Application of Neolinin in quickly-acting anti-depression
By using the C19 diterpenoid alkaloid Neoline to prepare antidepressants, the problems of slow onset of action and large side effects of existing antidepressants have been solved, achieving a rapid onset of action and expanding the scope of drug application and improving drug adherence.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- CHINA JAPAN FRIENDSHIP HOSPITAL
- Filing Date
- 2026-03-31
- Publication Date
- 2026-05-19
AI Technical Summary
Existing antidepressants are slow to take effect and have significant side effects, and some are addictive, making it difficult to meet the need for rapid relief of depressive symptoms.
Using the C19 diterpenoid alkaloid Neoline as the active ingredient, an antidepressant drug was prepared via oral administration or other routes of administration. It significantly improved behavioral indicators in animal models of depression and had a rapid onset of antidepressant effect.
Neoline exhibited significant and rapid antidepressant activity in corticosterone-induced mouse depression models and chronic restraint stress mouse depression models. Its efficacy was comparable to that of the positive control drug esketamine, but the effective dose was much lower, resulting in better drug compliance and usability.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, and in particular to the application of neoryl in rapid-acting antidepressants. Background Technology
[0002] In today's increasingly competitive society, the high-intensity, high-pressure lifestyle is seriously impacting people's physical and mental health, leading to a rise in depression and severely affecting people's normal work and life. Currently, most medications for treating depression have significant side effects, such as slow onset of action (e.g., fluoxetine) and addictive potential (e.g., esketamine). S (e.g., )-Ketamine). Summary of the Invention
[0003] This invention covers the following technical solution: the application of niorin in the preparation of antidepressant drugs.
[0004] The C19 diterpenoid alkaloid Neoline provided by this invention exhibited significant, rapid-onset antidepressant activity in both corticosterone-induced mouse depression and chronic restraint stress mouse depression models. Its efficacy was comparable to that of the positive control drug esketamine. S The effective dose is comparable to that of ketoconazole (Ketamine), but the effective dose is much lower than that of the positive control drug (Ketamine). S )-Ketamine, and can be administered orally, resulting in better drug adherence and usability, can be used to develop fast-acting antidepressants. Detailed Implementation
[0005] Reference will now be made to detailed embodiments of the present invention, one or more of which are described below. Each example is provided for explanation and not for limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the invention without departing from its scope or spirit. For example, features described or illustrated as part of one embodiment may be used in another embodiment to produce further embodiments.
[0006] Unless otherwise stated, all terms used to disclose this invention (including technical and scientific terms) should be understood to have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of protection of this invention. Unless the context clearly defines otherwise, the scientific and technical terms used herein, as well as terms and laboratory procedures in related fields such as neurobiology, animal behavior, physiology, psychology, medicinal chemistry, and pharmacology, are all conventional terms and standard methods well-known and widely used in the art. To facilitate understanding of the technical solutions of this invention, some related terms are further defined and explained below.
[0007] The terms “containing,” “comprising,” and “including” as used in this invention are synonyms and are inclusive or open-ended, not excluding additional, uncited members, elements, or method steps.
[0008] In this invention, the numerical range represented by endpoints includes all numerical values and fractions contained within that range, as well as the endpoints mentioned.
[0009] Furthermore, in describing representative embodiments of the invention, this specification may present the methods and / or processes of the invention as a specific sequence of steps. However, the method or process should not be limited to the specific order of the steps described herein, to the extent that the method or process does not depend on the specific order of the steps presented herein. As will be understood by those skilled in the art, other sequences of steps are also possible. Therefore, the specific order of steps presented in the specification should not be construed as a limitation of the claims. Additionally, the claims relating to the methods and / or processes of the invention should not be limited to the execution of their steps in the order they are written, and those skilled in the art will readily recognize that the sequence can be changed while still remaining within the spirit and scope of the invention.
[0010] This invention relates to concentration values, which include fluctuations within a certain range. For example, fluctuations are allowed within a corresponding precision range. For instance, 2% can fluctuate within ±0.1%. For larger values or values that do not require overly precise control, even greater fluctuations are permitted.
[0011] As used in this invention, unless otherwise stated, the singular forms of the articles “a,” “an,” and “the” include plural referents.
[0012] In this invention, the terms "multiple" or "various" are used unless otherwise specified, referring to a quantity of 2 or more.
