Epigenau / 11: a natural matrix with therapeutic activity

Abstract

The present invention relates to a 100% natural product consisting of natural matrices showing emerging properties, which allows to re-establish a correct metabolism in tissues infiltrated by cancer cells, adjuvating cancer treatment and tissue homeostasis. The product of the invention, as demonstrated by the inventors, is itself a natural matrix, representing native natural intelligence, said natural intelligence being the only capable to allow a physiological endogenous interconnection with other entities which are self-assembled in nature, such as the human species. By modulating tumor microenvironment and thus selectively inducing cancer cells mortality, the product achieves reconstitution of conditions favourable to tissue homeostasis in tissues infiltrated by cancer cells. Factually, the invention allows for a shift of paradigm based on the passage from a deterministic validation of properties to a probabilistic one based on functional redundancy logics, that will grant an industrially viable source of innovation for manufacturers in the field of 100% natural therapeutic or beneficial products.

Description

Abstract This invention relates to a 100% natural product composed of a natural matrix that exhibits novel properties, allowing for the re-establishment of proper metabolism in cancer-infiltrated tissues, aiding in cancer treatment and tissue homeostasis. As demonstrated by the inventors, the product of this invention is itself a natural matrix, representing primordial natural wisdom—the only intelligence capable of physiological endogenous interconnection with other entities in nature (such as humans) that self-assemble. By modulating the tumor microenvironment and thus selectively inducing cancer cell death, the product achieves the conditioned re-establishment of tissue homeostasis favorable to cancer cell infiltration. In fact, this invention allows for a paradigm shift from deterministic property verification to probabilistic property verification based on functional redundancy logic, which will provide an industrially viable source of innovation for manufacturers in the field of 100% natural therapeutics or beneficial products.

Claims

1. A product consisting of: 20-50% in weight of component a. 49-80% in weight of component b. and 0.6-1.2% in weight of component c. for a total of 100% wherein component a. is a coextract of Filipendula leaves and flowers, Laurus leaves, Brassica seeds and Withania roots, the % in weight of the raw materials for the preparation thereof consisting of 17.5-32.5% in weight of Filipendula leaves and flowers, 17.5-32.5% in weight of Laurus leaves, 17.5-32.5% in weight of Brassica seeds and 17.5-32.5% in weight of Withania roots for a total of 100%, and component b. is a coextract of Cynara leaves, Curcuma roots and Tanacetum flowers, the % in weight of the raw materials for the preparation thereof consisting of 10-19% in weight of Cynara leaves, 29-55% in weight of Curcuma roots, 29-55% in weight of Tanacetum flowers for a total of 100% and component c. is an extract of Agave leaves.

2. The product according to claim 1 consisting of 30-40% in weight of component a. 60-70% in weight of a component b. and 0.6-1.2% in weight of component c. for a total of 100%.

3. The product according to claim 1 or 2 having the following formula 36.05% in weight of component a. 63.06% in weight of a component b. and 0.89% in weight of component c. for a total of 100% or 30.00% in weight of component a. 69.11% in weight of a component b. and 0.89% in weight of component c. for a total of 100%4. The product of anyone of claims 1 to 3 wherein component a. is a freeze-dried coextract in water of Filipendula leaves and flowers, Laurus leaves, Brassica seeds and Withania roots, the % in weight of the raw materials for the preparation thereof consisting of 17.5-32.5% in weight of Filipendula leaves and flowers, 17.5-32.5% in weight of Laurus leaves, 17.5-32.5% in weight of Brassica seeds and 17.5-32.5% in weight of Withania roots for a total of 100%; component b. is a freeze-dried coextract in water of Cynara leaves, Curcuma roots and Tanacetum flowers, the % in weight of the raw materials for the preparation thereof consisting of 10-19% in weight of Cynara leaves, 29-55% in weight of Curcuma roots, 29-55% in weight of Tanacetum flowers for a total of 100%; and component c. is a freeze-dried extract in water of Agave leaves, preferably wherein component a. is a freeze-dried coextract in water of Filipendula leaves and flowers, Laurus leaves, Brassica seeds and Withania roots, the % in weight of the raw materials for the preparation thereof consisting of 25% in weight of Filipendula leaves and flowers, 25% in weight of Laurus leaves, 25% in weight of Brassica seeds and 25% in weight of Withania roots, and component b. is a (freeze-dry) coextract in water of Cynara leaves, Curcuma roots and Tanacetum flowers, the % in weight of the raw materials for the preparation thereof consisting of 14.30% in weight of Cynara leaves, 42.85% in weight of Curcuma roots, 42.85% in weight of Tanacetum flowers; component c. is a freeze-dried extract in water of Agave leaves.

