Application of sinapic acid and its derivatives in the preparation of drugs for the prevention and / or treatment of methamphetamine addiction withdrawal

Abstract

This invention belongs to the field of biomedicine and discloses for the first time the application of sinapic acid and its derivatives, methyl myrosate and ethyl myrosate, in the prevention and / or treatment of methamphetamine addiction withdrawal. By investigating the conditional position preference behavior of methamphetamine-addicted mice and mice treated with sinapic acid, methyl myrosate, and ethyl myrosate, the inventors demonstrated that sinapic acid and its derivatives, methyl myrosate and ethyl myrosate, can reduce dependence on and cravings for methamphetamine. Therefore, sinapic acid and its derivatives, methyl myrosate and ethyl myrosate, can serve as active ingredients in the preparation of addiction treatment drugs, providing a new option for the prevention and / or treatment of methamphetamine addiction and showing promising clinical application prospects.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to the use of sinapic acid and its derivatives, methyl sinapicate and ethyl sinapicate, in the preparation of drugs for the prevention and / or treatment of methamphetamine addiction withdrawal. Background Technology

[0002] The global drug problem continues to be rampant, with a growing number of drug users, seriously endangering physical and mental health and social stability. Methamphetamine (MA), commonly known as "ice," belongs to the amphetamine class of psychoactive substances and is highly addictive. It is usually found in its hydrochloride form, a bitter-tasting white crystalline powder, readily soluble in water and alcohol, and is typically inhaled or injected. Its CAS number is 537-46-2, and its molecular formula is C2. 10 H 15 N, with a molecular weight of 149.236, has the following structure:

[0003]

[0004] Methamphetamine can be ingested through various means. It can inhibit dopamine metabolism and uptake, promote dopamine synthesis, increase dopamine levels in reward-related brain regions, and alter the excitatory and reward effects, leading to psychological dependence. Under methamphetamine stimulation, a large amount of dopamine in the synaptic cleft is oxidized into quinones or semiquinones, resulting in a significant production of reactive oxygen species (ROS), inhibiting the production of mitochondrial adenosine triphosphate (ATP), causing mitochondrial dysfunction, damaging the shape or function of nerve cells, and even causing nerve cell death, resulting in severe neurotoxicity (Riddle EL, Fleckenstein AE, Hanson GR. Mechanisms of methamphetamine-induced dopaminergic neurotoxicity. AAPSJ, 2006, 8(2): E413-E418.). Methamphetamine poisoning can cause delusions, hallucinations, hyperactivity, cardiovascular disease, cognitive deficits, dilated pupils, loss of appetite, violence, and suicide. After discontinuation, withdrawal symptoms such as lethargy, drowsiness, irritability, anxiety, and suicidal tendencies may occur.

[0005] Currently, methadone and other low-toxicity substances are used domestically and internationally to replace the pharmacological effects of opioids, controlling cravings and reducing withdrawal symptoms. However, methadone itself is addictive, and withdrawal symptoms will still occur upon discontinuation. L-Tetrahydropalmatine (l-THP), belonging to the tetrahydroproberberine class of compounds, is a novel dopamine receptor blocker in the brain. Recent studies have shown its promising potential in treating addiction, but its clinical application is limited due to its significant sedative effects. Patents CN106176740A and CN107936008A report addiction treatment drugs based on optimized tetrahydroproberberine structures; however, the search for and development of safer and more effective new addiction treatment drugs is urgent and necessary.

[0006] Sinapic acid (SA) is a natural phenolic acid found in edible, functional, and medicinal plants, as well as berries, vegetables, grains, and oilseed crops. Its CAS number is 7362-37-0, and its molecular formula is C2. 11 H 12 O5, with a molecular weight of 224.21. Sinapic acid has antioxidant, anticancer, anti-inflammatory, anti-anxiety, antidiabetic, and cardioprotective, hepatic, renal, and antibacterial effects. Sinapic acid exerts its anti-anxiety effect by activating GABA receptors (Yoon BH, Jung JW, Lee JJ, et al. Anxiolytic-like effects of sinapic acid in mice. Life Sci, 2007, 81(3):234-240.), and its free radical scavenging function can provide neuroprotection. In addition, sinapic acid can improve behavioral deficits and dopaminergic neuron loss in Parkinson's disease, which is related to inhibiting abnormal mitochondrial division and improving mitochondrial function. Patent CN110840835A reports that sinapic acid has neuroprotective effects. Therefore, we speculate that sinapic acid may have a therapeutic effect on methamphetamine addiction, but there are currently no relevant reports.

