WO2020196694A1 - Agent thérapeutique et/ou prophylactique pour des troubles olfactifs et des maladies neurodégénératives - Google Patents

Agent thérapeutique et/ou prophylactique pour des troubles olfactifs et des maladies neurodégénératives Download PDF

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WO2020196694A1
WO2020196694A1 PCT/JP2020/013503 JP2020013503W WO2020196694A1 WO 2020196694 A1 WO2020196694 A1 WO 2020196694A1 JP 2020013503 W JP2020013503 W JP 2020013503W WO 2020196694 A1 WO2020196694 A1 WO 2020196694A1
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olfactory
disease
group
therapeutic
disorder
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PCT/JP2020/013503
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English (en)
Japanese (ja)
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忠 長谷
風人 湯浅
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セオリアファーマ株式会社
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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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses

Definitions

  • the present invention is a useful treatment for the treatment and / or prevention of neurodegenerative diseases such as olfactory dysfunction (airway olfactory dysfunction, olfactory neurological olfactory dysfunction, central olfactory dysfunction, etc.), Levy body disease, Parkinson's disease, Alzheimer's disease, etc. And / or prophylactic agents, and nasal drops useful for the treatment and / or prevention.
  • neurodegenerative diseases such as olfactory dysfunction (airway olfactory dysfunction, olfactory neurological olfactory dysfunction, central olfactory dysfunction, etc.), Levy body disease, Parkinson's disease, Alzheimer's disease, etc. And / or prophylactic agents, and nasal drops useful for the treatment and / or prevention.
  • the olfactory sense identifies "odor" molecules in olfactory cells and acts on the central nervous system and autonomic nervous system to produce emotional effects.
  • "odor" information from olfactory cells reaches the secondary olfactory center via the olfactory bulb and is transmitted to the limbic system (amygdala, hippocampus, orbitofrontal cortex, etc.) to the autonomic nervous system, endocrine system, immune system, etc. affect. Therefore, the decrease in olfaction also causes various diseases. For example, it has been reported that the sense of smell is lowered due to stress, head trauma (cerebral contusion), etc., and that the sense of smell is lowered as an initial sign of Parkinson's disease and Alzheimer's disease.
  • Patent Document 1 describes a therapeutic agent for olfactory dysfunction (suspension for nasal drops) containing loteprednol etabonate. This document describes that it promotes olfactory epithelial regeneration, is useful for olfactory epithelium and mixed olfactory disorders, and can restore lost or diminished olfactory sensation.
  • Patent Document 2 describes an olfactory disorder therapeutic agent (or nasal drop) containing at least one active ingredient selected from the group consisting of insulin, insulin analogs and insulin secretagogues. Is described. The literature also describes that it can promote the repair or regeneration of damaged olfactory epithelium and restore the deleted or diminished olfaction.
  • Patent Document 3 Japanese Unexamined Patent Publication No. 2008-531560 includes a therapeutic method comprising intranasally administering to a mammal a therapeutically effective amount of a composition composed of a polypeptide linked to an antibody fragment. It is also described that administration of the composition to the central nervous system of mammals treats neurological disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.
  • Patent Document 4 contains a predetermined thiazole compound or a pharmaceutically acceptable salt thereof as an active ingredient, and has frontal lobe dysfunction (cognitive impairment in Parkinson's disease, cognitive impairment due to chronic stress). , Cognitive disorders such as dementia with Lewy bodies, progressive supranuclear palsy or frontotemporal dementia) are described as treatments and / or prophylactic agents for treating and / or preventing them. This document also describes cognitive impairment (eg, cognitive impairment in Parkinson's disease), olfactory impairment, and the like as frontal lobe dysfunction. However, these Patent Documents 1 to 4 do not describe gangliosides or complexes thereof.
  • Patent Document 5 a predetermined sialic acid derivative activates choline acetyltransferase (ChAT) activity in cholinergic neurons, and senile dementia including Alzheimer's disease and the like are described. It is also described that it is useful for the prevention and treatment of central nervous system disorders and peripheral nervous system disorders such as diabetic neuropathy.
  • this document does not describe activation or activation of nerve cells including olfactory bulb cells and nasal administration of sialic acid derivatives.
  • side effects may occur depending on the administration route.
  • an object of the present invention is to treat and / or treat neurological disorders (airway olfactory disorder, olfactory nerve olfactory disorder, central olfactory disorder, etc.); neurodegenerative diseases (Levy body disease, Parkinson's disease, Alzheimer's disease, etc.).
  • the purpose is to provide therapeutic and / or prophylactic agents and nasal drops useful for prevention.
  • TrkA which is an NGF receptor of cells (olfactory epithelial cells, olfactory bulb cells, etc.), activate or activate the renewal and regeneration of the cells, and suppress apoptosis to suppress olfactory dysfunction.
  • NGF receptor of cells olfactory epithelial cells, olfactory bulb cells, etc.
  • olfactory epithelial cells olfactory epithelial cells, olfactory bulb cells, etc.
  • apoptosis to suppress olfactory dysfunction.
  • neurodegenerative diseases such as olfactory dysfunction associated with neurodegenerative diseases
  • neurodegenerative diseases Levy body disease, Parkinson's disease, Alzheimer's disease, etc.
  • Still another object of the present invention is a treatment useful for treating or preventing olfactory disorders (airway olfactory dysfunction, olfactory nerve olfactory disorder, central olfactory disorder, etc.) and cranial nerve degenerative diseases while suppressing side effects and / or.
  • the purpose is to provide prophylactic and nasal drops.
  • the present inventors repair olfactory epithelial cells or olfactory bulb cells by administering a predetermined ganglioside GM1 derivative even if the olfactory epithelium or olfactory bulb cells are injured. Or I found that it can be regenerated.
  • Such findings should be effective in the prevention and treatment of olfactory disorders (airway olfactory disorder, olfactory nerve olfactory disorder, central olfactory disorder, etc.); Levy body dementia, Parkinson's disease, Alzheimer's dementia, etc.
