WO2023036105A1 - Méthode de traitement d'une maladie neurodégénérative - Google Patents

Méthode de traitement d'une maladie neurodégénérative Download PDF

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WO2023036105A1
WO2023036105A1 PCT/CN2022/117178 CN2022117178W WO2023036105A1 WO 2023036105 A1 WO2023036105 A1 WO 2023036105A1 CN 2022117178 W CN2022117178 W CN 2022117178W WO 2023036105 A1 WO2023036105 A1 WO 2023036105A1
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disease
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PCT/CN2022/117178
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张寰
桑绍明
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上海日馨医药科技股份有限公司
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Publication of WO2023036105A1 publication Critical patent/WO2023036105A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention belongs to the field of biomedicine, and in particular relates to methods for preventing or treating neurodegenerative diseases, alleviating symptoms of neurodegenerative diseases, or delaying the progress of neurodegenerative diseases, which comprises administering a preventive or therapeutically effective dose to individuals in need thereof A first agent and a prophylactically or therapeutically effective amount of a second agent, wherein the first agent is benfotiamine or a pharmaceutically acceptable salt thereof; and the second agent is an acetylcholinesterase inhibitor.
  • AD Alzheimer's disease
  • GDP global gross domestic product
  • AD is a disease with multiple pathophysiological changes, including neuronal loss, glial cell activation, and characteristic senile plaques formed by extracellular ⁇ -amyloid (A ⁇ ) deposition, and neurofibrillary tangles caused by hyperphosphorylation of intracellular Tau protein. Knot and so on.
  • synaptic loss, brain glucose metabolism disorder, and oxidative stress are also constant pathological changes in the AD brain, and the decline in brain glucose metabolism is closely related to cognitive dysfunction. Due to the unclear pathogenesis, AD still lacks effective treatments.
  • the application provides methods for preventing or treating neurodegenerative diseases, reducing symptoms of neurodegenerative diseases, or delaying the progress of neurodegenerative diseases, which includes administering a preventive or therapeutically effective amount of the first An agent and a prophylactically or therapeutically effective amount of a second agent, wherein the first agent is benfotiamine or a pharmaceutically acceptable salt thereof; and the second agent is an acetylcholinesterase inhibitor.
  • the present application provides the preparation of the first medicament for preventing or treating neurodegenerative diseases, alleviating the symptoms of neurodegenerative diseases, or delaying the progress of neurodegenerative diseases in combination with the second medicament. Uses in medicine.
  • the present application provides the first medicament for use in combination with the second medicament to prevent or treat neurodegenerative diseases, alleviate symptoms of neurodegenerative diseases, or delay the progression of neurodegenerative diseases.
  • the neurodegenerative disease is preferably Alzheimer's disease; more preferably, the Alzheimer's disease is mild to moderate Alzheimer's disease.
  • Fig. 1 is the impact of each compound on the incubation period of animals in the embodiment
  • Fig. 2 is the impact of each compound on the number of times of animal crossing in the embodiment
  • Fig. 3 is the effect of each compound in the Examples on the target quadrant time of animals.
  • Donepezil molecular formula C 24 H 29 NO 3 , structural formula is Its common medicinal form is donepezil hydrochloride, which is the main drug for the clinical treatment of AD. It increases the level of acetylcholine by inhibiting cholinesterase to delay the progression of AD in the middle and early stages and improve the clinical symptoms of early AD.
  • Benfotiamine (benzoylthiamineomonophosphate, referred to as BTMP), the molecular formula C 19 H 23 N 4 O 6 PS, the structural formula is Benfotiamine can improve the shortcoming of low bioavailability of water-soluble vitamin B1, increase the concentration of vitamin B1 in blood and tissues, and thus improve the curative effect.
  • pharmaceutically acceptable salt includes acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, seabenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid Salt, Pam
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium, sodium, tromethamine and zinc salts.
  • first agent and said second agent when used in combination, this means that in one embodiment, said two compounds may be administered simultaneously. In another embodiment, when said first agent and said second agent are used in combination, this means that said two compounds are administered separately in suitable separate pharmaceutical compositions.
