Genotype-specific methods and systems for the treatment of neurodegenerative diseases

Abstract

This disclosure provides a method for treating neurodegenerative diseases in subjects requiring treatment for neurodegenerative diseases. A therapeutically effective dose of a suitable combination of a mast cell stabilizer and an NSAID may be administered to a suitable subject, where the subject's eligibility is determined by the subject's genotype. In certain embodiments, the combination therapy comprises a combination of a cromolyn homologous salt and an NSAID, and the suitable subject is not a carrier of the APOE ε4 variant of the APOE gene.

Description

Detailed Description of the Invention

[0001] [Cross - Reference to Related Applications] This application claims the priority and benefit of U.S. Provisional Application No. 63 / 494,064, filed on April 4, 2023. The provisional application is incorporated herein by reference in its entirety.

[0002] [Field of the Invention] The present disclosure relates to a treatment method in a suitable subject who needs treatment for neurodegenerative diseases.

[0003] [Background] Alzheimer's disease is a neurodegenerative disease of the brain, characterized by a decline in the formation and recall of short - term memory, a decline in the recall of long - term memory, behavioral abnormalities, disorientation, impairment of activities of daily living and life functions, loss of independence, and death. As of the end of 2020, it is estimated that 55 million people worldwide are suffering from Alzheimer's disease in some form (see ALZHEIMER’S DISEASE INT’L, Numbers of people with dementia around the world, https: / / www.alzint.org / resource / numbers - of - people - with - dementia - worldwide / (30 Nov. 2020)). This number is predicted to approximately double every 20 years.

[0004] Alzheimer's disease is complex. It is likely not a "single" disease, but rather a spectrum, type, or disease with similar causes and clinical presentations. The causes are thought to be multifactorial. There is a consensus that Alzheimer's disease is characterized by the accumulation of insoluble aggregates of amyloid-beta peptide (Aβ) (such as Aβ oligomers). These aggregates or oligomers are thought to be associated with cellular inflammatory responses and to bind to receptors on the surface of neurons, altering the synaptic structure of neurons and thereby disrupting communication between neurons. The amount of Aβ produced per day is very small (estimated 22-27 ng / day for the entire brain) and accumulates over many years (approximately 7-10 mg in the brains of individuals with Alzheimer's disease), so this routine inflammatory response is virtually invisible and unrelated to any of the major symptoms. Furthermore, abnormalities in tubulin-associated unit protein (tau protein or τ protein) are thought to play a role in the disease cascade leading to the onset and progression of Alzheimer's disease. Hyperphosphorylated tau protein is thought to pair and bind with other tau threads. Ultimately, these form tangles within the nerve cell body. When these tangles occur, microtubules break down, causing the neuronal transport system to malfunction. This can first lead to dysfunction in biochemical communication between neurons, and later to cell death.

[0005] In addition to the fact that our understanding of the causes and progression of Alzheimer's disease (including the importance of Aβ and tau proteins) is still developing, several genetic predictors of Alzheimer's disease development have been discovered. While Alzheimer's disease does not appear to be primarily hereditary in most cases, many people certainly carry a genetic predisposition to the disease. In some cases, a strong genetic predisposition to Alzheimer's disease in a given individual may predict with high certainty that they will eventually develop the disease.

[0006] As mentioned above, despite a good understanding of the specific characteristics of Alzheimer's disease, effective treatments have yet to be established. The failure of promising drug candidates highlights an even greater urgency in the search for new targets. New therapies are urgently needed. While researchers have known that genotype strongly influences the prediction of disease progression, investigators searching for drug candidates have not considered the target genotype. Because Alzheimer's disease is multifactorial and involves at least some genetic predisposition factors, there is a significant unmet need for more personalized treatments tailored to the target genotype.

[0007] [Summary of the Invention] In one embodiment, the present disclosure relates to an embodiment of a method for treating a neurodegenerative disease in a subject requiring treatment for the neurodegenerative disease. The method comprises administering to the subject an effective amount of a combination of a mast cell stabilizer and a nonsteroidal anti-inflammatory drug, wherein the subject is not a carrier of a genotype predisposing to the neurodegenerative disease.

[0008] In any embodiment of the treatment method, the neurodegenerative disease may be Alzheimer's disease ("AD"). In any embodiment of the treatment method, the method may treat an ongoing neurodegenerative disease and / or prevent the onset of a future neurodegenerative disease. In any embodiment, at the time of treatment, the neurodegenerative disease may be diagnosed or undiagnosed. At the time of treatment, the neurodegenerative disease may be early-onset. In any embodiment, the mast cell stabilizer may be cromolyn, a cromolyn derivative, a cromolyn homolog; a salt of cromolyn, a cromolyn derivative, or a cromolyn homolog; or any combination thereof. In any embodiment, the salt may be a biocompatible salt. In any embodiment, the biocompatible cromolyn salt may be cromolyn sodium.

[0009] In any embodiment of the treatment method, the subject does not have to be a carrier of any variant of apolipoprotein E that is predisposing to neurodegenerative diseases (including Alzheimer's disease). In any embodiment, the subject does not have to be a carrier of APOE ε4.

[0010] In any embodiment of the treatment method, cromolyn or its biocompatible salt may be formulated as a dry powder for inhalation. In any such embodiment, cromolyn or its biocompatible salt may be formulated as a dry powder with a particle size of less than approximately 3 microns for inhalation.

[0011] In any embodiment of the treatment method, cromolyn or its biocompatible salt may be administered at a dose of approximately 16 mg / day to approximately 20 mg / day.

[0012] [Brief explanation of the drawing] [Figure 1] Figure 1 shows a typical primary structure of a common human ApoE protein, indicating the sites where specific differences exist between common ApoE isoforms. Many isoforms have been reported, but the most common are the ApoE2, ApoE3, and ApoE4 isoforms, which are encoded by the ε2, ε3, and ε4 homologs of the APOE gene, respectively. The E2, E3, and E4 isoforms differ from each other at amino acid residues 112 and / or 158 (shown as gray circles in Figure 1). ApoE2 has cysteine ​​residues at both positions 112 and 158; ApoE3 has a cysteine ​​residue at position 112 and an arginine residue at position 158; ApoE4 has arginine residues at both positions 112 and 158; the ApoE protein has two structural domains; the N-terminal domain contains a receptor-binding region (residues 136-150); the C-terminal domain contains a lipid-binding region (residues 244-272); and the two domains are linked by a "hinge" region. Analysis showed a significant positive correlation between possessing one or two ApoE4 alleles and the early onset of Alzheimer's disease.

[0013] [Figure 2] Figure 2 shows a table of the approximate incidence and average age of onset of Alzheimer's disease in individuals who do not possess the apoE ε4 allele, individuals who are heterozygous for apoE ε4, and individuals who are homozygous for apoE ε4.

