Enzymatic debridement therapy for abnormal cell proliferation

• US 20080044459A1
• Filed: 05/14/2007
• Published: 02/21/2008
• Est. Priority Date: 05/12/2006
• Status: Active Grant

• Current Assignee: Alex Getahoun
• Original Assignee: James Livingston
• Inventors: Livingston, James
• Granted Patent: US 8,754,045 B2
• Time in Patent Office: Days
• US Class Current: 424/445
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 38/45 Transferases (2)
• CPC Class Codes: A61K 38/482 Serine endopeptidases (3.4.21)
• CPC Class Codes: A61K 38/4826 Trypsin (3.4.21.4) Chymotrypsin (3.4.21.1)
• CPC Class Codes: A61K 38/4873 Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
• CPC Class Codes: A61K 38/488 Aspartic endopeptidases (3.4.23), e.g. pepsin, chymosin, renin, cathepsin E
• CPC Class Codes: A61K 38/4886 Metalloendopeptidases (3.4.24), e.g. collagenase
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61L 15/38 containing enzymes
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 15/64 specially adapted to be resorbable inside the body
• CPC Class Codes: A61L 2300/254 Enzymes, proenzymes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B42D 15/045 Multi-part cards or sheets, i.e. combined with detachably mounted articles
• CPC Class Codes: C12Y 304/21004 Trypsin (3.4.21.4)
• CPC Class Codes: C12Y 304/21064 Peptidase K (3.4.21.64)
• CPC Class Codes: C12Y 304/22002 : Papain (3.4.22.2)
• CPC Class Codes: C12Y 304/22003 : Ficain (3.4.22.3)
• CPC Class Codes: C12Y 304/22032 : Stem bromelain (3.4.22.32)
• CPC Class Codes: C12Y 304/22033 : Fruit bromelain (3.4.22.33), i.e. juice bromelain

Abstract

Compositions and methods are provided to destroy internal cancerous lesions selectively by the administration of a combination of a debridement protease enzyme and a denaturant of cell structural proteins and or cell adhesion proteins.

Claims

1. A method for the treatment of a neoplasm, comprising administering to a patient in need thereof a treatment effective amount of a composition consisting essentially of one or more debridement enzyme and one or more denaturant, wherein the neoplasm is not a disorder of the skin.

2. The method of claim 1 wherein the debridement enzyme is selected from the group consisting of a plasma enzyme, a pancreatic enzyme, a cysteine protease, a serine protease, and a metallopeptidase.

3. The method of claim 1 wherein the debridement enzyme is selected from the group consisting of fibrinolysin, desoxyribonuclease, trypsin, chymotrypsin, krillase, bromelain, papain, ficin, subtilisins, proteinase K, collagenase, vibriolysin, thermolysin, streptokinaseand streptodornase.

4. The method of claim 1 wherein the debridement enzyme is papain.

5. The method of claim 1 wherein the debridement enzyme is administered in a dose in the range 1×

10⁴ to 1×

10⁸ USP per gram.

6. The method of claim 1 wherein the debridement enzyme is administered in a dose of about 1.1×

10⁶ USP per gram.

7. The method of claim 1 wherein the denaturant is selected from the group consisting of urea, lactic acid, citric acid, an aliphatic alcohol, β

-mercaptoethanol, a detergent, sodium dodecyl sulfate, formaldehyde, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, propylene carbonate, ethylene carbonate;

a metal scavenger;

crown ethers;

a crown amine;

a polyether;

polyethyleneoxide;

a polyamine;

polyethyleneamine;

cryptands;

ethylenediaminetetraacetic acid or its salts;

silver sulfadiazine;

gentamicin;

penicillin;

a strong acid;

hydrochloric acid;

phosphoric acid;

sulfuric acid;

an acid with a pK_a less than about 4,;

a strong base;

sodium hydroxide;

potassium hydroxide;

sodium carbonate; and

a base with a pK_a greater than about 10.