  • the separate compositions can be administered simultaneously, e.g., in the morning or evening, once a day, at regular intervals; or they can be administered independently, e.g., one compound twice a day after breakfast and dinner , at regular intervals, and the other compound is administered at regular intervals once a day after dinner.
  • prevention refers to the prior administration of a drug to avoid or prevent the occurrence of one or more symptoms of a disease or disorder.
  • prophylactic administration of a drug is understood to mean substantially reducing the likelihood or severity of a disorder or symptoms of a disorder, and this is the intended meaning in this disclosure.
  • Prevention is divided into primary prevention (to prevent the development of the disease) and secondary prevention (whereby the disease has already developed and the patient is protected from worsening of the process).
  • treating means reversing, alleviating, inhibiting the disorder or condition to which such term applies or the progression of one or more symptoms of such disorder or condition, or Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.
  • the term “treating” may include reducing or alleviating cognitive impairment (such as impaired memory and/or orientation) or overall functional impairment (activities of daily living (ADL)) and/or slowing or reversing progressive deterioration in ADL or Cognitive impairment in individuals with mild to moderate Alzheimer's disease.
  • cognitive impairment such as impaired memory and/or orientation
  • ADL overall functional impairment
  • the term “treating” can also refer to delaying disease progression in patients with additional symptoms associated with Alzheimer's disease, such as, but not limited to, using ADAS-cog, MMSE, ADCS-ADL criteria, CDR-sb, or NPI overall criteria One or more of those identified.
  • the term “delayed progression” refers to a slower than expected progression or persistence or worsening of an individual's disease compared to untreated patients or patients treated with only a single agent (eg, donepezil). can be determined using, for example, the Alzheimer's Disease Assessment Scale (ADAS-cog) or the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) cognitive performance.
  • ADAS-cog Alzheimer's Disease Assessment Scale
  • ADCS-ADL Alzheimer's Disease Cooperative Study-Activities of Daily Living
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • an “effective amount” is a clinically observable amount associated with Alzheimer's disease (as measured by ADAS-cog) (Rosen WG et al., A new scale for Alzheimer's disease, Am J Psychiatry, 1984; 141:1356-64). An amount sufficient to provide an observable prophylactic or therapeutic benefit compared to a baseline of observed signs and symptoms.
  • ADAS-cog was measured according to Huali Wang et al. The cognitive subscale of Alzheimer's Disease Assessment Scale, Chinese version in staging of Alzheimer disease, Alzheimer Dis Assoc Disord. Oct-Dec 2004; 18(4): 231-5.
  • ADCS-ADL was measured according to Galasko et al. An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997; 11 Suppl 2: S33-9.
  • Neuropsychiatric Inventory comprehensive assessment of psychopathology in dementia. Neurology, 1994;44:2308-2314 , measuring the Neuropsychiatric Inventory (NPI).
  • MMSE Mini-Mental State Examination
  • Moderate Alzheimer's disease may mean a score on the Mini-Mental State Examination (MMSE) scale between 11 and 19, inclusive.
  • reduced rate of deterioration in score is meant a decrease in the change in score from baseline in the treatment group compared to the change in score from baseline in the placebo group (or without treatment).
  • the present application provides methods for preventing or treating neurodegenerative diseases, reducing symptoms of neurodegenerative diseases, or delaying the progress of neurodegenerative diseases, comprising administering a preventive or therapeutically effective amount of A first agent and a prophylactically or therapeutically effective amount of a second agent, wherein the first agent is benfotiamine or a pharmaceutically acceptable salt thereof; and the second agent is an acetylcholinesterase inhibitor.
  • the first agent and the second agent are administered separately.
  • the present invention provides the use of a first agent in the preparation of a medicament for preventing or treating a neurodegenerative disease, alleviating the symptoms of a neurodegenerative disease, or delaying the progression of a neurodegenerative disease in combination with a second agent. use.
  • the present invention provides the use of a second agent in the preparation of a medicament for preventing or treating a neurodegenerative disease, alleviating the symptoms of a neurodegenerative disease, or delaying the progression of a neurodegenerative disease in combination with the first agent. use.
  • the present invention provides the use of a first agent in the manufacture of a neurodegenerative disease in a subject being treated with a therapy comprising a second agent, to alleviate the symptoms of said neurodegenerative disease, or to delay the Use in medicines for the progression of neurodegenerative diseases.