  • olfactory dysosmia is impaired or injured in dysosmia
  • it is useful for prevention and treatment of olfactory degenerative diseases (Levy body disease, Parkinson's disease, Alzheimer's disease, etc.). It has been shown to be effective, and even if the pain receptor (TRPV1) is present downstream of the nerve growth factor (NGF) receptor TrkA, nasal administration can reduce the occurrence of side effects of nerve pain. It is shown that the ganglioside GM1 derivative can be expected to be transferred into the olfactory epithelium and olfactory bulb tissue.
  • the therapeutic and / or prophylactic agent of the present invention treats and / or prevents at least one disease selected from olfactory dysfunction and neurodegenerative diseases.
  • a therapeutic prophylactic agent treats and / or prevents at least one disease selected from olfactory dysfunction and neurodegenerative diseases.
  • Such therapeutic prophylaxis contains at least a ganglioside GM1 derivative.
  • the ganglioside GM1 derivative may be a compound represented by the following formula (1), a hydrate thereof, or a solvate thereof.
  • R 1 is a hydrogen atom or C 1-4 alkyl group
  • R 2 is a C 1-4 alkyl group, a phenyl group, or a phenyl-C 1-3 alkyl group
  • R 3 is a hydrogen atom or an acetyl group
  • R. 4 indicates a hydroxyl group or a C 1-4 acylamino group
  • X indicates an oxygen atom or a sulfur atom
  • the broken line portion of the steroid skeleton indicates a single bond or a double bond).
  • the ganglioside GM1 derivative is 3 ⁇ - [N- (5-acetamido-3,5-dideoxy-2-O-methyl- ⁇ -D-glycero-D-galact-2-nonuropyranosonyl). ) Amino] Cholestane or its hydrate or solvate may be used.
  • the therapeutic prophylactic agent of the present invention treats at least one disease selected from olfactory dysfunction or olfactory disease, and neurodegenerative disease by activating TrkA and suppressing the expression of active caspase-3 (caspase-3). / Or useful for prevention. That is, the therapeutic prophylactic agent of the present invention activates or activates the neoplasia and regeneration of olfactory epithelial cells or olfactory cells (olfactory bulb cells, etc.) by activating TrkA of nerve cells of olfactory epithelium and olfactory bulb tissue. Suppresses cell apoptosis.
  • the therapeutic prophylactic agent of the present invention may be in the form of an oral administration agent or a parenteral administration agent (intravenous administration agent such as an injection), or may be in the form of a nasal administration agent (nasal drop agent). Good.
  • the therapeutic prophylactic agent of the present invention can be applied to the prevention and / or treatment of at least one disease selected from various olfactory disorders or olfactory diseases and neurodegenerative diseases.
  • Olfactory disorders include, for example, anosmia, hypoolfactory, olfactory loss, hyperosmia, olfactory error, olfactory blindness, malodor and the like.
  • the pathological condition of the olfactory disorder may be at least one selected from the primary diseases of the airway olfactory disorder, the olfactory nerve olfactory disorder, and the central olfactory disorder.
  • the airway dysosmia may be, for example, at least one type associated with sinusitis, allergic rhinitis, nasal cavity tumor, and nasal septum fracture
  • the olfactory nerve olfactory dysosmia may be, for example, olfactory mucosa associated with sensation or influenza. It may be at least one selected from sexual olfactory disorder, drug-induced olfactory disorder, and peripheral neurological olfactory disorder associated with traumatic injury.
  • the central olfactory dysfunction is at least one selected from head trauma, brain tumor, cerebral bleeding, olfactory dysfunction associated with olfactory bulb injury due to aging, and olfactory dysfunction associated with neurodegenerative diseases (cranial nerve degenerative diseases, etc.).
  • the olfactory disorder may be an olfactory disorder associated with a neurodegenerative disease (at least one disease selected from Lewy body disease, Parkinson's disease, and Alzheimer's disease).
  • the diseases of olfactory dysfunction can be classified according to, for example, "Guidelines for diagnosing olfactory dysfunction" (Nippon Journal 56 (4). 2017).
  • the neurodegenerative disease may be a disease that does not involve olfactory injury.
  • Such neurodegenerative diseases include Lewy body disease (including Lewy body dementia), Parkinson's disease (including Parkinson's syndrome), Alzheimer's disease (including Alzheimer's dementia), and the like. At least one selected disease can be exemplified.
  • These diseases may be related to each other, and may be accompanied by both diseases (or symptoms) of, for example, Alzheimer-type dementia and olfactory disorder (odorlessness, etc.).
  • ganglioside GM1 derivative may be used synonymously with “similar”, and “derivative” is an atom or atom having similar atoms or atomic groups (functional groups) in the structure of GM1.
  • a compound substituted with a group for example, a compound in which an oxygen atom is substituted with a sulfur atom, a compound in which a hydroxyl group is substituted with an alkoxy group, etc.
  • a compound in which one or more compounds are bonded to ganglioside GM1, a part of the structure of ganglioside GM1. Includes compounds that have been altered or modified.
  • the olfactory epithelium, olfactory bulb cells and nerve cells can be repaired or regenerated, and at least one disease selected from olfactory dysfunction and neurodegenerative diseases (cerebral neurodegenerative diseases, etc.) can be treated and treated. / Or can be prevented.
  • olfactory dysfunction and neurodegenerative diseases cerebral neurodegenerative diseases, etc.
  • TrkA of nerve growth factor NGF
  • it activates the neoplasia and / or regeneration of the cells and suppresses the apoptosis of cells (olfactory epithelial cells, olfactory bulb cells, etc.) to cause olfactory dysfunction.
  • At least one selected from airway olfactory disorder, olfactory nerve olfactory disorder, central olfactory disorder) (eg, olfactory disorder associated with cranial nerve degenerative disease) and / or neurodegenerative disease (eg, Levy body disease, Parkinson) It is expected to be useful for treating or preventing diseases and at least one selected from neurodegenerative diseases such as Alzheimer's disease.
