Treatment for dementia

Abstract

The purpose of the present invention is to provide a pharmaceutical composition for preventing or treating dementia, and a method for preventing or treating dementia.　The present invention pertains to: a pharmaceutical composition for preventing or treating dementia, the pharmaceutical composition comprising methylcobalamin as an active ingredient and being administered parenterally; a prevention or treatment method for preventing or treating dementia; and use.

Description

Treatment for Dementia

[0001] This patent application claims priority and benefits under the Paris Convention based on Japanese Patent Application No. 2024-232051 (filed on December 27, 2024) and priority under Article 41 of the Japanese Patent Law. By incorporating the above application herein by reference, the entire contents described in the above application are incorporated into this specification.

[0002] The present invention relates to a pharmaceutical composition for preventing or treating dementia, specifically, a pharmaceutical composition for preventing or treating dementia, which is a parenterally administered pharmaceutical composition containing ultra-high-dose methylcobalamin as an active ingredient.

[0003] Methylcobalamin is a derivative of active vitamin B12. The present inventor has shown that by intramuscular injection of an ultra-high dose (25 mg / day for 14 consecutive days, or 50 mg / day twice a week), which far exceeds the amount for supplementing vitamin deficiency as a supplement, of methylcobalamin, it becomes a disease-modifying treatment for amyotrophic lateral sclerosis (ALS), a neurodegenerative disease (Patent Document 1). As the mechanism of action of this treatment method, it was considered that ultra-high-dose methylcobalamin significantly reduces the concentration of blood homocysteine with a very high significant difference (Non-Patent Document 1).

[0004] Conventionally, vitamin B12 has been inferred to have an effect of improving dementia through a decrease in blood homocysteine (Non-Patent Document 2). Patent Document 2 describes a pharmaceutical composition for treating Alzheimer's disease or Parkinson's disease containing azelastine or a pharmaceutically acceptable salt of azelastine and methylcobalamin. However, when looking at methylcobalamin, its administration method is oral. Also, there has been no example where an improvement in the objective indicators of dementia has been actually shown in relation to methylcobalamin.

[0005] Japanese Patent Application Laid-Open No. 10-218775 Japanese Patent Publication No. 2023-539405

[0006] Oki R, et al., Early-Stage Trial of Ultrahigh-Dose Methylcobalamin for ALSC. Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA Neurol. 2022;79(6):575-83Lin WZ, et al., O. Homocysteine, neurodegenerative biomarkers, and APOE epsilon4 in neurodegenerative diseases. Alzheimers Dement. 2024Kaji S, et al., Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis. Immunity. Online publication, Oct 16, 2024Braun DJ, et al., Microglial-associated responses to comorbid amyloid pathology and hyperhomocysteinemia in an aged knock-in mouse model of Alzheimer's disease. J Neuroinflammation. 2020;17(1):274

[0007] In recent years, the pathogenesis of Alzheimer's disease has become clearer, and it is believed that the apoE protein becomes the core within central nervous system microglia, initiating the aggregation of amyloid-beta protein (Non-Patent Literature 3). Therefore, it is expected that suppressing the activity of microglia, which are the carriers of neuroinflammation, can suppress the onset and progression of Alzheimer's disease (Non-Patent Literature 4). However, current therapies involve the use of expensive antibody drugs, or even inexpensive small molecule compounds, which only slightly suppress the progression of the disease, and have limitations in their therapeutic capacity. Therefore, there is a constant need for appropriate drug therapy that can fundamentally resolve Alzheimer's disease. In view of this situation, the present invention aims to provide a new drug therapy for treating and / or preventing Alzheimer's type dementia.

[0008] In this invention, the inventors have discovered that methylcobalamin (the active form of vitamin B12) can achieve significantly higher blood and cerebrospinal fluid concentrations than oral administration by intramuscular injection, which allows for the administration of ultra-high doses, rather than oral administration, where the amount transferred into the body is limited by intrinsic factor in the stomach. Furthermore, they have discovered that it can be used as an actual treatment for dementia, thus completing the present invention. Specifically, in two cases of patients with amyotrophic lateral sclerosis (ALS) and Alzheimer's disease, including the frontotemporal type, intramuscular injection of 25 mg / day for 14 consecutive days resulted in improvement in the Hasegawa Dementia Scale (HDS-R), an indicator of dementia, after 28 days.

