# US 11,026,922 B2 · Compositions comprising melatonin and flavonoids for use in the treatment of tumours resistant to chemotherapy

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- Number: US 11,026,922 B2
- Document ID: US11026922B2
- Status: Granted
- Kind: B2
- Application number: 15/326,627
- Filed: 2015-03-05
- Published: 2017-07-27
- Granted: 2021-06-08
- Earliest claimed: 2014-07-17
- Assignees: Probiotical S.P.A.
- Applicants: Probiotical S.P.A.
- Inventors: Giovanni Mogna
- Web page: https://patentgrep.com/patent/US11026922B2

## CPC

- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 36/28: Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
- A61K 36/29: Berberidaceae (Barberry family), e.g. barberry, cohosh or mayapple
- A61K 36/66: Papaveraceae (Poppy family), e.g. bloodroot
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 2236/17: involving drying, e.g. sun-drying or wilting
- A61K 2236/31: involving untreated material, e.g. fruit juice or sap obtained from fresh plants
- A61K 2236/333: using mixed solvents, e.g. 70% EtOH
- A61K 2236/53: Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization
- 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

## Abstract

Compositions having at least one flavonoid of natural or synthetic origin in association with melatonin to increase the effectiveness of chemotherapeutic treatments used in human and veterinary medicine for the treatment of tumours are described. The compositions are in particular for the treatment of tumours resistant to the chemotherapeutic agents currently in use. The at least one flavonoid is selected from rutin, oxerutin, diosmin and hesperidin, preferably rutin.

## Claims

### Claim 1

A method for treatment of chemoresistant tumours in an individual, the method comprising:
administering to the individual a mixture comprising in effective amounts therefor:
(i) rutin at a concentration of at least 20 μM; and
(ii) melatonin at a concentration of at least 0.1 mM,
wherein the chemoresistant tumour is breast cancer in woman.

### Claim 2 (depends on 1)

The method according to claim 1, wherein said mixture further comprises:
(iii) at least one chemotherapeutic agent and/or
(iv) at least one compound selected from the group consisting of arctigenin, arctiine, berberine, berbamine, sanguinarine, chelerythrine and Harpagophytum procumbens, in the form of at least one plant extract containing said at least one compound.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the at least one chemotherapeutic agent is selected from the group consisting of: cyclophosphamide, 5-fluoruracyl, methotrexate, platinum complexes, taxanes, doxorubicin, epirubicin and mitoxantrone.

### Claim 4 (depends on 3)

The method according to claim 3, wherein the component (iv) comprises at least one extract obtained from: a) a plant belonging to the family of Asteraceae, selected from the group consisting of Arctium lappa, Cnicus benedictus and Saussurea medusa; b) a plant belonging to the family of Berberidaceae, selected from the group consisting of Berberis vulgaris, Berberis aristata and Mahonia aquifolium; and c) a plant belonging to the family of Papaveraceae, selected from the group consisting of Eschscholzia californica, Macleaya cordata and Bocconia frutescens.

### Claim 5 (depends on 2)

The method according to claim 2, wherein the mixture comprises said at least one extract, the at least one extract obtained from a plant of the group consisting of:
a) Arctium lappa;
b) Berberis vulgaris; and
c) Eschscholzia californica.

### Claim 6 (depends on 2)

The method according to claim 2, wherein at least one of the components (i), (ii), (iii) and (iv) is in a micronized form.

### Claim 7 (depends on 2)

The method according to claim 2, wherein the chemoresistant tumour is a breast adenocarcinoma.

### Claim 8 (depends on 1)

The method according to claim 1, wherein said mixture comprises: (i) rutin, (ii) melatonin and (iii) methotrexate and/or cyclophosphamide.

### Claim 9 (depends on 1)

The method according to claim 1, wherein at least one of the components (i) and (ii) is in a micronized form.

### Claim 10 (depends on 9)

The method according to claim 9, wherein said mixture further comprises:
(iii) at least one compound selected from the group consisting of arctigenin, arctiine, berberine, berbamine, sanguinarine, chelerythrine and Harpagophytum procumbens, in the form of at least one plant extract containing said at least one compound.

### Claim 11 (depends on 10)

The method according to claim 10, wherein at least one of the components (i), (ii) and (iv) is in a micronized form.

### Claim 12

A method for treatment of neoplasias and for inhibition or suppression of chemoresistance to antiblastics in an individual and/or radioresistance to radiotherapy, the method comprising:
administering to the individual a mixture comprising in effective amounts therefor:
(i) rutin at a concentration of at least 20 μM; and
(ii) melatonin at a concentration of at least 0.1 mM; and optionally further comprising
(iv) at least one compound selected from the group consisting of arctigenin, arctiine, berberine, berbamine, sanguinarine, chelerythrine and harpagophytum procumbens, as such or in the form of plant extracts containing said compounds,
wherein the neoplasia is a breast cancer in woman.

### Claim 13 (depends on 12)

The method according to claim 12, wherein said mixture comprises: (i) rutin; and (ii) melatonin; and optionally further comprising (iv) the compounds arctigenin, arctiine, berberine, berbamine, sanguinarine and chelerythrine, as such or in the form of plant extracts containing said compounds.

### Claim 14 (depends on 13)

The method according to claim 13, wherein said mixture further comprises at least one compound selected from the group consisting of: apigenin, ursolic acid optionally obtained from asparagus, curcumin, lycopene, capsaicin optionally obtained from chili pepper, resveratrol, camellin B optionally obtained from green tea, and a compound obtained from Uncaria spp.

### Claim 15 (depends on 12)

The method according to claim 12, wherein said mixture further comprises at least one compound selected from the group consisting of: apigenin, ursolic acid optionally obtained from asparagus, curcumin, lycopene, capsaicin optionally obtained from chili pepper, resveratrol, camellin B optionally obtained from green tea, and a compound obtained from Uncaria spp.

### Claim 16 (depends on 12)

The method according to claim 12, wherein the neoplasias is a breast adenocarcinoma.

### Claim 17 (depends on 12)

The method according to claim 12, wherein said mixture comprises:
(iii) at least one compound selected from the group consisting of arctigenin, arctiine, berberine, berbamine, sanguinarine, chelerythrine and Harpagophytum procumbens, in the form of at least one plant extract containing said at least one compound.

### Claim 18

A method of treating metastatic breast cancer, the method comprising:
administering to an individual an antimetastatic composition comprising in effective amounts therefor:
(i) rutin at a concentration of at least 20 μM; and
(ii) melatonin at a concentration of at least 0.1 mM,
wherein the individual is a woman having metastatic breast cancer.

### Claim 19 (depends on 18)

The method of claim 18, said antimetastatic composition further comprising:
(iii) chemotherapeutic agents and/or
(iv) at least one compound selected from the group consisting of arctigenin, arctiin, berberine, berbamine, sanguinarine, chelerythrine and harpagophytum procumbens in the form of plant extracts containing said compounds.

### Claim 20 (depends on 18)

The method according to claim 18, wherein the breast cancer is a breast adenocarcinoma.