WO2025165207A1 - Pharmaceutical composition for preventing or treating neurological diseases comprising dextromethorphan as active ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating neurological diseases, comprising dextromethorphan as an active ingredient. When the compound is applied to damaged nerve cells, it was confirmed that nerve regeneration effects such as increased cell viability of the nerve cells and increased average neurite length and maximum neurite length are exhibited, and thus the composition can be effectively utilized as a composition for preventing, treating, or alleviating neurological diseases.

Description

Pharmaceutical composition for preventing or treating neurological diseases containing dextromethorphan as an active ingredient

The present invention relates to a pharmaceutical composition for preventing or treating neurological diseases, comprising dextromethorphan as an active ingredient.

The central nervous system (CNS) is the nervous system that includes the brain and spinal cord enclosed in the skull, and together with the peripheral nervous system (PNS), it controls the behavior and bodily functions of animals.

Damage to the central nervous system can manifest a variety of symptoms and signs, including muscle weakness, sensory disturbances, speech disorders, and motor impairments. Stroke (cerebral infarction and cerebral hemorrhage), a cerebrovascular disease, can cause weakness or numbness in one arm or leg, difficulty speaking or speaking, dizziness, and double vision. Severe headaches, nausea, and vomiting can also occur.

Furthermore, structural remodeling, including sprouting and new growth, is known to occur in axons originating from nerve cells surrounding the damaged nerve tissue after a stroke. However, functional recovery is extremely limited, and this can lead to persistent personal and social problems. Therefore, early treatment is crucial. However, in clinical practice, treatments that can induce functional recovery through early intervention are extremely limited, and currently, high-dose steroids are the only initial pharmacological treatment option.

The purpose of the present invention is to provide a composition for preventing, treating or improving a neurological disease.

To achieve the above purpose, the present invention provides a pharmaceutical composition for preventing or treating a neurological disease, comprising a dextromethorphan compound or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a health functional food composition for preventing or improving neurological diseases, which comprises the compound or a food-wise acceptable salt thereof as an active ingredient.

According to the present invention, when a dextromethorphan compound is applied to damaged nerve cells, it is confirmed that a nerve regeneration effect is exhibited, such as an increase in the cell survival rate of nerve cells and an increase in the average neurite length and maximum neurite length, and thus the composition can be usefully utilized as a composition for preventing, treating, or improving nerve diseases.

Figure 1 shows the results of analyzing the effects of dextromethorphan hydrobromide hydrate (hereinafter referred to as “sample”) on cell viability, average neurite length, and maximum neurite length in neurons. *p<0.05 vs C-

Figure 2 shows the results of analyzing the effect of the sample on the BBB (Basso, Bresnahan, and Beattie) score in a spinal cord injury animal model. *p<0.05 vs CTL

Figure 3 shows the results of analyzing the effect of the sample on cavity size in a spinal cord injury animal model. *p<0.05 vs CTL

Figure 4 shows the results of analyzing the effect of the sample on the number of ED1 positive cells expressing the ED1 antigen in a spinal cord injury animal model. *p<0.05 vs CTL

The terms used in this specification have been selected from widely used, current terms, taking into account the functions of the present invention. However, these terms may vary depending on the intentions of those skilled in the art, precedents, the emergence of new technologies, etc. Furthermore, in certain cases, terms may be arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the relevant description of the invention. Therefore, the terms used in this invention should not be defined simply as names, but rather based on their inherent meanings and the overall content of the present invention.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

Numerical ranges are inclusive of the numbers defined in the ranges above. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if that lower numerical limitation were explicitly stated. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if that higher numerical limitation were explicitly stated. Every numerical limitation given throughout this specification will include every better numerical range within that broader numerical range, as if that narrower numerical limitation were explicitly stated.

Hereinafter, the present invention will be described in more detail.

The present invention provides a pharmaceutical composition for preventing or treating a neurological disease, comprising a dextromethorphan compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound is represented by the following chemical formula 1, and its IUPAC name is (9α,13α,14α)-3-methoxy-17-methylmorphinan, and its chemical formula is C ₁₈ H ₂₅ NO.

[Chemical Formula 1]

A pharmaceutically acceptable salt of the above compound may include a compound represented by the following chemical formula 2, wherein the compound represented by the above chemical formula 2 is dextromethorphan hydrobromide hydrate, and the IUPAC name is (1S,9S,10S)-4-methoxy-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene;hydrate;hydrobromide, and the chemical formula is C ₁₈ H ₂₈ BrNO ₂ . In Example 1 below, the effect of dextromethorphan compound on nerve regeneration was confirmed using dextromethorphan hydrobromide hydrate.

