WO2019209065A1 - Composition pharmaceutique comprenant comme principe actif de l'ibrutinib, destinée à la prévention ou au traitement de maladies neurodégénératives - Google Patents

Composition pharmaceutique comprenant comme principe actif de l'ibrutinib, destinée à la prévention ou au traitement de maladies neurodégénératives Download PDF

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WO2019209065A1
WO2019209065A1 PCT/KR2019/005063 KR2019005063W WO2019209065A1 WO 2019209065 A1 WO2019209065 A1 WO 2019209065A1 KR 2019005063 W KR2019005063 W KR 2019005063W WO 2019209065 A1 WO2019209065 A1 WO 2019209065A1
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ibrutinib
microglia
treatment
disease
degenerative brain
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PCT/KR2019/005063
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English (en)
Korean (ko)
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허향숙
김정연
남혜연
이주영
남영표
강리진
이현주
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재단법인대구경북과학기술원
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Priority claimed from KR1020190048689A external-priority patent/KR102106821B1/ko
Application filed by 재단법인대구경북과학기술원 filed Critical 재단법인대구경북과학기술원
Priority to EP23206941.9A priority Critical patent/EP4331672A2/fr
Priority to US17/050,800 priority patent/US11826368B2/en
Priority to EP19793308.8A priority patent/EP3785715A4/fr
Priority to JP2020560335A priority patent/JP7120553B2/ja
Publication of WO2019209065A1 publication Critical patent/WO2019209065A1/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
    • A61K31/33—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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 relates to a pharmaceutical composition for the prevention or treatment of degenerative brain diseases comprising ibrutinib as an active ingredient.
  • Degenerative brain disease is a disease that occurs in the brain among degenerative diseases that occur with age.
  • the degenerative brain disease can be classified in consideration of major symptoms and invasive brain regions, including Alzheimer's disease and Parkinson's disease.
  • Degenerative brain diseases are known to be caused by the aggregation of proteins due to neurodegeneration and genetic and environmental factors caused by aging caused by neuronal cell death.
  • degenerative brain disease may be caused by the death or degeneration of certain brain cells temporarily or over a long period of time, and once killed, the brain cells are not regenerated, leading to fatal brain function loss.
  • Brain dysfunction accompanied by progressive decline in cognitive function, sensory function, motor function, and systemic function, eventually leads to changes in personality and behavior, leading to patients being unable to care for themselves.
  • the main pathways for brain cell death include oxidative stress caused by oxidative stress, excitatory toxicity, and apoptosis, each of which induces cell death through a specific signaling process.
  • oxidative damage of proteins, nucleic acids and lipids after accumulation of Reactive Oxygen Species has been suggested as a major cause of brain cell death in patients with stroke, brain injury, Alzheimer's disease (AD) and Parkinson's disease.
  • oxidative stress caused by free radicals has been reported as a major cause of cell death in tissues of the body, and has been suggested as one of the cycles of cell death in neurological diseases (Schapira, AH, Curr. Opin. Neurol., 9 (4): 260-264, 1996).
  • microglia are immune cells resident in the central nervous system (CNS). It is known to be activated by external stimuli to induce immune and inflammatory reactions.
  • CNS central nervous system
  • Microglia are cells that perform the primary immune function in the central nervous system. They maintain the shape of elongated branches and thin cell bodies, and when these toxins are introduced from the outside or internally generated, To protect the cells, they change to an activated shape with thick, short branches and fat cell bodies.
  • microglia when microglia are activated with a substance such as lipopolysaccharide (LPS), interferon- ⁇ , beta amyloid or ganglioside, which are endotoxins of bacteria, unlike the normal state of microglia, phagocytosis is active. And cell proliferation and inflammatory mediators by expressing genes such as cytokines such as TNF- ⁇ , IL-1 ⁇ and IL-6, chemokines, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2).
  • cytokines such as TNF- ⁇ , IL-1 ⁇ and IL-6
  • chemokines inducible nitric oxide synthase (iNOS)
  • COX-2 cyclooxygenase-2
  • microglial cells removes damaged cells and protects nerve cells from invading bacteria or viruses from outside, but the prostaglandins, TNFs produced by nitric oxide (NO) produced by iNOS and COX-2. Since - ⁇ and the like are also toxic to nerve cells, the activation of microglia results in worsening of nerve cell damage. Therefore, inhibiting the proper activation of microglia can be another way to treat degenerative brain diseases.
  • NO nitric oxide
  • astrocytes play an important role in maintaining normal brain activity as well as the development of the brain.
  • Astrocytes in the brain have been shown to play a role in assisting neuronal activity by appropriately removing neurotransmitters secreted by neurons or regulating ion concentrations in the brain.
  • neural stem cells differentiate into neurons. It has been found to play a decisive role.
  • astrocytes when astrocytes are injured in the brain, proliferation becomes active, swelling occurs, and they are activated by reactive astrocytes such as astrogliosis.
  • reactive astrocytes have been observed in AIDS dementia, brain injury, ischemic brain disease, Alzheimer's disease and the like.
  • continuous activation of astrocytes eventually leads to neuronal cell death. Therefore, proper inhibition of astrocytes could be another way to treat degenerative brain diseases.
  • Therapies currently used to treat degenerative brain diseases include drug therapy, surgical therapy, and physical therapy.
  • dopamine which is generally lacking in the brain, is supplemented.
  • Drugs are being used to balance imbalances, to prevent or delay the destruction of nerve cells, and to control other symptoms such as depression.
