Sustained-release injectable composition for treating or preventing neurological disorders, and method for preparing same

Abstract

The present invention relates to: a sustained-release injectable composition for treating or preventing neurological disorders; and a method for preparing same. The sustained-release injectable composition uses microparticles containing cannabidiol and continuously releases the cannabidiol for at least one month, and thus can be effective in treating or preventing neurological disorders. In addition, the sustained-release injectable composition includes cannabidiol, which is non-toxic and can be used continuously for a long time due to the absence of side effects from long-term use, and thus can exhibit a therapeutic or prophylactic effect on neurological disorder patients for at least one month through a single injection. Therefore, the sustained-release injectable composition can greatly improve the convenience of administration.

Description

Long-acting injectable composition for the treatment or prevention of neurological diseases and method for preparing the same

[0001] The present invention relates to a sustained-release injectable composition for treating or preventing a nervous system disease and a method for preparing the same.

[0002] Epilepsy is a disease characterized by intermittent neurological disturbances caused by paroxysmal discharges of brain neurons due to organic lesions or functional disorders, resulting in symptoms such as neurological symptoms, loss of consciousness, convulsions, and sensory disturbances. It is the third most common neurological disorder after Alzheimer's disease and stroke, affecting approximately 0.5% to 2% of the global population.

[0003] Furthermore, approximately 45 new cases per 100,000 people are diagnosed with epilepsy annually worldwide, and it is estimated that there are approximately 300,000 to 400,000 epilepsy patients in Korea. Looking at the age distribution of epilepsy patients, 70% of all epilepsy cases begin in childhood and adolescence, with a particularly high incidence rate in infancy. Furthermore, the incidence and prevalence rates follow a U-shaped pattern, peaking within the first year of life, then rapidly decreasing, and then rapidly increasing again in the elderly over 60 years of age. The lifetime prevalence of experiencing seizures is 10-15%.

[0004] Epilepsy is a chronic disease characterized by recurrent epileptic seizures. The causes are diverse and the exact cause is unknown. However, recent advancements in neuroimaging technology have made it possible to observe subtle pathological changes in the brain that were previously invisible, and this has led to a gradual expansion of the understanding of the causes of epilepsy. Some epidemiological studies have reported that more than one-third of patients have a history of pathological changes or brain damage in the brain. Major causes include stroke, congenital malformations, head trauma, encephalitis, brain tumors, degenerative encephalopathy, genetics, prematurity, and perinatal damage.

[0005] Meanwhile, the treatment of epilepsy can be broadly categorized into drug therapy and non-drug therapy, such as surgery, ketogenic diet, and vagus nerve stimulation. However, non-drug treatment is only performed on patients who show drug resistance, so drug therapy has been used as the main method for treating epilepsy. Conventional drugs include phenytoin (Dilantin), valproate (Orfil, Depakine, Depakote), carbamazepine (Tegretol), phenobarbital (Luminal), and ethosuximide (Zarontin). Recently, topiramate (Topamax), lamotrigine (Lamictal), vigabatrin (Sabril), and oxcarbazepine (Trilleptal) have been developed and commercialized. However, these drugs are known to have side effects such as rash, blood disorders, osteoporosis, hyponatremia, headache, behavioral changes, and immune reactions.

[0006] Among the main components of cannabis, cannabidiol (CBD) has been shown in numerous studies to have minimal psychoactive effects and to exhibit anticonvulsant effects by suppressing nervous hyperexcitation. Based on its efficacy and safety, Epidyolex, an oral liquid containing cannabidiol, has been developed. ® It was approved for sale in 2018 and is being used to treat rare epilepsy in children. However, because it is in liquid form, it is difficult to administer a fixed dose to children, and there is a risk of relapse due to rapid loss of blood drug concentration.

[0007] Therefore, there is a need to develop a product that has no side effects and can enhance the treatment or prevention effect of epilepsy through long-term continuous drug release through a single injection as a treatment or improvement for epilepsy.

[0008] [Prior Art Literature]

[0009] [Patent Document]

[0010] KR 10-2020-0105198 A1

[0011] The purpose of the present invention is to provide a sustained-release injectable composition for treating or preventing neurological diseases and a method for preparing the same.

[0012] Another object of the present invention is to provide a sustained-release injectable composition that can exhibit an effect of treating or preventing a nervous system disease by continuously releasing cannabidiol for more than one month using microparticles containing cannabidiol.

[0013] Another object of the present invention is to provide a sustained-release injectable composition containing cannabidiol that is non-toxic and has no side effects due to long-term use, allowing for long-term use, and a method for manufacturing a sustained-release injectable composition that can exhibit a treatment or prevention effect for a neurological disease for more than one month with a single injection, thereby greatly improving the convenience of administration.

[0014] To achieve the above object, the present invention relates to a sustained-release injectable composition for treating or preventing a nervous system disease, comprising microparticles that continuously release cannabidiol (CBD) for more than one month, wherein the microparticles comprise cannabidiol and a biodegradable polymer.

[0015] Additionally, the microparticles may contain cannabidiol and a biodegradable polymer in a weight ratio of 1:1 to 1:10.

[0016] Additionally, the biodegradable polymer may be selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof.

[0017] Additionally, the polylactide-co-glycolide may have a monomer ratio of lactide:glycolide of 40:60 to 90:10.

[0018] Additionally, the neurological disease may be epilepsy.

[0019] Additionally, the microparticles may be released at a rate of 35% to 80% relative to the weight of the total CBD after 18 hours as determined by the following release test:

[0020] [Emission test conditions]

[0021] The dissolution test solution was prepared by mixing Tween 20 to 0.05% (w / v) in 1 L of 10 mM PBS buffer (pH 7.4) to prepare a mixed solution, and then mixing sodium azide to 0.02% (w / v) and sodium ascorbate to 0.0625% (w / v) in the mixed solution.

[0022] 100 mL of the above dissolution test solution was placed in an injection vial, and the above microparticles were added thereto so that the total weight of the microparticles was 15 mg of CBD. After the injection vial was completely sealed, the temperature was maintained at 50°C and the test was conducted by shaking at a speed of 120 rpm. After 18 hours from the start of dissolution, the injection vial was taken out and left for 3 minutes. Then, 1 mL of the test solution was accurately taken using a syringe, centrifuged at 3000 rpm for 3 minutes, and the supernatant was used as the test solution to confirm the release of CBD.