[Chemical Formula 2]

In the present invention, "dextromethorphan" is a drug that suppresses coughing by acting on the cough center of the brain. It is used to suppress dry coughs without phlegm. It is not available as a single agent, but is mainly used in combination with cold remedies.

The above compound or a pharmaceutically acceptable salt thereof can induce neurite regeneration, thereby exhibiting a nerve regeneration, neuroprotection or nerve recovery effect.

In the present invention, the term “neural regeneration” means the growth of axons from the terminal end of a severed axon (axonotmesis) to the distal end.

In the present invention, the term “neural protection” means measures taken to prevent further damage to normal or damaged nerves.

In the present invention, the term “neural restoration” means the process of normalizing or normalizing the function of a damaged nerve.

In addition, the compound or a pharmaceutically acceptable salt thereof can inhibit nerve damage in the central or peripheral nerves or promote nerve regeneration.

The above neurological disease may be a central nervous system disease or a peripheral nervous system disease.

The above central nervous system disease may be caused by brain damage or spinal cord damage, and the above peripheral nervous system disease may be caused by peripheral nerve damage.

The pharmaceutical composition of the present invention can be manufactured in a unit dose form or can be manufactured by placing it in a multi-dose container by formulating it using a pharmaceutically acceptable carrier according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains.

The pharmaceutically acceptable carriers mentioned above are those commonly used in formulations, and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.

In the present invention, the content of the additive included in the pharmaceutical composition is not particularly limited and can be appropriately adjusted within the content range used in conventional formulations.

The above pharmaceutical composition may be formulated in the form of one or more external skin preparations selected from the group consisting of injectable formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules, tablets, creams, gels, patches, sprays, ointments, ointments, lotions, liniments, pastes, and cataplasmas, but is not limited thereto.

The pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable carriers and diluents for formulation. The pharmaceutically acceptable carriers and diluents include, but are not limited to, excipients such as starch, sugar, and mannitol; fillers and extenders such as calcium phosphate; cellulose derivatives such as carboxymethylcellulose and hydroxypropylcellulose; binders such as gelatin, alginates, and polyvinyl pyrrolidone; lubricants such as talc, calcium stearate, hydrogenated castor oil, and polyethylene glycol; disintegrants such as povidone and crospovidone; and surfactants such as polysorbates, cetyl alcohol, and glycerol. The pharmaceutically acceptable carriers and diluents may be biologically and physiologically compatible with the subject. Examples of diluents include, but are not limited to, saline, aqueous buffers, solvents, and/or dispersion media.

The pharmaceutical composition of the present invention may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method. In the case of oral administration, it may be formulated as tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, elixirs, etc. In the case of parenteral administration, it may be formulated as injections, suppositories, powders for respiratory inhalation, aerosols for sprays, ointments, powders for application, oils, creams, etc.

The dosage of the pharmaceutical composition of the present invention may vary depending on the patient's condition, weight, age, sex, health status, dietary constitution, nature of the formulation, severity of the disease, administration time of the composition, administration method, administration period or interval, excretion rate, and drug form, and may be appropriately selected by a person skilled in the art. For example, it may be in the range of about 0.1 to 10,000 mg/kg, but is not limited thereto, and may be administered once or several times a day in divided doses.

The pharmaceutical composition may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method. The pharmaceutically effective amount and effective dosage of the pharmaceutical composition of the present invention may vary depending on the formulation method, administration method, administration time, administration route, etc. of the pharmaceutical composition. A person skilled in the art can easily determine and prescribe an effective dosage for the intended treatment. The pharmaceutical composition of the present invention may be administered once a day or divided into several doses.

In addition, the present invention provides a health functional food composition for preventing or improving neurological diseases, which comprises a dextromethorphan compound or a food-wise acceptable salt thereof as an active ingredient.

The present invention can be generally used as a commonly used food.

The food composition of the present invention can be used as a health functional food. The term "health functional food" refers to a food manufactured and processed using raw materials or ingredients with functional properties useful to the human body as defined in the Health Functional Food Act. "Functionality" refers to ingestion for the purpose of obtaining beneficial effects for health purposes, such as regulating nutrients for the structure and function of the human body or physiological effects.

The above health functional food composition may contain conventional food additives, and its suitability as the above “food additive” is determined by the specifications and standards for the relevant item in accordance with the general provisions and general test methods of the Food Additive Code approved by the Ministry of Food and Drug Safety, unless otherwise specified.

Items listed in the above “Food Additives Code” include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high-molecular-weight pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, alkaline agents for noodles, preservative preparations, and tar color preparations.