  • Ibrutinib is known as an anticancer agent targeting B-cell malignancies, and has been shown to act to block signals that stimulate malignant tumor B cells to grow and divide uncontrollably. This ibrutinib was approved by the US FDA for the treatment of mantle cell lymphoma in November 2013 and the treatment of chronic lymphocytic leukemia in February 2014.
  • Ibrutinib can be used as a therapeutic agent to treat degenerative brain disease.
  • ibrutinib known as an anticancer agent
  • an anticancer agent can be used as a therapeutic agent for preventing or treating degenerative brain disease.
  • an object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of degenerative brain disease, comprising ibrutinib or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is also to inhibit the activity of microglia or astrocytes, comprising treating ibrutinib or a pharmaceutically acceptable salt thereof to the neuronal cells in vitro. To provide a way.
  • Another object of the present invention is also to inhibit cell migration of LPS-induced microglia, which comprises treating ibrutinib or a pharmaceutically acceptable salt thereof to neuronal cells in vitro. To provide a way.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of degenerative brain disease, comprising ibrutinib or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the composition inhibits the activity of microglia or astrocytes to inhibit the damage of activated microglia or activated astrocytes to nerve cells. It may be to have.
  • the composition may have an activity of inhibiting cell migration of microglia.
  • the activity of the microglia or astrocytic cells may be induced by LPS (Lipopolysaccharides).
  • the composition may be one having amyloid plaque inhibition or phosphorylation inhibitory activity of tau protein.
  • the composition increases the number of dendritic spine (syndritophysin) and synaptophysin (puncta number) of PSD-95 involved in memory and learning in neurons To increase functional synapses.
  • the composition may be to improve long-term memory in the Alzheimer's disease model.
  • the degenerative brain disease Alzheimer's, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple neurotrophic, epilepsy, brain disease (encephalopathy), stroke, memory disorders, cognitive disorders and learning disorders group It may be selected from.
  • the present invention also provides a method for inhibiting the activity of microglia or astrocytes, which comprises treating ibrutinib or a pharmaceutically acceptable salt thereof to the cranial nerve cells in vitro. Provide a method.
  • the present invention also provides a method of inhibiting cell migration of LPS-induced microglia, which comprises treating ibrutinib or a pharmaceutically acceptable salt thereof to the cranial nerve cells in vitro. to provide.
  • the present invention relates to the use of ibrutinib for the treatment of degenerative brain diseases, and effectively inhibits the activity of microglia and astrocytes, thereby reducing the production of inflammatory cytokines, inhibiting inflammation, and activating microglia and stellate. Not only does it protect the cells against damage to nerve cells, but it also inhibits amyloid plaque and tau phosphorylation, which is the cause of degenerative brain diseases, and increases the level of IDE, an amyloid beta degrading enzyme. It inhibits the production of amyloid plaques and enhances long-term memory in animal models of Alzheimer's disease, and also increases the number of dendritic spines associated with memory and learning to prevent degenerative neuropathy by promoting memory and learning.
  • Ibrutinib can be used to treat, improve and treat degenerative brain diseases It can be useful as a preventive or therapeutic agent.
  • Figure 1 shows the results of confirming the cytotoxicity of Ibrutinib for microglia cells
  • 1a is to analyze the cell viability after treatment of ibrutinib for each concentration of 100, 250, 500, 750, 1000 nM
  • 1b is an analysis of cell viability after treatment with ibrutinib for 1, 5, 10, 25, 50 ⁇ M concentration
  • 1c is LPS-stimulated BV2 microglia and IPS-stimulated BV2 after pretreatment Microscopic view of the cell morphology of microglia shows the picture.
  • Figure 2 shows the results of pretreatment with ibrutinib to BV2 microglia, the expression level of each proinflammatory cytokine via RT-PCR (Figs. 2a-2f),
  • Figure 2g shows the anti- Cells stained with CD11b antibody, COX-2 antibody or anti-CD11b and IL-1 ⁇ antibody were observed under a microscope, and 2h and 2i showed expression levels of IL-1 ⁇ and COX-2 following ibrutinib treatment. It shows the result confirmed.
  • Figure 3 shows the results of confirming the level of pro-inflammatory cytokines induced by LPS following Ibrutinib pretreatment in BV2 microglia via RT-PCR ( Figures 3a-3f).
  • Figure 4 shows the result of confirming the expression level of proinflammatory cytokines induced by LPS after pretreatment of ibrutinib to the primary culture microglia through RT-PCR (Figs. 4A to 4F).
  • Figure 5 shows the results of confirming the expression level of proinflammatory cytokines induced by LPS after pretreatment of ibrutinib to primary cultured astrocytic cells through RT-PCR (FIGS. 5A-5F).
  • TLR4 inhibitors TAK242, ibrutinib, and LPS in BV2 microglia for each condition, and mRNA levels of L-1 ⁇ and COX-2 expressed in cells were analyzed using RT-PCR.
  • 8a to 8c shows the degree of phosphorylation of AKT after pretreatment of ibrutinib to BV2 microglia (1 hour), and 8d to 8f after treatment of Ibrutinib for a longer time (5 hours). The results show the degree of phosphorylation.
  • 8g ⁇ 8i shows the results of confirming the COX-2 and IL-1beta mRNA levels in the group treated with Ibrutinib and LPS.
  • Figure 9 shows preliminary treatment of BV2 microglia with Ibrutinib (1 ⁇ M), followed by intracellular subcellular fractionation to confirm p-STAT3 levels in Western blots in nuclear and cytosol fractions (FIGS. 9C-9D).
  • Anti-p-STAT3 (s727) and anti-CD11b antibodies were used to confirm the results of microscopic observation through immunocytochemical staining (Fig. 9e) and the level of p-STAT3 (Fig. 9f).