  • the present invention provides a second agent in the manufacture of a neurodegenerative disease for the prevention or treatment of a subject being treated with a therapy comprising the first agent, to alleviate the symptoms of said neurodegenerative disease, or to delay the Use in medicines for the progression of neurodegenerative diseases.
  • the present invention provides a first agent for use in combination with a second agent to prevent or treat a neurodegenerative disease, alleviate the symptoms of a neurodegenerative disease, or delay the progression of a neurodegenerative disease.
  • the present invention provides a second agent for use in combination with a first agent to prevent or treat a neurodegenerative disease, alleviate the symptoms of a neurodegenerative disease, or delay the progression of a neurodegenerative disease.
  • the present invention provides a first agent for preventing or treating a neurodegenerative disease, alleviating the symptoms of said neurodegenerative disease, or delaying progression of neurodegenerative diseases.
  • the present invention provides a second agent for preventing or treating a neurodegenerative disease, alleviating the symptoms of said neurodegenerative disease, or delaying progression of neurodegenerative diseases.
  • the neurodegenerative disease is Alzheimer's disease, more preferably, the Alzheimer's disease is mild to moderate Alzheimer's disease.
  • the first agent is benfotiamine, or a pharmaceutically acceptable salt thereof; and the second agent is an acetylcholinesterase inhibitor.
  • the second agent is donepezil, rivastigmine, galantamine, tacrine or a pharmaceutically acceptable salt thereof; preferably donepezil or a pharmaceutically acceptable salt thereof; most Preferred is donepezil hydrochloride.
  • the first agent is administered in an amount of about 0.005 mg/day to about 5000 mg/day, such as about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000mg/ daily dosage.
  • the first agent is administered in an amount of about 600 mg/day.
  • the first agent is administered in an amount of about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg body weight per day, For example, at about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg, about 200 ⁇ g/kg, about 225 ⁇ g/kg, about 250 ⁇ g/kg, about 275 ⁇ g/kg, about 300 ⁇ g/kg, about 325 ⁇ g/kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg, about 450 ⁇ g/kg, about 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇ g/kg, or about 1
  • the second agent is administered in an amount of about 0.005 mg/day to about 5000 mg/day, such as about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000mg/ daily dosage.
  • the second agent is administered in an amount of about 5 mg/day.
  • the second agent is administered in an amount of about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg body weight per day, For example, at about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg, about 200 ⁇ g/kg, about 225 ⁇ g/kg, about 250 ⁇ g/kg, about 275 ⁇ g/kg, about 300 ⁇ g/kg, about 325 ⁇ g/kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg, about 450 ⁇ g/kg, about 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇ g/kg, or about 1
  • the daily dose of the first agent and/or the second agent is administered in one dose or in two, three or four divided doses.
  • the daily dose of the first agent is administered in two divided doses.
  • the daily dose of said second agent is administered as a single dose.
  • the first agent and/or the second agent are administered continuously for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks , at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 24 weeks, at least 25 weeks, at least 30 weeks, at least 35 weeks, at least 40 weeks, at least 45 weeks, at least 50 weeks, at least 51 weeks, at least 52 weeks , at least 53 weeks, at least 54 weeks, or at least 55 weeks.
  • the first agent and/or the second agent are administered for one or more (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) courses of treatment , wherein each course of treatment lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, At least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; week, three weeks or four weeks.
  • each course of treatment lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least
  • said first agent and/or said second agent is administered by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or Administration is oral, buccal, nasal, transmucosal, topically, in the form of ophthalmic preparations or by inhalation.
  • injection e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation
  • transdermally e.g., oral, buccal, nasal, transmucosal, topically, in the form of ophthalmic preparations or by inhalation.
  • said first agent and said second agent are administered orally.
  • the first medicament and/or the second medicament are selected from tablets, capsules, lozenges, hard lozenges, powders, sprays, creams, ointments, suppositories, gelatin Dosage forms of gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups are administered.
  • said first agent and said second agent are administered in the dosage form of a tablet.
  • the method improves the following pathophysiological manifestations in the individual: cognitive behavioral abnormalities, neurodegenerative changes (e.g., progressive synapse/neuron loss and brain atrophy), ⁇ -amyloid deposition, Tau Aberrant phosphorylation and its resulting neurofibrillary tangles, glial cell activation and inflammation and/or impaired glucose metabolism in the brain.