  • neurodegenerative diseases such as Alzheimer's disease.
  • TRPV1 pain receptor
  • the side effects of neuralgia can be reduced, and the ganglioside GM1 derivative can be transferred into the olfactory epithelium and olfactory bulb tissue, and the olfactory sensation can be described. It is expected that disorders and / or neurodegenerative diseases can be effectively treated or prevented.
  • FIG. 1 is a graph showing the result of the staying time in the dark room on the second day in Test Example 1.
  • FIG. 2 is a graph showing the result of the staying time in the dark room on the 4th day in Test Example 1.
  • FIG. 3 is a graph showing the result of the staying time in the dark room on the 8th day in Test Example 1.
  • FIG. 4 is a graph showing the result of the staying time in the bright room on the second day in Test Example 1.
  • FIG. 5 is a graph showing the result of the staying time in the bright room on the 4th day in Test Example 1.
  • FIG. 6 is a graph showing the result of the staying time in the bright room on the 8th day in Test Example 1.
  • FIG. 7 is a graph showing the result of the staying time in the dark room on the 6th day in Test Example 2.
  • FIG. 8 is a graph showing the result of the staying time in the bright room on the 6th day in Test Example 2.
  • the therapeutic prophylactic agent of the present invention contains at least a ganglioside GM1 derivative as an active ingredient or an active ingredient.
  • Ganglioside means a general term or family of glycosphingolipids to which sialic acid (N-acetylneuraminic acid) is bound, and among such gangliosides, "ganglioside GM1" is a neuron that controls calcium constancy. It is a major ganglioside glycolipid that constitutes the cell membrane of.
  • Ganglioside GM1 derivative means a derivative or an analog derived from “ganglioside GM1", and the derivative of "ganglioside GM1" includes a carboxyl group of N-acylneuraminic acid or deaminomylamic acid and a steroid skeleton 3 Derivatives such as amides having an amide bond at the position, alkoxys of hydroxyl groups of such amides, acyls and esters are included.
  • the "ganglioside GM1 derivative” is a complex of these derivatives (combination or mixture or complex of ganglioside GM1 and the derivative, combination or mixture or complex of a plurality of the derivatives), these derivatives, and ganglioside GD1a. Or an analog thereof, a combination or a mixture or a complex with at least one selected from ganglioside GD1b or an analog thereof, ganglioside GT1b or an analog thereof, and the like.
  • ganglioside GM1 derivative for example, a compound represented by the following formula (1), a hydrate thereof, or a solvate thereof can be used.
  • R 1 represents a hydrogen atom or a C 1-4 alkyl group
  • R 2 is a C 1-4 alkyl group, a phenyl group, or a phenyl-C 1-3 alkyl group
  • R 3 is a hydrogen atom or an acetyl group
  • R 4 represents a hydroxyl group or a C 1-4 acylamino group
  • X represents an oxygen atom or a sulfur atom
  • the broken line portion of the steroid skeleton indicates a single bond or a double bond).
  • the connecting line indicated by the wavy line indicates that the configuration may be either ⁇ -type or ⁇ -type.
  • Examples of the C 1-4 alkyl group represented by R 1 and R 2 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a t-butyl group.
  • R 1 is often a hydrogen atom or a C 1-2 alkyl group (such as a methyl group).
  • Examples of the phenyl-C 1-3 alkyl group represented by R 2 include a benzyl group and a phenethyl group.
  • R 2 is, C 1-2 alkyl group such as methyl group, phenyl group, or often a benzyl group.
  • X may be either an oxygen atom or a sulfur atom, but is often an oxygen atom.
  • R 3 is often a hydrogen atom.
  • Examples of the C 1-4 acylamino group represented by R 4 include a formylamino group, an acetylamino group, and a propionylamino group.
  • Preferred R 4 is a hydroxyl group or an acetylamino group, in particular acetylamino group.
  • the broken line portion of the steroid skeleton (broken line portion at positions 5 and 6) may be either a single bond or a double bond, but in many cases it is a single bond.
  • the configuration of the 3-position of the steroid skeleton may be either ⁇ -form or ⁇ -form, and is usually ⁇ -form in many cases.
  • the compound represented by the formula (1) may be a hydrate or a solvate (a solvate of an alcohol such as methanol, ethanol or isopropanol).
  • Preferred compounds are the compound (1-1): 3 ⁇ - [N- (5-acetamide-3,5-dideoxy-2-O-methyl- ⁇ -D-glycero-D-galact-2-nonuropyrano). Sonyl) amino] cholestane or its hydrate or solvate.
  • Patent Document 5 Details of the ganglioside GM1 derivative, the above-mentioned Patent Document 5 can be referred to including the production method.
  • Such a ganglioside GM1 derivative is useful for treating and / or preventing at least one disease selected from olfactory dysfunction (including olfactory dysfunction associated with neurodegenerative disease) and neurodegenerative disease. That is, nerve growth factor (NGF) maintains the survival of nerve cells, promotes the elongation of nerve processes, promotes the synthesis of neurotransmitters, etc. via high affinity receptors (Tropomyosin receptor kinase A: TrkA).
  • TrkA Tropomyosin receptor kinase A
  • In the peripheral nervous system it is specific for sensory neurons (small cells in the posterior root ganglion) and sympathetic postganglionic neurons, and in the central nervous system, it is specific for basal cholinergic neurons that project to the cerebral cortex and hippocampus. Is known to act on.
  • caspase cysteine-aspartic acid specific protocol: Caspase
  • Caspase-3 apoptotic signaling factor caspase-3 is an important protease involved in the early stages of apoptosis.
  • the present inventors suppress the expression of active caspase-3 (caspase-3), effectively suppress the apoptosis of nerve cells (olfactory epithelial cells, olfactory bulb cells, etc.), and delete or reduce the ganglioside GM1 derivative.