  • FIG. 10 shows the results confirming that ibrutinib can regulate the migration of LPS-stimulated microglial cells. After pretreatment of ibrutinib to cultured microglial cells, cell scratches were applied to ibrutinib treatment. The result of confirming the degree of cell migration by the microscope (10a) and the result of confirming the moved cell number (10b) are shown.
  • FIG. 11 shows the effect of LPS-induced microglial activation and the inhibition of microglial activation by ibrutinib in cortex and hippocampus of a mouse animal model. Immunohistochemical staining results using the IBa-1 antibody are shown (FIGS. 11A-11C).
  • FIG. 12 shows the effect of LPS-induced activation of astrocytes and inhibition of astrocyte activation by ibrutinib in the cortex and hippocampus of mouse animal models. The histological staining results are shown (FIGS. 12A-12C).
  • Figure 13 shows the results of the Y labyrinth experiment and the new substance search test for the analysis of memory and learning behavior according to ibrutinib treatment in Alzheimer-induced disease model (5x FAD mice) (FIGS. 13A-13B).
  • FIG. 14 illustrates the results of a Y maze experiment and a new substance search test for analyzing memory and learning behavior according to ibrutinib treatment in an Alzheimer-induced disease model (PS19 mice overexpressing Tau) (FIGS. 14A to 14B). ).
  • FIG. 15 shows Ibrutinib (1 ⁇ M) after transforming GFP into primary hippocampal neurons to analyze changes in the number of dendritic spine during cognitive behavioral mechanisms of ibrutinib (1 ⁇ M). Or 24 hours after the vehicle, immunohistochemical staining is performed to show the result of change in the number of dendrtiic spines (FIGS. 15A-15B).
  • FIG. 16 shows Ibrutinib (5 ⁇ M) after transforming GFP into primary hippocampal neurons in order to analyze the increase in the number of dendritic spines during cognitive behavioral mechanisms of ibrutinib (5 ⁇ M). After 24 hours of vehicle treatment, immunohistochemical staining was performed to show the result of the change in the number of dendrtiic spines (FIGS. 16A-16B).
  • Figure 17 shows the immune system using anti-ynaptophysin and anti-PSD-95 antibodies after transforming GFP in primary hippocampal neurons to determine whether ibrutinib affects functional synapse. It shows the results of confirming the puncta number change by performing histochemical staining (Figs. 17A to 17D).
  • FIG. 18 shows the results of a study of molecular mechanisms for improving cognitive behavior of ibrutinib. After transforming GFP into primary hippocampal neurons, immunohistochemistry was performed using anti-p-FAK antibody. The results of staining are shown (FIGS. 18A-18B).
  • Figure 19 is to confirm the dendritic spine numebr changes caused by ibrutinib, Iblotim (10 mg / kg, IP) or vehicle intraperitoneally administered for 2 weeks daily in the normal mouse brain, Golgi staining at hippocampus CA1 site Dendrtic spine number results are shown (FIGS. 19A-19D).
  • FIG. 20 shows intraperitoneal injection of Ibrutinim (10 mg / kg, IP) or vehicle in Alzheimer's animal model (PS 19 mice) brain for two weeks daily to confirm dendritic spine numebr changes by ibrutinib in Alzheimer's disease animal model. After administration, Golgi staining was performed at hippocampus CA1 and cortical layer V to show dendritic spine number results (FIGS. 20A-20H).
  • Figure 21 confirms the amyloid plaque inhibitory effect of ibrutinib treatment in the cortex and hippocampus of the Alzheimer's disease animal model (5xFAD), showing the results of immunohistochemical staining using anti-4G8 antibody (Figs. 21A-21E).
  • Figure 22 shows the results of immunohistochemical staining using anti-IDE antibodies to confirm the molecular mechanism of the reduction of amyloid plaques following ibrutinib treatment in cortex and hippocampus of the Alzheimer's disease animal model (5xFAD) (FIGS. 22A-22E).
  • FIG. 23 shows the results of immunohistochemical staining using anti-Tau-5 antibody to confirm expression changes of total Tau protein following ibrutinib treatment in cortex and hippocampus of Alzheimer's disease animal model (5xFAD). (FIGS. 23A-23E).
  • FIG. 24 shows the results of immunohistochemical staining using anti-AT8 antibody to confirm the effect of Tau phosphorylation following Ibrutinib treatment in cortex and hippocampus of Alzheimer's disease animal model (5xFAD) ( Figures 24A-24E).
  • FIG. 25 shows the results of immunohistochemical staining using anti-AT100 antibody to confirm Tau phosphorylation changes following Ibrutinib treatment in cortex and hippocampus of the Alzheimer's disease animal model (5xFAD) ( 25A-25E).
  • FIG. 26 shows the results of immunohistochemical staining using an anti-AT180 antibody to confirm the effect of Tau phosphorylation following Ibrutinib treatment in cortex and hippocampus of the Alzheimer's disease animal model (5xFAD). ( Figures 26A-26E).
  • FIG. 27 uses anti-p-CDK5 antibody to identify changes in p-CDK, a gene that regulates phosphorylation of Tau protein following ibrutinib treatment in cortex and hippocampus of the Alzheimer's disease animal model (5xFAD) It shows the results of performing an immunohistochemical staining (Figs. 27A-27E).
  • the present invention is characterized by providing a pharmaceutical composition for the prevention or treatment of degenerative brain disease, comprising ibrutinib or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Ibrutinib as mentioned in the prior art, is known as an anticancer agent targeting B-cell malignancies, and studies on the treatment potential of immune diseases have been reported. However, Ibrutinib has not been studied for possible treatment of brain diseases.