[0013] In this invention, the technical features described in an open-ended manner include both closed-ended technical solutions composed of the listed features and open-ended technical solutions that include the listed features.
[0014] In this invention, terms such as "preferred," "better," "more suitable," and "ideal" merely describe implementation methods or embodiments with better effects and should be understood not to limit the scope of protection of this invention. In this invention, terms such as "optionally," "optionally," and "optional" mean that something is optional, that is, selected from either "with" or "without" a parallel solution. If multiple "optional" statements appear in a technical solution, unless otherwise specified and without contradiction or mutual constraint, each "optional" statement is independent.
[0015] In this invention, "Neoline" refers to Aconitum carmichaelii, a plant derived from the Ranunculaceae family and the Aconitum genus. Aconite of Carichalcus A C19 diterpenoid alkaloid compound from Aconitum carmichaelii (Debx.), a processed root product, and its stereoisomers, tautomers, hydrates, solvates, and pharmaceutically acceptable salts thereof, formed without altering its basic pharmacological activity. The compound has the CAS number 466-26-2 and the molecular formula C19. 24 H 39 NO6, molecular weight 437.57; white powder, soluble in methanol, ethanol, DMSO, and acetone, slightly soluble in water. The pharmaceutically acceptable salts include addition salts formed from inorganic or organic acids, such as hydrochlorides, sulfates, phosphates, methanesulfonates, tartrates, citrates, oxalates, etc., as well as salts formed from inorganic or organic bases. These salts exhibit good biological compatibility and are suitable for pharmaceutical preparations and clinical applications.
[0016] In this specification, the terms "treatment," "treatment of depression," or "antidepressant effect" refer to the process and effect of partially or completely relieving, improving, controlling, or eliminating depression-related symptoms in a subject by administering niorin or a pharmaceutical composition containing niorin, including but not limited to the improvement of symptoms such as low mood, loss of interest, anhedonia, psychomotor retardation, anxiety, tension, and sleep disorders, as well as the effects of preventing depressive states, reducing the risk of relapse, and maintaining stable condition.
[0017] In this specification, the term "effective dose" or "therapeutic effective dose" refers to the dosage of niorin or its pharmaceutical compositions that can induce the desired antidepressant biological effect or therapeutic effect without producing unacceptable toxic side effects. The effective dose may be adjusted based on factors such as the subject's age, weight, severity of illness, route of administration, frequency of administration, and individual differences, and shall be reasonably determined by those skilled in the art based on conventional medical and pharmacological knowledge.
[0018] In this specification, the terms “depressive disorder,” “depression,” or “depressive state” include, but are not limited to, major depressive disorder, mild to moderate depressive disorder, and stress-related depressive disorder caused by chronic stress, psychosocial factors, or endocrine dysfunction. These diseases or states are usually accompanied by abnormalities in emotional, cognitive, and behavioral functions.
[0019] In this invention, the terms "subject" and "patient" are used interchangeably and refer to a mammalian individual, including preferred humans and non-human primates, as well as common laboratory animals (such as rabbits, rats, mice, dogs, monkeys, etc.). The term specifically refers to an individual to whom the compounds, compositions, or formulations of this invention may be administered. Suitable subjects can be determined through conventional screening methods and are typically individuals diagnosed with a relevant disease or pathological condition requiring treatment, relief, prevention, or improvement.
[0020] This invention relates to the use of niorin in the preparation of fast-acting antidepressants.
[0021] Studies have found that neoryl, a C19 diterpenoid alkaloid, can significantly improve multiple behavioral indicators in animal models of depression. Its antidepressant effect is characterized by rapid onset and stable action, meeting the clinical need for rapid relief of depressive symptoms. Therefore, this invention utilizes neoryl in the preparation of a rapidly acting antidepressant to achieve effective treatment and rapid regulation of depressive states.
[0022] In some embodiments of the present invention, the antidepressant is used to treat major depressive disorder, mild to moderate depressive disorder, or stress-related depressive disorder.