  • caspase-3 active caspase-3
  • nerve cells olfactory epithelial cells, olfactory bulb cells, etc.
  • ganglioside GM1 derivative delete or reduce the ganglioside GM1 derivative.
  • the ganglioside GM1 derivative enhances or activates intracellular signal transduction via the nerve growth factor (NGF) receptor TrkA of the olfactory epithelium and olfactory bulb tissue, and at the same time suppresses caspase 3, thereby olfactory epithelium and olfactory bulb. It has a protective effect on nerve cells in tissues.
  • NGF nerve growth factor
  • olfactory pathway is impaired from an early stage, the olfactory threshold rises, odor identification disorder occurs, and olfactory dysfunction occurs in many cognitively impaired patients. It is also known to be closely related to disability. For example, it is known that olfactory dysfunction appears as an initial symptom of Alzheimer's disease, and olfactory abnormality (odorlessness) is one symptom of Alzheimer's disease. In addition, when the sense of smell is reduced, the transmission of information to the limbic system is also reduced, which may impair mental activities such as emotional and emotional control. Therefore, maintaining or enhancing the olfactory pathway leads to the treatment and prevention of neurodegenerative diseases.
  • the prophylactic therapeutic agent of the present invention is suitable for treating and / or preventing various olfactory disorders or olfactory diseases and / or neurodegenerative diseases.
  • Dysosmia or olfactory disorders include, for example, anosmia, hypoolfactory, olfactory loss, olfactory hypersensitivity, parosmia (parosmia such as parosmia and spontaneous olfactory disorder), olfactory blindness, It may be an olfactory disorder accompanied by symptoms such as malodor.
  • the pathophysiology of olfactory disorder or olfactory disorder is at least one selected from airway olfactory disorder, olfactory nerve olfactory disorder (olfactory mucosal olfactory disorder, peripheral nerve olfactory disorder, etc.), central olfactory disorder, and the like.
  • the airway olfactory dysfunction include olfactory dysfunction associated with sinusitis (for example, chronic sinusitis), allergic rhinitis, nasal tumor, and fracture of the nasal septum.
  • the olfactory nerve olfactory disorder includes, for example, olfactory mucosal olfactory disorder associated with (or caused by) sensation, influenza, etc.
  • the central olfactory dysfunction includes, for example, head trauma (cerebral contusion, etc.), brain tumor, cerebral hemorrhage, olfactory bulb due to aging, etc.
  • olfactory bulb disorder associated with (or caused by) an injury an olfactory bulb disorder associated with (or caused by) a neurodegenerative disease (cerebral neurodegenerative disease, etc.), or the like.
  • neurodegenerative diseases associated with olfactory dysfunction include Lewy body disease (including dementia with Lewy bodies) and Parkinson's disease (Parkinson syndrome (multisystem atrophy, progressive nuclear paralysis, etc.). ), Huntington's disease, spinal cerebral degeneration, progressive supranuclear palsy, spastic vs.
  • Alzheimer's disease including Alzheimer's dementia
  • cortical basal nuclear degeneration chronic It may be at least one disease selected from cognitive impairment due to stress, cognitive impairment due to trauma, frontotemporal dementia, Gillan Valley syndrome, Fisher syndrome, diabetes, schizophrenia, Micklitz's disease, Bechet's disease and the like.
  • neurodegenerative diseases such as Alzheimer's disease may be caused by stress, a cold, head trauma (cerebral contusion), or the like.
  • these diseases may be related to each other, for example, odorlessness, hypoolfactory sensation, etc. may appear as symptoms of neurological olfactory disorder, and neurodegenerative diseases (Levy body including Levy body type dementia).
  • Parkinson's disease including Parkinson's syndrome, Alzheimer's disease including Alzheimer's dementia, etc.
  • olfactory dysfunction odorlessness, hypoolfactory dysfunction, etc.
  • olfactory dysfunction is a combination of the above-mentioned diseases. It may be ill.
  • these olfactory disorders may be accompanied by cognitive or memory disorders and the like.
  • the prophylactic and therapeutic agents of the present invention include neurodegenerative diseases such as Lewy body disease (including Lewy body dementia), Parkinson's disease (including Parkinson's syndrome), and Alzheimer's disease (including Parkinson's syndrome), regardless of the presence or absence of olfactory dysfunction. It is also useful for the treatment and / or prevention of neurodegenerative diseases (including Alzheimer-type dementia) and other neurodegenerative diseases (such as cerebral neurodegenerative diseases), and at least as an inhibitor to suppress the progression of neurodegenerative diseases (such as cerebral neurodegenerative diseases). Is. These disorders may be associated with olfactory dysfunction.
  • neurodegenerative diseases and olfactory disorders central olfactory disorders, etc.
  • central olfactory disorders etc.
  • neurodegenerative diseases can be treated or prevented by repairing or regenerating lost olfactory cells (olfactory epithelial cells, olfactory bulb cells, etc.).
  • Lewy body disease can be positioned as the above concept of Parkinson's disease (including Parkinson's disease dementia). That is, these diseases are diseases on the same spectrum having Lewy body-related pathology containing ⁇ -synuclein aggregate as a main component, and can be collectively referred to as Lewy body diseases.
  • Lewy body disease and Parkinson's disease can be distinguished by the difference in the order of appearance between Parkinsonism (motor symptoms) and dementia, and are clinical types based on the difference in the mode of progression of Lewy body pathology in the brain. It is considered a difference.
  • cortical atrophy in the olfactory-related brain regions was particularly correlated with olfactory disease, right pear cortex and moderate progression in patients with early Parkinson's disease
  • a positive correlation was found between olfactory performance and gray mass volume in the right tongue of the patient, and olfactory injury in Parkinson's disease was associated with the olfactory-sensitive region of the peri-cerebral limbus and para-peri-cerebral limbal cortex.
  • olfactory injury As an early symptom of Parkinson's disease appears to be associated with hyperblackness.
