the antioxidant effect depending on the content of the antioxidant when BHA was used as an antioxidant. The experimental results are shown in Figures 9, 5 and 6 below: According to the above experimental results, it can be confirmed that when BHA is contained in an amount of 0.05% by weight based on the total weight of cannabidiol and biodegradable polymer, the antioxidant effect is slight.

[0137] Furthermore, when the content is 0.1% by weight relative to the total weight of cannabidiol and biodegradable polymer, the color changes to yellow when observed with the naked eye, and the encapsulation rate measurement results confirm that the oxidation inhibitory effect of cannabidiol is apparent.

[0138] Furthermore, when BHA was contained in an amount of 10% by weight based on the total weight of cannabidiol and biodegradable polymer, it was confirmed that the problem of microsphere aggregation occurred, resulting in the problem of unsuitable quality.

[0139] Test result 2 Average diameter measurement results The average diameter and the standard deviation of the average diameter of the microparticles in FIGS. 7 to 9 were confirmed by PSA analysis, and the experimental results are shown in Tables 4 to 6 below.

[0140] [Table 4]

[0141] [Table 5]

[0142] [Table 6]

[0143] According to the above experimental results, the microparticles of the present invention may have an average diameter of 30 to 60 μm with a standard deviation of 1 to 30 μm. Furthermore, microparticles containing BHT or BHA as an antioxidant and falling within the preferred range of the present invention have an average diameter of 30 to 40 μm with a standard deviation of 1 to 7 μm, confirming that the particles are distributed very uniformly.

[0144] Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concept of the present invention defined in the following claims also fall within the scope of the present invention. [Example]

[0145] The present invention relates to cannabidiol-containing microparticles comprising cannabidiol (CBD), a time-release agent, and an antioxidant. [Industrial Applicability]

[0146] The present invention relates to microparticles containing cannabidiol and methods for making the same.

Claims

1. Contains cannabidiol (CBD), a sustained-release agent, and an antioxidant. Microparticles containing cannabidiol.

2. The sustained-release agent is a biodegradable polymer.

10. A microparticle comprising cannabidiol according to claim 1.

3. The biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof.

3. A microparticle comprising cannabidiol according to claim 2.

4. The antioxidant is selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), vitamin C, vitamin E, propyl gallate, and mixtures thereof.

10. A microparticle comprising cannabidiol according to claim 1.

5. The antioxidant is present in an amount of 0.11% to 9.9% by weight based on the total weight of cannabidiol and the sustained-release agent.

10. A microparticle comprising cannabidiol according to claim 1.

6. Dissolving cannabidiol (CBD), a time-release agent, and an antioxidant in an organic solvent to produce an oil phase solution; dissolving a surfactant in water to produce an aqueous phase solution; mixing the oil phase solution and the aqueous phase solution to form an emulsion; A method for producing microparticles containing cannabidiol.

7. obtaining the prepared emulsion in an aqueous phase solution and removing residual solvent; and washing and freeze-drying the emulsion from which the residual solvent has been removed. A method for producing microparticles comprising cannabidiol according to claim 6.

8. The antioxidant is selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), vitamin C, vitamin E, propyl gallate, and mixtures thereof. A method for producing microparticles comprising cannabidiol according to claim 6.

9. The antioxidant is present in an amount of 0.06% to 9.9% by weight based on the total weight of cannabidiol and the sustained-release agent. A method for producing microparticles comprising cannabidiol according to claim 6.

10. The oil phase solution and the aqueous phase solution are injected into each microchannel and allowed to flow, and an emulsion comprising cannabidiol, an antioxidant, and a time-release agent is formed at a point where the oil phase solution stream and the aqueous phase solution stream intersect with each other. A method for producing microparticles comprising cannabidiol according to claim 6.

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