The food composition of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. For example, among health functional foods in capsule form, hard capsules can be manufactured by mixing and filling a composition according to the present invention with additives such as excipients into a conventional hard capsule, and soft capsules can be manufactured by mixing a composition according to the present invention with additives such as excipients and filling a capsule base such as gelatin. The soft capsules may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative, etc., as necessary.

The definitions of terms for the above excipients, binders, disintegrants, lubricants, flavoring agents, etc. are described in documents known in the art and include those with the same or similar functions. There is no particular limitation on the type of food, and all health functional foods in the conventional sense are included.

In the present invention, the term “prevention” refers to any act of suppressing or delaying the disease by administering a composition according to the present invention.

In the present invention, the term “treatment” refers to any act of improving or beneficially changing the symptoms of the disease by administering a composition according to the present invention.

In the present invention, the term “improvement” refers to any act of improving the bad condition of the disease by administering the composition according to the present invention.

In addition, the present invention provides a method for treating a neurological disease, comprising a step of administering a pharmaceutical composition for preventing or treating a neurological disease in a pharmaceutically effective amount to a mammal other than a human suffering from a neurological disease.

In the present invention, the term "administration" means introducing the pharmaceutical composition by any suitable method, and the route of administration of the composition of the present invention may be administered through any common route as long as it can reach the target tissue. It may be administered orally, intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, intranasally, intrapulmonary, rectal, intracavitary, intraperitoneally, or intrathecally, and preferably, oral administration.

Hereinafter, to aid understanding of the present invention, examples will be given in detail. However, the following examples are intended only to illustrate the scope of the present invention and are not intended to limit its scope. These examples are provided to more fully explain the present invention to those of average skill in the art.

[ Experimental example 1] Experiment preparation

1-1. Sample

Dextromethorphan hydrobromide hydrate (a salt compound of dextromethorphan) used as a sample in the present invention was purchased from GLPBIO, and the compound was dissolved in a PBS (phosphate-buffered saline) solution at 5 mg/ml to prepare a stock, which was then diluted and used.

1-2. Cell model

In the present invention, primary cortical neurons derived from the cortex of a 16-day-old Sprague-Dawley rat fetus (Koatecth, Korea) were used as a cell model, and the method is as follows. The abdominal cavity of the pregnant rat was disinfected with 70% ethanol, and after incision, the fetus was removed, the head and neck were cut, and stored in HBSS (Hank's Balanced Salt Solution). Thereafter, the skin and skull were cut to remove the brain, and the meninges were removed under a dissecting microscope, the cortex was separated, and the tissue was pulverized to isolate neurons.

For cell culture, a 96-well plate double-coated with poly-D-lysine and laminin was prepared, and Neurobasal medium (culture medium) was added to the isolated neurons, which were then stained with Trypan blue. Cells were then seeded at a density of 5 × 10 ³ cells/ml using a hemocytometer under a microscope, and cultured for 10 days at 37°C and 5% CO ₂ .

[ Example 1] Analysis of nerve regeneration effects using cell models

To determine the effect of the sample on nerve regeneration, the cultured primary neurons were treated with 150 μM hydrogen peroxide (H ₂ O ₂ ) for 30 minutes to induce oxidative stress, and after removing the hydrogen peroxide with phosphate-buffered saline (PBS), the cells were treated with the sample (1, 5, 10, 25, or 50 μM) for 15 hours. The untreated group was treated with culture media instead of the sample. Afterwards, for immunofluorescence staining, the cells were fixed with 4% paraformaldehyde at room temperature for 10 minutes. Mouse Tuj1 monoclonal antibody was used to stain the axons of the neurons, and DAPI (4',6-diamidino-2-phenylindole) solution was used to stain the nuclei. Afterwards, the neurons expressing Tuj1 were counted using an ImageJ plugin, and the maximum axonal length was measured. The experimental group was specifically set up as follows.

1) Normal group (C+): No hydrogen peroxide treatment + culture medium treatment

2) Control group (C-): Hydrogen peroxide (150 μM) + culture medium treatment

3) Sample treatment group 1 (1 μM): Hydrogen peroxide (150 μM) + sample (1 μM) treatment

4) Sample treatment group 2 (5 μM): Hydrogen peroxide (150 μM) + sample (5 μM) treatment

5) Sample treatment group 3 (10 μM): Hydrogen peroxide (150 μM) + sample (10 μM) treatment

6) Sample treatment group 4 (25 μM): Hydrogen peroxide (150 μM) + sample (25 μM) treatment

7) Sample treatment group 5 (50 μM): Hydrogen peroxide (150 μM) + sample (50 μM) treatment

As a result, as shown in Fig. 1 and Table 1, the cell viability, average neurite length, and maximum neurite length of nerve cells in the control group (C-) significantly decreased compared to the normal group (C+), whereas the cell viability, average neurite length, and maximum neurite length of nerve cells in the sample-treated group significantly increased compared to the control group. From the above results, it was confirmed that dextromethorphan induces nerve regeneration.