[0009] Accordingly, the present invention includes the following embodiments: <Pharmaceutical Compositions> [Claim 1] A pharmaceutical composition for preventing or treating dementia, comprising methylcobalamin as an active ingredient, to be administered parenterally. [Claim 2] The pharmaceutical composition according to [Claim 1], wherein the daily dose is 15 to 100 mg of methylcobalamin. [Claim 3] The pharmaceutical composition according to [Claim 1] or [Claim 2], to be administered twice a week to daily for at least two consecutive weeks. [Claim 4] The pharmaceutical composition according to any one of [Claim 1] to [Claim 3], wherein the parenteral administration is by intramuscular injection. [Claim 5] The pharmaceutical composition according to any one of [Claim 1] to [Claim 4], wherein the dementia is Alzheimer's type, vascular, Lewy body type, or frontotemporal type. [Claim 6] The pharmaceutical composition according to [Claim 5], wherein the dementia is Alzheimer's type.

[0010] <Methods of Treatment> [Clause 11] A method for preventing or treating dementia, comprising administering methylcobalamin parenterally to a subject in need of such prevention or treatment. [Clause 12] The method according to [Clause 11], wherein the daily dose is 15 to 100 mg of methylcobalamin. [Clause 13] The method according to [Clause 11] or [Clause 12], administered twice a week to daily for at least two consecutive weeks. [Clause 14] The method according to any one of [Clause 11] to [Clause 13], wherein the parenteral administration is by intramuscular injection. [Clause 15] The method according to any one of [Clause 11] to [Clause 14], wherein the dementia is Alzheimer's type, vascular, Lewy body type, or frontotemporal type. [Clause 16] The method according to [Clause 15], wherein the dementia is Alzheimer's type.

[0011] <Limited Uses> [Clause 21] Methylcobalamin administered parenterally for the prevention or treatment of dementia. [Clause 22] Methylcobalamin according to [Clause 21], wherein the daily dose is 15 to 100 mg of methylcobalamin. [Clause 23] Methylcobalamin according to [Clause 21] or [Clause 22], administered twice a week to daily for at least two consecutive weeks. [Clause 24] Methylcobalamin according to any one of [Clause 21] to [Clause 23], wherein the parenteral administration is by intramuscular injection. [Clause 25] Methylcobalamin according to any one of [Clause 21] to [Clause 24], wherein the dementia is Alzheimer's type, vascular, Lewy body type, or frontotemporal type. [Clause 26] Methylcobalamin according to [Clause 25], wherein the dementia is Alzheimer's type.

[0012] <Uses> [Clause 31] Use of methylcobalamin for the manufacture of a medicine administered parenterally for the prevention or treatment of dementia. [Clause 32] Use according to [Clause 31], wherein the daily dose is 15 to 100 mg of methylcobalamin. [Clause 33] Use according to [Clause 31] or [Clause 32], administered twice a week to daily for at least two consecutive weeks. [Clause 34] Use according to any of [Clause 31] to [Clause 33], wherein the parenteral administration is by intramuscular injection. [Clause 35] Use according to any of [Clause 31] to [Clause 34], wherein the dementia is Alzheimer's type, vascular, Lewy body type, or frontotemporal type. [Clause 36] Use according to [Clause 35], wherein the dementia is Alzheimer's type.

[0013] This invention applies to patients with dementia, such as Alzheimer's disease, using the dosage and administration methods approved for ALS. Methylcobalamin has a long history of use as a pharmaceutical drug, its safety is guaranteed, and its synthesis method is well established. The dosage and administration methods to be used in this invention have been proven safe in clinical trials targeting ALS. This invention presents one possible drug therapy that can fundamentally resolve dementia.