[0007] Methyl sinapate (MSA) is a derivative formed by the esterification reaction of sinapic acid and methanol. Its CAS number is 20733-94-2, and its molecular formula is C2. 12 H 14O5, with a molecular weight of 238.24. Methyl myrosinate can be hydrolyzed to sinapic acid by ferulic acid esterase (Laguna, O., Odinot, E., Bisotto, A., et al. Release of Phenolic Acids from Sunflower and Rapeseed Meals Using Different Carboxylic Esters Hydrolases from Aspergillus niger. Ind. Crops Prod., 2019, 139:111579.), and can be used as a prodrug of sinapic acid. Therefore, we speculate that methyl myrosinate may have a therapeutic effect on methamphetamine addiction, but there are currently no relevant reports.

[0008] Ethyl sinapate (SE) is a derivative formed by the esterification of sinapic acid and ethanol. Its molecular formula is C1. 13 H 16 O5, with a molecular weight of 252.26. Ethyl sinigrin can effectively scavenge free radicals and inhibit lipid peroxidation, exhibiting antioxidant activity. N,Polak T,Makuc D,Poklar Ulrih N,etal. A Kinetic Approach in the Evaluation of Radical-Scavenging Efficiency of Sinapic Acid and Its Derivatives. Molecules, 2017, 22(3):375.). Therefore, we speculate that ethyl sinapic acid may have a therapeutic effect on methamphetamine addiction, but there are currently no relevant reports. Summary of the Invention

[0009] Purpose of the invention

[0010] This invention addresses the lack of safe and effective treatments for drug addiction by proposing for the first time the potential role of sinapic acid compounds in the prevention and / or treatment of methamphetamine addiction.

[0011] Technical solution

[0012] This invention provides the use of sinapic acid compounds in the preparation of drugs for the prevention and / or treatment of methamphetamine addiction withdrawal, characterized in that the structure of the sinapic acid compounds is as follows:

[0013]

[0014] R = CH3, CH2CH3, CH2CH2CH3 or CH2(CH2)2CH3.

[0015] The application is characterized in that the sinapic acid compound is a formulation formed by combining sinapic acid, methyl sinapicate or ethyl sinapicate with pharmaceutically acceptable excipients.

[0016] This invention protects the use of sinapic acid and its derivatives, methyl sinapicate and ethyl sinapicate, in the preparation of drugs for the prevention and / or treatment of methamphetamine addiction withdrawal.

[0017] Specifically, the molecular structure of the sinapic acid is as follows:

[0018]

[0019] Specifically, the molecular structure of the methyl sinapicate is as follows.

[0020]

[0021] Specifically, the molecular structure of the ethyl sinapicate is as follows:

[0022]

[0023] As a preferred option, the effective dose of sinapic acid, methyl sinapicate, and ethyl sinapicate is 50 mg / kg.

[0024] Preferably, the methamphetamine addiction withdrawal drug is formulated as a pharmaceutically acceptable dosage form with sinapic acid, methyl sinapicate or ethyl sinapicate as the sole active ingredient or main effective ingredient, and pharmaceutically acceptable excipients.

[0025] The pharmaceutically acceptable excipients include one or more of the following: fillers, diluents, binders, excipients, penetration enhancers, absorption enhancers, surfactants, pH adjusters, antioxidants, stabilizers, chelating agents, pore-forming agents, film-forming agents, solvents, cosolvents, flavorings, sweeteners, and colorings.

[0026] The gastrointestinal dosage forms mentioned above can be tablets, capsules, soft capsules, liquid capsules, granules, pellets, syrups, dry suspensions, oral solutions, oral suspensions, orally disintegrating tablets, oral fast-dissolving films, sustained-release tablets, controlled-release tablets, sustained-release capsules, controlled-release capsules, enteric-coated tablets, and enteric-coated capsules. The non-gastrointestinal dosage forms mentioned above can be aqueous injections, lyophilized powder injections, sterile powder injections, infusions, eye drops, nasal drops, nasal sprays, pulmonary inhalers, transdermal patches, liniments, ointments, creams, suppositories, subcutaneous implants, long-acting injections, and microneedle formulations. This invention does not limit the above dosage forms; any medically recognized dosage form is within the scope of protection of this invention.

