阅读说明：本技术 包括白藜芦醇苷类和姜黄素类化合物的组合物 (Compositions comprising resveratrol glycosides and curcuminoids ) 是由 G·拉瓦尼安 M·博努奇 于 2019-08-01 设计创作，主要内容包括：本发明涉及用于治疗人类中枢神经系统自发性肿瘤的新方法,更具体地是治疗第3和第4级肿瘤的新方法,甚至更具体地是治疗神经胶质瘤的新方法,并且涉及包括治疗有效量的白藜芦醇苷类和姜黄素类化合物的组合物的给药,特别是包括所述两种成分的特定天然提取物的组合物的给药。本发明还涉及包括白藜芦醇苷类和姜黄素类化合物的药物和营养保健组合物的实现。更具体地,本发明涉及配制用于舌下给药来释放活性成分的组合物。(The present invention relates to a novel method for the treatment of spontaneous tumors of the central nervous system of humans, more particularly to a novel method for the treatment of stage 3 and 4 tumors, even more particularly to the treatment of gliomas, and to the administration of a composition comprising therapeutically effective amounts of resveratrol glycosides and curcuminoids, in particular a composition comprising specific natural extracts of the two components. The invention also relates to the implementation of the medicine and the nutritional health-care composition containing the resveratrol glycosides and the curcumin compounds. More particularly, the invention relates to compositions formulated for sublingual administration to release active ingredients.)

1. A composition comprising a combination of polydatin and curcumin for use in a method of treating a glioma selected from the group consisting of a glioma and a glioblastoma, wherein said composition is administered sublingually.

2. The composition according to the preceding claims, wherein curcumin consists of a mixture of curcumin I, curcumin II and curcumin III.

3. The composition according to any one of claims 1-2, which is a pharmaceutical or nutraceutical composition.

4. The composition of claim 2, wherein the composition is administered intranasally.

5. The composition according to any one of claims 1-4, for use in the treatment of one of the following pathologies: astrocytomas, oligodendrogliomas, ependymomas, more specifically, anaplastic astrocytomas and glioblastomas.

6. The composition of any one of claims 1-5, wherein polydatin is combined with one or more resveratrol glycoside compounds having the general formula (I):

and curcumin is combined with one or more curcuminoids having a linear diarylheptane structure, having 2 phenolic groups linked by a chain of 7 carbon atoms; or has a cyclized structure for internal cyclization or has a hydrogenated structure containing no unsaturated bond; and corresponding mixtures.

7. The composition of claim 6, wherein the resveratrol glycoside compound is selected from the group consisting of: polydatin, piceatannol glucoside, (2R,3S,4S,5R,6S) -2- (hydroxymethyl) -6- (4- ((E) -3-hydroxystyryl) phenoxy) -tetrahydro-2H-pyran-3, 4, 5-triol, and corresponding mixtures; and the curcuminoid is selected from: curcumin I, curcumin II, curcumin III, hydrocurcumin, cyclocurcumin and corresponding mixtures.

8. The composition of any one of claims 1-7, formulated as a solid, liquid, gel, aerosol; formulated as liposome formulations with unilamellar and multilamellar liposomes, formulated as phospholipid complexes; or formulated with bioadhesive polymers, with dextran arrays, or based on graphene; or in combination with carbon nanoparticles.

9. The composition of any one of claims 1-8, comprising: from about 4.5% to about 7.5%, preferably from about 5.5% to about 6.5%, by weight of polydatin; from about 5.5% to about 8.5%, preferably from about 6% to about 8%, by weight of curcumin, and a pharmaceutically acceptable carrier.

10. The composition of any one of claims 1-9, for administration in combination with:

-an active ingredient selected from: an anti-edema compound in an amount of about 0.0% to about 1.5%, more preferably about 1.2% to about 1.4% by weight; anti-cancer agents; antineoplastic agents, such as temozolomide, dacarbazine, lomustine, cisplatin; anti-angiogenic agents, such as trastuzumab; a radioprotectant; preoperative or postoperative drug delivery to reduce or remove tumors; and related combinations;

-whole brain radiotherapy techniques; gamma knife radiosurgery; helical tomotherapy; hydrotherapy; stereotactic radiosurgery (radio knife).

11. The composition of any one of claims 1-10, which is administered in a daily dose of at least about 400mg of total active compound; preferably, the administration is performed daily on a patient per kilogram body weight basis at a dosage of about 2mg to about 4mg polydatin, and about 2mg to about 5mg curcumin.