[0014] [Figure 3] Figure 3 shows a typical diagram of amyloid-beta protein clearance pathways. These include receptor-mediated uptake by neurons and glial cells, efflux into the interstitial fluid or efflux across the blood-brain barrier (BBB), and protease degradation by insulin-degrading enzymes (IDEs) or neprilysin (NEPs). Impaired Aβ clearance can lead to Aβ accumulation in the brain parenchyma, resulting in the formation of neurotoxic Aβ oligomers and amyloid plaques. Aβ accumulation in the perivascular region can lead to cerebral amyloid angiopathy (CAA), impairing vascular function. ApoE is mainly synthesized by astrocytes and microglia and is lipid-degraded by the ATP-binding cassette A1 (ABCA1) transporter to form lipoprotein particles. Lipidized ApoE binds to soluble Aβ and promotes Aβ uptake via cell surface receptors (including low-density lipoprotein receptor-associated protein 1 (LRP1), low-density lipoprotein receptor (LDLR), heparan sulfate proteoglycan (HSPG) 175, and HSPG 177). This effect may depend on the ApoE isoform and its lipidization level. ApoE promotes the binding and internalization of soluble Aβ by glial cells and inhibits Aβ clearance in the BBB in an isoform-dependent manner (ApoE4 > ApoE3 > ApoE2), further influencing the pathogenesis of CAA. In Figure 3, LXR refers to the hepatic X receptor.

[0015] [Detailed explanation] This disclosure provides a method for treating neurodegenerative diseases in individuals requiring treatment for neurodegenerative diseases.

[0016] (Failures in developing safe and effective treatments for neurodegenerative diseases.) Neurodegenerative diseases such as Alzheimer's disease (AD) have attracted the attention of the medical and pharmaceutical industries since at least the 19th century. While basic science and treatments have advanced significantly in the 21st century, safe and effective treatment options remain in their early stages. Despite an estimated 55 million people worldwide being affected, there are few treatments for neurodegenerative diseases. Aside from the controversial 2021 approval of aducanumab by the U.S. Food and Drug Administration, the most recent FDA-approved drug for Alzheimer's disease was memantine in 2003. While memantine alleviates some symptoms, current treatments offer no hope of reversing disease progression.

[0017] Why are there still no solutions for neurodegenerative diseases? One problem is the difficulty in designing and conducting clinical trials with appropriate clinical efficacy endpoints. Researchers lack the diagnostic and quantitative measurement tools necessary to explain and assess disease progression. Furthermore, the causes of neurodegenerative diseases are multifactorial, and measuring one factor may overlook others. Therefore, depending on the selected evaluation metrics, a clinical trial may appear unable to reject the null hypothesis. However, if designed and interpreted from a different perspective, the same study may demonstrate efficacy (for example, for a specific subgroup of the clinical population).

[0018] Finding safe and effective treatments for neurodegenerative diseases is challenging. One reason is that they are not single, diagnosable illnesses, but complex health problems with over 50 underlying causal factors. Alzheimer's disease is the most widely recognized form of neurodegenerative disease and should be understood as a collective term for progressive neurodegenerative disorders characterized by impaired short-term memory formation and retrieval, progressive decline in long-term memory retrieval, behavioral abnormalities, disorientation, impairment of activities of daily living and functional capacity, loss of independence, and eventual death. Alzheimer's disease accounts for 60–70% of all dementia cases, and the majority of pharmacological therapeutic research has focused on it. The scientific foundation for Alzheimer's disease drug development is extensive and conceptually based on a solid foundation of basic science, and has been substantially validated in vitro and in vivo using animal models. However, in practice, the results of clinical trials since the 1990s have not consistently aligned with the underlying hypotheses and rationale, and have failed to reach pre-defined clinical efficacy endpoints.

[0019] Many obstacles exist in developing promising treatments for neurodegenerative diseases. These include (1) a lack of basic scientific understanding of the complex physiology of neurodegenerative diseases; (2) a lack of practical primary efficacy metrics; and (3) excessive reliance on biomarkers as substitutes for clinical efficacy.

[0020] The initial hurdle is a lack of fundamental scientific understanding of the complex physiology of neurodegenerative diseases. While the research community has made significant progress in understanding the underlying biology and multifactorial causes of these diseases, much remains unclear. For example, scientists still do not fully understand what controls the harmful build-up of amyloid plaques and tau protein entanglements in the brains of Alzheimer's patients, the reasons and influences of underlying genetic predisposition, environmental influences, and why the rate of disease progression differs among diverse individuals. However, researchers have developed robust scientific approaches for drug development and validated them in vitro and in animal models. Therefore, it is unlikely that the failures are solely due to a lack of scientific background.

[0021] The lack of practical primary efficacy metrics means that study design and tools for accurately diagnosing and evaluating disease progression remain the greatest challenges. Most clinical trial designs and available measurement tools (i.e., CDR-SB and all ADS-cogs) tend to result in high failure rates rather than substantial clinical efficacy. This is due to many incomplete measurement tools and the multifactorial causes of disease progression. For example, the results of the Clinical Dementia Assessment (CDR) for Alzheimer's are susceptible to many variables (such as mood or caregiver assessments). These tools do not represent absolutely measurable changes (e.g., differences in tumor size or extent, as is the case with cancer). Available CDR measurements for Alzheimer's disease are, at best, semi-quantitative.

[0022] Furthermore, the likelihood of novel drugs significantly reversing chronic cognitive and functional decline in the damaged brains of Alzheimer's patients is far smaller than the likelihood of stabilizing or slowing progression; therefore, cognitive rating scales such as the CDR-SB tend to measure significant decline rather than stabilization, slowing, or mild improvement in Alzheimer's disease, and may not be optimal endpoints for many novel therapies. In other words, it may not be realistic to expect therapeutic interventions to achieve measurable improvement in a disease that takes several years to manifest clinical symptoms. Evaluating treatment efficacy in asymptomatic populations is even more complex. Many cognitive rating scales that are useful outcome measures in established neurodegenerative diseases may have insufficient sensitivity in the pre-clinical stage of the disease (see Vellas B et al., Endpoints for Pre-Dementia Alzheimer's Disease Trials: A Report From the EU / US / CTAD Task Force, J PREV ALZHEIMERS DIS 2015 Jun; 2(2): 128-35). Other factors that influence trial results include significant inter- and intra-subject variability due to disease heterogeneity and covariates (such as age, diagnosis of progression rate, timing of diagnosis, and other registration criteria).

[0023] Finally, regarding the over-reliance on biomarkers as a substitute for clinical efficacy, biomarkers cannot replace the improvement in clinical symptoms as an indicator of efficacy. While biomarkers may help predict the direction of drug development to achieve efficacy, protein measurements alone simply cannot tell us what cognitive experience a patient is having. Nevertheless, when deciding to move to a pivotal trial, some clinical studies have relied on changes in established biomarker values ​​(e.g., amyloid-beta and / or tau) as a surrogate clinical endpoint, without sufficient evidence of confirming changes in cognitive function / functional ability / overall neurological function. These functional assessment trials are conducted despite the fact that they are the primary clinical measure in Phase III clinical trials for dementia-type neurodegenerative diseases. Ultimately, these trials failed because they did not meet the clinical efficacy endpoint (see Kim CK et al., Alzheimer's Disease: Key Insights from Two Decades of Clinical Trial Failures, J ALZHEIMERS DIS 2022 May 87(1) 83-100).

[0024] The treatment of neurodegenerative diseases—or, more realistically, the path to safe and effective therapies that can slow disease progression and positively impact the quality of life for patients and their families—is complex. However, it is achievable.

[0025] Neurodegenerative diseases such as Alzheimer's disease are chronic illnesses that often have an insidious and long-term onset process. Alzheimer's disease typically presents with a long preclinical and prodromal phase, starting about 20 years before the onset of prominent symptoms. The appearance of symptoms reflects brain networks that are "already" damaged, associated with massive neuronal loss and rapidly expanding neuroinflammatory responses. Unfortunately, current scientific technology cannot diagnose Alzheimer's disease 20 years before the first symptoms appear.