[0023] A method for preparing a sustained-release injectable composition for treating or preventing a nervous system disease according to another embodiment of the present invention may include the steps of preparing an oily solution by dissolving cannabidiol (CBD) and a biodegradable polymer in an organic solvent; preparing an aqueous solution by dissolving a surfactant in water; and forming an emulsion by mixing the oily solution and the aqueous solution.

[0024] In addition, the emulsion thus manufactured may further include a step of obtaining a water solution to remove residual solvent; a step of washing and freeze-drying the emulsion from which the residual solvent has been removed to manufacture microparticles; and a step of mixing the freeze-dried microparticles with water for injection.

[0025] In addition, the oily solution and the aqueous solution can be injected into each microchannel and allowed to flow, and an emulsion containing cannabidiol and a release agent can be formed at the point where the flow of the oily solution and the flow of the aqueous solution intersect each other.

[0026] Additionally, the oily solution may additionally contain butylated hydroxytoluene (BHT).

[0027] The present invention utilizes microparticles containing cannabidiol to continuously release cannabidiol for more than one month, thereby exhibiting an effect of treating or preventing a nervous system disease.

[0028] In addition, it is a sustained-release injectable composition containing cannabidiol, which is known to have a wide safety margin when exposed to the whole body, and has fewer side effects due to long-term use, and can exhibit a treatment or preventive effect on nervous system diseases for more than one month with a single injection, which can greatly improve the convenience of taking it.

[0029] Figure 1 shows the results of a CBD elution test of microparticles according to one embodiment of the present invention.

[0030] Figure 2 shows the results of a CBD elution test of microparticles according to one embodiment of the present invention.

[0031] Figure 3 shows the pK results from a rat pharmacokinetic test of microparticles according to one embodiment of the present invention.

[0032] Figure 4 shows the test results for changes in body weight of rats after administration of microparticles according to one embodiment of the present invention.

[0033] Figure 5 shows the results of a seizure analysis for a PTZ-induced seizure rat model of microparticles according to one embodiment of the present invention.

[0034] Figure 6 shows the results of changes in distribution within the Seizure grade group for the PTZ-induced seizure rat model of microparticles according to one embodiment of the present invention.

[0035] Figure 7 shows the results of mortality analysis by Seizure for a PTZ-induced seizure rat model of microparticles according to one embodiment of the present invention.

[0036] Figure 8 shows the results of a stability test of microparticles according to one embodiment of the present invention.

[0037] The present invention relates to a sustained-release injectable composition for the treatment or prevention of neurological diseases, comprising microparticles that continuously release cannabidiol (CBD) for more than one month, wherein the microparticles comprise cannabidiol and a biodegradable polymer.

[0038] Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily implement them. However, the present invention may be implemented in various different forms and is not limited to the embodiments described herein.

[0039] The cannabidiol (CBD) of the present invention is a physiologically active substance isolated from hemp, and may be directly extracted from hemp, or may utilize extracted CBD, or may be manufactured by chemical synthesis, and includes all salts thereof, but is not limited to the above examples.

[0040] Hemp, also known as hemp, was traditionally used as a fabric. More specifically, hemp fibers are used for fabrics, mosquito nets, ropes, fishing nets, and papermaking materials. Hemp seeds are pressed for oil, which is used for edible purposes or in lamp oil, soap, varnish, and paint. Hemp cake is used as feed and fertilizer.

[0041] Delta-9-tetrahydrocannabinol (THC), a psychoactive chemical and a key component of cannabis, is derived from the Cannabis sativa or Cannabis indica plant. Commonly referred to as marijuana, it is regulated as an illegal drug in some countries. In these countries, storing and handling it without special permission is illegal. Another key component is cannabidiol (CBD), which, unlike THC, is known to have no psychoactive effects. Therefore, various studies are currently being conducted on its use in pharmaceuticals and cosmetics.

[0042] The World Health Organization (WHO) has published a report stating that cannabidiol oil, which is made from cannabis extract, is effective in treating epilepsy and Alzheimer's disease.

[0043] The World Anti-Doping Agency (WADA) released its "2018 International Standard for the Prohibited List," removing CBD from its list of banned substances starting this year. CBD is widely used by athletes for pain relief. While other cannabis-derived substances, such as hashish and marijuana, are prohibited, CBD oil for medical purposes is permitted.

[0044] As mentioned above, the use of CBD for medical purposes is permitted in various countries.

[0045] In 2018, Epidyolex, an oral liquid containing CBD, was launched for the treatment of rare pediatric diseases such as Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). ® This has been approved. The mechanism of action of CBD is not clearly known, but it is known to reduce neuronal hyperexcitability by regulating intracellular calcium concentration, and its efficacy has been confirmed in many in vitro and in vivo test systems. Epidiolex ® In clinical trials, it was confirmed that the frequency and severity of convulsions were significantly reduced when applied to a patient group.

[0046] However, as mentioned above, CBD is used for medical purposes in its CBD oil form. Because it requires long-term, continuous administration to treat or prevent certain diseases, there is currently no formulation that enhances ease of administration. Furthermore, currently approved products are oral liquid formulations, making it difficult to administer a precise dosage and causing rapid loss of blood drug concentrations.

[0047] Accordingly, the present invention provides an injectable composition that can be used for the treatment or prevention of nervous system diseases using CBD, and is particularly characterized by including microparticles that can continuously release CBD for more than one month through a single injection.

[0048] The above microparticles are characterized by containing CBD and a biodegradable polymer.

[0049] Accordingly, when the microparticles of the present invention are used as an injection, a sustained CBD administration effect can be achieved with a single administration. Specifically, a single administration can maintain the concentration of CBD in the blood above the effective concentration for more than one month, a single administration can maintain the concentration of CBD in the blood above the effective concentration for several months, a single administration can maintain the concentration of CBD in the blood above the effective concentration for three months, a single administration can maintain the concentration of CBD in the blood above the effective concentration for six months, and a single administration can maintain the concentration of CBD in the blood above the effective concentration for 12 months.