  • olfactory injury is a useful biomarker for revealing progressive cortical atrophy, and olfactory function assessment as well as physiometry in patients with pre-symptomatic Parkinson's disease It has been reported to be associated with the identification of.
  • olfactory injury is a precursor to Parkinson's disease dementia
  • olfactory injury is local, including the amygdala and other limbic systems. It has been reported that it has been clarified that it is associated with cerebral atrophy, and that the olfactory test is considered to play an important role in the treatment of progressive Parkinson's disease in the future.
  • Alzheimer's disease including Alzheimer's disease
  • olfactory dysfunction As a result of the relationship between Alzheimer's disease (including Alzheimer's disease) and olfactory dysfunction, "Am J Psychiatry” April 1985, 142, pp524-525, entitled “Smell deficiency and primary degenerative cognition”, in Alzheimer's disease It has been reported that olfactory deficiency (or deletion) may be one of the early neurological symptoms in primary degenerative cognition. "Neurology” August 1988, 38, pp1228-1232 states that "in early Alzheimer's disease, olfactory sensing and identification performance are separated", and the chemical sensing injury in early Alzheimer's disease is central rather than peripheral. It has been reported that there is already a deficiency in odor detection and identification in Alzheimer's disease, entitled “Nature” Vol.
  • Neuropsychology Vol. 33, No. 3, pp167-176, has many reports that olfactory dysfunction is associated with dementia, and is often prominent in Alzheimer's disease and dementia with Lewy bodies. It is stated that the disorder is recognized from an early stage.
  • the therapeutic prophylactic agent of the present invention repairs or regenerates olfactory cells (olfactory epithelial cells, olfactory bulb cells, etc.) whose activity has decreased. Therefore, the prophylactic therapeutic agent of the present invention is useful at least for suppressing the progression of neurodegenerative diseases (cranial nerve degenerative diseases, etc.) and for the treatment and / or prevention of neurodegenerative diseases (cranial nerve degenerative diseases, etc.). is there.
  • the therapeutic prophylactic agent (formulation or pharmaceutical composition) of the present invention may contain at least a ganglioside GM1 derivative, and is used for treating or preventing olfactory disorders and / or other agents for neurodegenerative diseases, such as olfactory disorders.
  • Pharmaceutical or physiologically active ingredients eg, insulin, IGF, etc.
  • pharmaceuticals or physiologically active ingredients for the treatment or prevention of neurodegenerative diseases eg, levodopa, dopamine receptor agonists, monoamine oxidase B inhibitors, anticholinergic agents, etc. It may contain amantadine hydrochloride, norepinephrine agonists, donepezil hydrochloride, memantine hydrochloride, galantamine hydrobromide, rivastigmine, etc.).
  • non-steroidal anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs, antiallergic agents, antibiotics, antibacterial agents, and vasoconstrictors may be used in combination with preparations such as nasal drops.
  • the dosage form of the preventive agent is not particularly limited, and solid preparations (powder, powder, granules (granule, fine granule, etc.), pills, pills, tablets such as orally disintegrating tablets, capsules (soft capsules) , Hard capsules, etc.), dry syrups, suppositories, etc.), semi-solid preparations (creams, ointments, gummy, etc.), liquids (injections, syrups, etc.), powders as solid preparations
  • the liquid agent may be a spray agent such as a spray agent or an aerosol agent. Further, the liquid agent may be a solution agent or a suspension agent.
  • the therapeutic prophylactic agent of the present invention may be either an orally administered agent (powder, granule, tablet, capsule, etc.) or a parenteral administration agent.
  • Parenteral agents include topical agents (transdermal agents such as ointments and paps, inhalants, nasal agents, transmucosal agents such as ear drops, intravenous agents such as injections, and vagina. It may be an internal administration agent, a subcutaneous administration agent, etc.).
  • the therapeutic prophylactic agent of the present invention may be used as a pharmaceutical composition or a bioactive composition in combination with a carrier.
  • the carrier can be selected according to the dosage form of the therapeutic prophylactic agent, the route of administration, and the like, and at least one carrier selected from excipients, binders, and disintegrants is often used.
  • excipients for solid preparations include sugars or sugar alcohols such as lactose, glucose, sucrose, mannitol, sorbitol, and xylitol; starches such as corn starch; crystalline cellulose (including microcrystalline cellulose); and light anhydrous silicic acid. Etc. can be exemplified.
  • Binders include soluble starches such as pregelatinized starch and partially pregelatinized starch; polysaccharides such as dextrin and sodium alginate; polyvinylpyrrolidone (PVP), carboxyvinyl polymers, polyacrylic acid polymers, polylactic acid, polyethylene glycol and the like.
  • Methyl cellulose (MC), ethyl cellulose (EC), sodium carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC) and the like can be exemplified.
  • the disintegrant include carboxymethyl starch sodium, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, and low-degree-of-substitution hydroxypropyl cellulose. These carriers can be used alone or in combination of two or more.
  • the solid preparation includes coating agents such as saccharides, ethyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, and eudragit (methacrylic acid.
  • coating agents such as saccharides, ethyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, and eudragit (methacrylic acid.
  • Acrylic acid copolymer) or the like coating may be applied.
  • Examples of the carrier or excipient of the semi-solid preparation include dextrin, vaseline, paraffin, squalane, glycerin fatty acid ester (glyceride such as olive oil, corn oil, sesame oil, and saflower oil), and polyhydric alcohol (polyethylene such as macrogol).
  • examples include glycols, propylene glycols, glycerin, etc.), polyoxyethylene fatty acid esters (polyoxyethylene hydrogenated castor oil, etc.), sorbitan fatty acid esters (polysorbates such as sorbitan laurate), stearyl alcohols, higher alcohols such as oleyl alcohols, etc. it can.
  • Liquid carriers or excipients include liquid media such as water (distilled water, water for injection, etc.), alcohols (ethyl alcohol, isopropyl alcohol, etc.), polyhydric alcohols (ethylene glycol, polyethylene glycol, glycerin, etc.), benzyl. Alcohol and the like can be exemplified.