[0026] Currently, available drugs (such as those that block the action of enzymes (acetylcholinesterase inhibitors) that reduce active neurotransmitters for memory in the brain, or those that prevent the toxic effects of another neurotransmitter, glutamate (memantine)) only provide temporary symptom relief. The recently approved biological agent aducanumab is a monoclonal Ig1 antibody that binds to amyloid-β protein and is expected to lead to dose-dependent removal of β-amyloid pathology, but the evidence of clinical efficacy is probably insufficient (Tampi RR et al., Aducanumab: Evidence from Clinical Trial Data and Controversies, DRUGS CONTEXT 2021 Oct 4; 10: 2021-7-3). However, new treatments will act on the underlying biology of the disease and halt or slightly improve the disease process.

[0027] Furthermore, due to the chronic nature and multifactorial etiology of Alzheimer's disease, newly developed treatments will act on one or more pathways (for example, combine treatments that suppress or remove plaques and tangles with treatments that halt or treat the spread of neuroinflammation, or treatments that enhance the function of microglia and macrophages that remove damaged neurons and harmful debris). Unfortunately, the long-term and costly research that takes several years until proven treatments are established can inhibit the willingness to invest. In contrast, the development of drugs (such as antibiotics) for which researchers can quickly determine the effectiveness of the drug is more attractive. The technology giant Pfizer decided to discontinue research on treatments for Alzheimer's disease and Parkinson's disease after numerous attempts that ended unsuccessfully at great expense, and develop treatments for easier drug development and approval. Nevertheless, the potential and unmet needs for neurodegeneration will continue to attract innovative approaches to treatment by the government and industry.

[0028] To address the longstanding problems and industry failures described above, the present disclosure provides a method of treating neurodegenerative diseases that can be adjusted based on specific multivariate factors. In particular, clinical trials and treatment designs for treating neurodegenerative diseases can be adjusted based on the genotype of the patient, as described below.

[0029] (Therapeutic agent) Disclosed herein is a method of treating or preventing a neurodegenerative disease for a subject in need thereof, the method comprising administering a therapeutically effective amount of at least a mast cell stabilizer and a non-steroidal anti-inflammatory drug (NSAID) to a subject who is not a carrier of a genotype that predisposes to the disease.

[0030] The mast cell stabilizer may be cromolyn, a cromolyn derivative, or a biocompatible salt of any cromolyn homolog. The cromolyn homolog may be generally defined according to the following formula I:

[0031] [Chemical formula]

[0032] In formula I, R1, R2, and R3 may be the same as or different from each other, where each may be -H, -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -SH, -C(O)NH2, -CN, alkyl, haloalkyl, aryl, haloaryl, ether, ester, or aldehyde.

[0033] NSAIDs are non-steroidal anti-inflammatory compounds that tend to reduce pain, suppress inflammation, lower fever, and prevent blood clotting. NSAIDs generally inhibit the cyclooxygenase enzymes COX-1 and / or COX-2. Representative NSAIDs include, but are not limited to, acetylsalicylic acid, celecoxib, dexibprofen, dexketoprofen, diclofenac, diflunisal, droxicam, etodolac, fenoprofen, figwort, flufenamic acid, flurbiprofen, hyperforin, ibuprofen, indomethacin, isoxicam, ketoprofen, ketrolac, lycopherone, lornoxicam, loxoprofen, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sarsalate, sulindac, tenoxicam, tolmetine, and tolfenamic acid.

[0034] (Genetic factors) By the early 1990s, researchers had noticed a correlation between specific genotypes and the onset of Alzheimer's disease (see, for example, Pericak-Vance MA, et al. (1991) Linkage studies in familial Alzheimer's disease: evidence for chromosome 19 linkage. AM. J. HUM. GENET. 48, 1034-50). Further research revealed that the genotype of the cholesterol transporter protein apolipoprotein E (apoE) is a major predictor of Alzheimer's disease (see Strittmatter WJ, et al., Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer's disease. PROC. NATL. ACAD. SCI. USA 1993;90, 1977-81).

[0035] ApoE is one of several classes of apolipoproteins (including ApoA, ApoB, ApoD, and ApoJ) that are responsible for intracellular and intercellular lipid transport. ApoE is an important cholesterol transporter protein that is mainly synthesized in liver parenchymal cells, but is also synthesized in the adrenal glands, brain, adipose tissue, kidneys, lungs, and spleen. ApoE is polymorphic and exists as three major isoforms, which are represented as "ApoE2," "ApoE3," and "ApoE4." The corresponding gene variants are represented as APOE ε2, APOE ε3, and APOE ε4, respectively. The APOE gene is located on the long arm of chromosome 19, contains four exons and three introns, and is approximately 3,639 bp long. Because humans possess two copies of the gene on their somatic cell chromosomes, a human APOE genotype may be expressed as ε2 / ε2;ε2 / ε3;ε2 / ε4;ε3 / ε3;ε3 / ε4; or ε4 / ε4. Other apoE variants exist, but are considered extremely rare. Of the three major isoforms, the distribution of alleles in the general population is approximately 8% ε2, 78% ε3, and 14% ε4. Approximately 86% of the general population are not carriers of APOE ε4.

[0036] APOE ε2 is a minority variant in late-onset Alzheimer's disease. The APOE ε4 variant is significantly overpopulated in late-onset Alzheimer's disease. This finding is reliable and has been demonstrated across racial and ethnic groups, as well as in both early-onset and late-onset Alzheimer's disease. While approximately 14% of the general population carries APOE ε4, this figure rises to approximately 40% among those diagnosed with Alzheimer's disease.

[0037] (Appropriate treatment targets) Surprisingly and unexpectedly, human clinical trials using this method revealed that specific combinations of therapeutic agents showed remarkably high efficacy against APOE ε4 non-carriers.

[0038] In subjects who are carriers of APOE ε4, it was hypothesized that the influence of apoE4 protein variants on the onset and progression of Alzheimer's disease might counteract the mechanism of action of certain therapeutic agents. Therefore, the combination therapy disclosed herein was found to be most effective in non-APOE ε4 carriers.

[0039] (definition) When used herein, the following terms and phrases shall have the meanings defined below.

[0040] In this specification and in the claims, the indefinite articles "a" and "an" should be interpreted as meaning "at least one" unless otherwise indicated.