[0050] That is, it can show the continuous release effect of CBD for more than 1 month, more than 3 months, more than 6 months, and more than 12 months.

[0051] The sustained release effect of CBD as described above may be influenced by the rate of degradation of the release agent, i.e. the biodegradable polymer.

[0052] The biodegradable polymer may be selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof.

[0053] As an example, the polylactide-co-glycolide may have a molar ratio of glycolide to lactide of about 40:60 to about 90:10, about 40:60 to about 85:15, about 40:60 to about 80:20, about 40:60 to about 75:25, about 45:55 to about 90:10, or about 45:55 to about 80:20, but is not limited to the above examples, preferably, the molar ratio of glycolide to lactide in the polylactide-co-glycolide may be about 75:25 or about 50:50. When a polylactide-co-glycolide having the above range of molar ratios of glycolide to lactide is used as a sustained-release agent, CBD can be continuously released in the body for more than one month.

[0054] The biodegradable polymer may include one or more kinds of polymers, and specifically, may include one or more kinds of polylactides, one or more kinds of polylactide-co-glycolides, or polylactide and polylactide-co-glycolides. In the present invention, the biodegradable polymer may include, for example, a combination of two kinds of polylactides, one kind of polylactide and one kind of polylactide-co-glycolides, two kinds of polylactides-co-glycolides, three kinds of polylactides, two kinds of polylactides and one kind of polylactide-co-glycolides, one kind of polylactide and two kinds of polylactide-co-glycolides, and in particular, may include one kind of polylactide and one kind of polylactide-co-glycolides, or one kind of polylactide and one kind of polylactide-co-glycolides, but is not limited thereto.

[0055] The above biodegradable polymer may contain polylactide or polylactide-co-glycolide alone, or may contain one type of polylactide-co-glycolide and one type of polylactide, but is not limited to the above examples and any polymer that can continuously release CBD in the body for more than one month may be used without limitation.

[0056] The above microparticles contain CBD and a biodegradable polymer in a weight ratio of 1:1 to 1:10, and may be contained in a weight ratio of 1:2 to 1:9. Microparticles contained within the above range can be used as sustained-release injectables that continuously release CBD within an injectable dosage range when used as an injectable composition. That is, when the CBD is contained in an amount less than the above range relative to the biodegradable polymer, the amount of the injectable composition increases in order to match the total dosage for administering CBD as an injectable, which causes a problem of exceeding the amount of injectable composition that can be administered at one time to a human. In addition, when the CBD is contained in an amount exceeding the above range relative to the biodegradable polymer, it is not easy to manufacture microparticles in which CBD is uniformly distributed.

[0057] The neurological disease described above may be epilepsy. The microparticles of the present invention are not limited to epilepsy, and can be used to improve or treat other neurological diseases. Any disease for which CBD has been proven to be effective in treating or improving epilepsy can be applied without limitation. However, they are preferably used for the treatment or improvement of epilepsy.

[0058] The above microparticles may be released at a rate of 35% to 80% relative to the weight of the total CBD after 18 hours as determined by the following release test:

[0059] [Emission test conditions]

[0060] The dissolution test solution was prepared by mixing Tween 20 at 0.05% (w / v) in 1 L of 10 mM PBS buffer (pH 7.4), and then mixing sodium azide at 0.02% (w / v) and sodium ascorbate at 0.0625% (w / v) in the mixed solution.

[0061] 100 mL of the above dissolution test solution was placed in an injection vial, and the microparticles were added thereto so that the total weight of the microparticles was 15 mg of CBD. After the injection vial was completely sealed, the temperature was maintained at 50°C and the test was conducted by shaking at a speed of 120 rpm. After 18 hours from the start of dissolution, the injection vial was taken out and left for 3 minutes. Then, 1 mL of the test solution was accurately taken using a syringe, centrifuged at 3000 rpm for 3 minutes, and the supernatant was used as the test solution to confirm the release of CBD.

[0062] The above CBD release test was performed to confirm the sustained release of CBD using a dissolution test solution. As described above, in order for the microparticles containing CBD to continuously release CBD for more than one month, the release test shows that 35% to 80% of the total CBD weight should be released after 18 hours, 40% to 80% should be released, and 50% to 80% should be released. When CBD is released within the above range, the microparticles can continuously exhibit the CBD release effect for more than one month. That is, when it is released below the above range value, the initial CBD release effect is too small to exhibit the treatment or improvement effect of CBD on a nervous system disease, and when it is released above the above range value, the release amount of CBD is too large to exhibit the CBD release effect continuously for more than one month.

[0063] Additionally, the microparticles of the present invention may additionally contain butylated hydroxytoluene (BHT).

[0064] The above CBD may be a compound represented by the following chemical formula:

[0065] [chemical formula]

[0066]

[0067] CBD, a compound represented by the above chemical formula, is a stable compound that does not oxidize upon contact with oxygen in the air. However, when formulated into microparticles containing a biodegradable polymer, as in the present invention, there is a problem that oxidation of CBD occurs.

[0068] As described above, when CBD is oxidized, the color may change to yellow as described above, and as the structure of the compound changes due to oxidation, a decrease in efficacy may occur.

[0069] The above-mentioned butylated hydroxytoluene (BHT) is contained within the microparticles and can prevent the oxidation of CBD. That is, since butylated hydroxytoluene (BHT) is oxidized in place of CBD within the microparticles, the oxidation of cannabidiol can be prevented.

[0070] The microparticles of the present invention are spherical microparticles, as described below, and when the solvent is completely removed through the manufacturing process, cannabidiol, a release agent, and butylhydroxytoluene (BHT) can be uniformly distributed.

[0071] At this time, in an environment where the above microparticles come into contact with oxygen, an oxidation reaction of CBD occurs, but the oxidation reaction of butylhydroxytoluene (BHT) occurs first compared to the CBD, so that the oxidation reaction of CBD can be prevented.