  • the present invention first identified that it can be used as a therapeutic agent for ibrutinib degenerative brain disease.
  • ibrutinib inhibits the activity of microglia or astrocytes and thus damages to neurons by activated microglia or activated astrocytes. It was confirmed that there was an inhibitory effect.
  • the cell migration of the activated microglia is effectively suppressed when ibrutinib is treated, it was found that the onset of degenerative brain disease due to the cell migration of the activated microglia is suppressed.
  • Microglial cells which act as macrophages in the brain, are important effector cells that regulate the immune response in the central nervous system (CNS). Their activation plays an important role in maintaining homeostasis of the CNS by removing foreign substances caused by drugs or toxins and releasing nerve growth factors.
  • CNS central nervous system
  • the activity of microglial cells is excessively increased, causing neuronal damage, resulting in Alzheimer's disease, It can cause degenerative brain diseases such as Parkinson's disease, multiple sclerosis and cerebral infarction. Therefore, the method of inhibiting excessive activity of microglia may be a new treatment method for degenerative brain disease.
  • microglial cells unlike normal microglial cells, activate phagocytosis, proliferate, and cytokines such as TNF- ⁇ , IL-1 ⁇ and IL-6, chemokines, and iNOS ( Inducible nitric oxide synthase), COX-2 (cyclooxygenase-2), and other genes are expressed to produce inflammatory mediators.
  • cytokines such as TNF- ⁇ , IL-1 ⁇ and IL-6, chemokines, and iNOS ( Inducible nitric oxide synthase), COX-2 (cyclooxygenase-2), and other genes are expressed to produce inflammatory mediators.
  • Activation of microglial cells removes damaged cells and protects nerve cells from invading bacteria or viruses from outside, but the prostaglandins, TNF- produced by nitric oxide (NO) produced by iNOS and COX-2.
  • ⁇ and the like are also toxic to nerve cells, and as a result, the activation of microglia worse
  • astrocytes are known to play an important role in maintaining normal brain activity, in particular, they are known to play a role in neuronal synapse formation, synaptic number regulation, synaptic function, and neural stem cell differentiation into nerves. .
  • these stellate cells become excessively reactive, that is, maintain excessive activation, they cause neuronal cell death and the death of neighboring neurons, thereby causing degenerative brain diseases. Therefore, excessive inhibition of astrocyte activation may be a new treatment for degenerative brain disease.
  • Excessive activation of the microglia and astrocytes may include lipopolysaccharides (lipopolysaccharides, LPS), interferon- ⁇ , beta amyloid, and gangliosides, which are bacterial endotoxins.
  • lipopolysaccharides lipopolysaccharides, LPS
  • interferon- ⁇ interferon- ⁇
  • beta amyloid beta amyloid
  • gangliosides which are bacterial endotoxins.
  • LPS lipopolysaccharide
  • ibrutinib can significantly inhibit the expression level of proinflammatory cytokines that are maintained as LPS in BV2 microglia, in particular ibrutinib ( The pro-inflammatory cytokine inhibitory effect of ibrutinib) was also confirmed by neuronal cell type. In primary cultured astrocytes, ibrutinib showed no inhibitory effect on pro-inflammatory cytokine, whereas in microglial cells, COX- 2 and IL-6 have been shown to effectively inhibit the levels of proinflammatory cytokines.
  • the present inventors confirmed the mechanism of ibrutinib on the neuroprotective effect of brain neurons, and it was confirmed that ibrutinib can inhibit the interaction between TRL4 and LPS, thereby inhibiting the LPS-stimulated proinflammatory response.
  • the regulation of proinflammatory responses of Ibrutinib was found to be dependent on AKT signaling.
  • the analysis of the effects of Alzheimer's treatment according to ibrutinib treatment in the mouse animal model induced Alzheimer's disease the expression of the amyloid degrading enzyme IDE during ibrutinib treatment is increased It was confirmed that this resulted in a significant reduction in the number of amyloid plaques that cause Alzheimer's disease.
  • the group treated with ibrutinib was found to significantly reduce the phosphorylation of Tau protein, which causes Alzheimer's disease, compared to the group not treated with ibrutinib.
  • the group treated with ibrutinib increases dendritic spine number and increases synaptophysin or PSD-95 puncta number compared to the group not treated with ibrutinib (that is, functional synapse (functional synaspe), and long-term memory is improved.
  • ibrutinib or a pharmaceutically acceptable salt thereof of the present invention can be used as a therapeutic agent for degenerative brain disease, and ibrutinib or a pharmaceutically acceptable salt thereof can be applied to an individual in need thereof. It can provide a method of treating degenerative brain disease, comprising the step of administering.
  • the degenerative brain disease according to the present invention is not limited thereto, but is composed of Alzheimer's, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple nerve atrophy, epilepsy, brain disease (encephalopathy), stroke, memory disorder, cognitive impairment and learning disorder It may be selected from the group.
  • composition for preventing or treating degenerative neurological disease of the present invention may include a pharmaceutically acceptable carrier.
  • the composition comprising a pharmaceutically acceptable carrier may be in various oral or parenteral formulations. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.
  • Solid form preparations for oral administration include tablet pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, sucrose or lactose in one or more compounds. ) And gelatin. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like are also used.
  • Liquid preparations for oral administration include suspensions, solution solutions, emulsions, and syrups, and various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the pharmaceutical composition is any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories. It can have one formulation.
  • these pharmaceutical compositions may be administered the pharmaceutical compositions of the present invention to treat a variety of diseases, including neurodegeneration and / or symptoms associated therewith, as described above.
  • composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level is determined by the type and severity of the subject, age, sex, activity of the drug, drug Sensitivity, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts.
  • compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. In consideration of all the above factors, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects.
  • Typical dosages of the pharmaceutical compositions of the invention are in the range of 0.001-100 mg / kg on an adult basis.
  • the route of administration of the pharmaceutical composition may be administered via any general route as long as it can reach the target tissue.
  • the composition of the present invention may be administered as desired, but is not limited to intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, intranasal administration, pulmonary administration, rectal administration.
  • the composition may also be administered by any device in which the active agent may migrate to the target cell.
  • composition of the present invention can be used alone or in combination with methods using surgery, hormonal therapy, drug treatment and biological response modifiers for the prevention and treatment of degenerative brain diseases.
  • the present invention further provides a method of inhibiting the activity of microglia or astrocytes, comprising treating ibrutinib or a pharmaceutically acceptable salt thereof to the cranial nerve cells in vitro. Can be provided.
  • the present invention also provides a method of inhibiting cell migration of LPS-induced microglia, which comprises treating ibrutinib or a pharmaceutically acceptable salt thereof to the cranial nerve cells in vitro. Can provide.
  • the present invention may provide a method for inhibiting amyloid plaque, inhibiting tau phosphorylation, or improving long-term memory, comprising treating ibrutinib or a pharmaceutically acceptable salt thereof in a cranial nerve cell in vitro.
  • BV2 microglial cells obtained from Dr. Kyung-Ho Suk
  • DMEM / high glucose containing 5% fetal bovine serum FBS, Invitrogen, Carlsbad, CA, USA
  • FBS Invitrogen, Carlsbad, CA, USA
  • C57BL6 / N mice were purchased from OrientBio Company and male C57BL6 / N (8 weeks, 25-30 g) mice were bred under a 12-hour light cycle at 22 ° C. in a pathogen free facility.
  • Drug injection into reared mice was administered ibrutinib (10 mg / kg) or vehicle (DMSO) for 3 days intraperitoneally (i.p) and continuously injected with LPS (10 mg / kg, i.p) for 3 hours.
  • mice After 3 hours, wild-type mice were perfused and fixed using 4% paraformaldehyde (PFA) solution, flash frozen brain tissue and sectioned to cryostat 40 mm thick. Each brain section was used for immunohistochemistry. Brain sections were washed with PBS, incubated for 1 hour in PBS containing 0.2% Triton X-100 and 1% BSA at room temperature to ensure permeability, after 1 hour the primary antibody was reacted at 4 ° C. overnight, The tissues were washed three times with 0.5% BSA and then the secondary antibody was reacted for 1 hour at room temperature (Biotin-bound anti rabbit antibody (1: 400, Vector laboratory).
  • PFA paraformaldehyde
  • the brain sections were then washed with 0.5% BSA and Incubated for 1 hour in avidin-biotin complex solution (Vector Laboratories, Burlingame, CA) at room temperature Three sections washed three times with 0.1M PB buffer 0.5mg / ml 3,3 in 0.1M PB containing 0.003% H2O2 The signal of the reaction result was detected using '-Diaminobenzidine (DAB, Sigma-Aldrich) The sections were rinsed with 0.1 M PB and placed on gelatin coated slides and image analysis was performed using a light field microscope (Leica). It was.
  • DAB '-Diaminobenzidine
  • 5xFAD mice (stock. 008730, B6SJL-Tg APPSwFlLon, PSEN1 * M146L * L286V6799Vas / Mmjax) F1 generation were obtained from Jacson laboratory and transgenic male mice (5xFAD) were placed with female C57BL / 6J purchased from Jacson laboratory. .
  • 5xFAD is a mutant human APP (695) with K670N, M671L (Swedish), I716V (Florida), and V717I (London) and human familial Alzheimer's disease accompanying human PS1 with two FAD mutations (M146L and L286V) Familial Alzheimers Disease (FAD) is known to overexpress mutations.
  • the transformation was controlled by the mouse Thy1 promoter to overexpress in the brain, and genotyping for 5xFAD transformation was performed by PCR method provided by Jackson Lab's genotyping protocol.
  • Tails were cut from 4 week old mice and genomic DNA was extracted therefrom. The tail was incubated at 95 ° C. for 2 hours in a basic dissolution solution, and then the reaction was terminated with a neutralization solution. PCR reactions were performed using Prime Taq Premix (GeNetBio, Korea), and PCR products were separated by electrophoresis on 1.5% agarose gel. Primer sequences used in the present invention are as follows:
  • Translocation primer 5-AATAGAGAACGGCAGGACCA-3
  • PCR amplification was repeated 35 cycles of denaturation at 94 ° C. for 30 seconds, annealing at 60 ° C. for 30 seconds, and extension at 90 ° C. for 90 seconds, and the PCR product was 1.5% agar with Eco Dye (1: 5000, Korea). It was separated by electrophoresis on Sgel.
  • tissues were washed with PBS containing 0.5% BSA and incubated with 555-conjugation-anti-rabbit IgG (1: 200, Molecular Probe) for 1 hour at room temperature.
  • Tissue was placed on gelatin coated coverglass and DAPI-containing mounting solution (Vector Laboratories) was added above. Stained tissue was photographed by confocal microscopy (TI-RCP, Nikon).
  • TI-RCP confocal microscopy
  • the flakes were washed with PBS and incubated and treated with 0.2% Triton X-100 and 1% BSA in PBS for 1 hour at room temperature to ensure permeability.
  • the primary antibody was then incubated overnight at 4 ° C. with slow shaking.