[0041] For the purposes of this disclosure, “amyloidosis-related conditions” refers to diseases associated with amyloid deposition, including: Alzheimer’s disease, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down syndrome, scrapie, medullary thyroid carcinoma, focal atrial amyloid, β2-microglobulin amyloid in dialysis patients, inclusion body myositis, β2-amyloid deposition in muscular atrophy, islet-derived diabetes mellitus (Type 1) and insulinoma. Type 2 diabetes, hereditary hemorrhagic amyloidosis (Dutch type), amyloid A (reactive), secondary amyloidosis, familial Mediterranean fever, familial amyloid nephropathy with urticaria and hearing loss (Muckle-Wells syndrome), amyloid λL chain or amyloid κL chain (idiopathic, myeloma or macroglobulinemia-related) Aβ2M (chronic hemodialysis) amyloidosis, ATTR (familial amyloid polyneuropathy (Portuguese type, Japanese type, Swedish type)), familial amyloid cardiomyopathy (Danish type), focal cardiac amyloidosis, systemic senile amyloidosis, AIAPP or amylin insulinoma, atrial natriuretic factor (focalcitonin), procalcitonin (medullary thyroid carcinoma), Gelsoli N (familial amyloidosis (Finnish type)), cystatin C (hereditary cerebral hemorrhage with amyloidosis (Icelandic type)), AApo-A-1 (familial amyloid polyneuropathy (Iowa type)), AApo-A-II (accelerated aging in mice), head trauma (traumatic brain injury), dementia, fibrinogen-associated amyloid; and, in the case of a person who is homozygous for Asor or PrP-27 (scrapie, Creutzfeldt-Jakob disease, Gerstmann-Streussler-Scheinker syndrome, bovine spongiform encephalopathy) or the apolipoprotein E4 allele, and conditions associated with apolipoprotein E4 allele homozygosity, or Huntington's disease (but not limited to these).

[0042] Amyloidosis is a condition in which various insoluble fibrous proteins accumulate in the tissues of a patient. Amyloid deposition is formed by the aggregation of amyloid proteins, followed by aggregates and / or further combinations of amyloid proteins.

[0043] Amyloidosis exists in many forms, and the disease is classified into the following four groups: primary amyloidosis, secondary amyloidosis, hereditary amyloidosis, and amyloidosis associated with normal aging. Primary amyloidosis (light chain amyloidosis) occurs with abnormalities in plasma cells, and some people with primary amyloidosis also have multiple myeloma (plasma cell carcinoma). Typical sites of amyloid buildup in primary amyloidosis are the heart, lungs, skin, tongue, thyroid gland, intestines, liver, kidneys, and blood vessels. Secondary amyloidosis can occur in response to various diseases that cause persistent infection or inflammation (such as tuberculosis, rheumatoid arthritis, and familial Mediterranean fever). Typical sites of amyloid buildup in secondary amyloidosis are the spleen, liver, kidneys, adrenal glands, and lymph nodes. Hereditary amyloidosis is found in certain families, particularly in Portugal, Sweden, and Japan. Abnormal amyloid production results from mutations in specific proteins in the blood. Typical sites of amyloid buildup in hereditary amyloidosis are the nerves, heart, blood vessels, and kidneys.

[0044] In this specification and claims, the phrase "and / or" should be understood to mean "either one or both" of the combined elements; that is, in some cases the elements exist together, and in other cases only one of the elements exists. Multiple elements listed using "and / or" are similarly interpreted as "one or more" of the combined elements. Other elements other than those specified by the "and / or" clause may exist, whether relevant or not. Thus, as an example without limitation, when combined with an open-ended expression (such as "includes"), the statement "A and / or B" may refer to A only in one embodiment (optionally including elements other than B); B only in another embodiment (optionally including elements other than A); and both A and B in yet another embodiment (optionally including other elements), and so on.

[0045] When used herein and in the claims, “or” should be understood to be synonymous with “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” is interpreted as inclusive; that is, it includes at least one of the number of elements or the list, and may also include any additional items not listed. Only when there is a clear indication to the contrary, a term (such as “one only” or “exactly one,” or “consisting of” as used in a claim) means that it includes exactly one element of the number of elements or the list. In general, as used herein, the term “or” is interpreted to mean an exclusive choice (i.e., “one or the other, but not both”) only when preceded by an exclusive term (such as “either one,” “one,” “one only,” or “exactly one”). When used in the claims, “essentially consisting of” shall have its usual meaning in the field of patent law.

[0046] As used herein and in the claims, the phrase “at least one” should be understood to mean at least one element selected from any one or more elements contained in a list of one or more elements. However, the phrase does not necessarily mean that the list must contain at least one of each of the elements specifically enumerated in the list, nor does it exclude any combination of elements in the list. This definition also allows for the presence of other elements other than those identified in the list referred to by the phrase “at least one,” whether or not they are related to those identified elements. Therefore, as an example without limitation, the expression "at least one of A and B" (or synonymously, "at least one of A or B" or "at least one of A and / or B") can refer to, in one embodiment, at least one optionally containing one or more A's but no B (optionally containing elements other than B); in another embodiment, at least one optionally containing one or more B's but no A (optionally containing elements other than A); and in yet another embodiment, at least one optionally containing one or more A's and at least one optionally containing one or more B's (optionally containing other elements).

[0047] Unless otherwise clearly indicated, it should be understood that in any method claimed herein that includes one or more steps or actions, the order of the steps or actions in such method is not necessarily limited to the order described.

[0048] The term "enhancement" or "enhancement" refers to a combination of compounds administered to a patient in which one of the compounds increases or enhances the therapeutic effect of another compound or a combination of compounds. In some cases, enhancement may improve the efficacy, tolerability, or safety of a particular treatment, or any combination thereof.

[0049] In the claims and the above specification, all transitional phrases ("comprising," "including," "possessing," "having," "containing," "involving," "holding," "composed of," and similar phrases) are understood to be open-ended, meaning "including but not limited to." However, the transitional expressions "consisting of" and "essentially consisting of" are considered closed or semi-closed transitional expressions, respectively, as defined in the United States Patent Office Manual of Patent Examining Procedures (MPEP), Section 2111.03.

[0050] The definitions of each expression (e.g., alkyl, m, n, and similar ones) are intended to be independent of their definitions elsewhere within any given structure, even if they appear multiple times.

[0051] A comprehensive list of abbreviations used by those skilled in the art in the field of organic chemistry is published in the first issue of each volume of the Journal of Organic Chemistry. This list is usually presented in a table titled "Standard List of Abbreviations."

[0052] The terms "hydroxy" and "hydroxyl" refer to the -OH group.

[0053] The term "oxo" refers to the =O group.

[0054] The term "carboxylate" or "carboxyl" is -COO - It refers to a group, or a -COOH group.

[0055] The term "cyano" refers to the -CN group.

[0056] The term "nitro" refers to the -NO2 group.

[0057] The term "amino" refers to the -NH2 group.

[0058] The terms "acyl" or "aldehyde" refer to the -C(=O)H group.

[0059] The term "amido" or "amide" is 、 - Refers to the C(O)NH2 group.

[0060] The term "aminoacyl" or "acylamino" refers to the -NHC(O)H group.

[0061] The term "thiol" refers to the -SH group.

[0062] The term "thioxo" refers to the S group.

[0063] The term "sulfinyl" refers to the -S(=O)H group.

[0064] The term "sulfonyl" refers to the -SO2H group.

[0065] The term "sulfonylamide" or "sulfonamide" refers to the -SO2NH2 group.

[0066] The term "sulfonic acid" refers to the SO3H group, including groups in which hydrogen is substituted (e.g., with a C1-C6 alkyl group ("alkyl sulfonic acid"), an aryl group ("aryl sulfonic acid"), an aralkyl group ("aralkyl sulfonic acid"), etc.). C1-C3 sulfonic acids are preferred (e.g., SO3Me, SO3Et, and SO3Pr).

[0067] As used herein, the term "isomer" refers to stereoisomers, diastereomers, enantiomers, and tautomers. A "tautomer" may be an isomer that is readily convertible by rapid equilibrium. For example, carbonyl compounds having a hydrogen atom at the α-carbon are rapidly converted to their corresponding enols.