[0014] Figure 1A is a graph showing the time course of blood vitamin B12 concentration after a single 25 mg dose of ultra-high-dose methylcobalamin was administered by intramuscular injection. Figure 1B is a graph showing the results of measuring blood vitamin B12 concentration up to day 27 after administering 50 mg of ultra-high-dose methylcobalamin for 14 consecutive days by intramuscular injection. The results are the average values ​​for two ALS patients. Figure 1C is a graph showing the results of measuring B12 concentration in cerebrospinal fluid (CSF) up to day 28 after administering 25 mg of ultra-high-dose methylcobalamin for 14 consecutive days by intramuscular injection.

[0015] In one embodiment, the present invention relates to a pharmaceutical composition for preventing or treating dementia, comprising methylcobalamin as an active ingredient, which is administered parenterally. The inventors have now completed the present invention based on their discovery in a clinical study of ultra-high doses of methylcobalamin that patients with both amyotrophic lateral sclerosis (ALS) and Alzheimer's disease showed improvement not only in ALS but also in cognitive function after administration of ultra-high doses of methylcobalamin.

[0016] Patent Document 2 describes a pharmaceutical composition containing methylcobalamin for treating patients with Alzheimer's disease or Parkinson's disease, but the method of administration of that pharmaceutical composition is oral, not parenteral. Furthermore, the pharmacokinetics of intramuscular injection have been established for ALS. In the present invention, "parenteral" means administration intramuscularly, subcutaneously, intravenously, into the synovial bursa, or into the abdominal cavity. Preferably, intramuscular administration, specifically intramuscular injection.

[0017] Furthermore, Patent Document 2 states that the maximum oral dose of methylcobalamin is 1 mg, and even if more is administered, intrinsic factor is present in the stomach and it is not absorbed. In the present invention, the daily dose of methylcobalamin is 15 to 100 mg, preferably 30 to 70 mg, more preferably 40 to 60 mg, and most preferably 50 mg.

[0018] This invention relates, in one embodiment, to a pharmaceutical composition of the present invention that is administered twice a week to daily for at least two consecutive weeks. A typical administration method involves daily administration for 14 days, and if an effect is observed, administration twice a week is continued for two weeks to two years, specifically from two weeks to six months, or from two weeks to one year.

[0019] In this invention, dementia includes Alzheimer's disease, vascular dementia, Lewy body dementia, or frontotemporal dementia, or any combination thereof. Preferably, dementia is Alzheimer's disease. "Dementia" is a condition in which the function of nerve cells in the brain gradually declines due to various brain diseases, leading to a decline in cognitive functions such as memory and judgment, and causing difficulties in social life. There are several types of dementia, and the progression of symptoms and causes differ depending on the type. The most common type of dementia is Alzheimer's disease, in which abnormal proteins accumulate in the brain and the number of nerve cells in the brain decreases. In addition, there are various other types, such as "vascular dementia" caused by damage to blood vessels in the brain, "Lewy body dementia," and "frontotemporal dementia."

[0020] The Hasegawa Dementia Scale (HDS-R) is used to assess the symptoms and severity of dementia in an elderly individual. This test was developed to screen for dementia in the general elderly population and can provide a general indication of cognitive impairment, particularly in memory.

[0021] The following describes the evaluation items of the Hasegawa Dementia Scale. The Hasegawa Dementia Scale is a test that focuses on evaluating memory, and there are a total of nine evaluation items as follows. It is scored out of 30 points, and a score of 20 or less is considered to indicate a high possibility of dementia. 1. Age: A test to see if the person can state their own age. 2. Orientation to Date: A test to see if the person can understand their current situation, such as by asking about the date and day of the week. 3. Orientation to Place: A test to see if the person can understand their current situation, such as by asking where they are. 4. Word Encoding: The person is asked to remember three words ("cherry blossom, train, cat" or "plum blossom, dog, car"). This is a test to see if the person can remember new things. The person is also told that they will be asked about it later. 5. Calculation: Test to see if the subject can do simple subtraction. 6. Reverse Recall: Test to see if the subject can say the numbers the questioner says in reverse. 7. Delayed Recall: Test to see if the subject can recall the words they memorized in question 4. 8. Object Recall: Test to see if the subject can recall five items such as a clock, pencil, and glasses after they are shown and then hidden, and then asked to identify what was there. 9. Language Fluency: Test to see if the subject can name as many vegetables as possible that they know.