  • These carriers or excipients can be used alone or in combination of two or more.
  • Treatment preventive agents include additives such as lubricants, disintegrant aids, antioxidants or antioxidants, stabilizers, preservatives or preservatives, bactericides or antibacterial agents, depending on the dosage form. It may contain an antistatic agent, a flavoring agent or a masking agent, a coloring agent, a deodorant or a fragrance, a cooling agent, a defoaming agent, a dissolving agent, a solubilizing agent, a painless agent, a pH adjusting agent and the like. These additives can be used alone or in combination of two or more.
  • Preferred therapeutic preventive agents are often transmucosal preparations (inhalants, nasal drops, etc.), especially nasal drops, and transmucosal preparations (nasal drops, etc.) are powders, liquids (solutions, suspensions, etc.). In many cases, it is a turbid liquid agent, etc., and may be an aqueous liquid agent.
  • nasal drops examples include preservatives (parabens such as methyl paraoxybenzoate and propyl paraoxybenzoate; inverted soaps such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, and chlorhexidine gluconate.
  • preservatives parabens such as methyl paraoxybenzoate and propyl paraoxybenzoate
  • inverted soaps such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, and chlorhexidine gluconate.
  • the amount of these additives used may be, for example, about 0.1 to 15% by mass, preferably about 1 to 10% by mass.
  • the pH of the nasal drops may be adjusted to, for example, about pH 5 to 8, and the osmotic pressure of the nasal drops is, for example, 150 to 1140 mOsm (for example, 175 to 1000 mOsm), preferably 200 to 850 mOsm (for example, 220). It may be about 500 mOsm), more preferably about 250 to 300 mOsm.
  • the viscosity of the nasal drops is about 1 to 5000 mPa ⁇ s (for example, 1.5 to 1000 mPa ⁇ s), preferably about 2 to 500 mPa ⁇ s (for example, 3 to 300 mPa ⁇ s) at a temperature of 20 ° C. You may.
  • the content of the ganglioside GM1 derivative can be selected from the range of about 0.001 to 50% by mass depending on the dosage form, administration form and the like, and is preferably 0.01 to 10% by mass, for example. May be selected from the range of about 0.1 to 5% by mass.
  • the content of the ganglioside GM1 derivative is 0.01 to 5% by mass, preferably 0. It may be about 1 to 3% by mass, more preferably 0.2 to 1% by mass (for example, 0.25 to 0.5% by mass).
  • the prophylactic agent (pharmaceutical composition or formulation) of the present invention is applied to humans and non-human animals, usually mammals (for example, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.). On the other hand, it can be safely administered.
  • the dose can be selected according to the dosage form, the species to be administered, age, body weight, medical condition, presence or absence of complications, administration time, administration route, and the like.
  • the dose (daily dose) to humans may be, for example, 0.001 to 1000 mg / day, preferably about 0.1 to 500 mg / day in terms of the compound represented by the formula (1). ..
  • the number of administrations is not particularly limited, and may be, for example, once a day, or may be a plurality of times a day (for example, 2 to 3 times) as needed.
  • transmucosal administration agents such as nasal drops, an appropriate number of times per day, for example, once a day, multiple times a day as needed, at the application site (for example, one-sided nostril or two-sided nostril), 1 It may be administered by dropping about 1 to 5 drops (for example, 2 to 3 drops) per dose.
  • the inhalant may be inhaled at a predetermined concentration once or a plurality of times a day by using an inhaler such as a nebulizer or a steam inhaler.
  • Test Example 1 When a mouse is placed in a light-dark box consisting of a bright room and a dark room for a certain observation time, the mouse stays in the dark room longer than the bright room according to the instinct of preferring the dark place.
  • TMT 2,4,5-trimethylthiazole
  • fox was placed in a dark room where the mouse instinctively prefers to stay, and the odor causes the mouse to stay in the dark room. I set up an environment that is difficult to enter.
  • a light-dark box was used in which two boxes (width 200 mm ⁇ depth 200 mm ⁇ height 300 mm) were connected by a passage (width 100 mm ⁇ depth 100 mm ⁇ height 50 mm) and one box was used as a dark room.
  • 0.4 ⁇ L of a stock solution (97% solution) of 2,4,5-trimethylthiazole (Tokyo Chemical Industry Co., Ltd.) in which mice show repellent behavior (or fear reaction) was applied to filter paper (0.5 cm). It was soaked in ( ⁇ 0.5 cm) and placed near the wall facing the entrance to the darkroom, and the pharmacological action of the test drug on the olfactory dysfunction model (mouse) was investigated.
  • the olfactory disorder model was created by administering methimazole to mice by utilizing the fact that methimazole destroys olfactory epithelial cells.
  • test drug was administered to the olfactory disorder model (mouse) to which methimazole was administered, and the effect of the test drug was examined.
  • the filter paper impregnated with 2,4,5-trimethylthiazole was replaced every time the mice were replaced in the behavior observation in the light-dark box. The details of the test are as follows.
  • mice mice (strain: JCI: ICR, microbiological grade: SPF, male, 6 weeks old at the time of purchase) (Nippon Claire Co., Ltd.) were pre-reared for 1 week and subjected to the test at 7 weeks old.
  • mice were subjected to 15 (5 x 3) control group, 24 (8 x 3) methimazole alone administration group (methimazole group), and 24 (8 x 3) methimazole + test. It was divided into a drug group (test drug group). After administration of methimazole, each group was further divided into 3 groups for behavioral observation in a light-dark box on the 2nd, 4th, and 8th days.
  • Control group (C group) The control group (Group C) was an untreated group and was not administered with methimazole and the test drug.
  • Metimazole (Fujifilm Wako Pure Chemical Industries, Ltd.) is dissolved in dimethyl sulfoxide DMSO (manufactured by Sigma) to prepare a solution with a concentration of 500 mg / ml, and physiological saline (Otsuka Pharmaceutical Factory, Inc.) is added to a concentration of 5 mg / ml. A ml of methimazole administration solution was prepared.