[0023] The aforementioned depressive disorders typically manifest as persistent low mood, diminished interest and pleasure, cognitive decline, slowed mental activity, and disrupted sleep rhythms. Their pathogenesis involves the combined effects of multiple factors, including neurotransmitter imbalance, hypothalamic-pituitary-adrenal axis dysfunction, and abnormal neuroplasticity. This invention utilizes neorylene in the preparation of an antidepressant, enabling it to exert a comprehensive regulatory effect against these multiple pathogenic mechanisms, thus achieving good therapeutic effects in patients with different types of depressive disorders. Experimental results show that the drug prepared using the methods described in this invention significantly improves depressive-like behaviors in both corticosterone-induced mouse depression models and chronic restraint stress mouse depression models. This indicates that it is not only suitable for the treatment of patients with severe depressive disorder but also for the intervention and control of mild to moderate depressive states and stress-related depressive disorders, thereby expanding the clinical applicability of the antidepressant of this invention and enhancing its clinical application value.
[0024] In some embodiments, the neorin is combined with pharmaceutically acceptable excipients to form a pharmaceutical composition.
[0025] Pharmaceutical compositions can be formulated using methods known to those skilled in the art. For example, they can be administered parenterally as a sterile solution or suspension of water or a pharmaceutically acceptable solution other than water. For example, suitable combinations of pharmacologically acceptable carriers or media, specifically sterile water, physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, excipients, mediators, preservatives, binders, etc. It is considered to be formulated by mixing in a commonly accepted unit dosage form required for pharmaceutical administration. The amount of the active ingredient in these formulations is set to obtain an appropriate volume within the indicated range.
[0026] Sterile compositions for injection can be formulated using excipients such as distilled water for injection, following conventional formulation methods.
[0027] Examples of aqueous solutions for injection include isotonic solutions containing, for example, physiological saline, lactose, glucose, and other supplements (such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride). Appropriate dissolving aids can be used in combination, such as alcohols (ethanol, etc.), polyols (propylene glycol, polyethylene glycol, etc.), and nonionic surfactants (polysorbate 80(TM), HCO-50, etc.).
[0028] As an oily liquid, sesame oil and soybean oil can be examples, and benzyl benzoate and / or benzyl alcohol can be used in combination as a solubilizing agent. The composition can be mixed with buffers (e.g., phosphate buffer solutions and sodium acetate buffer solutions), analgesics (e.g., procaine hydrochloride), stabilizers (e.g., benzyl alcohol and phenol), and antioxidants. The prepared injection solution is typically packaged in appropriate ampoules.
[0029] In some embodiments, the pharmaceutical composition is an oral formulation, an injectable formulation, a mucosal administration formulation, or a sustained-release formulation. This adapts to different clinical application scenarios and patient needs. The oral formulation is suitable for long-term maintenance therapy or outpatient use, the injectable formulation is suitable for rapid onset of action or intervention during acute attacks, the mucosal administration formulation is suitable for improving absorption rate and bioavailability, and the sustained-release or controlled-release formulation is suitable for prolonging the duration of drug action and reducing the frequency of administration. By rationally selecting the formulation type and prescription composition, the release behavior and pharmacokinetic characteristics of neoryl in vivo can be further optimized, thereby improving its antidepressant therapeutic effect.
[0030] In some embodiments, the oral formulation is a tablet, capsule, granule, pill, oral liquid, suspension, or drop. Tablets and capsules can be prepared by wet granulation, dry granulation, or direct compression, and can be coated with a film or enteric coating as needed. Granules and pills can be obtained by extrusion spheronization, spray drying, or coating molding. Oral liquids and suspensions can be prepared by dissolving or dispersing nystatin in a suitable solvent system. Drops can be obtained by melt dripping or cold forming. These oral formulations have the advantages of convenient administration and high patient compliance, making them suitable for the routine treatment of depressive disorders.
[0031] In some embodiments, the injectable formulation is an injectable solution or a lyophilized powder for injection. The injectable solution can be prepared by dissolving nystatin in sterile water for injection or a solution containing a suitable buffer system and solubilizer, followed by sterile filtration and aseptic filling. The lyophilized powder for injection can be prepared by first preparing a nystatin solution, then aseptically dispensing and freeze-drying it to form a solid formulation, which is then reconstituted and injected before use. Preparing an injectable formulation allows nystatin to rapidly enter the systemic circulation, thereby facilitating a faster onset of antidepressant therapeutic effect.
