# US 11,110,097 B2 · Combination therapies for the treatment of alzheimer's disease and related disorders

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- Number: US 11,110,097 B2
- Document ID: US11110097B2
- Status: Granted
- Kind: B2
- Application number: 16/570,377
- Filed: 2019-09-13
- Published: 2020-03-12
- Granted: 2021-09-07
- Earliest claimed: 2012-10-25
- Assignees: The General Hospital Corporation
- Applicants: The General Hospital Corporation
- Inventors: David R. Elmaleh
- Web page: https://patentgrep.com/patent/US11110097B2

## CPC

- A61K 31/5415: ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
- A61K 31/047: having two or more hydroxy groups, e.g. sorbitol
- A61K 31/075: Ethers or acetals
- A61K 31/13: Amines {(A61K31/04 takes precedence)}
- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 31/194: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
- A61K 31/225: Polycarboxylic acids
- A61K 31/352: condensed with carbocyclic rings, e.g. methantheline {(cannabinoids A61K31/658)}
- A61K 31/353: 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/438: The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/185: {Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3}
- A61K 39/0005: {Vertebrate antigens (from snakes A61K39/38)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 51/0453: {having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole}
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: 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
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/18: against material from animals or humans
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention relates to combination therapies for treating Alzheimer's disease or an amyloidosis-associated pathological condition comprising co-administering a therapeutically effective amount of a first compound, and a therapeutically effective amount of a second compound. In certain embodiments, the first compound or the second compound inhibits AB peptide polymerization; is an anti-inflammatory; improves cognitive function, mood, or social behavior; is associated with Tau or alpha-synuclein; or regulates amyloid peptide washout.

## Claims

### Claim 1

A method of treating or slowing the progression of a disease or condition in a human subject in need thereof comprising administering sublingually, intranasally, or to mucous membranes in the subject, a therapeutically effective amount of cromolyn or a salt thereof, wherein the disease or condition is Alzheimer's disease, dementia, an amyloidosis-associated condition, or a head injury.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disease or condition is Alzheimer's disease.

### Claim 3 (depends on 1)

The method of claim 1, wherein the disease or condition is an amyloidosis-associated condition selected from idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome, Scrapie, medullary carcinoma of the thyroid, isolated atrial amyloidosis, β2-microglobulin amyloidosis, inclusion body myositis, muscle wasting disease, Islets of Langerhans diabetes, Type 1 diabetes, insulinoma, Type 2 diabetes mellitus, hereditary cerebral hemorrhage amyloidosis (Dutch), amyloid A (reactive) amyloidosis, secondary amyloidosis, familial Mediterranean fever, familial amyloid nephropathy with urticaria and deafness (Muckle-wells Syndrome), amyloid lambda L-chain amyloidosis, amyloid kappa L-chain amyloidosis, idiopathic associated amyloidosis, myeloma-associated amyloidosis, macroglobulinemia-associated amyloidosis, A beta 2M amyloidosis (chronic hemodialysis), ATTR amyloidosis (familial amyloid polyneuropathy (Portuguese, Japanese, Swedish)), familial amyloid cardiomyopathy (Danish), isolated cardiac amyloidosis, systemic senile amyloidosis, AIAPP or amylin insulinoma, atrial natriuretic factor amyloidosis (isolated atrial amyloidosis), procalcitonin amyloidosis (medullary carcinoma of the thyroid), gelsolin amyloidosis (familial amyloidosis (Finnish)), cystatin C (hereditary cerebral hemorrhage with amyloidosis (Icelandic)), AApo-A-I amyloidosis (familial amyloidotic polyneuropathy-Iowa), AApo-A-II amyloidosis, traumatic brain injury, fibrinogen-associated amyloidosis, Creutzfeldt-Jakob disease, Gertsmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis, condition associated with homozygosity for the apolipoprotein E4 allele, and Huntington's disease.

### Claim 4 (depends on 1)

The method of claim 1, wherein the disease or condition is dementia.

### Claim 5 (depends on 1)

The method of claim 1, wherein the disease or condition is a head injury.