  • the methimazole administration solution was used as a disposable syringe made of polypropylene (manufactured by Terumo Corporation) and a 26G needle (manufactured by Terumo Corporation) at 0. 1 ml (50 mg / kg) was intraperitoneally administered to prepare a model of olfactory dysfunction (a model in which olfactory bulb olfactory epithelial cells were destroyed).
  • Test drug group (S group) As a test drug, compound (1-1) 3 ⁇ - [N- (5-acetamido-3,5-dideoxy-2-O-methyl- ⁇ -D-glycero-D-galact-2-nonuropyranosonyl) Amino] Cholestane was used.
  • Compound (1-1) was prepared according to Example 3 of Patent Document 5.
  • the methimazole administration solution was administered on the first day (Day 1) in the same manner as above, and one hour later, the above test drug administration solution was administered.
  • the test drug was continuously administered daily from the 2nd day (Day 2) to the 8th day (Day 8). That is, the test drug administration solution was administered once a day to unanesthetized mice by nasal instillation (nasal administration) to both noses at a dose of 2 ⁇ L / one nose using a micropipette.
  • Administration protocol The administration protocol is shown in Table 1 below.
  • mice The behavior of the mice was observed for 10 minutes from 1 hour after the administration of the test drug, and the staying time of the mice in a bright place and a dark place was measured. In the control group and the methimazole group, the staying time was measured in the same manner as described above for 10 minutes from 1 hour after the administration of the test drug. In the significant difference test, after confirming the homoscedasticity by the F test, the significant difference was tested by the two-sided t-test.
  • FIGS. 1 The results of the staying time in the dark room of the light-dark box are shown in FIGS. 1 (2nd day), 2 (4th day), and 3 (8th day), and the results of the staying time in the bright room are shown in FIG. It is shown in 4 (2nd day), 5 (4th day), and 6 (8th day).
  • the time spent in the dark room of the mice on the 4th and 8th days after the administration of methimazole are shown in FIGS. 2 and 3.
  • the time spent in the darkroom of the mice in the methimazole group (Group M) was significantly longer than the time spent in the darkroom of the mice in the control group (Group C) (p ⁇ 0.05).
  • the light chamber of the mice in the methimazole group (Group M) was compared with the time spent in the bright room of the mice in the control group (Group C) not receiving methimazole.
  • the length of stay in the mouse was significantly shortened (p ⁇ 0.05).
  • mice sensitivity of mice to the odor of TMT is clearly reduced due to the olfactory disorder caused by the administration of methimazole.
  • mice of the test drug group (Group S) in which the test drug was administered 1 hour after the administration of metimazole and then the administration of the test drug was continued every day the residence time in the dark room increased by the administration of metimazole was extended after the administration of the test drug.
  • the level recovered to the level of the control group (C group) (p ⁇ 0.01).
  • the staying time in the bright room was also restored to the level of the control group (C group) by the administration of the test drug (p ⁇ 0.01).
  • Test Example 2 Instead of the olfactory disorder model (mouse) administered with methimazole, amyloid ⁇ protein (1-42) (hereinafter, may be referred to as amyloid ⁇ protein or amyloid ⁇ ), which is considered to be the cause of Alzheimer's disease, is used in the ventricle. The same test as in Test Example 1 was carried out using the Alzheimer's disease model (mouse) administered to.
  • Accumulation of amyloid ⁇ protein is known as a characteristic neurological finding of Alzheimer's disease (Glenner, GC & Wong, CW Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. (Biochem.Biophys). .Rec.Commun 120,885-890, 1984: Document I)), the accumulation of this amyloid ⁇ protein is considered to be the cause of the onset of Alzheimer's disease.
  • olfactory dysfunction develops in human Alzheimer's disease prior to or in the early stage of the onset of the main symptom (Yong-ming Zou, Da Lu, Li-ping Liu, Hui-hong Zhang).
  • amyloid ⁇ protein accumulation is considered to be the cause of the onset of Alzheimer's disease, and Alzheimer's disease is often accompanied by olfactory dysfunction.
  • An Alzheimer's disease model was created by administering ⁇ -protein (1-42).
  • test drug was nasally administered to the Alzheimer's disease model to which amyloid ⁇ protein (1-42) was administered, and the effect of the test drug was examined.
  • the filter paper impregnated with 2,4,5-trimethylthiazole (TMT) was installed at the time of behavior observation in the light-dark box on the 6th day, and was replaced every time the mouse was replaced in the behavior observation. did.
  • TMT 2,4,5-trimethylthiazole
  • mice mice (mice similar to Test Example 1), 19 control group, 17 amyloid ⁇ protein alone administration group (amyloid ⁇ group), and 10 amyloid ⁇ protein + test drug group (test) It was divided into a drug group).
  • Control group (C1 group and C2 group) The control group (C1 group and C2 group) was an untreated group and did not receive amyloid ⁇ protein (1-42) and the test drug. Of the 19 animals in the control group, 10 were in the C1 group and 9 were in the C2 group. The C1 group does not have a TMT in the dark room, whereas the C2 group has a TMT in the dark room during behavior observation.
  • Amyloid ⁇ group (A group) Amyloid ⁇ protein (1-42) (manufactured by Peptide Research Institute Co., Ltd.) was dissolved in PBS (Phosphate buffered salts) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) to prepare an amyloid ⁇ solution having a concentration of 1 mg / ml. ..
  • amyloid ⁇ group (Group A), on the first day (Day 1), using a 10 ⁇ l microsyringe (manufactured by Terumo Corporation) and a 30G needle (manufactured by Terumo Corporation) connected via a tube, amyloid ⁇ was used. 10 ⁇ l of the solution was administered into the right ventricle to prepare a model for Alzheimer's disease. In the amyloid ⁇ group (group A), TMT is installed in a dark room during behavior observation.