Relative viability 　 C+ C- 1μM 5μM 10μM 25μM 50μM Mean 1.00 0.64 0.28 0.53 0.54 0.75 0.75 Standard deviation (S.D) 0.17 0.13 0.03 0.05 0.05 0.11 0.07 T-test 　 　 0.01 0.23 0.25 0.23 0.20 Average neurite length (μm) Mean 189.63 171.26 143.15 162.78 228.52 233.80 215.61 Standard deviation (S.D) 18.38 22.54 30.56 12.58 29.80 20.25 20.43 T-test 　 　 0.26 0.54 0.00 0.01 0.04 Maximum neurite length (μm) Mean 272.38 235.40 248.51 244.84 368.00 324.30 299.80 Standard deviation (S.D) 17.67 28.84 4.53 30.20 20.17 28.49 22.82 T-test 　 　 0.51 0.72 0.00 0.01 0.04

[ Example 2] Analysis of nerve regeneration effects through animal models

To confirm the nerve regeneration effect of the sample, an animal model experiment was conducted. The animal model was a female Sprague-Dawley rat (KOATECH, 12 weeks, 310-340 g) and was housed in an environment with a 12-h light-dark cycle, 23±1℃, and 45-50% humidity. After that, an animal model of moderate contusion spinal cord injury (200 kdyn) was created using an Infinite Horizon impactor (IH-400, Precision Systems and Instrumentation, LLC, KY, USA) exposed to the T9 spinal cord. Samples at various concentrations (5, 25, 100, 500, 1,000, or 10,000 μM) were diluted in phosphate-buffered saline (PBS) immediately before use, and 1 ml of the sample was injected intraperitoneally 30 minutes after spinal cord injury for 4 weeks. The control group was injected intraperitoneally with the same volume of PBS without the sample.

All behavioral assessments were recorded by two independent individuals uninvolved in spinal cord injury and sample administration, and the average score was used. For behavioral assessment, all animal models had their BBB (Basso, Bresnahan, and Beattie) scores measured weekly after spinal cord injury.

Eight weeks after surgery (spinal cord injury), all animal models were perfused with 0.9% saline through the left ventricle, blood was removed, and the tissues were dissolved in 0.1 M PBS (pH 7.4) and perfused and fixed with 4% paraformaldehyde before the spinal cords were excised. The spinal cords were fixed in 4% paraformaldehyde for 1 day and in 30% sucrose for 3 days. Afterwards, they were embedded in M1 compound (Thermo Fisher Scientific Inc.), rapidly frozen, and 16 μm-thick sections were prepared using a microtome, and H&E staining and immunohistochemical staining were performed.

As a result, as shown in Fig. 2, there was a significant difference in the BBB score between the sample treatment group (1 mM, 10 mM) and the control group (CTL), and as shown in Fig. 3, the cavity size decreased in a concentration-dependent manner in the sample treatment group compared to the control group (CTL), and as shown in Fig. 4, the number of ED1 positive cells expressing the ED1 antigen decreased in a concentration-dependent manner in the sample treatment group compared to the control group (CTL). Based on the above results, it was confirmed that dextromethorphan has the potential as a drug that can induce nerve regeneration because it can reduce tissue damage, reduce the inflammatory response caused by secondary damage, and induce functional recovery.

While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions merely represent preferred embodiments and are not intended to limit the scope of the present invention. In other words, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (8)

A pharmaceutical composition for preventing or treating a neurological disease, comprising a dextromethorphan compound or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition according to claim 1, characterized in that the compound is a compound represented by the following chemical formula 1. [Chemical Formula 1] A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of the compound comprises a compound represented by the following chemical formula 2. [Chemical Formula 2] A pharmaceutical composition characterized in that, in claim 1, the compound or a pharmaceutically acceptable salt thereof inhibits nerve damage in the central or peripheral nerves or promotes nerve regeneration. A pharmaceutical composition according to claim 1, characterized in that the neurological disease is a central nervous system disease or a peripheral nervous system disease. A pharmaceutical composition according to claim 5, wherein the central nervous system disease is caused by brain damage or spinal cord damage, and the peripheral nervous system disease is caused by peripheral nerve damage. A health functional food composition for preventing or improving neurological diseases, comprising a dextromethorphan compound or a food-based acceptable salt thereof as an active ingredient. A method for treating a neurological disease, comprising administering a pharmaceutical composition of any one of claims 1 to 6 in a pharmaceutically effective amount to a mammal other than a human suffering from a neurological disease.