  • the tissues were washed three times with PBS with 0.5% BSA and incubated for 1 hour at room temperature with the following secondary antibody: Biotin-conjugated anti rabbit antibody (1: 400, Vector Laboratories).
  • the flakes were washed again with PBS with 0.5% BSA and incubated for 1 hour at room temperature in an avidin-biotin complex solution.
  • 0.1 M PB phosphate buffer
  • 0.5 mg / ml 3,3-diaminobenzidine (3,3-diaminobenzidine) (DAB, in 0.1 M PB containing 0.003% H 2 O 2 ) Sigma was incubated with flakes to detect the signal.
  • the flakes were then washed with 0.1 M PB and then placed on gelatin coated slides and observed with a bright field microscope (Leica).
  • Primary antibodies include rat-anti-mouse CD11b (1: 400, abcam), rabbit-anti-COX2 (1: 1000, abcam), rabbit-anti-IL-1b (1: 200, abcam), rabbit-anti- GFAP (1: 5000, neuromics), rabbit-anti-Iba1 (1: 1000, Wako), goat-anti-IbaI (1: 500, Wako), rabbit-anti-AKT (1: 1000, Santa Cruz), p -AKT (Ser473, Thr308) (1: 1000, Cell Signaling), rabbit-anti-ERK (1: 1000, Santa Cruz), rabbit-anti-p-ERK (Thr42 / 44) (1: 1000, Cell Signaling) , rabbit-anti-STAT3 (1; 1000, Cell Signaling), rabbit-anti-p-STAT3 (Ser727, abcam), mouse-anti-synaptophysin (1: 200, Sigma), mouse-anti-PSD95 (1: 200 , Neuromab), rabbit-anti-pFAK (1: 500, Cell signaling),
  • Cell viability was used with 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) assay.
  • MTT 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide
  • Cells were aliquoted into 96-well plates and treated with various concentrations of ibrutinib (100 nM-1 ⁇ M, 1 Mm-50 ⁇ M) for 24 hours in the presence or absence of FBS. Cells were then treated with 0.5 mg / ml MTT and incubated in a 5% CO 2 incubator at 37 ° C. for 3 hours, and then absorbance was measured at 580 nm.
  • the primary mixed glia cells were isolated and cultured from the cerebral cortex of 1 day old Sprague Dawley mice, i.e. the mouse cortex was cultured with 10% FBS and penicillin-streptomycin solution (5000 units / ml penicillin, 5 mg / ml). Single glucose in high glucose DMEM medium containing streptomycin, Corning, USA) was soaked and soaked in a 75-cm 2 T flask (0.5 hemisphere / flask) for 2 weeks.
  • the plate was shaken constantly at 120 rpm for 2 hours, then the medium was collected and centrifuged at 1500 rpm for 15 minutes, and then the cell pellet was regenerated to 1x10 5 cells / 24 wells on the plate. It was cloudy. Once microglia were collected, the remaining cells in the flask were harvested using 0.1% trypsin to obtain astrocyte populations. Astrocytes and microglia were cultured in a 12-well plate (35 mm) pre-coated with Poly-D-Lysine (Sigma) and used for experiments.
  • BV2 microglia were fixed for 4 minutes with 4% paraformaldehyde for 10 minutes, washed three times with PBS, and then anti-CD11b and anti-IL-1 ⁇ or anti-CD11b and anti-COX2 antibodies were added in GOB buffer (0.1% gelatin, 0.3% Triton X-100, 16 mM sodium phosphate pH 7.4 and 450 mM NaCl) at 4 ° C overnight. The following day, cells were washed three times with PBS and reacted with secondary antibody for 1 hour at room temperature. As a secondary antibody, mouse AlexaFluor 488 and rabbit AlexaFluor 555 (1: 200, Molecular Probes, USA) were used. Images were then taken in a single plane using a confocal microscope (Nikon, Japan) and analyzed using Image J software.
  • BV2 microglia were treated with Ibrutinib (1 ⁇ M) or vehicle for 1 hour, followed by 45 LPS (1 ⁇ g / ml) or PBS. Treated for a minute. After 45 minutes, cells were lysed using RIPA buffer containing protease and phosphatase inhibitors (Roche, USA). Western blots were performed by conventional Western blot methods, and images were analyzed using Fusion software or Image J software.
  • BV2 microglia were seeded in 12-well plates, cultured to 80-90% of cells, and scraped with a cell scratcher (SPL, Korea). Images were taken immediately after the scratcher and then treated with Ibrutinib (500 nM) or vehicle for 1 hour followed by LPS or PBS for 24 hours. After 24 hours, the images were taken again to analyze the extent of ound healing (Nam et al., 2017).
  • BV2 microglia were lysed using buffer for cytoplasmic fractions (10 mM HEPES pH 8.0, 1.5 mM MgCl 2, 10 mM KCl, 0.5 mM DTT, 300 mM sucrose, 0.1% NP-40 and 0.5 mM PMSF). Five minutes after the solution was added, the cell lysates were centrifuged at 10,000 rpm for 4 minutes at 4 ° C., and the supernatant was separated and stored in the cytosolic fraction.
  • buffer for cytoplasmic fractions (10 mM HEPES pH 8.0, 1.5 mM MgCl 2, 10 mM KCl, 0.5 mM DTT, 300 mM sucrose, 0.1% NP-40 and 0.5 mM PMSF). Five minutes after the solution was added, the cell lysates were centrifuged at 10,000 rpm for 4 minutes at 4 ° C., and the supernatant was separated and stored in the cytosolic fraction.