[0022] In the present invention, “treatment” means a method or process aimed at (1) delaying the onset of dementia; (2) slowing or stopping the progression, exacerbation, or worsening of the symptoms of dementia; (3) bringing about remission of the symptoms of dementia; or (4) curing dementia. Treatment may be administered as a preventive measure before the onset of the disease or condition, or treatment may be administered after the onset of the disease.

[0023] In this invention, "prevention" means preventing the onset of dementia in advance.

[0024] The method of administration can be appropriately selected depending on the patient's age and symptoms. While the dosage and method of administration will vary depending on the patient's weight, age, and symptoms, a person skilled in the art can determine an appropriate dosage and method of administration by considering these factors.

[0025] The parenterally administered compositions of the present invention typically contain about 10 mg to about 50 mg, preferably 15 mg to 40 mg, and most preferably 25 mg of methylcobalamin in solution. Preservatives and buffers may also be advantageously used. To minimize or eliminate irritation at the injection site, such compositions may preferably contain a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such compositions is preferably in the range of about 5% to about 15% by weight. The surfactant may be a single component having the above HLB or a mixture of two or more components having the desired HLB.

[0026] The pharmaceutical compositions of the present invention can be administered parenterally, i.e., intramuscularly, subcutaneously, intravenously, intrabursally, or intraperitoneally, for injection, preferably as sterile liquids or liquid mixtures, such as water, saline solution, aqueous dextrose and related sugar solutions, alcohols, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-1,1-dioxolane-4-methanol, ethers, such as poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters, or fatty acid glycers or acetylated fatty acid glycers, in a pharmaceutical carrier for injection, preferably with a pharmaceutically acceptable diluent.

[0027] Examples of surfactants used in parenteral compositions include the polyethylene sorbitan fatty acid ester class, such as sorbitan monooleate, and high molecular weight adducts of ethylene oxide and hydrophobic bases formed by the condensation of propylene oxide and propylene glycol.

[0028] The pharmaceutical compositions of the present invention may be in the form of sterile aqueous suspensions for injection. Such suspensions can be formulated according to known methods using a suitable dispersant or wetting agent and suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; natural phospholipids, such as lecithin; condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxide and long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol; condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydride, such as polyoxyethylene sorbitan monooleate.

[0029] Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents. Possible diluents and solvents include, for example, water, Ringer's solution, isotonic sodium chloride solution, and isotonic glucose solution. Furthermore, sterile fixatives may be used as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, may be used in the preparation of injectable preparations.

[0030] The pharmaceutical composition of the present invention may typically be a formulation containing 15 to 50 mg of methylcobalamin per ampoule. Alternatively, it may be a formulation containing 15 to 50 mg of methylcobalamin dissolved in 1 to 4 ml of ethanol, physiological saline, or buffer solution per ampoule.

[0031] In another embodiment, the present invention relates to a method for preventing or treating dementia, comprising administering methylcobalamin parenterally to a subject in need of such prevention or treatment. Furthermore, in yet another embodiment, the present invention relates to parenterally administered methylcobalamin for preventing or treating dementia. In yet another embodiment, the present invention relates to the use of methylcobalamin for manufacturing a parenterally administered medicament for preventing or treating dementia.

[0032] The present invention will be described in detail below with reference to examples and embodiments, but it should be noted that these are merely illustrative and not intended to limit the scope of the present invention.