[0027] In this invention, addiction refers to a chronic relapsing brain disease characterized by compulsive drug seeking and persistent drug use, knowing that it will have adverse consequences.

[0028] Beneficial effects

[0029] This invention, through observation of conditional position preference behavior in mice, discovered that sinapic acid compounds, i.e. compounds with a sinapic acid core, have a therapeutic effect on methamphetamine addiction withdrawal symptoms. Specifically:

[0030] Sinapic acid, methyl sinapicate, and ethyl sinapicate can improve conditioned position preference behavior in methamphetamine-treated mice and inhibit methamphetamine-induced excitatory and manic behaviors. Experiments demonstrate that sinapic acid, methyl sinapicate, and ethyl sinapicate are potential strategies for the prevention and / or treatment of methamphetamine addiction.

[0031] (1) This invention first proposed the role of sinapic acid in the prevention and / or treatment of methamphetamine addiction, discovered a new use for sinapic acid, expanded the application scope of sinapic acid, and has good clinical application prospects.

[0032] (2) This invention first proposed the role of methyl sinamate and ethyl sinamate, derivatives of sinapic acid, in the prevention and / or treatment of methamphetamine addiction, and discovered the potential therapeutic effects of sinapic acid esters, providing a new strategy for the treatment of methamphetamine addiction.

[0033] (3) This invention is the first to observe mouse behavior using a conditional place preference (CPP) model, and found that sinapic acid and its derivatives, methyl sinapicate and ethyl sinapicate, can alleviate methamphetamine-induced excitement, agitation, and drug-seeking behavior in mice to varying degrees. This indicates that sinapic acid and its derivatives, sinapic acid esters, have a significant effect in improving methamphetamine addiction. Attached Figure Description

[0034] Figure 1 This is a schematic diagram of the experimental procedure for this invention: Wherein: A is the experimental procedure for establishing a mouse methamphetamine conditioned position preference (CPP) model and administering the drug via gavage during withdrawal; Saline represents physiological saline, MA represents methamphetamine, SA represents sinapic acid, MSA represents methyl sinapicate, and SE represents ethyl sinapicate. Withdrawperiod indicates the withdrawal period after establishing the methamphetamine conditioned position preference model in mice; Test1 represents the baseline test; Test2 represents the CPP test after establishing the methamphetamine addiction model; and Test3 represents the CPP test after treatment with sinapic acid, methyl sinapicate, and ethyl sinapicate, respectively.

[0035] B is a schematic diagram showing that, under CPP test conditions, the mouse is first placed in the middle area and allowed to move freely between the black box, white box, and the middle area for 15 minutes.

[0036] C is a schematic diagram showing that, under the conditions of establishing a methamphetamine conditioned position preference model in mice, control group mice were injected intraperitoneally with saline, and model group mice were injected intraperitoneally with methamphetamine. All mice were then placed in a black box for 30 minutes for training.

[0037] D is a schematic diagram showing that, under the condition of establishing a methamphetamine conditioned position preference model in mice, all mice were placed in a white box for 30 minutes of training after intraperitoneal injection of physiological saline.

[0038] Figure 2 The CPP scores for sinapic acid, methyl sinapicate, and ethyl sinapicate treatments for methamphetamine addiction are shown below. Control represents the control group, Model represents the methamphetamine model group, SA represents the sinapic acid treatment group (50 mg / kg), MSA represents the methyl sinapicate treatment group (50 mg / kg), and SE represents the ethyl sinapicate treatment group (50 mg / kg). Two-way ANOVA was used for statistical analysis. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, and ns indicate no statistically significant difference.

[0039] Figure 3 The data represents the behavioral trajectories of the control group mice during the CPP test on days 1, 10, and 23. Their movement patterns in the black box and white box were similar, and the overall results indicate that the mice did not show a significant preference for the black box or the white box.

[0040] Figure 4 These are the behavioral trajectories of mice in the methamphetamine-induced model group during CPP tests on days 1, 10, and 23. On day 1, the mice exhibited similar movement patterns in the black and white boxes. After 8 days of methamphetamine modeling, on day 10, the mice tended to be active in the black box, and their movement patterns in the black box were more chaotic and denser than in the white box, indicating that the mice developed strong drug-seeking behavior and exhibited excited and manic behavior in the black box. After a 12-day withdrawal period, on day 23, the mice still tended to be active in the black box, and their manic behavior in the black box did not diminish. This indicates that the mice had developed methamphetamine addiction.