5. The product of anyone of claims 1 to 4 wherein Filipendula is selected between Filipendula ulmaria and Filipendula vulgaris or a mixture thereof, Laurus is selected from Laurus azorica and Laurus nobilis or a mixture thereof, Brassica is selected from Brassica rapa , Brassica nigra, Brassica oleracea botrytis cymosa or a mixture thereof, Withania is selected from Withania siniensis and Withania somnifera or a mixture thereof, Cynara is selected from Cynara cardunculus scolymus and Cynara flavescens or a mixture thereof, Curcuma is selected from Curcuma zedoaria and Curcuma longa or a mixture thereof, Tanacetum is selected from Tanacetum cinerariifolium, Tanacetum parthenium and Tanacetum vulgare or a mixture thereof, Agave is selected from Agave americana and Agave sisalana or a mixture thereof, preferably wherein Filipendula is Filipendula vulgaris, Laurus is Laurus nobilis, Brassica is Brassica oleracea botrytis cymosa, Withania is Withania somnifera, Cynara is Cynara cardunculus scolymus , Curcuma is Curcuma longa or a mixture thereof, Tanacetum is Tanacetum, Agave is Agave sisilana.

6. The product according to anyone of claims 1 to 5 wherein 0.66 mg / ml of said product administered, separately, to HuDe, FaDu and A431 cells in culture, induce, after 24 hours from said administration, the following cell mortality: A mortality ≤ 61% of HuDe healthy cells, A mortality ≥ 71% of FaDu tumour cells, and A mortality ≥ 55% of A431 tumour cells in a cell culture plate wherein HuDe cells seeded at about 7,000 cells per well in 200 µl of the appropriate medium; FaDu cells, seeded at about 12,500 cells per well in 200 µl of the appropriate medium, and A431 cells seeded at about 8,500 cells per well in 200 µl of the appropriate culture medium; cells are cultured for 24 hours after treatment with said product and cell mortality is measured by assessing cell viability through nuclear staining.

7. A unit of activity of the product according to anyone of claims 1 to 6, said unit being the defined as the necessary and sufficient amount of said product that, when administered, separately, to HuDe, FaDu and A431 cells in culture, induces after 24 hours from said administration, the following cell mortality A 40-50% mortality of healthy cells HuDe; A ≥ 90% mortality of FaDu tumour cells; A ≥ 65% mortality of A431 tumour cells; in a cell culture plate wherein HuDe cells seeded at about 7,000 cells per well in 200 µl of the appropriate medium; FaDu cells, seeded at about 12,500 cells per well in 200 µl of the appropriate medium, and A431 cells seeded at about 8,500 cells per well in 200 µl of the appropriate culture medium; cells are cultured for 24 hours after treatment with said product and cell mortality is measured by assessing cell viability through nuclear staining.

8. A composition comprising the product according to anyone of claims 1 to 6 and at least one of an anticancer active principle and a pharmaceutically acceptable carrier preferably wherein said anticancer active principle is a chemotherapeutic, an antibody or a therapeutically active fragment thereof, a therapeutically active small molecule.

9. The composition according to claim 8 wherein said chemotherapeutic is selected from Cisplatin, Paclitaxel, Gemcitabine, Epirubicin, Cyclophosphamide, Carboplatin, Oxaliplatin, Mitomycin C, Bleomycin, Doxorubicin, Busulfan, Dacarbazine, Temozolomide, Ifosfamide, Melphalan, Clofosfamide, Lomustine, Bendamustine and / or wherein said antibody is a monoclonal antibody selected from monoclonal antibodies such as Rituximab, Trastuzumab, Bevacizumab, Pembrolizumab, Ipilimumab, Nivolumab, Atezolizumab, Cetuximab.

10. A therapeutic adjuvant or a vehicle for anticancer therapy consisting of the product according to claims 1 to 6 and a pharmaceutically acceptable carrier.

11. The composition according to anyone of claims 8 to 9 or the therapeutic adjuvant according to claim 10 formulated for oral, nasopharyngeal, oropharyngeal, aerosol, systemic injection, microneedle injection, intratissutal injection, endovenous, topical, rectal, vaginal, ocular, intratissutal administration, preferably in the form of a suspension, a solution, a freeze-dried material, a cream, an ointment, a spray, a tablet, a soft gelatine capsule, a hard gelatine, a gel, an emulsion, an eye drop, an enema, a suppository, a vaginal ovule, a powder, a granule, loaded vesicles, loaded liposomes.

12. A kit of parts for concomitant, simultaneous or sequential administration comprising separate vials of the therapeutic adjuvant or vehicle according to claims 10 to 11 and of at least one anticancer active principle, preferably wherein said anticancer active principle is is a chemotherapeutic, an antibody or a therapeutically active fragment thereof, a therapeutically active small molecule.