[0068] As used herein, the terms “alkyl,” “alkenyl,” and the prefix “alk-” encompass linear groups, branched groups, and cyclic groups (e.g., cycloalkyl and cycloalkenyl). Unless otherwise specifically stated, these groups contain 1 to 20 carbon atoms and are accompanied by alkenyl groups containing 2 to 20 carbon atoms. In some embodiments, these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have 3 to 10 ring carbon atoms. Representative cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl.

[0069] The term "heterocyclic" includes a non-aromatic cycloalkyl ring or cycloalkenyl ring, or ring system, that contains at least one ring heteroatom (e.g., O, S, N).

[0070] Unless otherwise specified, "alkylene" and "alkenylene" refer to the divalent forms of the "alkyl" and "alkenyl" groups defined above. The terms "alkylenyl" and "alkenylene" are used when "alkylene" and "alkenylene" are substituted, respectively. For example, an arylalkylenyl group includes an alkylene moiety to which an aryl group is bonded.

[0071] The term "haloalkyl" encompasses groups substituted with one or more halogen atoms (including perfluoro groups). This also applies to other groups containing the prefix "halo-". Examples of appropriate haloalkyl groups include difluoromethyl, trifluoromethyl, and similar groups. "Halogen" refers to elements including chlorine, bromine, fluorine, and iodine.

[0072] As used herein, the term "aryl" includes monocyclic or polycyclic aromatic hydrocarbons or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl, and indenyl. Aryl groups may be substituted or unsubstituted. Aryl groups include aromatic annulenes, condensed aryl groups, and heteroaryl groups. In this specification, the term aryl also refers to an aryl ring.

[0073] Unless otherwise specified, the term "heteroatom" refers to an O, S, or N atom.

[0074] The term "heteroaryl" includes aromatic rings or ring systems containing at least one ring heteroatom (e.g., O, S, N). In some embodiments, the term "heteroaryl" includes rings or ring systems containing 2 to 12 carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and / or N as heteroatoms. Suitable heteroaryl groups include: furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthylidinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidepyridyl, pyridadinyl, triazinyl, tetradinyl, oxadiazolyl, thiadiazolyl, etc.

[0075] The terms "alylene" and "heteroalylene" refer to the divalent forms of the "aryl" and "heteroaryl" groups defined above. The terms "alylene" and "heteroalylene" are used when "alylene" and "heteroalylene" are substituted, respectively. For example, an alkylallylenyl group contains an allylene moiety to which an alkyl group is attached.

[0076] The term "condensed aryl ring" includes condensed carbon-cyclic aromatic rings or ring systems. Examples of condensed aryl rings include benzos, naphthos, fluorenos, and indenos.

[0077] The term "annulene" refers to an aryl group, which is a fully conjugated monocyclic hydrocarbon. Examples of annulenes include cyclobutadiene, benzene, and cyclooctatetraene. In an aryl group, the annulene typically has one or more hydrogen atoms substituted by other atoms (e.g., carbon).

[0078] In any chemical formula or reaction equation described herein, if a group appears multiple times, each group (or substituent), whether explicitly stated or not, is selected independently. For example, in formula —C(O)NR2, each of the two R groups is selected independently.

[0079] To simplify the explanation and description of certain terms used throughout this specification, the terms “group” and “moiety” are used to distinguish between chemical species (which are or may be substituted) and chemical species (which are or may not be substituted) in certain embodiments of the present invention. Therefore, when the term “group” is used to describe a chemical substituent, the chemical being described includes unsubstituted groups as well as groups having, for example, non-peroxidizing O, N, S, Si, or F atoms in the chain, and groups having carbonyl groups or other conventional substituents. When the term “moiety” is used to describe a chemical compound or substituent, it is intended to include only unsubstituted chemicals. For example, the phrase “alkyl group” is intended to include not only pure open-chain saturated hydrocarbon alkyl substituents (such as methyl, ethyl, propyl, tert-butyl, and similar) but also further substituents known in the art (such as hydroxy, alkoxy, alkylsulfonyl, halogen atoms, cyano, nitro, amino, and carboxyl). Therefore, "alkyl group" includes ether groups, haloalkyl groups, nitroalkyl groups, carboxyalkyl groups, hydroxyalkyl groups, sulfoalkyl groups, etc. On the other hand, the term "alkylmoiety" is limited to only pure open-chain saturated hydrocarbon alkyl substituents (methyl, ethyl, propyl, tert-butyl, and similar groups).

[0080] The present invention encompasses the compounds described herein (including intermediates) in any pharmaceutically acceptable form (including isomers (e.g., diastereomers and enantiomers), tautomers, salts, solvates, polymorphs, prodrugs, and the like). In particular, where the compound is optically active, the present invention explicitly includes each enantiomer of the compound and racemic mixtures thereof. The term “compound” should be understood to include any or all of such forms, whether explicitly stated or not (although “salt” may be explicitly stated).

[0081] As used herein, “pharmaceutically acceptable” means that a compound, composition, or carrier is suitable for administration to a subject to achieve the treatment described herein without excessive adverse side effects, taking into account the need for treatment.

[0082] As used herein, the terms “therapeutically effective dose” or “pharmaceutically appropriate dose” refer to the amount or dosage of a compound that elicits a biological or medical response in a subject, tissue, or cell, as determined by researchers, veterinarians, physicians, or other clinicians.

[0083] As used herein, “pharmaceutically acceptable carrier” includes all dry powders, solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, absorption retarders, and similar substances. A pharmaceutically acceptable carrier is a material useful for administering compounds in the methods of the present invention, preferably non-toxic, and may be a solid, liquid, or gaseous material, otherwise inert, pharmaceutically acceptable, and compatible with the compounds of the present invention. Examples of such carriers include oils such as corn oil, buffers such as PBS, physiological saline, polyethylene glycol, glycerin, polypropylene glycol, amides such as dimethyl sulfoxide and dimethylacetamide, proteins such as albumin, and detergents such as Tween 80, monosaccharides and oligosaccharides (such as glucose, lactose, cyclodextrin, and starch).

[0084] As used herein, the terms “administering” or “administration” refer to providing the compound or pharmaceutical composition of the present invention to a person suffering from or at risk of suffering from a disease or condition that is the target of treatment or prevention.

[0085] As used herein, the term “systemic delivery” refers to any suitable method of administration that has the potential to deliver the compound of the present invention throughout the body. In one embodiment, systemic delivery may be selected from the group consisting of oral, non-enteral, nasal, inhaler, sublingual, rectal, and transdermal administration.

[0086] In pharmacology and toxicology, the route of administration is the path by which a drug, solution, poison, or other substance enters the body. Routes of administration may generally be classified according to the site of application of the substance. Common examples include oral administration and intravenous administration. Routes can also be classified based on the site where the target of action exists. Actions may be classified as topical (local), enteral (systemic effect but delivered via the gastrointestinal tract), or non-enteral (systemic effect but delivered via a route other than the gastrointestinal tract).

[0087] Local administration emphasizes local effects, applying the substance directly to the site where the effect is desired. However, the term "local" may not necessarily involve targeted effects of the substance, and may be defined as application to a specific site or surface of the body; this classification can be considered a variant of a classification based on the application site. In enteral administration, the desired effect is systemic (non-local), and the substance is delivered via the gastrointestinal tract. In non-enteral administration, the desired effect is systemic, and the substance is delivered via a route other than the gastrointestinal tract.