  • Test drug group (S group) As the test drug, the same test drug as in Test Example 1 (Compound (1-1) 3 ⁇ - [N- (5-acetamido-3,5-dideoxy-2-O-methyl- ⁇ -D-glycero-D-galacto) -2-Nonuropyranosonyl) amino] cholestane) was used.
  • test drug group (Group S)
  • the amyloid ⁇ solution was administered in the same manner as above on the first day (Day 1), and one hour later, the above test drug administration solution was nasally administered.
  • the test drug was continuously administered daily from the 2nd day (Day 2) to the 6th day (Day 6). That is, the test drug administration solution was administered once a day to unanesthetized mice by nasal instillation (nasal administration) to both noses at a dose of 2 ⁇ L / one nose using a micropipette.
  • the test drug group (S group) also has a TMT in a dark room during behavior observation.
  • administration protocol The administration protocol is shown in Table 2 below.
  • FIG. 7 The result of the staying time in the dark room of the light-dark box is shown in FIG. 7, and the result of the staying time in the bright room is shown in FIG.
  • mice instinctively prefer to stay in the dark room in the untreated C1 group in which the TMT is not installed in the laboratory equipment. It was also revealed that in the C1 and C2 groups of FIGS. 7 and 8, mice avoid the odor of TMT.
  • mice to TMT to odor were clearly reduced by intracerebroventricular administration of amyloid ⁇ protein.
  • the Alzheimer's disease model (mouse) prepared by intracerebroventricular administration of amyloid ⁇ protein has decreased olfaction (olfactory disorder). It is suggested that it is doing.
  • mice of the test drug group (Group S) in which the test drug was nasally administered 1 hour after the intracerebroventricular administration of amyloid ⁇ and then the administration of the test drug was continued every day the stay in the dark room was prolonged by the administration of amyloid ⁇ .
  • the time recovered to the level of the control group (C2 group) on the 6th day after the administration of the test drug (p ⁇ 0.05).
  • the time spent in the bright room was restored to the level of the control group (C2 group) by the administration of the test drug (p ⁇ 0.01).
  • the therapeutic and / or prophylactic agent (nasal drops) of the present invention is useful for treating and / or preventing olfactory dysfunction. It was also found that the therapeutic prophylactic agent (nasal drops) of the present invention is useful for treating and / or preventing olfactory disorders associated with Alzheimer's disease. It has been reported that Alzheimer's disease is accompanied by decreased olfaction (olfactory disorder), and the therapeutic prophylactic agent (nasal drops) of the present invention is expected to be useful for the treatment and / or prevention of Alzheimer's disease. ..
  • the active ingredient may be transferred from the nasal cavity to the olfactory epithelium and the olfactory bulb, and the enhancement of intracellular signal transduction from TrkA may suppress apoptosis via Bcl-2.
  • active caspase-3 promotes tau protein cleavage in Alzheimer's disease-type dementia and is associated with neurodegeneration (D'Amelio M, et al., Trends Neurosci. 2012). Therefore, the therapeutic prophylactic agent including the nasal drops of the present invention is expected to be effective for the treatment and prevention of various olfactory disorders and / or neurodegenerative diseases.
  • the present invention can be used as a prophylactic and / or therapeutic agent for the various olfactory disorders (odorlessness, hypoolfactory disorder, etc.) and / or neurodegenerative diseases.
  • sinusitis for example, chronic sinusitis
  • airway olfactory disorder associated with allergic rhinitis airway olfactory disorder associated with allergic rhinitis
  • olfactory neurological olfactory disorder associated with sickness central olfactory disorder (olfactory disorder due to head trauma, Levy body)
  • neurodegenerative diseases including cerebral neurodegenerative diseases
  • diseases including Levy body disease type dementia
  • Parkinson's disease Alzheimer's disease
  • Alzheimer's disease type dementia including Alzheimer's disease type dementia
  • neurodegenerative diseases including neurodegenerative diseases
  • body diseases including Levy body disease type dementia
  • Parkinson's disease including Parkinson's syndrome
  • Alzheimer's disease including Alzheimer's disease type dementia
  • the above-mentioned treatment and / or preventive agent is nasally administered (intranasal administration) to transfer the active ingredient to the olfactory epithelium and the olfactory bulb to cause the expression of neuronal apoptosis. It can be suppressed to increase the number of new cells, and the olfactory dysfunction and / or disease can be treated and / or prevented.

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Abstract

L'invention concerne un agent thérapeutique et/ou prophylactique et un spray nasal utiles pour la thérapie et la prévention de troubles olfactifs. L'agent thérapeutique et/ou prophylactique selon la présente invention contient au moins un dérivé de ganglioside GM1, et est utilisé pour la thérapie et/ou la prévention de troubles olfactifs (par exemple, des troubles olfactifs associés à des maladies neurodégénératives). Le dérivé de ganglioside GM1 peut, par exemple, être représenté par la formule (1). (Dans la formule, R1 représente un atome d'hydrogène ou un groupe alkyle en C1-4, R2 représente un groupe alkyle en C1-4, un groupe phényle ou un groupe phénylalkyle en C1-3, R3 représente un atome d'hydrogène ou un groupe acétyle, R4 représente un groupe hydroxyle ou un groupe acylamino en C1-4, X représente un atome d'oxygène ou un atome de soufre, et la partie en ligne pointillée du squelette de stéroïde représente une liaison simple ou une liaison double.)
PCT/JP2020/013503 2019-03-27 2020-03-26 Agent thérapeutique et/ou prophylactique pour des troubles olfactifs et des maladies neurodégénératives WO2020196694A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07228592A (ja) * 1993-12-24 1995-08-29 Mitsubishi Chem Corp シアル酸誘導体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07228592A (ja) * 1993-12-24 1995-08-29 Mitsubishi Chem Corp シアル酸誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KUMBALE, R. ET AL.: "GMI delivery to the CSF via the olfactory pathway", DRUG DELIVERY, vol. 6, no. 1, 1999, pages 23 - 30, XP008166790, DOI: 10.1080/107175499267129 *

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