8. The method of claim 1 wherein the denaturant is urea.

9. The method of claim 4 wherein the denaturant is urea.

10. The method of claim 1 wherein the denaturant is present in concentration range of 0.1-40 weight percent.

11. The method of claim 1 wherein the denaturant is present in concentration range of about 10 weight percent.

12. The method of claim 1 wherein the denaturant is present in concentration range of over 15 weight percent.

13. The method of claim 1 wherein the denaturant is present in concentration range of 1-5 weight percent.

14. The method of claim 1, wherein the enzyme retains at least 80% activity at the concentrations of the denaturant.

15. The method of claim 1, wherein the enzyme retains at least 90% activity at the concentrations of the denaturant is provided.

16. The method of claim 1, wherein the enzyme retains at least 95% activity at the concentrations of the denaturant is provided.

17. The method of claim 1, wherein the composition further comprises an enzyme stabilizing compound.

18. The method of claim 17, wherein the enzyme stabilizing compound is selected from the group consisting of a sugar, monosaccharides, disaccharides, oligosaccharides, pyranose sugars, furanose sugars, glucose, lactose, sucrose, glycerol, pentaerythritol, polyhydric alcohols, O-phosphate derivatives of any of those compounds, 2,3-bisphosphoglycerate, manganese salts, iron salts, cobalt salts, nickel salts, copper salts, zinc salts, magnesium salts, calcium salts, sodium salts, potassium salts, and ammonium salts.

19. The method of claim 17, wherein the combination is selected from:

(a) papain, about 50 weight percent of lactose; and

10 weight percent urea;

(b) proteinase K, glucose, and a denaturant selected from the group consisting of urea, sodium dodecyl sulfate and ethylenediaminetetraacetic acid (EDTA); and

(c) porcine trypsin that has been modified by reductive methylation, glucose and a denaturant selected from the group consisting of 1M urea, 0.1% sodium dodecyl sulfate, 10% acetonitrile, and 2M guanidine hydrochloride;

wherein the composition has a pH selected from the range of 7-9.

20. The method of claim 1, wherein the composition is a hydrophilic ointment that additionally comprises:

(a) an excipient selected from the group consisting of emulsifying wax fragrance, isopropyl palmitate, lactose, methylparaben, potassium phosphate monobasic, propylparaben, and purified water; and

(b) a buffer;

and wherein the ointment is administered in combination or alternation with one of the following;

(c) a supplemental agent that minimizes damage to healthy normal cells from compounds released by dying cells, wherein the agent is optionally sodium copper chlorophyllin;

or

(d) a cofactor selected from the group consisting of ATP, ADP, NAD, NADH, NADP, NADPH, oxidized and reduced flavins, folic acid, and folic acid derivatives.

21. The method of claim 1 wherein the lesion is selected from the group consisting of abdominal neoplasms, bone neoplasms, breast neoplasms, digestive system neoplasms, endocrine gland neoplasms, eye neoplasms, head and neck neoplasms, hematologic neoplasms, nervous system neoplasms, pelvic neoplasms, soft tissue neoplasms, splenic neoplasms, thoracic neoplasms, and urogenital neoplasms.

22. The method of claim 1 wherein the composition is administered by cannulation, injection or orally.

23. The method of claim 22 wherein the composition is in the form of a pill, a tablet, a capsule, a troche, or a medium comprising a controlled release polymer.

24. The method of claim 1 wherein the composition is in the form of a biodegradable surgical dressing that comprises the debridement enzyme and the denaturant.

25. A method for the treatment of a neoplasm that is a disorder of the skin, comprising administering to a patient in need thereof a treatment effective amount of a composition consisting essentially of one or more debridement enzyme and one or more denaturant, wherein the composition is administered in combination with one or more of the following:

a. an antioxidant;

b. an organic redox reagent;

c. an irradiation by infrared, ultraviolet, or ultrasonic energy;

or

d. an enzyme that is capable of cleaving the backbone of a glycosaminoglycan.