[0088] Examples of local administration include epicutaneous administration (application to the skin) (such as allergy testing or general local anesthesia), inhalation administration (such as asthma medications), enema administration (such as contrast agents for imaging diagnostics of the intestinal tract), eye drop administration (administered to the conjunctiva) (such as antibiotics for conjunctivitis), ear drop administration (such as antibiotics and corticosteroids for otitis externa), and administration via the mucous membranes of the body.

[0089] Enteral administration may involve any part of the gastrointestinal tract and have systemic effects. Examples include oral administration (many drugs as tablets, capsules, or drops), administration via gastric tube, duodenal tube, or gastrostomy (many drugs and enteral nutrition formulas), and rectal administration (various suppositories).

[0090] Examples of non-enteral administration include intravenous administration (into a vein) (e.g., many drugs, complete non-enteral nutrition), intra-arterial administration (into an artery) (e.g., vasodilators in the treatment of vasospasm, and thrombolytics in the treatment of embolism), intraosseous injection (into the bone marrow), intramuscular administration, intracerebral administration (into the brain parenchyma), intraventricular administration (into the ventricular system), intrathecal administration (injection into the spinal canal), and subcutaneous administration (into the subcutaneous tissue). Of these, intraosseous injection is essentially an indirect form of intravenous access because the bone marrow flows directly into the venous system. In emergency medicine and pediatrics, intraosseous injection may be used to administer drugs and liquids when intravenous administration is difficult.

[0091] Any route of administration may be suitable for the present invention. In one embodiment, the compound of the present invention may be administered to a subject by intravenous injection. In another embodiment, the compound of the present invention may be administered to a subject via any of the other suitable systemic delivery methods (such as oral, non-enteral, nasal, sublingual, rectal, and transdermal administration).

[0092] In another embodiment, the compound of the present invention may be administered to a subject via the nasal system or oral cavity (for example, by inhalation).

[0093] In another embodiment, the compound of the present invention may be administered to a subject by intraperitoneal injection or IP injection.

[0094] As used herein, the terms “intraperitoneal injection” or “IP injection” refer to the injection of a substance into the peritoneum (body cavity). IP injections are more commonly applied to animals than to humans. Generally, IP injections may be preferred when a large volume of blood substitute is required, or when suitable veins for intravenous injection are unavailable due to hypotension or other problems.

[0095] In animals, IP injection is easier to administer compared to other non-enteral methods, and is therefore primarily used in veterinary medicine and animal experiments for the administration of systemic drugs and liquid preparations.

[0096] In humans, IP injection is widely used to administer chemotherapy drugs in the treatment of certain cancers, particularly ovarian cancer. While controversial, this specific use is recommended as standard treatment.

[0097] Certain compounds contained in the compositions of the present invention may exist in the form of specific geometric isomers or stereoisomers. Furthermore, the polymers of the present invention may also be optically active. The present invention considers all of these compounds (including cis and trans isomers, R and S enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures) to be within the scope of the present invention. Substituents such as alkyl groups may have additional chiral carbon atoms. All of these isomers and mixtures thereof are intended to be included in the present invention.

[0098] For example, if a specific enantiomer of the compound of the present invention is desired, it may be prepared by asymmetric synthesis or by derivatization using a chiral auxiliary group. In this case, the resulting diastereomer mixture can be separated and the auxiliary group can be cleaved to obtain the desired pure enantiomer. Alternatively, if the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomer salt can be formed using a suitable optically active acid or base. The obtained diastereomer can then be separated by fractional crystallization or chromatographic means well known to those skilled in the art, and the pure enantiomer can be recovered.

[0099] The terms "substitution" or "substituted with" should be understood to include the fact that the substitution conforms to the allowable valencies of the atom and substituent being substituted, and that it results in a stable compound that does not change spontaneously (e.g., through rearrangement, cyclization, elimination, or other reactions).

[0100] The term "substituted" may also include all acceptable substituents of an organic compound. In a broad sense, acceptable substituents include acyclic and cyclic, branched and unbranched, carboncyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described above. There may be one or more acceptable substituents for a given organic compound, and they may be the same or different. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any of the acceptable substituents of the organic compounds described herein that satisfy the valence of the heteroatom. The present invention is not intended to be limited in any way by the acceptable substituents of the organic compound.

[0101] For the purposes of this invention, chemical elements are identified based on the periodic table of elements (CAS edition) ("Handbook of Chemistry and Physics", 67th Ed., 1986-87, inside front cover).

[0102] As used herein, the terms “subject” or “individual” refer to a human or other vertebrate. The terms are intended to encompass “patient.”

[0103] The term "synergistic" refers to a combination of two or more agents that is more effective than the sum of their individual effects. Synergistic effects allow for effective treatment of a disease even with reduced dosages of individual therapies. This reduction in dosage can decrease toxicity without diminishing efficacy. Furthermore, synergistic effects can improve efficacy. Finally, synergistic effects may lead to improved disease avoidance or mitigation compared to any single treatment.

[0104] Combination therapy can yield products with doses lower than those typically required when using either the first or second therapeutic agent alone (referred to herein as "apparent one-way synergy"), or lower than those typically required when using both therapeutic agents alone (referred to herein as "two-way synergy").

[0105] As used herein, “pharmaceutically acceptable carrier” includes all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, absorption retarders, and similar substances. A pharmaceutically acceptable carrier is a material useful for administering a compound in the method of the present invention, preferably non-toxic, and may be a solid, liquid, or gaseous material, otherwise inert, pharmaceutically acceptable, and compatible with the compound of the present invention. Examples of such carriers include oils such as corn oil, buffers such as PBS, physiological saline, polyethylene glycol, glycerin, polypropylene glycol, amides such as dimethyl sulfoxide and dimethylacetamide, proteins such as albumin, and detergents such as Tween 80, monosaccharides and oligosaccharides (such as glucose, lactose, cyclodextrin, and starch).

[0106] The formulations used in the present invention may contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those skilled in the art. The use of such media and agents with pharmacoactive substances is well known to those skilled in the art. Auxiliary active compounds can also be incorporated into the imaging agents of the present invention. The imaging agents of the present invention may be administered to an organism in a suitable diluent or adjuvant, in combination with an enzyme inhibitor, or in a suitable carrier (such as human serum albumin or liposomes). Pharmaceutically acceptable diluents include sterile saline and other aqueous buffer solutions. Adjuvants assumed herein include resorcinol, nonionic surfactants (such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether). Enzyme inhibitors include pancreatic trypsin inhibitors, diethyl pyrocarbonate, and transilol. Liposome inhibitors include water-in-oil-in-water CGF emulsions and conventional liposomes (see J. Neuroimmunol. 1984, 7, 27).

[0107] As described herein, certain embodiments of the compound may contain basic functional groups (such as amino groups or alkylamino groups) and therefore have the ability to form pharmaceutically acceptable acids and pharmaceutically acceptable salts. In this regard, the term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic and organic acid addition salts of the compound of the present invention. These salts may be prepared in situ in the administration vehicle or during the dosage form manufacturing process, or they may be prepared by separately reacting the purified compound of the present invention in free base form with a suitable organic or inorganic acid and then separating the salts produced in a subsequent purification process. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate, and similar salts (see J. Pharm. Sci. 1977, 66, 1-19).