13. The kit of parts according to claim 12 wherein said chemotherapeutic is selected from Cisplatin, Paclitaxel, Gemcitabine, Epirubicin, Cyclophosphamide, Carboplatin, Oxaliplatin, Mitomycin C, Bleomycin, Doxorubicin, Busulfan, Dacarbazine, Temozolomide, Ifosfamide, Melphalan, Clofosfamide, Lomustine, Bendamustine and / or wherein said antibody is a monoclonal antibody selected from monoclonal antibodies such as Rituximab, Trastuzumab, Bevacizumab, Pembrolizumab, Ipilimumab, Nivolumab, Atezolizumab, Cetuximab.

14. The product according to anyone of claims 1 to 6, the composition according to anyone of claims 8 to 9 or 11, the adjuvant according to claims 10 to 11, or the kit of parts according to anyone of claims 12 to 13 for use in the treatment of cancer, preferably wherein the cancer is osteosarcoma, breast cancer, bladder cancer, endometrial cancer, gastric cancer, ovarian cancer, squamous cell carcinoma, head cancer and neck cancer.

15. The product of anyone of claims 1 to 6 or the therapeutic adjuvant as defined in anyone of claims 10 to 11, for use according to claim 14 wherein said product or therapeutic adjuvant exerts its therapeutic or adjuvant effect on cancer through a physiological mechanism of action, through the modulation of a network of biological activities, on the altered physiological state underlying said cancer condition and shows therapeutic or adjuvating functional resilience among different batches of said product or adjuvant, said functional resilience being intended as the maintenance of the therapeutic or adjuvating properties among different batches of said product or adjuvant, notwithstanding their different batch to batch qualitative and quantitative composition.

16. The product or therapeutic adjuvant of anyone of claims 1 to 6 or 10 to 11 wherein said product or adjuvant is itself a natural matrix and represents native natural intelligence, said natural intelligence allowing a physiological endogenous interconnection with other entities which are self-assembled in nature, such as the human species wherein the presence of said native natural intelligence is determined through the validation of the product's or adjuvant's emerging properties in anticancer activity when the following conditions are met: the product's or adjuvant's 14C activity measured with ISO-16620-2;2019 (AMS) method is ≥99.00%, miRNAs and exosomes are detected in said product or adjuvant, the product or adjuvant shows batch-to-batch therapeutic or beneficial functional resilience between different batches of said product or adjuvant and said product or adjuvant modulates a whole altered pathological condition.

17. A method for determining the presence of native natural intelligence in the product or therapeutic adjuvant as defined in anyone of claims 1 to 6 or 10 to 11, said product comprising or consisting of natural matrices, through the validation of its therapeutic or beneficial emerging properties, the method comprising the following steps a. assessing the product or adjuvant naturality by:

1. measuring the 14C activity in said product or adjuvant with ISO-16620-2;2019 (AMS) method, 2. assessing the presence of miRNAs in said product or adjuvant, 3. assessing the presence of exosomes in said product or adjuvant, b. assessing the presence of therapeutic or beneficial functional resilience between different batches of said product by comparing, batch to batch, the modulation of one or more biological activities underlying the product's desired therapeutic or beneficial effect on a relevant altered physiological state and / or on the pathological condition treated by said product or adjuvant in a cell-based assay whose read-out is representative of the modulation of said one or more biological activities; c. assessing from the read-out of said cell-based assay, whether the modulation of said biological activities underlying the desired therapeutic or beneficial effect results in the modulation of a whole altered physiological state or pathological condition; and determining that said product or adjuvant is itself a natural matrix, representing native natural intelligence when: the measured value for the 14C activity is ≥99.00%, miRNAs, exosomes and therapeutic or functional resilience are detected in said product or adjuvant thereby demonstrating the naturality of the product or adjuvant, and said modulation in c. results in the modulation of a whole altered physiological state or pathological condition, preferably further comprising: (1) providing a list of hallmarks representative of said altered metabolism and / or pathological state; (2) identifying for each of said hallmarks one or more biological activities modifications underlying said pathological state thereby pinpointing a network of biological activities whose modulation concurs to said pathological state and (3) identifying one or more parameters whose modulation concurs to the modulation of said one or more biological activities underlying the therapeutic effect of the product tested and determining the modulation trend in terms of up or down modulation of said one or more biological activities, in said network, concurring to said pathological state or to a healthy state.

18. The method of claim 17 wherein said pathological condition is cancer and said hallmarks are selected from: angiogenesis, immune system and inflammatory process, tumour viability and proliferation, metastatisation, premetastatic niche formation, preferably wherein the biological activities of (2) for said hallmarks are selected from the biological activities depicted in figures 17 or 32.

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