12. The composition according to claim 11, which is administered in a single unit or several dosage units per day.

13. The composition according to any one of claims 1-11, which is administered daily for at least 6 weeks for at least 1 year (6-12 cycles of temozolomide) during the treatment period of radiotherapy and chemotherapy, preferably daily for the rest of the patient's life; preferably, the administration is carried out in two cycles of administration, a cycle relative to the acute phase and a cycle relative to the maintenance phase; preferably, the composition is administered in single or divided doses in an amount of at least 500mg per daily dose during an acute phase lasting from 6 months to 1 year; preferably, the composition is administered in a single or divided dose in an amount of at least 300mg per daily dose during a maintenance period, which may last for the remainder of the patient's life.

14. The composition of any one of claims 1-13, which is a pediatric composition.

Technical Field

The present invention relates to a novel method for the treatment of tumors of the human Central Nervous System (hereinafter also referred to as CNS), more specifically of tumors of grade 3 and grade 4, even more specifically of glioblastomas (hereinafter also referred to as GBL), and to the administration of a composition comprising therapeutically effective amounts of resveratrol glycosides (hereinafter also referred to as piceids) and curcuminoids, in particular a composition comprising natural extracts of both said components.

The invention also relates to the implementation of the medicine and the nutritional health-care composition containing the resveratrol glycosides and the curcumin compounds. More particularly, the invention relates to compositions formulated for sublingual administration to release active ingredients.

It is an object of the present invention to provide pharmaceutical and nutraceutical compositions with improved efficacy in the context of comprehensive anti-cancer treatment regimens. More specifically, the present invention relates to tumors of the human central nervous system, even more specifically to tumors of the 3 ° and 4 ° grade, in particular to glioblastoma. The improvement associated with the composition according to the invention consists in being able to control the factors that lead to the pathological progression of tumours with poor prognosis (for example glioblastoma).

Resveratrol glycosides, in particular, glucuronides, particularly glucuronide stilbenoids (known names of piceid (CAS number: 38963-95-0)) and polydatin (CAS number: 27208-80-6), are of particular interest in the present invention.

Background

Tumors of the Central Nervous System (CNS) comprise a variety of pathological entities. Since gliomas (glia tumor) alone account for nearly 40% of all CNS tumors, it is customary in the literature to distinguish gliomas (or gliomas) from non-gliomas.

Gliomas include: astrocytomas (which originate from glial astrocytes), oligodendrogliomas (which originate from oligodendrocytes), and ependymomas (which originate from ependymal cells).

Different systems have been proposed for the (malignant) grading of CNS tumors over time. Since 1993, the World Health Organization (WHO) proposed a 4-stage fractionation system, has proven to be the most widely accepted and used. It is based on four histological features: abnormal shape of cell nucleus, mitosis, endothelial hyperplasia and necrosis. Apparently, the worst-outcome tumors were grade 3 and 4 tumors. Grade 3 tumors are anaplastic astrocytomas and grade 4 tumors are glioblastomas.

Glioblastoma is the most aggressive primary brain tumor. It belongs to a disease that is defined as incurable by "orphan drugs", seehttps://www.osservatoriomalattierare.it/glioblastoma。

Despite advances in neurosurgery and neurooncology, the survival of glioblastoma patients remains short, averaging only 15 months after diagnosis. Approximately 1,500 italians are affected by this tumor each year, with peak morbidity between 50 and 65 years of age.

Glioblastomas are produced by abnormal stem cells, but not normal tissue, but rather highly malignant brain tumors. Unlike other tumors, early diagnosis that can lead to recovery is not possible in glioblastomas. In fact, glioblastoma stem cells, in addition to being resistant to drug therapy, have the ability to migrate from the tumor and spread to different brain regions. This is why surgical treatment can only try to prolong the survival of patients with this disease, but never cure it.

GBL tumorigenesis is characterized by a high yield of lipids derived from arachidonic acid. These molecules stimulate the development of paraneoplastic cerebral edema and the progression of the tumor. Glucocorticoids are currently the most effective drugs for the treatment of cerebral edema, but they have many side effects. As available therapies are not very effective, over 50% of GBL patients use adjunctive and alternative approaches, the most common of which is herbal therapy, but with little success.

The sugar acid stilbenes, also known as piceid, and the curcuminoids are natural or synthetic compounds. Natural sources are mainly Vitis vinifera, dicotyledonous plants of the Polygonaceae family (e.g., Polygonum cuspidatum (Fallopia japonica)), and Curcuma longa, and can be extracted from these natural sources by known methods (EP1292319, "Botanics, a Photosymetric Desk Reference" Frank S.D' Amelio, CRC Press, pgs.39-48). Piceid and curcuminoids are widely used alone or in combination with each other in the pharmaceutical field (e.g. pharmaceuticals) and the nutraceutical field (as food supplements).

US 2009/0047371 describes resveratrol and curcumin compositions for the treatment of prostate tumours and other inflammation-based diseases such as psoriasis and skin diseases, but there is no indication that the combination of piceid and curcumin can be used for the treatment of Central Nervous System (CNS) tumours.

