Pharmaceutical composition for use in prevention or treatment of cognitive impairment

Abstract

To provide a pharmaceutical composition for preventing or treating cognitive dysfunction.SOLUTION: The pharmaceutical composition contains benzoic acid or a benzoic acid salt.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 681,271, filed in the U.S. Patent and Trademark Office on August 9, 2024, the entire contents of which are incorporated by reference.

[0002] The present technology relates to the prevention or treatment of cognitive dysfunction, and in particular, to the prevention or treatment of cognitive dysfunction caused by COVID or other inflammation-related diseases using benzoic acid or a salt thereof. [Background technology]

[0003] COVID-19 (also known as novel coronavirus disease) has claimed millions of lives worldwide and may cause chronic symptoms for survivors ( Richardson et al., 2020 ), raising concerns about its long-term effects on many human characteristics, particularly neurocognitive function ( Helms et al., 2020 ; Yang et al., 2021 ).

[0004] Many people infected with COVID-19 appear to have mild or no symptoms. However, many patients suffer from a variety of symptoms, including cognitive impairment, that persist for much longer than typical viral infections (Crivelli et al., 2022). The WHO defines "post-COVID-19 symptoms" as symptoms that appear three months after SARS-CoV-2 (novel coronavirus) infection, persist for at least two months, and cannot be explained by another diagnosis (Cabrera Martimbianco et al., 2021). Instead, the term "long COVID" is more commonly used. The three main symptom clusters of long COVID-19 are lethargy, cognitive impairment, and shortness of breath (Slomski, 2022).

[0005] Among the long COVID syndromes, "brain fog" is a very common neuropsychiatric syndrome. It refers to a wide range of cognitive symptoms, including slowness or sluggishness of thought, poor concentration, blurred thinking, memory impairment and forgetfulness, confusion, loss of words, and mental fatigue (Heesakkers et al., 2022). In general, people infected with COVID-19 exhibit lower cognitive function than healthy individuals (Crivelli et al., 2022).

[0006] Approximately 10% of people infected with COVID-19 suffered from long COVID (Ladds et al., 2020). 35.4% of long COVID cases developed cognitive impairment (Douaud et al., 2022). People hospitalized due to acute infection require a long recovery period (approximately 15.1% of patients who survived one year after infection continued to have long COVID) (Wulf Hanson et al., 2022).

[0007] Brain fog can have serious consequences for patients' quality of life, the healthcare system, and society ( Murtas et al., 2021 ; Heesakkers et al., 2022 ). Patients typically experience a reduced ability to perform daily tasks and many remain unable to work ( Callan et al., 2022 ; Wulf Hanson et al., 2022 ), thereby increasing healthcare needs and associated declines in clinical capacity and professional productivity ( Ladds et al., 2020 ; Callan et al., 2022 ).

[0008] Common practices such as exercise, good sleep, healthy eating, and brain exercise (e.g., playing games) have been suggested to help patients recover from brain fog. However, the effectiveness of these common practices remains unclear. A significant proportion of patients still suffer from brain fog (Krishnan et al., 2022).

[0009] Some researchers have used noninvasive brain stimulation (NIBS) technology to treat long COVID patients, based on the hypothesis that it improves vascular regulation (Sabel et al., 2021). Although several researchers found that cognitive function improved in some patients after NIBS treatment, the results were insufficient to draw conclusions due to the small sample size of the open-label study. Furthermore, some patients experienced a recurrence of cognitive symptoms after discontinuing NIBS treatment. Summary of the Invention [Problem to be solved by the invention]

[0010] Therefore, the development of safer and more effective treatments for cognitive impairment associated with long COVID-19 is urgently needed (Hampshire et al., 2022). [Means for solving the problem]

[0011] In view of the above, the present disclosure provides a method for preventing or treating cognitive impairment in a subject in need thereof, comprising administering to the subject an effective amount of benzoic acid or a benzoate salt.

[0012] In another aspect, the present disclosure further provides the use of benzoic acid or a benzoate in the manufacture of a composition for preventing or treating cognitive impairment.

[0013] In another aspect, the present disclosure further provides a pharmaceutical composition for preventing or treating cognitive impairment in a subject in need thereof, the pharmaceutical composition comprising benzoic acid or a benzoate salt thereof and a pharmaceutically acceptable excipient thereof.

[0014] In one embodiment of the present disclosure, the benzoate is sodium benzoate, potassium benzoate, calcium benzoate, 2-aminobenzoate, 3-aminobenzoate, 4-aminobenzoate, benzyl benzoate, or methyl benzoate.