### Claim 6 (depends on 1)

The method of claim 1, wherein the disease or condition is traumatic brain injury.

### Claim 7 (depends on 1)

The method of claim 1, wherein the disease or condition is glial inflammation.

### Claim 8 (depends on 1)

The method of claim 1, wherein a cromolyn salt is administered; and the cromolyn salt is cromolyn sodium.

### Claim 9

A method of treating or slowing the progression of a disease or condition in a human subject in need thereof comprising co-administering ibuprofen and sublingually, intranasally, or to mucous membranes in the subject, cromolyn or a salt thereof, wherein the disease or condition is Alzheimer's disease, dementia, an amyloidosis-associated condition, or a head injury.

### Claim 10 (depends on 9)

The method of claim 9, wherein the disease or condition is Alzheimer's disease.

### Claim 11 (depends on 9)

The method of claim 9, wherein the disease or condition is an amyloidosis-associated condition selected from idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome, Scrapie, medullary carcinoma of the thyroid, isolated atrial amyloidosis, β2-microglobulin amyloidosis, inclusion body myositis, muscle wasting disease, Islets of Langerhans diabetes, Type 1 diabetes, insulinoma, Type 2 diabetes mellitus, hereditary cerebral hemorrhage amyloidosis (Dutch), amyloid A (reactive) amyloidosis, secondary amyloidosis, familial Mediterranean fever, familial amyloid nephropathy with urticaria and deafness (Muckle-wells Syndrome), amyloid lambda L-chain amyloidosis, amyloid kappa L-chain amyloidosis, idiopathic associated amyloidosis, myeloma-associated amyloidosis, macroglobulinemia-associated amyloidosis, A beta 2M amyloidosis (chronic hemodialysis), ATTR amyloidosis (familial amyloid polyneuropathy (Portuguese, Japanese, Swedish)), familial amyloid cardiomyopathy (Danish), isolated cardiac amyloidosis, systemic senile amyloidosis, AIAPP or amylin insulinoma, atrial natriuretic factor amyloidosis (isolated atrial amyloidosis), procalcitonin amyloidosis (medullary carcinoma of the thyroid), gelsolin amyloidosis (familial amyloidosis (Finnish)), cystatin C (hereditary cerebral hemorrhage with amyloidosis (Icelandic)), AApo-A-I amyloidosis (familial amyloidotic polyneuropathy-Iowa), AApo-A-II amyloidosis, traumatic brain injury, fibrinogen-associated amyloidosis, Creutzfeldt-Jakob disease, Gertsmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis, condition associated with homozygosity for the apolipoprotein E4 allele, and Huntington's disease.

### Claim 12 (depends on 9)

The method of claim 9, wherein the disease or condition is dementia.

### Claim 13 (depends on 9)

The method of claim 9, wherein the disease or condition is a head injury.

### Claim 14 (depends on 9)

The method of claim 9, wherein the disease or condition is traumatic brain injury.

### Claim 15 (depends on 9)

The method of claim 9, wherein the disease or condition is glial inflammation.

### Claim 16 (depends on 9)

The method of claim 9, wherein a cromolyn salt is co-administered; and the cromolyn salt is cromolyn sodium.

### Claim 17 (depends on 9)

The method of claim 9, wherein the ibuprofen is formulated as a pill, capsule, or liquid.

### Claim 18 (depends on 9)

The method of claim 9, wherein the ibuprofen is co-administered orally.

### Claim 19 (depends on 9)

The method of claim 9, wherein the ibuprofen is co-administered in an amount of about 0.1 to about 25 mg/kg body weight.

### Claim 20 (depends on 9)

The method of claim 9, wherein the ibuprofen is co-administered in an amount of about 10 mg/day, about 15 mg/day, about 20 mg/day, or about 30 mg/day.

### Claim 21 (depends on 1)

The method of claim 1, wherein the cromolyn or the salt thereof is administered to mucous membranes in the mouth.

### Claim 22 (depends on 9)

The method of claim 9, wherein the cromolyn or the salt thereof is administered to mucous membranes in the mouth.