  • the pellet was dissolved in ice for 15 minutes in buffer for nuclear fractions (10 mM HEPES pH 8.0, 20% glycerol, 100 mM KCl, 100 mM NaCl, 0.2 mM EDTA, 0.5 mM DTT and 0.5 mM PMSF). After centrifugation at 10,000 rpm for 15 minutes at 4 °C, Western blot analysis was performed using anti-STAT3 (s727), PCNA and ⁇ -actin antibody and analyzed using Fusion software.
  • each arm was 42cm long, 3cm wide and 12cm high.
  • BV2 microglia were treated with vehicle or Ibrutinib (100, 250, 500, 750, 1000 nM) for 24 hours, respectively, and MTT analysis was performed.
  • BV2 microglia were treated with vehicle or Ibrutinib at higher concentrations of 1, 5, 10, 25, 50 ⁇ M for 24 h and MTT assay was performed.
  • Ibrutinib can modify cell morphology in LPS-induced BV2 microglia
  • Ibrutinib was pretreated with BV2 microglia at a concentration of 1 ⁇ M for 30 minutes and then treated with LPS (1 ⁇ g / ml) or PBS for 5 hours 30 minutes. RNA was then isolated and inflammatory cytokine levels were measured using RT-PCR. At this time, mRNA level analysis measured the levels of inflammatory cytokines IL-1 ⁇ , COX-2, IL-6, TNF- ⁇ .
  • the present inventors re-validated the above-described results of RT-PCR through immunocytochemical analysis, and the cells used in the experiment were treated with anti-CD11b antibody and COX-2 antibody or anti-CD11b and IL-1 ⁇ antibody. It was confirmed after immunostaining.
  • a vehicle treated group instead of ibrutinib was used.
  • the present inventors have found that the ibrutinib of the present invention can suppress the inflammatory response occurring in BV2 microglia.
  • microglia were treated with vehicle or ibrutinib (1 uM) for 30 minutes and LPS (1 ⁇ g / ml) Or 5 hours 30 minutes treatment with PBS, then inflammatory cytokine levels were analyzed by RT-PCR.
  • pretreatment with ibrutinib in microglial cells significantly reduced the levels of proinflammatory cytokines of COX-2 and IL-6 compared to other cytokines (see FIGS. 4A-4F).
  • the present inventors pretreated with vehicle or ibrutinib (1 ⁇ M) for 30 minutes to the primary cultured astrocytes, in order to determine whether Ibrutinib can affect the expression level of proinflammatory cytokines in primary cultured astrocytic cells, After treatment for 5 hours and 30 minutes with LPS (1 ⁇ g / ml) or PBS, inflammatory cytokine levels were measured using RT-PCR.
  • ibrutinib does not affect the expression level of proinflammatory cytokines in supercultured astrocytes (see FIG. 5). These results indicate that the effect of ibrutinib on proinflammatory cytokines is responded by cell type.
  • BV2 microglia were pretreated with TAK242 (TLR4 inhibitor, 500 nM) or vehicle for 30 minutes, treated with Ibrutinib (1 ⁇ M) or vehicle for 30 minutes, followed by LPS (1 ⁇ g / ml) or PBS for 5 hours. Treated during. Total RNA was then isolated and RT-PCR was used to measure mRNA levels of IL-1 ⁇ and COX-2.
  • Ibrutinib was found to significantly reduce the mRNA levels of COX-2 and IL-1 in LPS-induced BV2 microglia (see FIGS. 6A-6C).
  • inhibition of TLR4 was shown to further reduce IL-1 ⁇ and COX-2 mRNA levels in the presence of Ibrutinib in LPS-induced BV2 microglia (see FIGS. 6A-6C).
  • ibrutinib may inhibit LPS-stimulated proinflammatory response by preventing the interaction between TRL4 and LPS.
  • Ibrutinib did not alter p-ERK in LPS-induced BV2 cells (see FIGS. 7A-7C). However, Ibrutinib was found to significantly reduce LPS-induced p-AKT levels in BV2 microglia (see FIGS. 8A-8C).
  • BV2 microglia were pretreated with Ibrutinib (1 ⁇ M) or vehicle for 5 hours and treated with LPS (1 ⁇ g / ml) or PBS for 45 minutes and then subjected to Western blot using anti-p-AKT.
  • the inventors have determined whether Ibrutinib modulates the inflammatory response through AKT signaling, for which pretreatment of BV2 microglia with MK2206 (AKT inhibitor, 10 ⁇ M) or vehicle for 30 minutes, and Ibrutinib (1 ⁇ M) or vehicle After 30 minutes of treatment, LPS (1 ⁇ g / ml) or PBS for 5 hours and RT-PCR was used to measure the mRNA levels of COX-2 and IL-1.
  • mRNA levels of COX-2 and IL-1 were decreased in the group treated with Ibrutinib and treated with LPS (see FIG. 8G-8i), and also treated with MK2206, Ibrutinib and LPS.
  • One group was shown to have reduced COX-2 and IL-1beta mRNA levels compared to the group treated with LPS and MK2206 (see FIGS. 8G-8I).
  • the transcription factor STAT3 is known to play an important role in regulating inflammation-induced cytokine levels by LPS.
  • Ibrutinib needs STAT3 to change the inflammatory response.
  • BV2 microglia were pretreated with Ibrutinib (1 ⁇ M) or vehicle for 30 minutes and treated with LPS (1 ⁇ g / ml) or PBS for 5 hours and 30 minutes. Next, intracellular subcellular fractions were performed.
  • Ibrutinib decreased the p-STAT3 level of the LPS-stimulated nucleus (FIGS. 9A-9B), and the p-STAT3 level of the cytosol also tended to decrease (see FIGS. 9C-9D).