[0108] pharmaceutically acceptable salts of the target compound include conventional non-toxic salts or quaternary ammonium salts (e.g., derived from non-toxic organic or inorganic acids). For example, such conventional non-toxic salts include salts derived from inorganic acids (such as hydrochlorides, hydrobroms, sulfates, sulfamates, phosphates, nitrates, and similar salts), as well as salts prepared from organic acids (such as acetates, propions, succinates, glycolates, stearates, lactates, malates, tartrates, citrates, ascorbic acid, palmitates, maleates, hydroxymaleates, phenylacetates, glutamates, benzoates, salicylates, sulfanilates, 2-acetoxybenzoates, fumarates, toluenesulfonates, methanesulfonates, ethanedisulfonates, oxalates, isothionates, and similar salts).

[0109] In other cases, the compounds of the present invention may contain one or more acidic functional groups and therefore have the ability to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In this context, the term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic base and organic base addition salts of the compounds of the present invention. These salts may be prepared in situ during the manufacturing process of the dosage medium or dosage form, or the purified compound obtained may be prepared by separately reacting the resulting purified compound in free acid form with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine). Typical alkali salts or alkaline earth salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, and similar salts. Typical organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and similar salts (see, for example, J. Pham. Sci. 1977).

[0110] More specifically, compounds that can be incorporated into a pharmaceutical composition include a therapeutically effective amount of the first compound, a therapeutically effective amount of the second compound, and a pharmaceutically acceptable carrier. The therapeutically effective amount of the compound, as well as a specific pharmaceutically acceptable carrier, may vary depending, for example, the age, weight, sex, route of administration, and type of viral disease being treated.

[0111] In certain embodiments, the usable pharmaceutical composition contains the compound of the present invention in an effective unit dosage form. As used herein, the term “effective unit dosage” or “effective unit dose” means a predetermined amount sufficient to be effective against AD, etc. Examples include an amount that enables the treatment of amyloid deposition in vivo or in vitro, resulting in an acceptable level of toxicity and bioavailability for pharmaceutical use, and / or preventing cytopathogenesis and toxicity involved in fibrillation.

[0112] The first or second compound used in the method of the present invention may be contained in the pharmaceutical composition in an amount ranging from 0.01 to 99% of the total composition weight, preferably from 0.1 to 80% of the total composition weight. For oral administration, the first or second compound is generally administered in an amount of 0.1 g / body weight to 15 g / body weight, preferably from 0.5 g / body weight to 5 g / body weight. For intravenous injection, the dose is about 0.1 to about 30 mg / kg / day, preferably from about 0.5 to about 10 mg / kg / day. When applied topically as a liquid, ointment, or cream, the first or second compound may be present in the composition in an amount of about 0.1 to about 50 mg / mL, preferably from about 0.5 to 30 mg / mL.

[0113] For systemic administration, the daily dose used for adult treatment is in the range of approximately 0.1 mg / kg to approximately 150 mg / kg, preferably approximately 0.2 mg / kg to approximately 80 mg / kg.

[0114] All U.S. patents and U.S. patent application publications cited herein are incorporated herein by reference.

[0115] Those skilled in the art will recognize, or confirm by ordinary experimentation, many equivalents to specific embodiments of the invention described herein. Such equivalents are intended to be encompassed in the following claims.

[0116] [Treatment method] The compound combinations described above may be administered to the subject as a single dosage form or by separate administration of each active agent. These agents may be formulated as a single tablet, pill, capsule, or non-enteral solution, and similar forms. Individual therapeutic agents may be separated from other therapeutic agents in a single dosage form. Formulating the dosage form in this way may help maintain its structural integrity until a potentially reactive therapeutic agent is administered. The therapeutic agent may be contained in a compartmentalized region within a capsule or in individual caplets, etc. The therapeutic agent may be provided as a separated layer within a tablet.

[0117] Alternatively, the therapeutic agents may be administered as separate compositions (e.g., separate tablets or solutions). One or more active agents may be administered simultaneously with other active agents, or they may be administered intermittently. The administration interval of the therapeutic agents may be adjusted to achieve the desired therapeutic effect. In certain cases, one or more therapeutic agents may be administered just a few minutes after the administration of other therapeutic agents (e.g., about 1, 2, 5, 10, 30, or 60 minutes). Alternatively, one or more therapeutic agents may be administered several hours after the administration of other therapeutic agents (e.g., about 2, 4, 6, 10, 12, 24, or 36 hours). In certain embodiments, it may be advantageous to administer one or more therapeutic agents once or twice during the administration interval of the remaining therapeutic agents. For example, one therapeutic agent may be administered 2 hours after the administration of another therapeutic agent, and then again 10 hours later. The therapeutic effects of each active ingredient should overlap for at least a portion of their duration, so that the overall therapeutic effect of the combination therapy is partly due to the combined or synergistic effect of the combination therapy.

[0118] The dosage of an active agent generally depends on several factors, including the pharmacodynamic properties of each agent in the combination, the method and route of administration, the health status of the patient being treated, the scope of treatment desired, the nature and type of combination therapy (if any), the frequency of treatment, and the nature of the desired effect. Generally, the dosage range for an active agent is often in the range of approximately 0.001 to 250 mg / kg (body weight) per day. For a normal adult weighing approximately 70 kg, the dosage would be in the range of approximately 0.1 to 25 mg / kg (body weight). However, this general dosage range may require some variation depending on the age and weight of the patient being treated, the intended route of administration, the specific agent being administered, and similar factors. Since combination therapy involves the use of two or more different active agents, the potency of each agent and the interactions achieved by the combination must be considered. Importantly, determining the dosage range and optimal dosage for a particular mammal is feasible within the capabilities of those skilled in the art who benefit from this disclosure.

[0119] The dosage range of the drug may be as low as 5 ng / day. In certain embodiments, the drug of the present invention is administered in the following doses: about 10 ng / day, about 15 ng / day, about 20 ng / day, about 25 ng / day, about 30 ng / day, about 35 ng / day, about 40 ng / day, about 45 ng / day, about 50 ng / day, about 60 ng / day, about 70 ng / day, about 80 ng / day, about 90 ng / day, about 100 ng / day, about 200 ng / day, about 300 ng / day, about 400 ng / day, about 500 ng / day, about 600 ng / day, about 700 ng / day, about 800 ng / day, about 900 ng / day, about 1 μg / day, about 2 μg / day, about 3 μg / day, about 4 μg / day, about 5 μg / day Approximately 10 μg / day, 15 μg / day, 20 μg / day, 30 μg / day, 40 μg / day, 50 μg / day, 60 μg / day, 70 μg / day, 80 μg / day, 90 μg / day, 100 μg / day, 200 μg / day, 300 μg / day, 400 μg / day, 500 μg / day, 600 μg / day, 700 μg / day, 800 μg / day, 900 μg / day, 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 10 mg / day, 15 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, or 50 mg / day.