[0015] In another embodiment of the present disclosure, the benzoate is sodium benzoate.

[0016] In one embodiment of the present disclosure, the cognitive impairment is caused by long COVID.

[0017] In one embodiment of the present disclosure, the cognitive dysfunction is caused by COVID-induced microglial activation, systemic inflammation, or neuroinflammation. Also, in one embodiment, the cognitive dysfunction is caused by COVID or other inflammation-related diseases.

[0018] In one embodiment of the present disclosure, benzoic acid or a benzoate may be administered to a subject in an amount ranging from 200 mg / day to 3000 mg / day, e.g., 250 mg / day to 1500 mg / day, 450 mg / day to 1000 mg / day, and 500 mg / day to 750 mg / day.

[0019] In one embodiment of the present disclosure, benzoic acid or a benzoate is administered one to four times daily.

[0020] In one embodiment of the present disclosure, benzoic acid or a benzoate may be administered to the subject for a period ranging from one month to one year, for example, from eight weeks to six months. In another embodiment of the present disclosure, benzoic acid or a benzoate is administered to the subject for a period of about six months. [Effects of the Invention]

[0021] Thus, a favorable pharmacological treatment for Long COVID-related cognitive impairment is provided. DETAILED DESCRIPTION OF THE INVENTION

[0022] The following embodiments are used to illustrate the present disclosure. Those skilled in the art can understand other advantages of the present disclosure based on the disclosure herein. The present disclosure can also be implemented or applied as described in other specific embodiments.

[0023] Although the primary target of COVID-19 is the respiratory system, infected patients can also suffer from neurocognitive symptoms (Theoharides et al., 2021). Brain changes can occur not only in moderate to severe COVID-19 but also in mild cases (Abbasi, 2022). There are several possible causes of brain fog caused by long COVID (Yang et al., 2021). For example, COVID infection can alter the types of choroid plexus cells and brain structures, such as the gray matter above the parahippocampal gyrus, the orbitofrontal cortex, and the primary olfactory cortex, leading to a decrease in total brain volume (Yang et al., 2021; Abbasi, 2022; Douaud et al., 2022; Huang et al., 2022).

[0024] In terms of molecular mechanisms, COVID induces microglial activation, systemic inflammation, and neuroinflammatory changes, thereby affecting the brain and cognitive function ( Steardo et al., 2020 ; Boldrin et al., 2021 ; Theoharides et al., 2021 ).

[0025] Furthermore, COVID also induces oxidative stress, thereby causing neurotoxicity and inhibiting neurocognitive function ( Chernyak et al., 2020 ; Laforge et al., 2020 ).

[0026] Overactivated microglia produce numerous inflammatory cytokines, ultimately damaging neurons and causing neurodegeneration (Kaur et al., 2019). Sodium benzoate reduced inflammatory responses in rodents (Brahmahari and Pahan, 2007; Brahmahari et al., 2009). Furthermore, sodium benzoate could preserve cognitive performance by preventing glial cell activation in animals (Modi et al., 2015).

[0027] This project will explore the topic of evaluating whether sodium benzoate treatment can help improve cognitive performance in Long COVID patients.

[0028] Additionally, it should be noted that as used herein, the singular forms "a," "an," and "the" include plural referents unless expressly and unambiguously limited to one referent. The term "or" is used interchangeably with the term "and / or" unless the context clearly indicates otherwise.

[0029] The present disclosure provides a method for preventing or treating cognitive impairment in a subject in need thereof, comprising administering to the subject an effective amount of benzoic acid or a benzoate salt.

[0030] As used herein, the terms "treating" or "treatment" refer to administering an effective amount of benzoic acid or a benzoate to a subject in need thereof, who can be identified by a medical professional based on the results of any appropriate diagnostic method, for the purpose of curing, alleviating, mitigating, treating, ameliorating or preventing a disease, its symptoms or predisposition thereto.

[0031] In one embodiment of the present disclosure, the subject treated by the methods of the present disclosure suffers from cognitive impairment. In a further embodiment of the present disclosure, the cognitive impairment is caused by long COVID.

[0032] Benzoic acid occurs naturally in many plants and animals. As such, benzoic acid is a natural component of many foods, including dairy products (IPCS, 1993). Benzoic acid and sodium benzoate are also legal food additives in the United States (FAO / WHO Joint Expert Committee on Food Additives, 1965, 1973), Taiwan (Ministry of Health), and the World Health Organization (IPCS, 1993), and are widely used in the production of fruit jellies, butter, soy sauce, and processed meats.