  • ibrutinib can be used as a therapeutic agent for degenerative brain diseases.
  • the present inventors analyzed the effects of ibrutinib on the activation of LPS-induced microglia and astrocytes in animal models.
  • wild-type mice were injected with ibrutinib (10 mg / kg, i.p) for 3 days at which time intraperitoneal injection (10 mg / kg / day) was performed in i.p. After performing for 3 hours, immunohistochemical staining was performed with anti-IBa-1 (FIGS. 11A-11C) and anti-GFAP antibodies (FIGS. 12A-12C).
  • Ibrutinib can modulate the activation of LPS-induced microglia and astrocytic cells in wild-type mice. In particular, we can prevent or treat degenerative brain diseases by inhibiting the activation of these cells. I could see that.
  • ibrutinib affects memory and learning
  • short-term memory behavioral evaluation after 14-day treatment of ibrutinib (10 mg / kg, ip) or vehicle in Alzheimer's-induced animal models (5xFAD, PS19 mice) Y-maze was performed for the study, and Novel object recognition test (NOR) was performed for the evaluation of long-term memory behavior.
  • ibrutinib improves learning and memory in Alzheimer's animal model mice.
  • ibrutinib To analyze the cognitive behavioral enhancement mechanism of ibrutinib, transfection of primary cultured primary hippocampal neurons (GFP) was followed by treatment with Ibrutinib 1 or 5 ⁇ M for 24 hours. Afterwards, the number of dendritic spine was observed, stained with synaptophysin antibody as a presynaptic index and PSD-95 antibody as a post-synaptic marker factor, and the puncta number and its expression level were confirmed.
  • GFP primary cultured primary hippocampal neurons
  • Ibrutinib (10 mg / kg, ip) was injected into the PS19 mice (3 months old), a normal and Alzheimer's-induced animal model, for 14 days, and the brain of the mouse was After extraction and Golgi staining, spine numbers of cortex and hippocampus region neurons (AO region, BS position) were analyzed.
  • ibrutinib can be used as a therapeutic agent for degenerative brain diseases
  • the present inventors have expressed the number of amyloid plaques, amyloid degrading enzyme IDE, and NEP when ibrutinib is treated in a mouse animal model of Alzheimer's disease. The amount was analyzed.
  • Alzheimer's animal mice (5xFAD mice) were injected with ibrutinib (10 mg / kg, ip) or vehicle for 14 days, and immunohistochemical staining and microscopy using anti-4G8 antibody and anti-IDE antibody. Observation was performed.
  • Alzheimer animals Mouse in Ibrutinib by Tau Phosphorylation Regulatory Effect Analysis
  • ibrutinib can be used as a therapeutic agent for degenerative brain diseases.
  • 5xFAD 3 month-old mice
  • ibrutinib Upon treatment, changes in Tau expression and Tau phosphorylation were analyzed.
  • Alzheimer's induced mice were injected with ibrutinib (10 mg / kg, ip) or vehicle for 14 days, and anti-Tau5 antibody, anti-CDK antibody, anti-AT8 antibody, anti-AT100 antibody and anti- Immunohistochemical staining and microscopic observation were performed using AT180 antibody.
  • ibrutinib can modulate amyloid plaque, tau phosphorylation, encephalitis inhibition and memory improvement, thereby enabling ibrutinib to be used as a new therapeutic agent to prevent, ameliorate or treat degenerative brain diseases. And it was found.

Abstract

La présente invention concerne une composition pharmaceutique comprenant comme principe actif de l'ibrutinib, destinée à la prévention ou au traitement de maladies neurodégénératives. L'ibrutinib selon la présente invention inhibe l'activité des cellules microgliales ou des astrocytes afin d'empêcher les cellules microgliales activées ou les astrocytes activés d'endommager les neurones, présente l'excellent effet de freiner la migration des cellules microgliales induite par le lipopolysaccharide (LPS), a comme action de réduire les plaques amyloïdes et d'inhiber la phosphorylation des protéines tau, et améliore les capacités de mémorisation et d'apprentissage, et peut donc être utilisée en tant qu'agent thérapeutique pour la prévention ou le traitement de maladies neurodégénératives.
PCT/KR2019/005063 2018-04-27 2019-04-26 Composition pharmaceutique comprenant comme principe actif de l'ibrutinib, destinée à la prévention ou au traitement de maladies neurodégénératives WO2019209065A1 (fr)

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EP23206941.9A EP4331672A2 (fr) 2018-04-27 2019-04-26 Composition pharmaceutique comprenant de l'ibrutinib en tant que principe actif pour la prévention ou le traitement d'une maladie dégénérative du cerveau
US17/050,800 US11826368B2 (en) 2018-04-27 2019-04-26 Pharmaceutical composition comprising ibrutinib as effective ingredient for preventing or treating degenerative brain disease
EP19793308.8A EP3785715A4 (fr) 2018-04-27 2019-04-26 Composition pharmaceutique comprenant comme principe actif de l'ibrutinib, destinée à la prévention ou au traitement de maladies neurodégénératives
JP2020560335A JP7120553B2 (ja) 2018-04-27 2019-04-26 イブルチニブを有効成分として含む退行性脳疾患の予防又は治療用薬学的組成物

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KR20150032340A (ko) * 2012-07-24 2015-03-25 파마시클릭스, 인코포레이티드 브루톤 티로신 키나제(btk)의 억제제에 대한 내성과 관련된 돌연변이
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US20170119760A1 (en) * 2015-10-28 2017-05-04 Ab Science Use of masitinib for the treatment of progressive supranuclear palsy
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