Substituted Fullerene Formulations and Their Use in Ameliorating Oxidative Stress Diseases or Inhibiting Cell Death

• US 20090197951A1
• Filed: 04/13/2009
• Published: 08/06/2009
• Est. Priority Date: 10/10/2003
• Status: Abandoned Application

• Current Assignee: Luna Innovations, Inc.
• Original Assignee: Tego Biosciences Corporation
• Inventors: Lam, My Phuong, Lebovitz, Russ
• Application Number:
  US12/422,678
• Publication Number:
  US 20090197951A1
• Time in Patent Office: Days
• US Class Current: 514/547
• CPC Class Codes: A61K 2800/522 Antioxidants; Radical scavengers
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 47/6949 inclusion complexes, e.g. clathrates, cavitates or fullerenes
• CPC Class Codes: A61K 8/19 containing inorganic ingredients
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: 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
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: B82Y 40/00 Manufacture or treatment of nanostructures
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C01B 32/15 Nano-sized carbon materials
• CPC Class Codes: C01B 32/156 After-treatment

Abstract

This patent discloses a composition comprising a substituted fullerene, wherein the substituted fullerene comprises a fullerene core (Cn), wherein n is an even integer greater than or equal to 60, and at least one substituent group bonded to at least one carbon atom of the fullerene core, and at least one adjuvant, wherein the adjuvant is an absorption enhancer or bioavailability enhancer. It also discloses methods of using such compositions to ameliorate oxidative stress diseases or inhibit cell death.

Claims

1. A composition, comprising:

a substituted fullerene, wherein the substituted fullerene comprises a fullerene core (Cn), wherein n is an even integer greater than or equal to 60, and at least one substituent group bonded to at least one carbon atom of the fullerene core, and

at least one adjuvant, wherein the adjuvant is an absorption enhancer or bioavailability enhancer.

2. The composition of claim 1, wherein the adjuvant is a central nervous system (CNS) bioavailability enhancer.

4. The composition of claim 1, further comprising at least one excipient selected from the group consisting of lubricants, solubilizers, controlled-release matrices, emulsifiers, permeation enhancers, surfactants, fatty acids, fatty esters, azone-like compounds, colorants, and flavorants.

5. The composition of claim 4, wherein the excipient is included in the U.S. FDA EAFUS list or GRAS list.

6. The composition of claim 1, wherein the substituted fullerene comprises at least one of i-iv:

(i) m (>

CX¹X²) groups bonded to the fullerene core, wherein;

(i-a) m is an integer from 1 to 6, inclusive,

(i-b) each X¹ and X² is independently selected from —

H;

—

COOH;

—

CONH₂;

—

CONHR′

;

—

CONR′

₂;

—

COOR′

;

—

CHO;

—

(CH₂)_dOR¹¹;

a peptidyl moiety;

—

R;

—

RCOOH;

—

RCONH₂;

—

RCONHR′

;

—

RCONR′

₂;

—

RCOOR′

;

—

RCHO;

—

R(CH₂)_dOR¹¹;

a heterocyclic moiety;

a branched moiety comprising one or more terminal —

OH, —

NH₂, triazole, tetrazole, or sugar groups;

or a salt thereof, wherein each R′

is a hydrocarbon moiety having from 1 to about 6 carbon atoms and each R′

is independently a hydrocarbon moiety having from 1 to about 6 carbon atoms, an aryl-containing moiety having from 6 to about 18 carbon atoms, a hydrocarbon moiety having from 1 to about 6 carbon atoms and a terminal carboxylic acid or alcohol, or an aryl-containing moiety having from 6 to about 18 carbon atoms and a terminal carboxylic acid or alcohol, and d is an integer from 0 to about 20, and each R¹¹ is independently —

H, a charged moiety, or a polar moiety;

(ii) p —

X³ groups bonded to the fullerene core, wherein;

(ii-a) p is an integer from 1 to 18, inclusive; and

(ii-b) each —

X³ is independently selected from —

N⁺(R²)(R³)(R⁴), wherein R², R³ and R⁴ are independently —

H or —

(CH₂)_d—

CH₃, wherein d is an integer from 0 to about 20;

—

N⁺(R²)(R³)(R⁸), wherein R² and R³ are independently —

H or —

(CH₂)_d—

CH₃, wherein d is an integer from 0 to about 20, and each R⁸ is independently —

(CH₂)_f—

SO₃⁻

, —

(CH₂)_f—

PO₄⁻

, or —

(CH₂)_f—

COO⁻

, wherein f is an integer from 1 to about 20;

—

C(R⁵)(R⁶)(R⁷), wherein R⁵, R⁶, and R⁷ are independently —

COOH, —

H, —

CH(═

O), —

CH₂OH, or a peptidyl moiety;

7. The composition of claim 1, wherein the substituted fullerene comprises a fullerene core (Cn) having 60 carbon atoms or 70 carbon atoms.

8. The composition of claim 1, wherein the substituted fullerene has the structure:

9. A method of ameliorating an oxidative stress disease, comprising:

administering to a mammal via a transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intrathecal, intraperitoneal, oral, buccal, rectal, or nasal route an effective amount of a composition comprising a substituted fullerene, wherein the substituted fullerene comprises a fullerene core (Cn), wherein n is an even integer greater than or equal to 60, and at least one substituent group bonded to at least one carbon atom of the fullerene core, and at least one adjuvant, wherein the adjuvant is an absorption enhancer or bioavailability enhancer.