[0033] As used herein, the term "effective amount" refers to a therapeutic amount sufficient to prevent the development, recurrence, or onset of cognitive impairment caused by Long COVID and one or more symptoms thereof, enhance or improve the prophylactic efficacy of another therapy, reduce the severity of the disorder, shorten the duration of the disorder, improve one or more symptoms of the disorder, prevent the progression of cognitive impairment caused by Long COVID, and / or enhance or improve the therapeutic efficacy of another therapy.

[0034] In some embodiments of the present disclosure, the effective amount of benzoic acid or a benzoate may range from 200 mg / day to 3000 mg / day. In one embodiment, the lower dosage limit may be 200 mg / day, 225 mg / day, 250 mg / day, 275 mg / day, 300 mg / day, 325 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 700 mg / day, 750 mg / day, or 800 mg / day, and the upper dosage limit may be 3000 mg / day, 2800 mg / day, 2500 mg / day, 2200 mg / day, 2000 mg / day, 1800 mg / day, 1500 mg / day, 1200 mg / day, 1000 mg / day, 900 mg / day, 800 mg / day, 750 mg / day, 700 mg / day, or 600 mg / day. For example, the dosage of benzoic acid or a benzoate may be 200 mg / day to 3000 mg / day, 250 mg / day to 1500 mg / day, 450 mg / day to 1000 mg / day, 500 mg / day to 750 mg / day, 550 mg / day to 1000 mg / day, 600 mg / day to 800 mg / day, about 1000 mg / day, about 900 mg / day, about 750 mg / day, or about 500 mg / day.

[0035] Where numerical values ​​or ranges are described herein, those skilled in the art will understand that they are intended to encompass ranges that are appropriate and reasonable in the particular field to which the present disclosure pertains.

[0036] By specifying at least 200 mg to 3000 mg, it is meant that all integer unit amounts within that range are specifically disclosed as part of this disclosure, and thus unit amounts of 200, 201, 202...250, 251, 252...1000, 1001, 1002...2997, 2998, 2999, and 3000 are included as embodiments of the disclosure.

[0037] In some embodiments of the present disclosure, benzoic acid or a benzoate may be administered one to four times daily, for example, once daily, twice daily, three times daily, or four times daily. In one embodiment, benzoic acid or a benzoate may be administered once daily.

[0038] In some embodiments of the present disclosure, benzoic acid or a benzoate may be administered to a subject for a period sufficient to prevent or treat cognitive impairment caused by long COVID. The sufficient period may depend on the subject's species, sex, weight, or age, the stage, symptoms, or severity of the disorder, and the method, timing, or frequency of administration. In some embodiments of the present disclosure, benzoic acid or a benzoate is administered daily for at least one month. For example, the administration period of benzoic acid or a benzoate may be continued for one, two, three, four, or six months, or for one, two, three, or four years, or even longer, as long as no side effects occur during the treatment period. In exemplary embodiments of the present disclosure, the period may range from one month to one year. In another embodiment, the period may range from eight weeks to six months. In yet another embodiment, benzoic acid or a benzoate is administered daily for six months.

[0039] In certain embodiments of the present disclosure, the method comprises the use of benzoic acid, a benzoate, or a derivative thereof, wherein the benzoic acid, benzoate, or a derivative thereof can be selected from the group consisting of benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, 2-aminobenzoate, 3-aminobenzoate, 4-aminobenzoate, benzyl benzoate, and methyl benzoate.

[0040] In certain embodiments of the present disclosure, benzoic acid or a benzoate is administered in an oral dosage form. In some embodiments of the present disclosure, the benzoic acid or a benzoate administered to a subject may be contained in a pharmaceutical composition. The pharmaceutical composition of the present disclosure comprises benzoic acid or a benzoate and a pharmaceutically acceptable excipient. In one embodiment, the composition of the present disclosure is formulated in a manner suitable for oral administration and can be administered to a subject by oral administration. Alternatively, the composition may be formulated in the form of a dry powder, tablet, lozenge, capsule, granule, or pill. Pharmaceutically acceptable excipients include, but are not limited to, fillers, binders, preservatives, disintegrants, lubricants, suspending agents, wetting agents, solvents, surfactants, acids, flavorings, polyethylene glycol (PEG), alkylene glycol, sebacic acid, dimethyl sulfoxide, alcohol, or any combination thereof.