[0072] Although the oxidation reaction of CBD can be prevented by the above-mentioned action, this oxidation prevention effect is not exhibited by antioxidants other than butylhydroxytoluene (BHT), and in the case of including butylhydroxytoluene (BHT), butylhydroxytoluene (BHT) may be oxidized before CBD, thereby exhibiting the oxidation prevention effect of CBD.

[0073] The above butylhydroxytoluene (BHT) may be included in an amount of 0.10 wt% to 1 wt%, 0.10 wt% to 0.50 wt%, 0.11 wt% to 0.40 wt%, or 0.12 wt% to 0.35 wt%, based on the total weight of the cannabidiol and biodegradable polymer, and within the above range, it can be manufactured into spherical microparticles, and can be used as a sustained-release formulation by maintaining an appropriate content range of CBD, and stability can be increased through the antioxidant effect of CBD by butylhydroxytoluene (BHT).

[0074] According to another embodiment of the present invention, a sustained-release injectable composition comprising cannabidiol may comprise microparticles comprising the cannabidiol and a suspending solvent.

[0075] The above-mentioned injectable composition may include a suspending agent, wherein the suspending agent includes a tonicity agent, a suspending agent and a solvent.

[0076] More specifically, the isotonic agent may 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 the above examples.

[0077] The above suspending agent is composed of 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, and mixtures thereof. Selected from the group, preferably sodium carboxymethylcellulose and polysorbate 80, but not limited to the above examples.

[0078] The above solvent can be used as injection water, and any solvent that can be used as injection water can be used without limitation.

[0079] A method for producing microparticles containing cannabidiol (CBD) according to another embodiment of the present invention may include the steps of dissolving CBD and a biodegradable polymer in an organic solvent to produce an oily solution; dissolving a surfactant in water to produce an aqueous solution; and mixing the oily solution and the aqueous solution to form an emulsion.

[0080] The above manufacturing method can form an emulsion using an oily solution prepared by dissolving CBD, a preservative, and an antioxidant in an organic solvent and an aqueous solution containing a surfactant.

[0081] As described below, the present invention manufactures the emulsion by a microfluidic method using a microchannel, but is not limited to the above manufacturing method, and any micro particle manufacturing method such as a solvent evaporation method or a membrane method can be applied.

[0082] The organic solvent may be one that can completely dissolve CBD and the biodegradable polymer. Specifically, it may be at least one selected from the group consisting of chloroform, chloroethane, dichloroethane, dichloromethane, trichloroethane, methylene chloride, methanol, and mixtures thereof, and preferably selected from the group consisting of methylene chloride, methanol, and mixtures thereof. The organic solvent is not limited to the above examples as long as it can completely dissolve CBD and the biodegradable polymer, and any organic solvent that can be easily selected by those skilled in the art may be used.

[0083] The CBD and biodegradable polymer in the organic solvent are included in a weight ratio of 1:1 to 1:10, and may be included in a weight ratio of 1:2 to 1:9.

[0084] The biodegradable polymer in the above oily solution is contained in an amount of 10 to 20 wt%, preferably 12 to 18 wt%, and more preferably 15 wt%, but is not limited to the above example. If it is contained in an amount less than the above range, it is impossible to manufacture an emulsion, and if it is contained in an amount exceeding the above range, there is a problem that the viscosity of the oily solution is too high, making it difficult to manufacture an emulsion.

[0085] The biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid and combinations thereof, preferably polylactide-co-glycolide (PLGA) and / or polylactide (PLA), but is not limited to the above examples.

[0086] The above oily solution may further include butylated hydroxytoluene (BHT). As described above, the butylated hydroxytoluene (BHT) may be included in the oily solution and may be incorporated into the microparticles, thereby preventing the oxidation of CBD. The butylated hydroxytoluene (BHT) may be included in an amount of 0.10 wt% to 1 wt%, 0.10 wt% to 0.50 wt%, 0.11 wt% to 0.40 wt%, or 0.12 wt% to 0.35 wt%, based on the total weight of the cannabidiol and the biodegradable polymer.

[0087] The surfactant contained in the above-mentioned aqueous solution may be contained in an amount of 0.1 to 1.0 wt%, 0.2 to 0.5 wt%, or 0.25 wt%. The remainder is water.

[0088] The above surfactant is at least one selected from the group consisting of methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol, sorbitan monooleate (e.g., Span™ 80), polyoxyethylene sorbitan fatty acid ester (e.g., Tween™ 80), polyoxyethylene castor oil derivatives, sodium lauryl sulfate, sodium stearate, ester amines, linear diamines, patty amines, and mixtures thereof, and may preferably be polyvinyl alcohol, but is not limited to the above examples, and any surfactant that can be prepared into a completely spherical emulsion may be used.

[0089] As described above, there is no limitation on the method of preparing an emulsion using the oily solution and the aqueous solution after preparing them respectively.

[0090] However, the present invention aims to describe a method for manufacturing microparticles using a microfluidic method.

[0091] A microchip for utilizing the above microfluidic method can be formed on a wafer or a glass substrate. A microchannel is formed in the microchip, and more specifically, the microchannel includes a channel through which an oily solution flows, a channel through which an aqueous solution flows, and a transport channel. The channel through which the oily solution flows and the channel through which the aqueous solution flows are formed to meet each other at one point, and one end of the transport channel can be connected to a portion where the two channels are joined.

[0092] The channel through which the oily solution flows and the channel through which the aqueous solution flows are respectively coupled with an injection unit for injecting the oily solution and the aqueous solution, and one end of the moving channel may be coupled with a recovery unit for recovering a solution containing an emulsion.

[0093] The above microchannel can 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 above materials are not limited to the above examples, and any material capable of forming a microchannel can be used.

[0094] 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 the above examples.

[0095] As an 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, the photoresist is removed, and the silicon is etched using DRIE (deep ion reactive etching) using the aluminum as a mask. After the aluminum is removed, glass is anodic bonded to the wafer to seal it, thereby fabricating the microchannels described above.

[0096] The above microchannels have an average diameter of 60 to 150 μm, preferably 80 to 100 μm, but are not limited thereto. When microchannels having an average diameter less than the above range are used, an emulsion having an excessively small diameter may be produced, which may affect the release and in vivo absorption of the effective drug.