[0033] Preparation Example Preparation of Ultra-High Dose Methylcobalamin Intramuscular Injection Formulation The therapeutic agent of the present invention, containing commercially available methylcobalamin as the active ingredient, was prepared for administration to the cases shown in the reference examples and examples below. Specifically, 30 ampoules of Eisai's "Methycobal Injection Solution 500 μg" were aseptically opened and the contents were combined to prepare a methylcobalamin preparation of the present invention with a total volume of 30 ml containing 25 mg of methylcobalamin.

[0034] Reference Example 1: Blood and Cerebrospinal Fluid Concentrations after Ultra-High Dose Methylcobalamin Intramuscular Injection Two ALS patients were each administered a methylcobalamin preparation prepared in the preparation example as a single 25 mg dose and then 50 mg for 14 consecutive days via intramuscular injection, and their blood vitamin B12 concentrations were measured by the HTLP method. The results obtained are shown in Figures 1A and 1B, respectively. With a single intramuscular injection (Figure 1A), the increase in blood concentration was transient. With 14 consecutive days of administration (Figure 1B), serum concentrations returned to normal about 3 days after the injections ended. These results indicate that the blood concentration was sustainably increased by continuous intramuscular injection of ultra-high dose methylcobalamin.

[0035] Furthermore, two ALS patients were administered 25 mg of the methylcobalamin preparation prepared using the example method via intramuscular injection for 14 consecutive days, and the vitamin B12 concentration in the cerebrospinal fluid (CSF) was measured. The results are shown in Figure 1C. The CSF concentration after 14 consecutive days of administration (Figure 1C) differed from the results in the blood (Figure 1B) in that it actually increased after administration and persisted for at least 14 days after the end of the injections. This result indicates that while the CSF concentration is usually below the detection range, continuous intramuscular injection of ultra-high doses of methylcobalamin leads to ultra-high CSF concentrations.

[0036] Case 1: Efficacy of ultra-high-dose methylcobalamin intramuscular injection in a 72-year-old male with ALS and Alzheimer's disease. Case 1 had been experiencing memory loss, such as being unable to remember people's names, for three years prior to his visit to the hospital. He had noticed weakness and muscle atrophy in his right hand for one year, and muscle atrophy in his left hand for six months. On the Hasegawa Dementia Scale (HDS-R), a score of 20 or less is considered to indicate a high probability of dementia, and Case 1 showed a borderline score of 20. Electromyography (EMG) confirmed a diagnosis of ALS. Case 1 received 25 mg of methylcobalamin, prepared using the prescribed method, intramuscularly for 14 consecutive days. Upon discharge 28 days later, his HDS-R score was 24, indicating normalization of cognitive function.

[0037] Example 2: Efficacy of ultra-high-dose methylcobalamin intramuscular injection in a 61-year-old male with ALS accompanied by dementia. Two years prior to his visit to the hospital, he experienced muscle spasms at night, and one year prior, he developed cognitive impairment and personality changes, such as repeatedly purchasing the same items for his work. Six months prior, he observed atrophy of the proximal muscles of both upper limbs, and was diagnosed with ALS by electromyography. Upon admission, he scored 7 on the Hasegawa Dementia Scale (HDS-R), indicating severe dementia. When 25 mg of methylcobalamin, prepared using the formulation method, was administered intramuscularly for 14 consecutive days, his HDS-R score was 17 at discharge 28 days later, showing significant improvement. Thus, it has been demonstrated that the formulation of the present invention can be used as a treatment for dementia.

Claims

1. A pharmaceutical composition for preventing or treating dementia, comprising methylcobalamin as an active ingredient, which is administered parenterally.

2. The pharmaceutical composition according to claim 1, wherein the daily dose is 15 to 100 mg of methylcobalamin.

3. The pharmaceutical composition according to claim 2, administered twice a week to daily for at least two consecutive weeks.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein parenteral administration is by intramuscular injection.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the dementia is of the Alzheimer's type, vascular type, Lewy body type, or frontotemporal type.

6. The pharmaceutical composition according to claim 5, wherein the dementia is of the Alzheimer's type.

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