[0041] Figure 5These are the behavioral trajectories of mice in the sinapic acid treatment group during the CPP test on days 1, 10, and 23. On day 1, the mice exhibited similar movement patterns in the black and white boxes. After 8 days of methamphetamine modeling, on day 10, the mice tended to be active in the black box, and their movement patterns in the black box were more chaotic and denser than in the white box, indicating strong drug-seeking behavior and agitated, manic behavior in the black box. After 12 days of gavage administration of sinapic acid, on day 23, the mice showed similar movement patterns in the black and white boxes, with no significant preference for the black box. This suggests that sinapic acid can improve methamphetamine-induced addiction in mice.

[0042] Figure 6 These are the behavioral trajectories of mice in the methyl sinapicate treatment group during the CPP test on days 1, 10, and 23. On day 1, the mice exhibited similar movement patterns in the black and white boxes. After 8 days of methamphetamine modeling, on day 10, the mice tended to be active in the black box, and their movement patterns in the black box were more chaotic and denser than in the white box, indicating strong drug-seeking behavior and agitated, manic behavior in the black box. After 12 days of gavage administration of methyl sinapicate, on day 23, the mice showed similar movement patterns in the black and white boxes, with no significant preference for the black box. This suggests that methyl sinapicate can improve methamphetamine-induced addiction in mice.

[0043] Figure 7 These are behavioral trajectories from the CPP test on days 1, 10, and 23 in the ethyl myrosinate treatment group of mice. On day 1, the mice exhibited similar movement patterns in the black and white boxes. After 8 days of methamphetamine modeling, on day 10, the mice tended to be active in the black box, and their movement patterns in the black box were more chaotic and denser than in the white box, indicating strong drug-seeking behavior and agitated, manic behavior in the black box. After 12 days of gavage administration of ethyl myrosinate, on day 23, the mice showed similar movement patterns in the black and white boxes, with no significant preference for the black box. This suggests that ethyl myrosinate can improve methamphetamine-induced addiction in mice. Detailed Implementation

[0044] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, further descriptions are provided below in conjunction with the implementation methods. All similar substitutions and modifications can be considered as included within the scope of the present invention without departing from its conceptual framework. The methods and applications of the present invention have been described through preferred embodiments. Those skilled in the art can modify or appropriately alter and combine the methods and applications described herein without departing from the content, spirit, and scope of the present invention to implement and apply the technology of the present invention.

[0045] Example 1: Synthesis of methyl sinapicate and ethyl sinapicate, derivatives of sinapic acid

[0046] The methyl sinanate and ethyl sinanate used in this invention are prepared as follows:

[0047]

[0048] Sinapic acid (Formula I) is reacted with alkyl alcohols under concentrated sulfuric acid and heating conditions to synthesize sinapic acid esters (Formula II).

[0049] In this case, R = CH3, methyl sinapic acid is prepared; R = CH2CH3, ethyl sinapic acid is prepared.

[0050] Alkyl sinapic acid esters were prepared according to previous literature (Gaspar A, Martins M, Silva P, et al. Dietary phenolic acids and derivatives. Evaluation of the antioxidant activity of sinapic acid and its alkyl esters. JAGric Food Chem, 2010, 58(21): 11273-80.).

[0051] Example 2: Treatment of methamphetamine-addicted mice with sinapic acid and its derivatives methyl sinapicate and ethyl sinapicate.

[0052] 1. Materials and medicines

[0053] 1.1 Experimental Animals: C57BL / 6J mice were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd., SPF grade, female, weighing 15-18g, with a Jiangsu Province laboratory animal facility use certificate provided by the Laboratory Animal Center of China Pharmaceutical University. Temperature was (23±1)℃, humidity was (50±10)%, and all animal-related experimental procedures complied with the requirements of the Medical Ethics Committee of China Pharmaceutical University.

[0054] 1.2 Medicines

[0055] (1) Methamphetamine, provided by the Narcotics Control Intelligence Technology Center of the Ministry of Public Security of China in Beijing, was dissolved in physiological saline and administered via intraperitoneal injection.