[0097] In addition, when the average diameter of the microchannel exceeds the above range value, the average size of the manufactured microparticles exceeds 120㎛, and foreign body sensation and pain may increase when administered as an injection, and as the diameter of the microchannel increases, the particle size distribution of the manufactured particles increases, making it difficult to manufacture microparticles with a uniform particle size.

[0098] Additionally, the average diameter of the microchannel is closely related to the average diameter of the particles, but is also closely related to the flow rate ratio (μl / min) of the oily solution and the aqueous solution.

[0099] In addition, the cross-sectional width (w) and the cross-sectional height (d) of the microchannel are closely related to the average diameter (d') of the microparticles being manufactured. The width (w) of the cross-sectional microchannel is in the ratio range of 0.7 to 1.3 with respect to the average diameter (d') of the microparticles, and the height (d) of the cross-sectional microchannel is in the ratio range of 0.7 to 1.3 with respect to the average diameter (d') of the microparticles.

[0100] That is, once the average diameter (d') of the microparticles to be manufactured is determined, the width (w) and height (d) of the microchannel cross-section must be set to a ratio range of 0.7 to 1.3 of d' to enable manufacturing of microparticles of the desired size.

[0101] In order to manufacture microparticles using the above microchip, an oily solution may be injected into the channel through which the oily solution flows, and an aqueous solution may be injected into the channel through which the aqueous solution flows, so that an emulsion may be formed at the portion where the two channels are joined.

[0102] When the above-described oily solution and aqueous solution are each injected into the microchannel, the flow rate ratio of the oily solution and aqueous 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 controlling the flow rate ratio of the oily solution and aqueous solution as described above, microparticles having a uniform diameter can be manufactured.

[0103] The emulsion formed at the above-described joint can be obtained using the previously prepared aqueous solution, i.e., a mixed solution of a surfactant and water. The prepared aqueous solution can be injected into a microchannel to form an emulsion, and can also be used to prevent the collected emulsions from clumping together by filling a tank.

[0104] The emulsion collected in the above tank can have residual organic solvents removed. The step of removing the residual organic solvent can be performed by stirring under constant temperature conditions and stirring speed to evaporate and remove the residual organic solvent present within the emulsion. At this time, the stirring conditions are a first stirring step at 15 to 20°C for 50 to 70 minutes; a second stirring step at 20 to 40°C for 50 to 70 minutes; and a third stirring step at 40 to 60°C for 1 to 3 hours.

[0105] The above stirring speed was the same for all of the first to third stirring stages, and the stirring speed was 300 to 500 rpm, and may be 400 rpm.

[0106] As described above, the temperature condition is gradually increased as the stirring process progresses, and the stirring is characterized by the stepwise increase in temperature, and the evaporation rate of the organic solvent present inside the emulsion can be controlled.

[0107] The temperature at which the oily solution and the aqueous solution flow through the microchannel is also 5°C to 20°C, and preferably 10°C. That is, after flowing through the microchannel and forming an intersection to create an emulsion, the temperature is maintained at a constant low temperature of 5°C to 20°C until the collected emulsion is stirred for the first time. Maintaining a low temperature during the emulsion production process is essential for producing and maintaining spherical particles. In other words, if the temperature is not low, it is difficult to produce particles with a consistent spherical shape.

[0108] Thereafter, the secondary stirring process gradually increases the temperature and increases the stirring time, so that the organic solvent present inside the emulsion gradually moves to the surface, and as the organic solvent evaporates from the surface, the influence on the properties of the emulsion can be minimized. That is, if the organic solvent evaporates rapidly, the surface of the microparticles finally manufactured due to the evaporation of the organic solvent may not be smooth and pores may be formed. In order to prevent this problem, the temperature conditions are gradually increased as described above, and the stirring process time is also increased, so that the evaporation rate of the organic solvent can be controlled, and due to the control of the evaporation rate of the organic solvent, the surface properties of the manufactured microparticles can be controlled.

[0109] The above third stirring process removes the saturated organic solvent from the water phase by stirring the external water phase while raising the temperature near the boiling point of the organic solvent after the organic solvent in the emulsion is extracted into the external water phase, thereby facilitating the removal of residual organic solvent in the emulsion.

[0110] Finally, in the step of washing and drying the microparticles from which residual organic solvent has been removed, the microparticles from which all organic solvents on the surface have been removed by stirring are washed several times with sterile filtered purified water to remove surfactants remaining in the microparticles, and then freeze-dried.

[0111] The final microparticles are formed in a form in which CBD is evenly distributed in microparticles made of a spherical biodegradable polymer, and contain CBD and the biodegradable polymer in a weight ratio of 1:1 to 1:10, and may contain the CBD and the biodegradable polymer in a weight ratio of 1:2 to 1:9.

[0112] In addition, as previously explained, the microparticles finally produced have butylhydroxytoluene (BHT) evenly distributed in addition to CBD, so that when they come into contact with oxygen in the air, butylhydroxytoluene (BHT) is preferentially oxidized, thereby preventing oxidation of CBD.

[0113] The weight ratio of CBD and biodegradable polymer contained in the above microparticles is the same as the weight ratio in the oily solution when producing an emulsion. By passing through the microchannel to form an emulsion and removing all organic solvents in the emulsion, microparticles containing CBD and biodegradable polymer in the same weight ratio as in the oily solution can be produced.

[0114] The above microparticles may have an average diameter of 30 to 70 μm, 30 to 65 μm, or 30 to 60 μm. In addition, the standard deviation for the average diameter may be 1 to 30 μm, 1 to 20 μm, 1 to 10 μm, or 1 to 7 μm. It can be confirmed that it is possible to manufacture uniform particles within the above diameter range, and when using the uniform particles as a sustained-release injection, the foreign body sensation can be reduced, the convenience of administration can be increased, and the initial over-release can be prevented when injected into the body and the effect of sustained CBD release can be exhibited.

