WO2018161808A1 - 维生素组合物在制备用于预防、治疗或延迟阿尔茨海默病的药物中的用途 - Google Patents

维生素组合物在制备用于预防、治疗或延迟阿尔茨海默病的药物中的用途 Download PDF

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WO2018161808A1
WO2018161808A1 PCT/CN2018/077107 CN2018077107W WO2018161808A1 WO 2018161808 A1 WO2018161808 A1 WO 2018161808A1 CN 2018077107 W CN2018077107 W CN 2018077107W WO 2018161808 A1 WO2018161808 A1 WO 2018161808A1
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vitamin
parts
composition
disease
effective amount
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French (fr)
Chinese (zh)
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周明东
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Zensun Shanghai Science and Technology Ltd
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Zensun Shanghai Science and Technology Ltd
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Priority to US16/491,560 priority Critical patent/US11464797B2/en
Priority to BR112019018652A priority patent/BR112019018652A2/pt
Priority to EP24189913.7A priority patent/EP4461361A3/en
Priority to CA3054972A priority patent/CA3054972A1/en
Priority to JP2019548652A priority patent/JP7169285B2/ja
Priority to ES18763903T priority patent/ES2989651T3/es
Priority to AU2018229920A priority patent/AU2018229920B2/en
Priority to EP18763903.4A priority patent/EP3593805B1/en
Priority to CN201880015481.XA priority patent/CN110520135A/zh
Application filed by Zensun Shanghai Science and Technology Ltd filed Critical Zensun Shanghai Science and Technology Ltd
Publication of WO2018161808A1 publication Critical patent/WO2018161808A1/zh
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Priority to US17/945,684 priority patent/US20230248756A1/en
Priority to JP2022172956A priority patent/JP2023011769A/ja
Priority to AU2024202678A priority patent/AU2024202678A1/en
Priority to JP2024198677A priority patent/JP2025024089A/ja
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • 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

