# US 8,772,265 B2 · Water soluble curcumin compositions for use in anti-cancer and anti-inflammatory therapy

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- Number: US 8,772,265 B2
- Document ID: US8772265B2
- Status: Granted
- Kind: B2
- Application number: 12/995,126
- Filed: 2009-05-26
- Published: 2011-10-20
- Granted: 2014-07-08
- Earliest claimed: 2008-05-29
- Assignees: Universite Libre de Bruxelles; Universite De Liege
- Applicants: Philippe Neven; Didier Serteyn; Robert Kiss; Veronique Mathieu; Didier Cataldo; Natacha Rocks; Eva Scheer
- Inventors: Philippe Neven; Didier Serteyn; Jacques Delarge; Robert Kiss; Veronique Mathieu; Didier Cataldo; Natacha Rocks
- Web page: https://patentgrep.com/patent/US8772265B2

## CPC

- A61K 47/6951: {using cyclodextrin (cyclodextrins used as simple excipients A61K47/40)}
- A61K 31/724: Cyclodextrins
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- 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 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- 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
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES

## Abstract

The present invention relates to the medical field. In a first aspect the present invention relates to novel water soluble cyclodextrin-curcumin complexes having a pharmacological activity, in particular an anti-tumor and/or anti-inflammatory activity, and improved physico-chemical properties. In a second aspect, the present invention relates to a method for preparation of said water soluble curcumin derivatives. The invention further relates in a third aspect to a pharmaceutical composition comprising an effective amount of said water soluble curcumin derivatives. In a fourth aspect, the present invention concerns the use of said water soluble cucumin derivatives as a medicament and the use of said water soluble curcumin derivatives for the preparation of a medicament for the treatment of cancer and inflammatory diseases. In a fifth aspect, the present invention relates to the use of a pharmaceutical composition comprising said water soluble curcumin derivatives in the treatment of cancer and inflammatory diseases and to a new pharmaceutical composition comprising said water soluble curcumin derivatives.

## Claims

### Claim 1

A water soluble curcumin compound for treating proliferative and/or inflammatory disorders, characterised in that the compound is a hydroxypropyl-beta-cyclodextrin complex of curcumin lysinate (NDS27).

### Claim 2 (depends on 1)

A pharmaceutical composition comprising at least a therapeutically sufficient amount of the water soluble hydroxypropyl-beta-cyclodextrin complex of curcumin lysinate (NDS27) according to claim 1 as active ingredient and a pharmaceutically acceptable vehicle or carrier.

### Claim 3 (depends on 2)

A pharmaceutical composition according to claim 2, wherein the therapeutically sufficient amount is comprised between 0.01 mg and 1000 mg per kilogram of body weight of the individual to which it is administered.

### Claim 4 (depends on 2)

A pharmaceutical composition according to claim 2, said pharmaceutical composition having a pharmaceutically acceptable administration form selected from the group consisting of tablets, pills, capsules, suppositories, syrups, solutions, creams, inhalator liquid or powder and sprays.

### Claim 5 (depends on 2)

A pharmaceutical composition according to claim 2, further comprising an adjuvant able to increase or regulate humoral and/or cellular response of the immune system against the active principle or against the vehicle or carrier so as to reduce or suppress side-effects or toxic effects associated to the active principle and/or the vehicle or carrier.

### Claim 6 (depends on 1)

A method of treating proliferative and/or inflammatory disorders in a subject in need thereof, comprising administering a pharmaceutically acceptable amount of the water soluble hydroxypropyl-beta-cyclodextrin complex of curcumin lysinate (NDS27) according to claim 1.

### Claim 7 (depends on 6)

The method of claim 6, wherein the proliferative disorder is neoplasm, dysplasia, premalignant or precancerous lesions, abnormal cell growths, benign tumours, malignant tumours, cancer or metastasis, or wherein said inflammatory disorder is selected from the group of: rheumatoid arthritis, psoriasis, ulcerative colitis, inflammatory diseases of gastro-intestinal tract, central nervous system diseases, atherosclerosis, diabetes, arthritis and graft-versus host diseases, fibromyalgia, asthma, chronic obstructive pulmonary disease (COPD), pneumonia, bronchitis, recurrent airway obstruction (RAO), multiple sclerosis, type-I diabetes, systemic lupus erythematosus, scleroderma, systemic sclerosis, Sjögren's syndrome, autoimmune disorders, chronic inflammation, allergic reactions and hypersensitivities, inflammatory bowel diseases, reperfusion injury and rheumatoid arthritis.

### Claim 8 (depends on 6)

The method of claim 6, wherein the patient is a mammal.

### Claim 9 (depends on 1)

A method for inhibiting release of Reactive Oxygen Species (ROS) and myeloperoxydase by neutrophils, comprising administering a pharmaceutically active amount of the water soluble hydroxypropyl-beta-cyclodextrin complex of curcumin lysinate (NDS27) according to claim 1.

### Claim 10 (depends on 2)

A method for inhibiting release of Reactive Oxygen Species (ROS) and myeloperoxydase by neutrophils, comprising administering a pharmaceutically active amount of the pharmaceutical composition according to claim 2.

### Claim 11 (depends on 2)

A method of treating proliferative and/or inflammatory disorders in a subject in need thereof, comprising administering a pharmaceutically acceptable amount of the pharmaceutical composition according to claim 2.

### Claim 12 (depends on 11)

The method of claim 11, wherein the proliferative disorder is neoplasm, dysplasia, premalignant or precancerous lesions, abnormal cell growths, benign tumours, malignant tumours, cancer or metastasis, or wherein said inflammatory disorder is selected from the group of: rheumatoid arthritis, psoriasis, ulcerative colitis, inflammatory diseases of gastro-intestinal tract, central nervous system diseases, atherosclerosis, diabetes, arthritis and graft-versus host diseases; fibromyalgia, asthma, chronic obstructive pulmonary disease (COPD), pneumonia, bronchitis, recurrent airway obstruction (RAO), multiple sclerosis, type-I diabetes, systemic lupus erythematosus, scleroderma, systemic sclerosis, Sjögren's syndrome, autoimmune disorders, chronic inflammation, allergic reactions and hypersensitivities, inflammatory bowel diseases, reperfusion injury and rheumatoid arthritis.

### Claim 13 (depends on 11)

The method of claim 11, wherein the patient is a mammal.

### Claim 14 (depends on 8)

The method of claim 8, wherein the mammal is a human or horse.

### Claim 15 (depends on 13)

The method of claim 13, wherein the mammal is a human or horse.

### Claim 16 (depends on 1)

A Process for producing a water soluble hydroxypropyl-beta-cyclodextrin complex of curcumin lysinate (NDS27) according to claim 1, comprising the following steps:
a) synthesis of pure curcumin using standard methodology,
b) synthesis of salts of curcumin lysinate comprising the steps of:
(i) dissolving curcumin under heat in methanol (solution 1),
(ii) dissolving lysine base in water (solution 2), and
(iii) stirring solution 2 into solution 1, followed by shaking and evaporation under vacuum,
(iv) redissolving the residue in ethanol and bringing to boiling point,
(v) filtering out the non-dissolved residue and placing the ethanol based solution at about −20° C. for about one hour,
(vi) collecting the precipitate of curcumin lysinate,
c) preparation of cyclodextrin complex of curcumin lysinate comprising the steps of:
(i) providing an aqueous hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solution,
(ii) adding curcumin lysinate to the cyclodextrin solution in one movement while stirring well,
(iii) filtering the resulting solution,
d) optionally esterifying curcumin resulting in an acylated derivative of curcumin or a derivative thereof or optionally using a glycosylation step.