[0032] In some embodiments, the mucosal administration formulation is a sublingual tablet, an orally disintegrating tablet, a nasal spray, or an oral spray. Sublingual tablets and orally disintegrating tablets can be rapidly disintegrated or dissolved in the oral cavity by controlling the excipient composition and tableting process, thereby promoting the absorption of nystatin via the oral mucosa. Nasal sprays and oral sprays can be prepared by formulating nystatin into a solution or microdispersion system and using a spray device to achieve quantitative administration. Mucosal administration can partially avoid the first-pass effect, increase the drug absorption rate, and facilitate the rapid antidepressant effect of nystatin.
[0033] In some embodiments, the sustained-release formulation is a sustained-release tablet, sustained-release capsule, or microsphere formulation. The sustained-release tablet or capsule can be designed using a sustained-release matrix material, coating material, or multilayer structure to allow for the slow release of neoryl in vivo. The microsphere formulation can be obtained through processes such as emulsification solvent evaporation, spray drying, or phase separation, and the controlled-release effect can be achieved by adjusting the properties of the carrier material. By preparing sustained-release or controlled-release formulations, the effective duration of action of neoryl in vivo can be prolonged, the frequency of dosing can be reduced, and patient compliance and treatment stability can be improved.
[0034] In some embodiments, the subjects of the antidepressant are mammals.
[0035] In some embodiments, the subjects of the antidepressant are primates.
[0036] In some embodiments, the subject of the antidepressant is a human being.
[0037] The present invention also relates to a method for treating depression, the method comprising administering to a subject with depression an effective amount of niorling or a pharmaceutical composition as described above.
[0038] In some embodiments of the present invention, the dosage of neorylene can be adjusted according to the subject's age, weight, severity of illness, route of administration, and individual differences. In exemplary embodiments, the dosage of neorylene can be 0.1–20 mg / kg, preferably 1–10 mg / kg, more preferably 1–5 mg / kg. For human formulations, the daily dosage of neorylene can be 0.5–50 mg, preferably 1–20 mg, and can be divided into single or multiple administrations to obtain a stable and effective therapeutic effect.
[0039] In some embodiments of the present invention, neoryl can be administered to subjects via various routes of administration, including but not limited to oral administration, injection administration, and transmucosal administration. Oral administration can be in the form of tablets, capsules, granules, oral solutions, or suspensions, suitable for long-term maintenance therapy; injection administration can be administered intravenously, intramuscularly, or subcutaneously, suitable for clinical scenarios requiring rapid relief of depressive symptoms; transmucosal administration can be achieved through sublingual tablets, orally disintegrating tablets, or nasal sprays to improve absorption rate and bioavailability. Those skilled in the art can rationally select the route of administration and frequency of administration according to specific clinical needs.
[0040] In some embodiments of the present invention, neorylene can be used alone as an active drug for the treatment of depression to fully utilize its rapid-onset antidepressant activity. In this embodiment, neorylene can be administered to the subject as the sole primary therapeutic ingredient, thereby achieving a significant antidepressant effect at lower doses and reducing the risk of adverse reactions associated with multiple drug combinations.
[0041] In another embodiment of the invention, niorin may also be used in combination with other psychotropic drugs to further enhance therapeutic efficacy or improve the therapeutic response in specific patient groups. The other psychotropic drugs may be selected from ketamine, (… S The list includes Ketamine, fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, bupropion, agomelatine, trazodone, reboxetine, imipramine, amitriptyline, clomipramine, doxepin, maprotiline, moclobemide, liver-soothing and mood-lifting capsules, St. John's wort extract, and flupentixol melitracen, among others. In combination therapy, neoryl can be administered concurrently, at different times, or alternately with the above-mentioned drugs. The specific dosing regimen can be adjusted according to the patient's condition and clinical experience.
[0042] In a further embodiment, the treatment method can be implemented using a phased or periodic dosing regimen. For example, during the acute phase, intensive treatment can be administered at a higher frequency or via injection, and after symptom relief, maintenance treatment can be switched to oral formulations to consolidate the therapeutic effect and reduce the risk of relapse. By rationally designing the dosing regimen and combination therapy strategy, neoryl can exert a stable and sustained antidepressant effect at different stages of treatment, thereby improving the overall treatment effect and the patient's quality of life.