  • the second agent is administered in a lower amount than the amount administered when the second agent is administered alone or in the absence of the first agent.
  • the first agent enhances the efficacy of the second agent in treating a neurodegenerative disease and/or reduces the side effects of the second agent in treating a neurodegenerative disease.
  • said individual has received monotherapy with said second agent prior to receiving the combined administration of said first agent and said second agent.
  • the method results in an improvement or no deterioration or a reduced rate of deterioration in at least one assessment selected from: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog); Clinical Dementia Rating Pencil Box (CDR-sb); Alzheimer's Disease Collaborative Study Activities of Daily Living Scale (ADCS-ADL); Neuropsychiatric Inventory (NPI); and Mini-Mental State Examination (MMSE).
  • ADAS-cog Alzheimer's Disease Assessment Scale-Cognitive Subscale
  • CDR-sb Clinical Dementia Rating Pencil Box
  • ADCS-ADL Alzheimer's Disease Collaborative Study Activities of Daily Living Scale
  • NPI Neuropsychiatric Inventory
  • MMSE Mini-Mental State Examination
  • the method results in a decreased rate of deterioration in the ADAS-cog score.
  • the method reduces the rate of deterioration of the ADAS-cog score by an average of 1-5 points, preferably 2-3.5 points.
  • the present invention encompasses any combination of the above embodiments.
  • Rodents have a strong motivation to escape from the water environment in water, and they can escape from the water environment in the fastest and most direct way.
  • the process of learning to escape from the water environment reflects the learning ability of animals.
  • Space positioning according to the surrounding environment and purposeful swimming to a safe place in the water (such as a platform) can reflect the spatial learning and memory ability of animals.
  • mice Male APP/PS1/Tau mice and C57BL/6 wild-type mice. Rats aged 8 months and weighing 250-300 g were purchased from The Jackson laboratory.
  • APP/PS1/Tau mice are APP/PS1/tau triple transgenic Alzheimer's disease (3 ⁇ Tg-AD) model mice.
  • the appearance of A ⁇ deposition is several months earlier than the pathological changes of tau protein, which can more realistically simulate Clinical course and pathological changes of Alzheimer's disease.
  • CMC-Na sodium carboxymethylcellulose
  • BTMP bisenfotiamine
  • Shanghai Rixin Biotechnology Co., Ltd. batch number 1908002
  • donepezil hydrochloride Eisai (China) Manufactured by Pharmaceutical Co., Ltd., lot number 1704019.
  • Preparation of 20mg/ml BTMP suspension (dosage 400mg/kg): Weigh 500mg BTMP, add 0.7% m/v CMC-Na to 25ml, and obtain 20mg/ml BTMP suspension.
  • Preparation of 10mg/ml BTMP suspension + 0.075mg/ml donepezil hydrochloride suspension dose 200mg/kg BTMP suspension + 1.5mg/kg donepezil hydrochloride suspension: prepare 20mg/ml BTMP suspension respectively liquid and 0.15mg/ml donepezil hydrochloride suspension, mixed in equal volumes before administration to obtain 10mg/ml BTMP suspension + 0.075mg/ml donepezil hydrochloride suspension.
  • Preparation of 5mg/ml BTMP suspension + 0.075mg/ml donepezil hydrochloride suspension dose 100mg/kg BTMP suspension + 1.5mg/kg donepezil hydrochloride suspension: prepare 10mg/ml BTMP suspension respectively liquid and 0.15mg/ml donepezil hydrochloride suspension, mixed in equal volumes before administration to obtain 5mg/ml BTMP suspension + 0.075mg/ml donepezil hydrochloride suspension.
  • mice in the blank control group, the model group and the experimental group were administered orally for 8 weeks according to 2.2.
  • Dosage/specification, and water maze training and testing began in the last week of administration.
  • the water maze training and testing lasted for 6 days, the training period was 5 days, and the testing period was 1 day.
  • the water maze training and testing period (a total of 6 days), keep the indoor lighting and other conditions consistent, keep the room quiet, and eliminate the environment, personnel and other interference.