[0115] Manufacturing example

[0116] Manufacturing of microparticles

[0117] 1) Preparation of oil solution

[0118] An oily solution was prepared by dissolving cannabidiol, a biodegradable polymer, a lactide-glycolide copolymer, lactide copolymer alone or in combination, and butylated hydroxytoluene (BHT) in methylene chloride (methylene chloride). At this time, the biodegradable polymer in the oily solution is included at a ratio of 15 wt%, and the weight ratio of cannabidiol and the biodegradable polymer is 1:1 to 1:10.

[0119] 2) Preparation of water solution

[0120] Polyvinyl alcohol was dissolved in water to prepare an aqueous solution, and the polyvinyl alcohol in the aqueous solution was contained at 0.25 wt%.

[0121] 3) Microparticle manufacturing

[0122] The above oil-phase solution and water-phase solution were injected into microchannels formed on a silicon wafer to produce microparticles. The oil-phase to water-phase flow ratio was 1:20, and the temperature condition was maintained at 10.0°C. The produced microparticles were collected in a tank containing the water-phase solution and stirred at 400 rpm for 1 hour at 10.0°C, 1 hour at 30.0°C, and 2 hours at 45.0°C.

[0123] 4) Washing and harvesting

[0124] The microparticles that had been stirred were washed with sterilized, filtered, purified water, and then freeze-dried to obtain a powder form.

[0125] Microspheres were manufactured using the ingredients and contents listed in Table 1 below using the method described below.

[0126] Compounding purpose Ingredient name Comparative example 1 Comparative example 2 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Quantity (mg) API: POLYMER ratio 1:11:10 1:21:31:41:41:9 1:41:4 Active ingredient Cannabidiol 100.00 Sustained release agent Lactide-glycolide copolymer (50:50) ---- 400.00 267.00 Lactide-glycolide copolymer (75:25) 100.00 1,000.00 200.00 300.00 400.00 900.00 133.00 267.00 Lactide Copolymer--------133.00 Antioxidant Butylhydroxytoluene1.00 Organic solvent Methylene chloride666.676,666.671,333.332,000.002,666.672,666.676,000.002,666.672,666.67 Total mass (mg)201.001,101.00301.00401.00501.00501.001,001.00500.00501.00

[0127] Experimental Example 1

[0128] CBD release experiment

[0129] 1) Preparation of standard solution

[0130] Approximately 15 mg of cannabidiol standard was placed in a 100 mL volumetric flask. Approximately 50 mL of diluted solution (acetonitrile) was added and sonicated for 10 minutes. After sufficient cooling, the test solution was adjusted to the mark and filtered through a 0.45 μm filter (water-soluble PTFE) to use as the standard solution (concentration: 0.15 mg / mL).

[0131] 2) Preparation of elution test solution

[0132] A dissolution test solution was prepared by adding Tween 20 to 1 L of 10 mM PBS buffer (pH 7.4) at 0.05% (w / v), and then mixing sodium azide and sodium ascorbate at 0.02% (w / v) and 0.0625% (w / v) of the mixture.

[0133] 3) Preparation of test solution

[0134] Each sample was precisely weighed to be 15 mg as the main ingredient, placed in an injection vial, 100 mL of the dissolution test solution was accurately added, sealed, and then shaken at a constant temperature of around 50°C at a speed of 120 rpm for testing. The injection vial was placed horizontally. After the start of dissolution, the injection vial containing the sample was taken out every 2, 18, and 72 hours, left for 3 minutes to allow the sample to settle in the test solution, and then 1 mL of the test solution was accurately taken using a syringe, centrifuged at 3000 rpm for 3 minutes, and the supernatant was used as the test solution.

[0135] 4) HPLC conditions

[0136] - Detector: UV (220nm)

[0137] - Column: ODS column (4.6*150mm, 5μm)

[0138] - Flow rate: 1.0mL / min

[0139] - Mobile phase: methanol: purified water = 85:15 (Isocratic method)

[0140] - Calculation formula: Main peak area of ​​the test solution * Amount of standard product taken * Standard product purity (%) * Dilution ratio / Peak area of ​​main component in the standard solution * Equivalent amount of cannabidiol in the test solution (mg)

[0141]

[0142] The results of the CBD dissolution test conducted under the above experimental conditions are as shown in Fig. 1, Fig. 2, and Table 2:

[0143] 2 hours 18 hours 72 hours Comparative Example 16 1.2 ± 1.1 10 0.0 ± 2.2 10 1.2 ± 0.5 Comparative Example 23.0 ± 3.9 32.2 ± 0.1 47.9 ± 0.1 Example 136.9 ± 0.1 79.6 ± 7.4 9 5.2 ± 0.1 Example 23 4.8 ± 0.9 7 8.6 ± 2.4 9 3.3 ± 2.8 Example 33 1.2 ±6.574.8±0.188.6±0.5Example 429.6±0.465.2±3.878.2±0.7Example 522.9±10.656.4±2.577.4±1.8Example 628.9±0.666.7±1.285.0±0.3Example 712.1±8.257.8±1.072.3±0.2

[0144] According to the above experimental results, Comparative Example 1 released 61.2% of CBD after 2 hours, 100% after 18 hours, and 101.2% after 72 hours, showing that release was almost complete. This has the problem that the initial CBD release amount is large, and thus, it cannot exhibit a sustained CBD release effect for a long period of time.

[0145] In addition, in the case of Comparative Example 2, although it can exhibit the effect of long-term sustained release by releasing 47.9% at the 72-hour mark, only 3% of CBD is released at the 2-hour mark, so the initial CBD release amount is too small, and there is a problem that the treatment and improvement effect of CBD on nervous system diseases is insufficient.

[0146] On the other hand, in the case of Examples 1 to 7, it can be confirmed that the CBD release effect of 50% to 80% can be shown at a time point of 18 hours, and the release is not completely completed even at a time point of 72 hours, showing a long-term continuous drug release effect.

[0147] Experimental Example 2

[0148] Rat pharmacokinetic study

[0149] The experimental conditions for conducting rat pharmacokinetic experiments are as follows:

[0150] Route of administrationSubcutaneous (SC) injectionNumber and period of administrationSingle administrationAdministration site and dosage (mg / kg)Back skin tissueIVL5005: 9 mg / head(SC administration)Administration methodSC: Subcutaneously injected into back skin tissue using a disposable 1 ml syringe. A single dose was administered at the time of initiation.