[0043] The embodiments of the present invention will be described in detail below with reference to the examples. It should be understood that these embodiments are only used to illustrate the technical content of the present invention and are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the specific experimental conditions in the following embodiments are given priority reference to the guidelines provided in this specification, or may be carried out according to generally accepted experimental manuals or conventional experimental conditions, or other experimental methods known in the art, or according to the conditions recommended by the relevant reagent or instrument manufacturers. In specific embodiments, unless otherwise specified, minor deviations within the weighing accuracy range are allowed for the measurement parameters involving raw material components; reasonable deviations due to instrument detection accuracy or operational accuracy are also allowed for parameters such as temperature and time.
[0044] Example 1 This embodiment discloses the rapid antidepressant effect of a C19 diterpenoid alkaloid, Neoline, on corticosterone-induced depression in mice, specifically verified through the following process: 1. Experimental materials and instruments ( S Ketamine was purchased from Jiangsu Hengrui Medicine Co., Ltd.; Higenamine, Bulleyaconitine A, Lappaconitine, and 3-Acetylaconitine were purchased from Shanghai Shidande Standard Technical Service Co., Ltd.; Neoline, Songorine, and total alkaloids from Aconitum carmichaelii were prepared in the laboratory.
[0045] ZIL-2 Mouse Autonomous Activity Box (Shanghai Xinman Educational Equipment Co., Ltd.); YLS-18A Mouse Tail Suspension Instrument (Anhui Zhenghua Biological Instrument Equipment Co., Ltd.); KW-PH-100 Mouse and Rat Sugar Water Preference Experiment System (Nanjing Calvin Biotechnology Co., Ltd.); Electronic Balance (Sartorius Scientific Instruments (Beijing) Co., Ltd.).
[0046] 2. Laboratory animals C57BL / 6J mice, male, weighing 18-22g, SPF grade, provided by Weishanglide, animal license number: SYXK (Beijing) 2021-0010. Animals were housed in an environment with a temperature of 23±2℃ and humidity of 50±10%, with 12 hours of lighting per day (7:00~19:00). Experiments were conducted on the animals 3 days after they were housed. They were fasted for 6 hours before the start of behavioral experiments, but had free access to water.
[0047] 3. Experimental Methods 144 male C57BL / 6J mice were randomly divided into 12 groups in descending order of spontaneous activity count: a control group (same volume of saline), a corticosterone model group (same volume of saline), and a positive control group (…). S The following groups were included: Ketamine (10 mg / kg), total aconite alkaloids (10 mg / kg), norcodonine (10 mg / kg), succinate (10 mg / kg), aconitine (10 mg / kg), high aconitine (10 mg / kg), 3-acetyl aconitine (10 mg / kg), low-dose Neoline (1 mg / kg), medium-dose Neoline (3 mg / kg), and high-dose Neoline (10 mg / kg), with 12 animals in each group, each numbered. All drugs were prepared by adding physiological saline to form a solution. Except for the control group, all other groups received intraperitoneal injections of corticosteroids 40 mg / kg for 21 consecutive days. On day 22, the positive control group (… S The )-Ketamine group received a single intraperitoneal injection, while the other groups received a single gavage. One hour after administration, a sucrose preference test was performed. On day 23, the administration method was the same as on day 22, and one hour after administration, a spontaneous activity test and a tail suspension test were performed.
[0048] Sugar water preference coefficient = [sucrose intake (mL) / sucrose intake (mL) + water intake (mL)] × 100%.
[0049] Data are expressed as mean ± standard error (Mean ± SD). Experimental results were analyzed using GraphpadPrism 10.0 software. One-way ANOVA was first performed among multiple groups, followed by statistical testing using Tukey's multiple comparisons test. P A value <0.05 is considered statistically significant.
[0050] 4. Experimental Results As shown in Table 1, compared with the corticosterone model group, 1 hour after administration, the low-dose Neoline group (1 mg / kg), medium-dose Neoline group (3 mg / kg), and high-dose Neoline group (10 mg / kg) all significantly increased the sucrose preference coefficient in mice during the sucrose preference experiment, demonstrating a significant and rapid antidepressant effect. The efficacy was comparable to that of the positive control group (…). S It is comparable to 10 mg / kg of Ketamine (a first-line drug for rapid clinical treatment of depression), and significantly superior to norcodonine (10 mg / kg), succinate (10 mg / kg), aconitine (10 mg / kg), eucommia ulmoides (10 mg / kg), 3-acetyl aconitine (10 mg / kg) and total alkaloids of Aconitum carmichaelii (10 mg / kg), and the effective dose is significantly lower than that of positive control drugs.