[0041] The pharmaceutical composition of the present disclosure may contain only benzoic acid or a benzoate as the active ingredient for preventing or treating cognitive dysfunction caused by long COVID. In other words, benzoic acid or a benzoate functions as the sole active ingredient for preventing or treating cognitive dysfunction caused by long COVID in the composition. In this embodiment, the present disclosure provides a safe and effective therapy for preventing or treating cognitive dysfunction caused by long COVID by using only benzoic acid or a benzoate as the active ingredient.

[0042] Alternatively, in another embodiment, the composition may be administered to a subject in combination with other active ingredients, as long as the effects of the present disclosure are not impaired. Benzoic acid or a benzoate salt and the other active ingredient may be provided in a single composition, or may be provided in separate compositions.

[0043] Many embodiments have been used to illustrate the present disclosure, and the following examples are not intended to limit the scope of the present disclosure. <Example>

[0044] This disclosure explored the efficacy and safety of benzoates for the treatment of cognitive dysfunction in patients with long COVID.

[0045] We conducted a 24-week, open-label clinical trial of sodium benzoate. Eleven individuals with long-term COVID-induced cognitive impairment were recruited and administered sodium benzoate at doses ranging from 250 mg to 3000 mg daily for 24 weeks. The Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cognitive, primary outcome) was measured every 8 weeks. An additional cognitive composite score was measured at baseline and endpoint. Of the 11 patients, two completed treatment with a final dose of 500 mg / day of sodium benzoate, six at 750 mg / day, and three at 1000 mg / day. The sodium benzoate dosing regimen was determined based on the amounts identified in previously reported studies ( Lin and Chen et al., 2014 ; Lane and Tu et al., 2021 ), which showed that sodium benzoate was safe and effective in patients with early-stage Alzheimer's disease after a 24-week treatment period.

[0046] (evaluation) The primary outcome was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) (43), measured at weeks 0, 8, 16, and 24. The ADAS-Cog is the most commonly used cognitive assessment tool in clinical trials for AD (Alzheimer's disease). This tool consists of 11 tasks, including word recall, naming, command, constructional behavior, ideomotor, orientation, word recognition, recall of commands, oral language ability, word finding difficulty, and comprehension. Scores range from 0 (highest) to 70 (lowest).

[0047] [Table 1]

[0048] As shown in Table 1, this pilot open-label clinical trial demonstrated improved cognitive function after 24 weeks of sodium benzoate treatment, with the ADAS-Cog score decreasing from a mean score of 12.8 ± 11.0 (SD) at baseline to 8.5 ± 8.6 at endpoint (p = 0.026). Furthermore, the safety profile was favorable, with no patients withdrawing due to adverse events. These promising findings are the first to demonstrate the efficacy of sodium benzoate in treating brain fog in long COVID syndrome.

[0049] The above description of the detailed embodiments is merely an example for disclosing the principles and functions of the present disclosure, and is not intended to limit the scope of the present disclosure. Those skilled in the art should understand that all modifications and variations that comply with the spirit and principles of the present disclosure are encompassed within the scope of the appended claims. The specification and examples are for illustrative purposes only, and the full scope of the present disclosure is intended to be indicated by the appended claims.

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Claims

1. A pharmaceutical composition for preventing or treating cognitive impairment, A pharmaceutical composition, wherein the pharmaceutical composition comprises benzoic acid or a benzoate salt.

2. 2. The pharmaceutical composition of claim 1, wherein the benzoate is sodium benzoate, potassium benzoate, calcium benzoate, 2-aminobenzoate, 3-aminobenzoate, 4-aminobenzoate, benzyl benzoate, or methyl benzoate.

3. 2. The pharmaceutical composition of claim 1, wherein the cognitive dysfunction is cognitive dysfunction caused by COVID or other inflammation-related diseases.

4. 10. The pharmaceutical composition of claim 1, wherein the benzoic acid or benzoate is administered in an amount of 200 mg / day to 3000 mg / day.

5. 10. The pharmaceutical composition of claim 1, wherein the benzoic acid or benzoate is administered from 1 to 4 times daily.

6. 10. The pharmaceutical composition of claim 1, wherein the benzoic acid or benzoate is administered for a period ranging from one month to one year.

7. 10. The pharmaceutical composition of claim 1, wherein the benzoic acid or benzoate is administered for a period ranging from 8 weeks to 6 months.