[0056] (2) Sinic acid, purchased from Nanjing Jingzhu Biotechnology Co., Ltd., was dissolved in 0.5% CMC-Na and administered by gavage.

[0057] (3) Methyl myrosinate, dissolved in 0.5% CMC-Na, was administered by gavage.

[0058] (4) Ethyl myrosinate, dissolved in 0.5% CMC-Na, was administered by gavage.

[0059] 1.3 Experimental Apparatus

[0060] The conditional positional preference (COP) test chamber was purchased from Jiangsu Saions Biotechnology Co., Ltd. The COP test chamber mainly consists of three areas: a black box, a white box, and a central section. The black box has a rough floor with a fence-like perforation, and all-black walls and doors. The central section has a rough floor with diamond-shaped perforations, and white walls and doors. The white box has a rough floor with circular perforations, and black and white striped walls and doors. Small doors separate the different areas, and partitions can be used to isolate or connect them. When the partitions separate the areas, the mice can only move within a specific area. When the partitions are removed, connecting the areas, the mice can move freely between the three areas, without being restricted to the black box, white box, or central section.

[0061] A video analysis system for spontaneous animal activity was developed to record the movement behavior of mice. The system consists of an open field (length × width × height: 45cm × 45cm × 45cm) and Any-maze software.

[0062] 2. Experimental Methods

[0063] The effects of sinapic acid and its derivatives, methyl sinapicate and ethyl sinapicate, on the behavior of methamphetamine-addicted mice were investigated using the conditional position preference (CPP) behavioral approach.

[0064] 2.1 Experimental Principle

[0065] Conditioned position preference is an experimental conditioning procedure based on Pavlovian learning, typically used to assess positive affective states (rewards) induced by different stimuli. This model uses a two- or three-compartment apparatus, each compartment having different characteristics. The characteristics of each compartment are described in section 1.3, Experimental Apparatus.

[0066] Conditioned Place Preferred (CPP) Test: When all areas of the Conditioned Place Preferred Box were connected, the mice were not treated with any drugs on the day of the test. The mice were first placed in the middle area and allowed to move freely between the black box, the white box, and the middle area for 15 minutes. Any-maze software was used to record the time spent in the black box, the white box, and the middle area, and the behavioral trajectory of the mice.

[0067] The model consists of three phases: a pre-test phase, a conditioning training phase, and a withdrawal phase. The pre-test phase involves performing a conditional position preference (CPP) test on all mice before any treatment, aiming to measure their baseline preference. In this experiment, the conditioning training phase involved pairing saline with a white box and methamphetamine with a black box, thus defining the white box as the non-drug side and the black box as the drug side. Specifically, when the areas of the conditioned position preference box were isolated, control group mice were first injected intraperitoneally with saline, while model group mice were injected intraperitoneally with methamphetamine. All mice were then confined to the black box (drug side) for 30 minutes. The following day, all mice were injected intraperitoneally with saline, and confined to the white box (non-drug side) for another 30 minutes. After 8 days of alternating training, a CPP test was performed to determine whether mice, upon re-exposure to the black box (drug side), could evoke pleasurable memories and exhibit drug-seeking behavior, increasing their activity time in the black box. This indicated that the mice had developed a dependence and craving for methamphetamine, thus forming methamphetamine addiction. The withdrawal period involved administering sinapic acid, methyl myrosate, or ethyl myrosate to mice by gavage for 12 days after stopping methamphetamine administration, followed by a CPP test. The purpose was to determine whether the mice's activity time in the black box decreased when they were re-exposed to methamphetamine-related environmental cues after treatment. This would demonstrate that sinapic acid, methyl myrosate, and ethyl myrosate could reduce methamphetamine dependence and craving in mice and improve methamphetamine addiction.

[0068] 2.2 Experimental Procedure

[0069] Fifty female C57BL / 6J mice (6 weeks old, weighing 15-18g) were housed in an SPF-grade animal facility and acclimatized for one week. They were then randomly divided into a control group (n=10) and a methamphetamine model group (n=40).

[0070] See the experimental procedure. Figure 1 On the following day, baseline determination (Test 1) was conducted: all mice underwent CPP testing, and after each mouse's test, each area was wiped with 75% ethanol to remove odor. After baseline determination, based on the time the mice spent in the black box and white box respectively, the mice's natural preference box was designated as the white box, and the mice's non-natural preference box was designated as the black box.