WO 2015/081319 describes resveratrol and curcumin compositions for in vitro and in vivo treatment of virus-dependent cervical tumours, but there is no indication that the combination of piceid and curcumin can be used for treatment of Central Nervous System (CNS) tumours, nor is it relevant to human trials.

US 7931922 describes natural multicomponent compositions with COX-2 inhibitory effect for the treatment of GBL, but the reported experiments involve oral administration. Of course, the chemical structural features of polydatin, compared to resveratrol itself, make it easy, fast and quantitative to enter the circulation, with important bioavailability. However, the more difficult it is to use curcuminoids and resveratrol therapeutically effectively, which is associated with their lower bioavailability. In fact, both resveratrol molecules and curcuminoids are poorly absorbed by the intestinal tract after oral administration and are degraded during their passage through the liver. For these reasons, only therapeutically ineffective levels are found in the blood. In order to have a therapeutic effect, very high doses should be used, but this can lead to adverse effects, such as upper abdominal pain and/or diarrhea.

In the treatment of gliomas, known compositions based on resveratrol and/or resveratrol glycosides and curcumin are all carried in the form of their liposomes, since curcumin and resveratrol are notoriously difficult to absorb in the intestine. The only tests reported in the literature are in vitro or in vivo tests on animals transplanted with tumors. Indeed, the efficacy of the compositions in human spontaneous tumours has never been tested, i.e. there is no clinical evidence that such compositions may be effective in humans, nor has sublingual administration been described or deduced in the prior art.

In addition, in practice, the true therapeutic efficacy in humans cannot be deduced from in vitro or animal tests, since any encouraging data is not a reasonable expectation of success, nor is it possible to make an objective scientific assessment of the available data. It is obvious that the reasonable expectation of success by the expert is not necessarily correct, not only when the results are clearly predictable, but also in cases where there is a reasonable expectation of success, and even if it is obvious for the skilled person to try to experiment on possibly encouraging data, by transferring the laboratory-obtained evidence to a clinical trial (i.e. to perform the trial on a real patient).

Thus, although combinations of resveratrol and/or piceid + curcumin are known to be useful in the treatment of tumours, no suggestion or suggestion that these combinations are truly effective in humans has been made from the teachings of the known art, nor that formulations other than oral formulations are particularly effective in CNS tumours in clinical trials.

Furthermore, there is currently no research or work on the use of natural substances, such as curcumin and/or polydatin, in combination with conventional therapies (chemo + radiotherapy and/or biotherapy).

Disclosure of Invention

Often the effect of the active ingredient is poor due to inappropriate methods of administration. It has now been found that the combination of piceid + curcuminoid has an unexpected synergistic effect in the treatment of tumours of the CNS, in particular of stage 3 and 4 tumours, more particularly gliomas, even more particularly glioblastoma; this unexpected synergistic effect is particularly evident when formulated into compositions for sublingual administration. Sublingual administration is also advantageous and useful over administration by injection of equal amounts. Not to mention that in some countries, for example in italy, administration of curcuminoids by injection is illegal.

The combination of piceid and curcuminoids according to the invention has shown an unexpected synergistic effect, also confirmed by the clinical results of glioblastoma patients, with a significant increase in the life expectancy of these patients.

Therefore, the object of the present invention is a pharmaceutical and/or nutraceutical composition comprising a therapeutically effective amount of piceid and curcuminoids in combination with each other for the treatment of CNS tumors, in particular grade 3 and 4 tumors, more in particular glioma, even more in particular glioblastoma.

Another object of the present invention is a pharmaceutical and nutraceutical composition designed to reduce side effects associated with CNS tumors, in particular edema. For this purpose, the composition of the invention can be administered in combination with other compounds having anti-edematous activity, in particular compounds of plant origin, more particularly boswellia serrata (boswellia serrata) extracts.

Another object of the invention is a formulation comprising a combination of piceid and curcuminoids for sublingual administration.

Another object of the present invention is the combination of piceid and curcuminoids according to the invention, its use in combination and in combination with traditional tumor therapies (e.g. surgery and/or chemotherapy or/and radiotherapy).

Still another object of the present invention is a formulation comprising, as active ingredients, a combination of piceid and curcuminoids, wherein piceid is polydatin (CAS No. 27208-80-6) and curcuminoids are represented by curcumin, which is itself a combination of curcumin I, curcumin II and curcumin III.