[0051] Table 1. Effects of Neoline on sucrose preference index in corticosterone-induced depression model mice
[0052] (Compared to the blank group, ### P <0.001; compared with the corticosterone model group, P <0.05, P <0.01) As shown in Table 2, compared with the corticosterone model group, 1 hour after administration, the low-dose Neoline group (1 mg / kg), medium-dose Neoline group (3 mg / kg), and high-dose Neoline group (10 mg / kg) all significantly shortened the immobility time of mice in the tail suspension experiment, demonstrating a significant and rapid antidepressant effect, and their efficacy was significantly better than that of the positive control drug. S )-Ketamine (10 mg / kg), norcodonine (10 mg / kg), succinyl alkaloid (10 mg / kg), aconitine (10 mg / kg), aconitine (10 mg / kg), 3-acetyl aconitine (10 mg / kg) and total alkaloids of Aconitum carmichaelii (10 mg / kg).
[0053] Table 2. Effects of Neoline on tail suspension immobility time in corticosterone-induced depression model mice.
[0054] (Compared to the blank group, ### P <0.001; compared with the corticosterone model group, P <0.05, P <0.01, P <0.0001) As shown in Table 3, compared with the corticosterone model group, 1 hour after administration, the low-dose Neoline group (1 mg / kg), medium-dose Neoline group (3 mg / kg), and high-dose Neoline group (10 mg / kg) all significantly increased the number of squares crossed and the number of foot lifts in the open field test, demonstrating a significant and rapid antidepressant effect. The efficacy was comparable to that of the positive control group (…). S It was comparable to )-Ketamine (10 mg / kg) and significantly superior to norcodonine (10 mg / kg), succinyl alkaloids (10 mg / kg), aconitine (10 mg / kg), eucommia ulmoides (10 mg / kg), 3-acetyl aconitine (10 mg / kg) and total alkaloids of Aconitum carmichaelii (10 mg / kg).
[0055] Table 3. Effects of Neoline on the number of open field traversal grids and the number of foot lifts in a corticosterone-induced depression model mouse.
[0056] (Compared to the blank group, ### P <0.001; compared with the corticosterone model group, P <0.0001) Example 2 This embodiment discloses the rapid antidepressant effect of Neoline, a C19 diterpenoid alkaloid, on mice with depression induced by chronic restraint stress, specifically verified through the following process: 1. Experimental materials and instruments Same as "1 Experimental Materials and Instruments" under Example 1.
[0057] 2. Laboratory animals Same as "2 Experimental Animals" under Example 1.
[0058] 3. Experimental Methods 144 male C57BL / 6J mice were randomly divided into 12 groups in descending order of spontaneous activity count, arranged in a serpentine pattern: a control group (same volume of saline), a chronic restraint stress model group (same volume of saline), and a positive control group (…). SThe mice were divided into four groups: 12 mice per group (Ketamine group, 10 mg / kg), 10 mg / kg total alkaloids of Aconitum carmichaelii group, 10 mg / kg norcodonine group, 10 mg / kg succinate group, 10 mg / kg high-acetyl aconitine group, 10 mg / kg 3-acetyl aconitine group, 1 mg / kg low-dose Neoline group, 3 mg / kg medium-dose Neoline group, and 10 mg / kg high-dose Neoline group. All drugs were prepared by adding physiological saline to the solution. Except for the control group, all other groups used restraint tubes to restrict the mice's activity for 4 hours daily for 21 consecutive days. On day 22, the positive control group (…) S The )-Ketamine group received a single intraperitoneal injection, while the other groups received a single gavage. One hour after administration, a sucrose preference test was performed. On day 23, the administration method was the same as on day 22, and one hour after administration, a spontaneous activity test and a tail suspension test were performed.
[0059] Sugar water preference coefficient = [sucrose intake (mL) / sucrose intake (mL) + water intake (mL)] × 100%.
[0060] Data are expressed as mean ± standard error (Mean ± SD). Experimental results were analyzed using GraphpadPrism 10.0 software. One-way ANOVA was first performed among multiple groups, followed by statistical testing using Tukey's multiple comparisons test. P A value <0.05 is considered statistically significant.