[0120] In certain embodiments, the drug of the present invention is administered at pM or nM concentrations. In certain embodiments, the drug is administered at the following concentrations: about 1 pM, about 2 pM, about 3 pM, about 4 pM, about 5 pM, about 6 pM, about 7 pM, about 8 pM, about 9 pM, about 10 pM, about 20 pM, about 30 pM, about 40 pM, about 50 pM, about 60 pM, about 70 pM, about 80 pM, about 90 pM, about 100 pM, about 200 pM, about 300 pM, about 400 pM, about 500 pM, about 600 pM, about 700 pM, about 8 00 pM, approximately 900 pM, approximately 1 nM, approximately 2 nM, approximately 3 nM, approximately 4 nM, approximately 5 nM, approximately 6 nM, approximately 7 nM, approximately 8 nM, approximately 9 nM, approximately 10 nM, approximately 20 nM, approximately 30 nM, approximately 40 nM, approximately 50 nM, approximately 60 nM, approximately 70 nM, approximately 80 nM, approximately 90 nM, approximately 100 nM, approximately 200 nM, approximately 300 nM, approximately 400 nM, approximately 500 nM, approximately 600 nM, approximately 700 nM, approximately 800 nM, or approximately 900 nM.

[0121] In certain embodiments, the size of the active ingredient is important. In certain embodiments, the diameter of the active ingredient is less than approximately 3 μm, less than approximately 2 μm, or less than approximately 1 μm. In certain embodiments, the diameter of the active ingredient is approximately 0.1 μm to approximately 3.0 μm. In certain embodiments, the diameter of the active ingredient is approximately 0.5 μm to approximately 1.5 μm. In certain embodiments, the diameter of the active ingredient is approximately 0.2 μm, approximately 0.3 μm, approximately 0.4 μm, approximately 0.5 μm, approximately 0.6 μm, approximately 0.7 μm, approximately 0.8 μm, approximately 0.9 μm, approximately 1.0 μm, approximately 1.1 μm, approximately 1.2 μm, approximately 1.3 μm, approximately 1.4 μm, or approximately 1.5 μm.

[0122] In pharmaceutical combinations, it can be advantageous to have a relatively larger amount of the first component compared to the second component. In certain cases, the ratio of the first active ingredient to the second active ingredient is approximately 200:1, 190:1, 180:1, 170:1, 160:1, 150:1, 140:1, 130:1, 120:1, 110:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1. Furthermore, it may be desirable for the pharmaceutical ingredients to be more evenly distributed. In certain cases, the ratio of the first active ingredient to the second active ingredient is approximately 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, or 1:4. Furthermore, in pharmaceutical combinations, it may be advantageous to include a relatively large amount of the second component compared to the first component. In certain cases, the ratio of the second active ingredient to the first active ingredient is approximately 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1. In certain cases, the ratio of the second active ingredient to the first active ingredient is approximately 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, or 40:1. In certain cases, the ratio of the second active ingredient to the first active ingredient is approximately 200:1, 190:1, 180:1, 170:1, 160:1, 150:1, 140:1, 130:1, 120:1, or 110:1. A composition comprising any combination of the first and second therapeutic agents identified above may be administered in divided doses approximately 1, 2, 3, 4, 5, or 6 times per day, or in a form that provides an effective release rate to achieve the desired result. The dosage form may contain both the first and second active agents. If the dosage form contains both the first and second active agents, the dosage form may be administered once daily.

[0123] For example, a formulation intended for oral administration to humans may contain approximately 0.1 mg to 5 g of the first therapeutic agent and approximately 0.1 mg to 5 g of the second therapeutic agent, both of which are mixed with an appropriate and convenient amount of carrier material, varying in the range of approximately 5% to 95% of the total composition. A unit dose would generally contain approximately 0.5 mg to 1500 mg of the first therapeutic agent and approximately 0.5 mg to 1500 mg of the second therapeutic agent. The dose of the first therapeutic agent could be approximately 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, with a maximum of approximately 1500 mg. The dosage of the second treatment agent is approximately 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, with a maximum of approximately 1500 mg. In one embodiment, the present disclosure relates to an embodiment of a method for treating a neurodegenerative disease in a subject requiring treatment for the neurodegenerative disease. The method comprises administering to the subject an effective amount of a combination of a mast cell stabilizer and a nonsteroidal anti-inflammatory drug, wherein the subject is not a carrier of a genotype predisposing to the neurodegenerative disease.

[0124] In any embodiment of the treatment method, the neurodegenerative disease may be Alzheimer's disease (AD). In any embodiment of the treatment method, the method may treat an ongoing neurodegenerative disease and / or prevent the onset of a future neurodegenerative disease. In any embodiment, at the time of treatment, the neurodegenerative disease may be diagnosed or undiagnosed. At the time of treatment, the neurodegenerative disease may be early-onset. In any embodiment, the mast cell stabilizer may be cromolyn, a cromolyn derivative, a cromolyn homolog; a salt of cromolyn, a cromolyn derivative, or a cromolyn homolog; or any combination thereof. In any embodiment, the salt may be a biocompatible salt. In any embodiment, the biocompatible cromolyn salt may be cromolyn sodium.

[0125] In any embodiment of the treatment method, the subject does not have to be a carrier of any variant of apolipoprotein E that predisposes the subject to Alzheimer's disease. In any embodiment, the subject does not have to be a carrier of APOE ε4.

[0126] In any embodiment of the treatment method, cromolyn or its biocompatible salt may be formulated as a dry powder for inhalation. In any such embodiment, cromolyn or its biocompatible salt may be formulated as a dry powder with a particle size of less than approximately 3 microns for inhalation.

[0127] In any embodiment of the treatment method, cromolyn or its biocompatible salt may be administered in a dose of approximately 16 mg / day to approximately 50 mg / day. In some embodiments, the dose may be approximately 16 mg / day to approximately 20 mg / day. [Brief explanation of the drawing]

[0128] [Figure 1] Figure 1 shows a typical primary structure of a common human ApoE protein, indicating the regions where specific differences exist between common ApoE isoforms. [Figure 2] Figure 2 shows a table of the approximate incidence and average age of onset of Alzheimer's disease in individuals who do not possess the apoE ε4 allele, individuals who are heterozygous for apoE ε4, and individuals who are homozygous for apoE ε4. [Figure 3] Figure 3 shows a typical diagram of the amyloid-beta protein clearance pathway.

Claims

1. A method for treating neurodegenerative diseases in patients who require treatment for neurodegenerative diseases, The method includes the step of administering an effective amount of a combination of a mast cell stabilizer and a nonsteroidal anti-inflammatory drug to the subject; Here, the subject is not a carrier of a genotype that predisposes the development of neurodegenerative diseases. method.

2. The method according to claim 1, wherein the neurodegenerative disease is Alzheimer's disease.

3. The method according to claim 1, wherein the nonsteroidal anti-inflammatory drug is ibuprofen.

4. The method according to claim 1, wherein the mast cell stabilizer is cromolin or a biocompatible salt thereof.

5. The method according to claim 2, wherein the subject is not a carrier of any variant of apolipoprotein E that is a predisposing factor for the development of Alzheimer's disease in the subject.

6. The method according to claim 5, wherein the subject is not a carrier of APOE ε4.

7. The method according to claim 4, wherein the cromolin or its biocompatible salt is cromolin sodium.

8. The method according to claim 4, wherein the cromolin or a biocompatible salt thereof is formulated as a dry powder for inhalation.

9. The method according to claim 8, wherein the cromolin or a biocompatible salt thereof is formulated for inhalation as a dry powder with a particle size of less than approximately 3 microns.

10. The method according to any one of claims 4 to 9, wherein the cromolin or a biocompatible salt thereof is administered in a dose of about 16 mg / day to about 20 mg / day.

Images