[0151] The experimental animals were 6-week-old male SD rats purchased from Coretech and acclimated for one week before testing. The animals were fed a general feed for experimental animals (Orient) and were reared with free access to water and feed.

[0152] General symptoms

[0153] During the experimental period, changes in general symptoms were observed twice a day (morning and afternoon) for all animals, and body weight was measured upon introduction and separation from the group.

[0154] blood sampling

[0155] Blood was collected at 500 to 1000 μL at 14 time points in total: 0 time before SC administration of the test substance to rats that had completed acclimatization, and 4 hr, 8 hr, 24 hr, 3 d, 5 d, 1 w, 2 w, 4 w, 6 w, 8 w, and 12 w after administration of the test substance. Serum was separated by centrifugation at 1000 g for 10 minutes and stored frozen at -70°C.

[0156] The results of measuring the blood drug concentration after administration of the microparticles of Examples 3 to 7 through the above experiment are as shown in Table 4 and Figure 3 below:

[0157] Rat PKExample 3Example 4Example 5Example 6Example 7hdw00-0000010.04-17.271415.402423.87333.414660.25840.17-69.466645.747237.225644.786444.463880.33-57.632658.498240.10477.684454.142241-46.79337.420429.238243.826842.2964723-51.734518.3102516.80514.7 8916.70021205-55.66230.33622.03130.604521.18441687115.344417.49622.324467.629417.29543361426.00529.63414.640214.1337.1075042130.31381.66845.60581.99164.58346722840.03560.59522.53940.78183.7714117649700.36440.761203.4008

[0158] (Unit: μg / mL)

[0159] According to the above experimental results, it can be confirmed that Examples 3 to 7 of the present invention maintain the blood CBD concentration for at least 1 month. That is, in Example 3, it was 0.0356 μg / mL at the 4-week point, in Example 4, it was 0.5952 μg / mL, in Example 5, it was 2.5394 μg / mL, in Example 6, it was 0.7818 μg / mL, and in Example 7, it was 3.7714 μg / mL.

[0160] Additionally, in the case of Examples 4, 5 and 7, it can be confirmed that a continuous CBD release effect is observed in that the blood CBD concentration can be confirmed even after 7 weeks.

[0161] Experimental Example 3

[0162] Induction of epilepsy by PTZ (Pentylenetetrazole) and administration of test substances

[0163] In order to confirm the anticonvulsant effect of administration of the microparticles of the present invention in an epilepsy-induced model, the administration groups were set up as follows.

[0164] Group Administration Route Number of Animals Dose (mg / head) Dose (ml / head) G1. Vehicle control SC10-2 G2. CBD solution IP10602 G3. IVL5005-30 SC10302 G4. IVL5005-60 SC10602

[0165] The administration method was as shown in Table 6 below and administered to rats.

[0166] Test substance administration routeIVL5005: Subcutaneous (SC) injectionCBD solution: Intraperitoneal (IP) injectionNumber and period of administrationIVL 5005: Single administration (D1)CBD solution: 2 administrations (D1, D14)Administration site and dose (mg / kg)IVL5005: Dorsal skin tissue, 30(G3)-60(G4) mg / head (SC administration)CBD solution: Dorsal abdominal area, 60 mg / head (IP administration)Administration methodSC: Subcutaneously injected into the dorsal skin tissue using a disposable 1 ml syringe. A single dose was administered at the start of the experiment.IP: Intraperitoneally injected using a disposable 1 ml syringe. Administered at the start of the experiment (D1) and at week 2 (D14).

[0167] The above G3 and G4 were administered to rats using the above-described Example 7, but with different dosages.

[0168] After acclimatization, rats were divided into groups and the test substances G1 to G4 were administered intraperitoneally and subcutaneously on Day 1 (D1). Thirty minutes later, PTZ (Pentylenetetrazole, Sigma, USA) dissolved in 0.9% sterile saline was administered intraperitoneally at a concentration of 37.5 mg / kg to induce epileptic convulsions. The normal group was administered only the same amount of saline. Thereafter, PTZ was repeatedly administered at time points D2, D3, D5, D7, D14, D21, and D28 to induce epileptic convulsions. The intensity of convulsions was graded and evaluated for 30 minutes immediately after PTZ administration at each time point according to the following criteria:

[0169] Seizure stage characteristics (Muhammad, 2009) 0 Unresponsive 1 Ear and facial twitching 2 Convulsive waves axially through the body 3 Myoclonic jerks and rearing 4 Clonic convulsions with the animal falling on its side 5 Repeated severe tonic-clonic convulsions or lethal convulsions 6 Death due to convulsions

[0170] test

[0171] Weight changes

[0172] The test results are shown in Figure 4. During the test period, body weight continued to increase in all groups without loss. Although the weight gain in the group administered CBD intraperitoneally was slightly smaller than in the other groups, no statistically significant difference was observed in any group.

[0173] Seizure seizure analysis

[0174] The results of quantitative analysis of the intensity of PTZ-induced convulsions classified into levels 0 to 6 are shown in Figure 5. As shown in Figure 5, in the vehicle administration group, convulsions of grade 3.4 were induced on the first day, after which the degree of convulsions gradually increased, and convulsions of grade 5 were maintained for the following 2 to 4 weeks.

[0175] In the intraperitoneal CBD solution group (G2), seizure intensity was lower than that of the vehicle group at grade 2.4 on Day 1, but increased to grade 3.9 in Week 1, showing no difference from the vehicle group. However, after additional CBD administration in Week 2, the intensity decreased again to grade 2.9, but increased again to grade 4.9 in Weeks 3 and 4, indicating a loss of anticonvulsant efficacy.

[0176] In the IVL5005 administration groups (G3, G4), the intensity of convulsions did not increase in both concentration groups from Day 1 to Week 2 and remained lower than the vehicle group. In particular, in Week 2, when the intensity of convulsions began to increase significantly in the vehicle group, the intensity of convulsions was observed to be statistically significantly lower than the vehicle in both concentration groups. In Weeks 3 and 4, the intensity of convulsions in the 30 mg / head group (G3) increased to Grade 4.4, but was still lower than that of the vehicle group. In the 60 mg / head administration group (G4), the intensity of convulsions was suppressed without increasing until Week 3 and then increased to Grade 4.1 in Week 4.