10. The method of claim 9, wherein the mammal suffers or is susceptible to an oxidative stress disease selected from central nervous system (CNS) neurodegenerative diseases, stroke, atherosclerosis, myocardial ischemia, myocardial reperfusion, diabetes, complications of diabetes, circulatory impairment, retinopathy, blindness, kidney disease, pancreas disease, neuropathy, gum disease, cataracts, skin disease, skin damage, radiation damage, damage caused by tobacco use, excessive angiogenesis, insufficient angiogenesis, hearing loss, collateral damage of chemotherapy, mucositis, or senescence.

11. The method of claim 10, wherein the CNS neurodegenerative disease is Parkinson'"'"'s disease, Alzheimer'"'"'s disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington'"'"'s disease.

12. The method of claim 9, wherein the adjuvant is a central nervous system (CNS) bioavailability enhancer.

13. The method of claim 9, wherein the composition further comprises at least one excipient selected from the group consisting of lubricants, solubilizers, controlled-release matrices, emulsifiers, permeation enhancers, surfactants, fatty acids, fatty esters, azone-like compounds, colorants, and flavorants.

14. A method of inhibiting cell death, comprising:

administering to a mammal via a transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intrathecal, intraperitoneal, oral, buccal, rectal, or nasal route an effective amount of a composition comprising a substituted fullerene, wherein the substituted fullerene comprises a fullerene core (Cn), wherein n is an even integer greater than or equal to 60, and at least one substituent group bonded to at least one carbon atom of the fullerene core, and at least one adjuvant, wherein the adjuvant is an absorption enhancer or bioavailability enhancer.

15. The method of claim 14, wherein the mammal suffers or is susceptible to cell death caused by heat, radiation, mechanical injury, a chemical toxin, a bacterial toxin, a viral toxin, a plant toxin, a biological toxin, or two or more thereof.

16. The method of claim 14, wherein the adjuvant is a central nervous system (CNS) bioavailability enhancer.

17. The method of claim 14, wherein the composition further comprises at least one excipient selected from the group consisting of lubricants, solubilizers, controlled-release matrices, emulsifiers, permeation enhancers, surfactants, fatty acids, fatty esters, azone-like compounds, colorants, and flavorants.

18. A method of protecting cells in vitro, comprising:

administering to the cells a composition comprising a substituted fullerene, wherein the substituted fullerene comprises a fullerene core (Cn), wherein n is an even integer greater than or equal to 60, and at least one substituent group bonded to at least one carbon atom of the fullerene core.

19. The method of claim 18, wherein the substituted fullerene comprises at least one of i-iv:

(i) m (>

CX¹X²) groups bonded to the fullerene core, wherein;

(i-a) m is an integer from 1 to 6, inclusive,

(i-b) each X¹ and X² is independently selected from —

H;

—

COOH;

—

CONH₂;

—

CONHR′

;

—

CONR′

₂;

—

COOR′

;

—

CHO;

—

(CH₂)_dOR¹¹;

a peptidyl moiety;

—

R;

—

RCOOH;

—

RCONH₂;

—

RCONHR′

;

—

RCONR′

₂;

—

RCOOR′

;

—

RCHO;

—

R(CH₂)_dOR¹¹;

a heterocyclic moiety;

a branched moiety comprising one or more terminal —

OH, —

NH₂, triazole, tetrazole, or sugar groups;

or a salt thereof, wherein each R is a hydrocarbon moiety having from 1 to about 6 carbon atoms and each R′

is independently a hydrocarbon moiety having from 1 to about 6 carbon atoms, an aryl-containing moiety having from 6 to about 18 carbon atoms, a hydrocarbon moiety having from 1 to about 6 carbon atoms and a terminal carboxylic acid or alcohol, or an aryl-containing moiety having from 6 to about 18 carbon atoms and a terminal carboxylic acid or alcohol, and d is an integer from 0 to about 20, and each R¹¹ is independently —

H, a charged moiety, or a polar moiety;

(ii) p —

X³ groups bonded to the fullerene core, wherein;

(ii-a) p is an integer from 1 to 18, inclusive; and

(ii-b) each —

X³ is independently selected from —

N⁺(R²)(R³)(R⁴), wherein R², R³, and R⁴ are independently —

H or —

(CH₂)_d—

CH₃, wherein d is an integer from 0 to about 20;

—

N⁺(R²)(R³)(R⁸), wherein R² and R³ are independently —

H or —

(CH₂)_d—

CH₃, wherein d is an integer from 0 to about 20, and each R⁸ is independently —

(CH₂)_f—

SO₃⁻

, —

(CH₂)_f—

PO₄—

, or —

(CH₂)_f—

COO⁻

, wherein f is an integer from 1 to about 20;

—

C(R⁵)(R⁶)(R⁷), wherein R⁵, R⁶, and R⁷ are independently —

COOH, —

H, —

CH(═

O), —

CH₂OH, or a peptidyl moiety;

20. The method of claim 18, wherein the composition further comprises at least one excipient selected from the group consisting of lubricants, solubilizers, controlled-release matrices, emulsifiers, permeation enhancers, surfactants, fatty acids, fatty esters, and azone-like compounds.