  • the training in the first quadrant After the training in the first quadrant, the training in the remaining three quadrants was performed sequentially, and it was not necessary to place the mice on the platform for 15 seconds before the training.
  • the training time interval between two quadrants of each mouse was 10-15 minutes. In this way of training, continuous training for 5 days.
  • Test period (Day 6) 24 hours after the last training session, the platform was removed, and the mice were dropped on the opposite side of the quadrant of the original platform (that is, the farthest position from the platform).
  • the quadrant where the platform is located) time, the times of passing through the original platform position (the number of times of crossing the platform) and the time of passing through the original platform position for the first time (latency period) are used as the indicators for the investigation of the mouse's spatial learning and memory ability.
  • the latency time of the mice in the model group was significantly increased, the times of crossing the platform were less, and the time in the target quadrant was significantly reduced, and there was a significant difference. It shows that there are differences between the transgenic model mice and normal mice in the ability of spatial learning and memory, and is suitable for training in spatial learning and memory. Compared with the model group, the incubation period, times of platform crossing and target quadrant time of the positive control group and the experimental group were significantly improved, and there were significant differences. The results are shown in Table 1.
  • the order is blank control group, BTMP+ donepezil hydrochloride, 1/2BTMP+ donepezil hydrochloride, BTMP, donepezil hydrochloride, VB1, model group (the one with the best performance) .
  • the results are shown in Figures 1 to 3. The results show that VB1 does not significantly improve the learning and memory of AD mice, and BTMP, donepezil hydrochloride, BTMP+ donepezil hydrochloride, and 1/2BTMP+ donepezil hydrochloride have significant improvements in the spatial memory learning ability of AD mice. And the combined administration of BTMP and donepezil hydrochloride has the best improvement effect, which is obviously better than that of BTMP and donepezil hydrochloride alone.
  • results of the water maze experiment of the present invention show that after the combined administration of benfotiamine and donepezil hydrochloride, a better synergistic effect can be achieved, which can better improve the spatial learning and memory ability of AD mice, and the effect is significantly better than that of benfotiamine Or the effect of donepezil hydrochloride when used alone is also better than the effect of vitamin B1, and the pharmaceutical composition of the present invention has better drug activity in the treatment of Alzheimer's disease.
  • ADAS-cog scale including 11 items in total (word recall, naming, executive instructions, structural exercises, intentional exercises, orientation, word recognition, recall test instructions, oral language skills, word finding skills, language comprehension skills)
  • word recall naming, executive instructions, structural exercises, intentional exercises, orientation, word recognition, recall test instructions, oral language skills, word finding skills, language comprehension skills
  • the score ranges from 0 to 70 points, the higher the score indicates the more severe cognitive impairment
  • the patients were scored after 12, 24, 36, and 52 weeks of administration.
  • the between-group differences in patient score changes from baseline are shown in the table below.
  • a 52-week clinical trial study was conducted in patients with moderate Alzheimer's disease (patients with an MMSE of 11-19 at the time of enrollment screening were classified as moderate AD patients).
  • the study grouping, dosing regimen and the number of patients who completed the experiment in each group are as follows:
  • Apolipoprotein E (APOE) genotype was measured before administration, and AD patients were divided into APOE ⁇ 4 allele carrier group and non-APOE ⁇ 4 allele carrier group.
  • the ADAS-cog score was performed on the patient after 52 weeks of administration, and the changes in the patient's score relative to the baseline are shown in the table below.

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Abstract

L'invention concerne une application d'une composition pharmaceutique composée d'un premier médicament et d'un second médicament pour la préparation d'un médicament destiné à la prévention ou au traitement d'une maladie neurodégénérative, au soulagement de symptômes de la maladie neurodégénérative ou au ralentissement de la progression de la maladie neurodégénérative. Le premier médicament est la benfotiamine ou un sel pharmaceutiquement acceptable de cette dernière, et le second médicament est un inhibiteur de l'acétylcholinestérase qui est le donépézil, la rivastigmine, la galantamine, la tacrine ou un sel pharmaceutiquement acceptable de ces derniers.
PCT/CN2022/117178 2021-09-09 2022-09-06 Méthode de traitement d'une maladie neurodégénérative WO2023036105A1 (fr)

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