[0061] 4. Experimental Results As shown in Table 4, compared with the chronic restraint stress model group, 1 hour after administration, the low-dose Neoline group (1 mg / kg), medium-dose Neoline group (3 mg / kg), and high-dose Neoline group (10 mg / kg) all significantly increased the sucrose preference coefficient in the sucrose preference test, demonstrating a significant and rapid antidepressant effect. The efficacy was comparable to that of the positive control group (…). S The effective dose was comparable to that of 10 mg / kg, and significantly superior to that of norcodonol (10 mg / kg), succinyl alkaloid (10 mg / kg), aconitine (10 mg / kg), eucommia ulmoides (10 mg / kg), 3-acetyl aconitine (10 mg / kg) and total alkaloids of Aconitum carmichaelii (10 mg / kg), and the effective dose was significantly lower than that of positive control drugs.
[0062] Table 4. Effects of Neoline on sucrose preference index in a chronic restraint stress-induced depression model mouse.
[0063] (Compared to the blank group, #### P <0.0001; compared with the chronic restraint stress model group, P <0.05, P <0.001, P <0.0001) As shown in Table 5, compared with the chronic restraint stress model group, 1 hour after administration, the low-dose Neoline group (1 mg / kg), medium-dose Neoline group (3 mg / kg), and high-dose Neoline group (10 mg / kg) all significantly shortened the immobility time of mice in the tail suspension experiment, demonstrating a significant and rapid antidepressant effect. The efficacy was comparable to that of the positive control group (…). S It was comparable to )-Ketamine (10 mg / kg) and significantly superior to norcodonine (10 mg / kg), succinyl alkaloids (10 mg / kg), aconitine (10 mg / kg), eucommia ulmoides (10 mg / kg), 3-acetyl aconitine (10 mg / kg) and total alkaloids of Aconitum carmichaelii (10 mg / kg).
[0064] Table 5. Effects of Neoline on tail suspension immobility time in mice with chronic restraint stress-induced depression.
[0065] (Compared to the blank group, ### P <0.001; compared with the chronic restraint stress model group, P <0.05, P <0.001, P <0.0001) As shown in Table 6, compared with the chronic restraint stress model group, 1 hour after administration, the low-dose Neoline group (1 mg / kg), medium-dose Neoline group (3 mg / kg), and high-dose Neoline group (10 mg / kg) all significantly increased the number of squares crossed and the number of foot lifts in the open field test, demonstrating a significant and rapid antidepressant effect. The efficacy was comparable to that of the positive control group (…). S It was comparable to )-Ketamine (10 mg / kg) and significantly superior to norcodonine (10 mg / kg), succinyl alkaloids (10 mg / kg), aconitine (10 mg / kg), eucommia ulmoides (10 mg / kg), 3-acetyl aconitine (10 mg / kg) and total alkaloids of Aconitum carmichaelii (10 mg / kg).
[0066] Table 6. Effects of Neoline on the number of open field grid crossings and foot lifts in a corticosterone-induced depression model mouse.
[0067] (Compared to the blank group, #### P <0.0001; compared with the chronic restraint stress model group, P <0.05, P <0.01, P <0.001, P <0.0001) In summary, the present invention describes a C 19 Neoline, a diterpenoid alkaloid, has a significant, rapid-onset antidepressant effect, comparable to first-line clinical antidepressants. S It is comparable to )-Ketamine, but has a smaller effective dose and is administered orally, resulting in better drug compliance and usability. It can be used as a candidate for a new drug for the rapid-acting treatment of depression.
[0068] Application Example 1 This invention discloses a capsule formulation using Neoline as the active pharmaceutical ingredient, the components of which are as follows: Neoline 3.5mg 6.0g of starch Sodium metabisulfite 0.2g Magnesium stearate 0.2g Anhydrous ethanol appropriate amount Make 100 pills.
[0069] The specific preparation process is as follows: Mix Neoline, starch, and sodium metabisulfite evenly, add anhydrous ethanol to make a soft material, pass it through a 24-mesh sieve to make granules, dry it, add magnesium stearate, mix well, and fill into capsules.
[0070] Application Example 2 This invention discloses a granule formulation using the compound Neoline as a raw material, the components of which are as follows: Neoline 4.0mg 6.0g of starch Sodium bisulfite 0.2g Magnesium stearate 0.2g Anhydrous ethanol appropriate amount Make 100 bags.