[0071] A methamphetamine CPP model was then established: the conditional position preference box was closed and unconnected to each other. On day 2, control group mice were injected intraperitoneally with saline, while model group mice were injected intraperitoneally with methamphetamine (2 mg / kg / d) and then placed in a black box for 30 minutes of training. On day 3, both control and model group mice were injected intraperitoneally with saline and placed in a white box for 30 minutes of training. The methamphetamine addiction model was established in mice for a total of 8 days. After the model was established, all mice underwent a CPP test (Test 2).

[0072] Based on CPP scores, mice induced by methamphetamine were randomly divided into four groups: a methamphetamine model group (Model), a sinapic acid treatment group (SA), a methyl myrosate treatment group (MSA), and an ethyl myrosate treatment group (SE). Ten mice were in each group. After cessation of methamphetamine administration, mice entered a withdrawal period. During this period, mice in the sinapic acid, methyl myrosate, and ethyl myrosate treatment groups were administered the drugs via gavage at a dose of 50 mg / kg / day. The control group and the methamphetamine model group received the same volume of 0.5% CMC-Na. After a 12-day withdrawal period, all mice underwent a second CPP test (Test 3).

[0073] 2.3 Experimental Statistical Analysis

[0074] (1) Conditional position preference score (CPP Score): The difference between the time the mouse spends on the drug-treated side and the time the mouse spends on the non-drug-treated side is the conditional position preference score.

[0075] (2) Statistical analysis was performed using the following method: data were uniformly represented as "mean ± standard error", and two-way ANOVA was conducted using Graph Prism 9.0 software to compare differences between groups. Figure 2 ).

[0076] 2.4 Experimental Results

[0077] like Figure 2 As shown, the CPP scores of the control group mice showed no significant differences at baseline, day 10, and day 23. In the methamphetamine-induced model group, the CPP scores on day 10 were significantly higher than baseline, indicating that intraperitoneal injection of methamphetamine induced a preference for and drug-seeking behavior in the mice. In the model group mice, no drugs were administered, and the CPP scores on day 23 showed no significant change compared to day 10. However, after oral administration of sinapic acid, methyl sinapicate, and ethyl sinapicate to the methamphetamine-induced model mice for 12 days, the CPP scores on day 23 were significantly lower than on day 10, indicating that these treatments improved the mice's preference for and drug-seeking behavior towards methamphetamine, thus reducing methamphetamine addiction.

[0078] The use of sinapic acid and its derivatives, methyl sinapicate and ethyl sinapicate, in the prevention and / or treatment of methamphetamine addiction is a first discovery by the inventors, and whether used alone as an active ingredient or in combination with other ingredients, it is within the scope of protection of this invention.

[0079] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention and do not exhaustively describe all details, nor do they limit the invention to the specific embodiments described. Many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. The use of sinapic acid compounds in the preparation of drugs for the prevention and / or treatment of methamphetamine addiction withdrawal, characterized in that, The structures of the sinapic acid compounds are as follows: R = H, CH3, CH2CH3.

2. The application according to claim 1, characterized in that, A drug is a preparation made of sinapic acid, methyl sinapicate or ethyl sinapicate and pharmaceutically acceptable excipients.

3. The application according to claim 2, characterized in that, The pharmaceutically acceptable excipients include one or more of the following: fillers, diluents, binders, penetration enhancers, absorption enhancers, surfactants, pH adjusters, antioxidants, stabilizers, chelating agents, pore-forming agents, film-forming agents, solvents, cosolvents, flavorings, sweeteners, and colorings.

4. The application according to claim 2, characterized in that, The formulation is a gastrointestinal dosage form and a non-gastrointestinal dosage form; The dosage forms administered via the gastrointestinal tract include one or more of the following: soft capsules, liquid capsules, granules, pellets, syrups, dry suspensions, oral solutions, oral suspensions, orally disintegrating tablets, oral fast-dissolving films, sustained-release tablets, controlled-release tablets, enteric-coated tablets, and enteric-coated capsules. Non-gastrointestinal dosage forms include one or more of the following: aqueous injections, infusions, eye drops, nasal drops, nasal sprays, pulmonary inhalers, liniments, ointments, creams, suppositories, subcutaneous implants, and microneedles.

Images