  • vitamins B1, B2, B3, B5, B7, B6, B9, and B12 are involved in the biological oxidation of the body and the physiological metabolism of carbohydrates, fats, and proteins, thereby promoting energy metabolism and production.
  • these vitamins can be used to help treat the symptoms and causes of metabolic-related diseases such as improving blood sugar regulation and promoting fat metabolism.
  • vitamin drugs have extremely high clinical value, and play an extremely important role in the prevention and treatment of energy metabolism diseases, regulation of the nervous system and even delaying the occurrence of AD.
  • the potential value of vitamin drugs in the treatment of energy metabolism and AD is unquestionable. It is of social and clinical significance to regulate the metabolism of energy in the brain and to delay the prevention and reduce the occurrence of AD.
  • the invention in another aspect, relates to a composition
  • a composition comprising an effective amount of a vitamin B, a C-group composition, and other effective amounts of a vitamin family compound.
  • the composition comprises an effective amount of vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (nicotinic acid), vitamin B5 (pantothenic acid), vitamin B6, B7 (biological , vitamin C and other effective amounts of vitamin compounds.
  • vitamin B group composition includes all vitamin B compounds or analogs or derivatives thereof, such as vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (nicotinic acid), Vitamin B5 (pantothenic acid) and vitamin B6.
  • Figure 1 Group of animals acquired test (D1-D5) on-stage latency
  • This study aimed to investigate the relationship between Alzheimer's disease and energy metabolism in the brain, and further study whether vitamin compound can play a role in the prevention and treatment of Alzheimer's disease by regulating energy metabolism in the brain.
  • Streptozotocin, vitamin BC tablets (Zesheng): The weight ratio of the components contains 100 parts of vitamin B1, 100 parts of vitamin B2, 100 parts of vitamin B3, 100 parts of vitamin B5, 100 parts of vitamin B6, 0.1 parts of B7, 0.4 parts B9, 0.1 part vitamin B12 and 150 parts vitamin C.
  • Solitaire mitochondrial enzyme activity kit (PDH article number MS2103, ⁇ -KGDH article number MS2100, ICDHm article number MS2104, SDH article number MS2102), TAKARA SYBR II, TIANGEN total RNA extraction kit, TOYOBO reverse transcription kit, primer (production synthesis) )
  • Microplate reader Molecular Devices SpectraMax M2
  • the model is an AD animal model (Icv-STZ model) that simulates sporadic AD (SAD). It is successful in the intracerebral glucose/energy metabolism caused by streptozocin (STZ) in the lateral ventricle.
  • SAD sporadic AD
  • STZ streptozocin
  • Various pathological manifestations of SAD were simulated, such as oxidative stress, activation of inflammatory responses, abnormalities of the cholinergic pathway, hyperphosphorylation of tau and aggregation of A ⁇ , and learning and memory dysfunction.
  • This model has a short modeling time and can display some cognitive dysfunction and pathological features of AD within a few weeks. It is a relatively fast and easy to construct AD model, which makes up for the adoption of APP/PS1/tauP301L triple transgenic AD. The time cost of model mice.
  • the specific Icv-STZ model is built as follows:
  • Wistar rats 250-320g Wistar rats were anesthetized, fixed on the brain stereotaxic instrument, the top of the head was depilated, the skin was disinfected, the middle of the head was incision, and the anterior iliac crest was exposed, 0.9 mm after the anterior iliac crest, 1.5 mm to the left and right sides of the midline, and a micro syringe.
  • the needle was inserted vertically from the brain surface by 3.6 mm, and 5 ⁇ l of STZ (3 mg/kg) was slowly injected into the left and right lateral ventricles. The injection time was 8 min, and the needle was left for 2 min, and the needle was slowly withdrawn. All procedures were performed under aseptic conditions, and the skin incision was antibacterial with penicillin to suture the wound.
  • the sham operation group was injected with the same amount of normal saline.
  • mice converted to rat dose 0.5 ⁇
  • CMC-Na solution preparation Weigh 2.0g of CMC-Na powder, slowly add 300ml of ultrapure water, stir it magnetically until completely dissolved, dilute to 400ml, prepare 0.5% clear solution, put it at 4 °C .
  • Vitamin BC tablet dosage
  • vitamin BC tablet suspension Take appropriate amount of vitamin BC tablets, add 0.5% CMC-Na after grinding, shake and mix to form a stable suspension, 1.025 tablets/kg per mouse and 0.516 tablets for rats. /kg, once in the morning and evening.
  • donepezil hydrochloride solution Take appropriate amount of donepezil hydrochloride powder, add 0.5% CMC-Na, shake and mix to form a stable suspension, and give donepezil hydrochloride to 1.025 mg/kg per mouse and 0.516 mg/kg per rat. The solution was administered twice a day, and the donepezil hydrochloride solution was administered in the morning, and an equal volume of 0.5% CMC-Na vitamin BC tablet adjuvant solution was administered in the afternoon.
  • mice and rats were intragastrically administered with a volume of 20 ml/kg and 10 ml/kg body weight respectively, and the normal control and model groups were given a corresponding volume of 0.5% CMC-Na vitamin BC tablet excipient solution by weight.
  • the Morris experimental system consists of a water maze device, an automatic collection of water maze images, and a software analysis system.
  • the Morris water maze unit consists mainly of a pool and a platform with adjustable height and movable position.
  • the water maze experiment is divided into two parts:
  • the pool is divided into 4 quadrants, the platform is placed in one quadrant, and the liquid surface floods the platform 1 cm.
  • Probe training was conducted 1.5 hours and 1 day after the acquired training.
  • the platform was removed before the start of the experiment, and the mice were placed in the water from the opposite side of the original platform quadrant and recorded for 60 s.
  • the spatial memory detection indicators are 1) the time it takes for the animal to cross the platform for the first time; 2) the time it takes for the animal to reach the target quadrant (ie, the quadrant where the platform was originally placed); 3) the number of times the animal enters the target quadrant.
  • Solitaire mitochondrial enzyme activity assay kit weigh about 0.1 g of the cerebral cortex and add 1 ml of reagent one and 10 ul of reagent three, and grind in an ice bath. Centrifuge at 4° and discard the precipitate. The supernatant was transferred to another centrifuge tube, centrifuged at 4°, and the supernatant was discarded. Two reagents of 200 ul and three ul of reagent were added to the precipitate, and ultrasonically disrupted for enzyme activity measurement.
  • TIANGEN total RNA extraction kit weigh about 0.1g of cerebral cortex and add 1ml of lysate RZ, homogenate, place at 15-30 °C for 5min, record 200ul of chloroform, violently shake for 15s, stand at room temperature for 3min, centrifuge at 4 °C, water The phase was transferred to a new tube, mixed with 0.5 volume of absolute ethanol, placed in a adsorption column CR3 at 4 ° C for centrifugation, and the waste liquid was discarded. Add the deproteinized solution, discard the waste liquid after centrifugation, rinse the rinse solution twice, and centrifuge to discard the waste liquid. Add 30-100 ul of RNase-Free ddH 2 O for 2 min at room temperature and centrifuge at 4 °C.
  • the TOYOBO reverse transcription kit was reverse transcribed and its expression was detected by real-time PCR.
  • the multivitamin BC enhances the key pyruvate dehydrogenase (PDH), ⁇ -ketoglutarate dehydrogenase, and mitochondria in the cerebral cortex involved in the Krebs cycle. Citrate dehydrogenase (ICDHm) and succinate dehydrogenase (SDH) activities improve mitochondrial metabolism.
  • PDH pyruvate dehydrogenase
  • ICDHm citrate dehydrogenase
  • SDH succinate dehydrogenase
  • the rats in ICV-STZ model had significantly lower learning and memory ability in the morris water maze test, but after continuous administration of vitamin BC for 2 months, the learning and memory ability of the rats was significantly improved.
  • the key enzyme activity of the cycle is increased, and the expression level of energy metabolism-related mRNA is increased. This drug has a certain effect on the treatment of AD cognitive dysfunction, and it is expected to provide a new class of drugs for AD patients.