[0071] The specific preparation process is as follows: Neoline was mixed with starch and sodium bisulfite, and then anhydrous ethanol was added to make a soft material. The mixture was passed through a 24-mesh sieve to form granules, dried, and then magnesium stearate was added. The mixture was then mixed and packaged.
[0072] Application Example 3 This invention discloses an oral liquid using the compound Neoline as a raw material, the components of which are as follows: Neoline 6.0mg 3.0g sucrose Sodium bisulfite 0.2g Methylparaben 0.2g Sodium bicarbonate 0.5g 1000.0 mL of water for injection Make 100 pieces.
[0073] The specific preparation process is as follows: After the above components are mixed, they can be dispensed using conventional oral liquid preparation methods.
[0074] Application Example 4 This invention discloses an injectable formulation using the compound Neoline as the active pharmaceutical ingredient, the components of which are as follows: Neoline 4.0mg Vitamin C 0.2g Sodium chloride 6.0g Sodium bicarbonate 0.5g 1000.0 mL of water for injection Make 100 pieces.
[0075] The specific preparation process is as follows: After the above components are mixed, 100 vials can be obtained by using conventional injection preparation methods.
[0076] Application Example 5 This invention discloses an application example of a compound Neoline and ( S Tablets containing ketamine as the active pharmaceutical ingredient have the following components: Neoline 3.5mg ( S )-Ketamine 20mg 18g of hydroxypropyl methylcellulose Talc powder 0.4g Lactose 0.2g Magnesium stearate 0.2g Anhydrous ethanol appropriate amount Make 100 pieces.
[0077] The specific preparation process is as follows: Mix Neoline, fluoxetine, hydroxypropyl methylcellulose, talc, lactose, and magnesium stearate evenly, add anhydrous ethanol to make a soft mass, pass it through a 24-mesh sieve to make granules, dry it, add magnesium stearate, mix well, and compress into tablets.
[0078] Application Example 6 This invention discloses a capsule formulation using compounds Neoline and fluoxetine as active pharmaceutical ingredients, the components of which are as follows: Neoline 3.5mg Fluoxetine 30.0mg 6.0g of starch Sodium metabisulfite 0.2g Magnesium stearate 0.2g Anhydrous ethanol appropriate amount Make 100 pills.
[0079] The specific preparation process is as follows: Neoline, Luyoutai, and sodium metabisulfite were mixed and then anhydrous ethanol was added to make a soft material. The material was passed through a 24-mesh sieve to make granules, dried, magnesium stearate was added, mixed well, and then filled into capsules.
[0080] Application Example 7 This invention discloses an injectable formulation using compounds Neoline and paroxetine as active pharmaceutical ingredients, the components of which are as follows: Neoline 5.0mg Paroxetine 20.0mg Vitamin C 0.2g Sodium chloride 6.0g Sodium bicarbonate 0.5g 1000.0 mL of water for injection Make 100 pieces.
[0081] The specific preparation process is as follows: After the above components are mixed, 100 vials can be obtained by using conventional injection preparation methods.
[0082] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims, and the specification can be used to interpret the content of the claims.
Claims
1. Application of niorin in the preparation of antidepressant drugs.
2. The application according to claim 1, wherein the antidepressant is used to treat major depressive disorder, mild to moderate depressive disorder, or stress-related depressive disorder.
3. The application according to claim 1, wherein the neorin is combined with pharmaceutically acceptable excipients to form a pharmaceutical composition.
4. The application according to claim 3, wherein the pharmaceutical composition is an oral formulation, an injectable formulation, a mucosal administration formulation, or a sustained-release formulation.
5. The application according to claim 4, wherein the oral preparation is a tablet, capsule, granule, pill, oral liquid, suspension, or drop.
6. The application according to claim 4, wherein the injectable formulation is an injection solution or a lyophilized powder for injection.
7. The application according to claim 4, wherein the transmucosal administration formulation is a sublingual tablet, an orally disintegrating tablet, a nasal spray, or an oral spray.
8. The application according to claim 4, wherein the sustained-release formulation is a sustained-release tablet, sustained-release capsule, or microsphere formulation.
9. The application according to any one of claims 1 to 8, wherein the subject of the antidepressant is a mammal.
10. The application according to claim 9, wherein the subject of the antidepressant is a human being.