[0177] Changes in distribution within seizure grade groups

[0178] The results of analyzing the % distribution of individuals corresponding to each grade by time-point at which seizure intensity was measured are shown in Figure 6. On Day 1, no severe seizures of grade 5 or higher were induced in the entire group, and as the first week passed, severe seizures of grade 5 or higher were observed in 1 to 3 animals in each group, but no animals of grade 5 or higher were observed in the groups administered IVL5005 (G3, G4). During the period from weeks 2 to 4, 80 to 90% of the animals in the vehicle group showed severe seizures of grade 5 or higher. In the CBD intraperitoneal administration group (G2), severe seizures were observed in only 10% of the animals at the time of additional administration in week 2, but the number of animals of grade 5 or higher gradually increased in weeks 3 and 4, and more than half of the animals showed grade 5 seizures in week 4. In the IVL5005 administration group (G3, G4), grade 5 or higher seizures were observed in less than 30% even after 2 to 3 weeks, and in particular, in the 60 mg / head administration group (G4), grade 5 or higher seizures were not observed until the 3rd week, and grade 5 seizures were observed in 50% even after the 4th week, showing the lowest frequency among all groups.

[0179] Mortality analysis by Seizure

[0180] The results of mortality analysis due to seizure are shown in Figure 7. In severely seized animals, a large amount of nasal and oral secretions were produced, and respiratory distress occurred, resulting in death. Analysis of mortality rates in each group showed that death occurred earliest in the vehicle control group (G1) at week 1, followed by two additional deaths in week 2. In the CBD intraperitoneal administration group (G2), no deaths occurred until week 3, and three died in week 4. In the IVL5005 administration groups (G3, G4), no deaths occurred until the end of the test.

[0181] Experimental Example 4

[0182] Stability assessment

[0183] Microparticles were manufactured in the same manner as in Example 1, except that BHT was not included.

[0184] Approximately 100 mg of the above microparticles were weighed into a 5 mL glass vial and placed in a capped or uncapped (close / open) stability chamber. For stability evaluation, long-term conditions (temperature: 25±2℃, relative humidity 60±5%) were used, and daily appearance changes were observed to confirm yellowing. Meanwhile, the initial samples and samples collected on the 6th day were subjected to a sealing rate test to confirm any changes in content.

[0185] The experimental results are as shown in Fig. 8.

[0186] It was confirmed that there was no change in color immediately after manufacturing the microparticles, and after 6 days, when checking whether there was yellowing, it was confirmed that the color changed to yellow when BHT was not included, regardless of whether the glass vial was capped.

[0187] On the other hand, when BHT was included at 1 wt% as in Example 1, it was confirmed that the color did not change, indicating excellent stability.

[0188] 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.

[0189] The present invention relates to a sustained-release injectable composition for treating or preventing a nervous system disease and a method for preparing the same.

Claims

1. Contains microparticles that continuously release cannabidiol (CBD) for more than one month. The above microparticles contain cannabidiol and biodegradable polymers. A sustained-release injectable composition for the treatment or prevention of neurological diseases.

2. In paragraph 1, The above microparticles contain cannabidiol and biodegradable polymers in a weight ratio of 1:1 to 1:

10. A sustained-release injectable composition for the treatment or prevention of neurological diseases.

3. In paragraph 1, The above biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof. A sustained-release injectable composition for the treatment or prevention of neurological diseases.

4. In paragraph 3, The above polylactide-co-glycolide has a monomer ratio of lactide:glycolide of 40:60 to 90:

10. A sustained-release injectable composition for the treatment or prevention of neurological diseases.

5. In paragraph 1, The above neurological disease is epilepsy. A sustained-release injectable composition for the treatment or prevention of neurological diseases.

6. In paragraph 1, The above microparticles are released at 35% to 80% of the total CBD weight after 18 hours according to the release test below. Long-acting injectable composition for the treatment or prevention of diseases of the nervous system: [Emission test conditions] The dissolution test solution was prepared by mixing Tween 20 to 0.05% (w / v) in 1 L of 10 mM PBS buffer (pH 7.4) to prepare a mixed solution, and then mixing sodium azide to 0.02% (w / v) and sodium ascorbate to 0.0625% (w / v) in the mixed solution. 100 mL of the above dissolution test solution was placed in an injection vial, and the microparticles were added thereto so that the total weight of the microparticles was 15 mg of CBD. After the injection vial was completely sealed, the temperature was maintained at 50°C and the test was conducted by shaking at a speed of 120 rpm. After 18 hours from the start of dissolution, the injection vial was taken out and left for 3 minutes. Then, 1 mL of the test solution was accurately taken using a syringe, centrifuged at 3000 rpm for 3 minutes, and the supernatant was used as the test solution to confirm the release of CBD.

7. A step of preparing an oily solution by dissolving cannabidiol (CBD) and a biodegradable polymer in an organic solvent; A step of preparing an aqueous solution by dissolving a surfactant in water; and A step of forming an emulsion by mixing the oily solution and the aqueous solution. A method for preparing a sustained-release injectable composition for the treatment or prevention of neurological diseases.

8. In paragraph 7, The emulsion manufactured above is obtained in an aqueous solution and the residual solvent is removed; A step of manufacturing microparticles by washing and freeze-drying the emulsion from which the residual solvent has been removed; and It further comprises a step of mixing the freeze-dried microparticles with water for injection. A method for preparing a sustained-release injectable composition for the treatment or prevention of neurological diseases.

9. In paragraph 7, The above oily solution and water solution are injected into each microchannel and allowed to flow, and an emulsion containing cannabidiol and a release agent is formed at the point where the flow of the oily solution and the flow of the water solution intersect each other. A method for preparing a sustained-release injectable composition for the treatment or prevention of neurological diseases.

10. In paragraph 7, The above oil solution additionally contains butylated hydroxytoluene (BHT). A method for preparing a sustained-release injectable composition for the treatment or prevention of neurological diseases.

Images