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PCT/CN2018/077107 2017-03-07 2018-02-24 维生素组合物在制备用于预防、治疗或延迟阿尔茨海默病的药物中的用途 Ceased WO2018161808A1 (zh)

Priority Applications (13)

Application Number Priority Date Filing Date Title
CN201880015481.XA CN110520135A (zh) 2017-03-07 2018-02-24 维生素组合物在制备用于预防、治疗或延迟阿尔茨海默病的药物中的用途
EP24189913.7A EP4461361A3 (en) 2017-03-07 2018-02-24 Use of vitamin composition in preparing drug for preventing, treating, or delaying alzheimer's disease
CA3054972A CA3054972A1 (en) 2017-03-07 2018-02-24 Use of vitamin composition in preparing drug for preventing, treating, or delaying alzheimer's disease
JP2019548652A JP7169285B2 (ja) 2017-03-07 2018-02-24 アルツハイマー病を予防し、治療し、又は遅延させるための薬物の調製におけるビタミン組成物の使用
ES18763903T ES2989651T3 (es) 2017-03-07 2018-02-24 Uso de una composición vitamínica para preparar un fármaco para prevenir, tratar o retrasar la enfermedad de Alzheimer
AU2018229920A AU2018229920B2 (en) 2017-03-07 2018-02-24 Use of vitamin composition in preparing drug for preventing, treating, or delaying Alzheimer's disease
EP18763903.4A EP3593805B1 (en) 2017-03-07 2018-02-24 Use of vitamin composition in preparing drug for preventing, treating, or delaying alzheimer's disease
US16/491,560 US11464797B2 (en) 2017-03-07 2018-02-24 Use of vitamin composition in preparing drug for preventing, treating, or delaying Alzheimer's disease
BR112019018652A BR112019018652A2 (pt) 2017-03-07 2018-02-24 uso de composição de vitaminas
US17/945,684 US20230248756A1 (en) 2017-03-07 2022-09-15 Use of vitamin composition in preparing drug for preventing, treating, or delaying alzheimer's disease
JP2022172956A JP2023011769A (ja) 2017-03-07 2022-10-28 アルツハイマー病を予防し、治療し、又は遅延させるための薬物の調製におけるビタミン組成物の使用
AU2024202678A AU2024202678A1 (en) 2017-03-07 2024-04-24 Use of vitamin composition in preparing drug for preventing, treating, or delaying Alzheimer's disease
JP2024198677A JP2025024089A (ja) 2017-03-07 2024-11-14 アルツハイマー病を予防し、治療し、又は遅延させるための薬物の調製におけるビタミン組成物の使用

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CN201710131111.X 2017-03-07
CN201710131111.XA CN108567792A (zh) 2017-03-07 2017-03-07 一种治疗阿尔茨海默病的复合维生素组合物

Related Child Applications (2)

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US16/491,560 A-371-Of-International US11464797B2 (en) 2017-03-07 2018-02-24 Use of vitamin composition in preparing drug for preventing, treating, or delaying Alzheimer's disease
US17/945,684 Continuation US20230248756A1 (en) 2017-03-07 2022-09-15 Use of vitamin composition in preparing drug for preventing, treating, or delaying alzheimer's disease

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US (2) US11464797B2 (enExample)
EP (2) EP4461361A3 (enExample)
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AU (2) AU2018229920B2 (enExample)
BR (1) BR112019018652A2 (enExample)
CA (1) CA3054972A1 (enExample)
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JP7442874B2 (ja) * 2019-08-02 2024-03-05 シャンハイ、レイジング、ファーマシューティカル、カンパニー、リミテッド アルツハイマー病における標的としてのｔｐｋの使用
KR102275981B1 (ko) * 2020-03-31 2021-07-13 고려은단주식회사 섬쑥부쟁이 추출물과 비타민 b 복합체의 혼합물을 포함하는 인지기능 개선용 조성물
AU2022464309A1 (en) * 2022-06-22 2025-01-23 Biomedical Research Group Inc. Prophylactic drug and therapeutic drug for diabetes-associated dementia
CN119055674B (zh) * 2024-11-06 2025-02-18 中国医学科学院北京协和医院 一种可改善认知的组合物及其在阿尔茨海默病防治中的应用

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