Yet another object of the present invention relates to a method of treating a CNS tumor, in particular a grade 3 and 4 tumor, more in particular a glioma, even more in particular a glioblastoma, in a human mammal of a subject, comprising the steps of: administering to the subject an effective amount of a composition comprising a therapeutically effective amount of piceid and a curcuminoid, wherein piceid is polydatin (CAS number 27208-80-6) and the curcuminoid is represented by curcumin, which is itself a combination of curcumin I, curcumin II and curcumin III, to treat the tumor or prevent recurrence of the tumor.

In a preferred aspect, the present invention relates to a method for treating a side effect associated with glioblastoma in a subject, the method comprising the steps of: administering to the subject an effective amount of a composition comprising piceid and a curcuminoid, administered separately or in combination with an anti-edema compound, to treat the side effect.

Other aspects will become apparent from the detailed description of the invention.

Drawings

The invention will be described hereinafter by means of some preferred embodiments, purely as non-limiting examples, with reference to the accompanying drawings.

FIG. 1: a 70 year old male patient with glioblastoma. The comprehensive therapy comprises Olibanum for treating cerebral edema, polydatin and curcumin. The subject follows an appropriate diet, controlling the intake of protein, carbohydrate and fat. Fig. 1A, radiation therapy and taimodal (Temodal) (2011 month 4); malignant tumors widely affect brain parenchyma; figure 1B, tadao (7 months 2011) was used weekly. After treatment with radiotherapy and Temozolomide (Temozolomide) (three months) and combination therapy (piceid and curcumin according to the invention), the tumors were greatly reduced; figure 1C, continuing with the combination therapy of the present invention, a significant further reduction can be noted: only contours can be identified; fig. 1D, after 30 months. Recovery from 12 months 2012 to today is very good. By continuing with the combination therapy, the damage is continuously reduced. The results obtained show that the lesions can be completely resolved with combination therapy, which is unexpected with conventional therapy.

FIG. 2: treatment was started in 2015. FIG. 2A: neoplastic lesions (white) occur in the brain parenchyma. FIG. 2B: after radiotherapy, temozolomide chemotherapy and comprehensive treatment of curcumin, polydatin and frankincense (for cerebral edema), the dose is obviously reduced. FIG. 2C: the residue is further reduced.

Detailed Description

The term "therapeutically effective amount" as used herein refers to the amount of active ingredient that contributes to the ability of the composition to treat a tumor.

As used herein, the term "treatment" refers to the partial or complete inhibition of the growth, spread or formation of metastatic tumors, particularly glioblastoma, and the partial or complete destruction of cancer cells. The term "treatment" includes the reduction or physiological elimination of tumors, particularly glioblastoma (apoptosis), as well as the reduction of the incidence of disease and its side effects. The terms "prevention" and "prevention" as used herein refer to both prevention of the onset of a tumor and prevention of its preclinically significant phase in an individual at risk. It also relates to the prevention of tumor recurrence, i.e., the growth of malignant glial cells following ablation of injury. This definition refers to preventing the onset of malignant cell proliferation, and to halting or reversing the progression of premalignant cells to malignant cells. The term "prevention" also includes the prevention of the growth or spread of tumors, particularly glioblastoma. This includes prophylactic treatment of humans at risk of developing tumors (particularly glioblastoma) due to the environment and/or home.

The term "glioblastoma (glioblastomas)" as used herein generally refers to glial cell tumors and other malignancies or gliomas of the central nervous system.

The term "subject" as used herein refers to any human mammalian subject, including children and pediatric subjects in general, having a CNS tumor, particularly a glioblastoma. For prophylactic methods, the subject is any human subject at risk of developing a tumor (particularly a glioblastoma) due to the environment and/or home. The subject may be at risk for exposure to chemical and/or physical agents of carcinogenic agents, and/or genetically predisposed to glioblastoma and CNS tumors in general. The subject may still be at risk after removal of low-grade (grade 1 and grade 2) gliomas and grade 3 and 4 tumors, particularly glioblastoma. Glioblastoma has a high incidence of local and metastatic recurrence.

The terms "tumor complex therapy" and "complex therapy", as used herein, generally refer to a combination of conventional therapies, such as surgery, and/or chemotherapy, and/or radiation therapy, in combination with a therapeutically effective amount of a composition of the present invention, alone or in combination with other active ingredients commonly used as supportive therapy in the tumor treatment arts.

According to the invention, the terms resveratrol glycoside compounds or piceid are considered synonymous and refer mainly to a class of compounds of natural origin having a trans-stilbene glycoside (stilbenic gluconate) core containing one or more hydroxyl groups variously distributed over the trans-stilbene glycoside core, which compounds may be used in the compositions of the invention either alone or in admixture with each other. These molecules of natural origin, belonging to the stilbenes of general formula (I):

wherein the phenyl group is substituted with a variable number of hydroxyl groups ranging from 1 to 3.

They may be obtained by chemical synthesis or by extraction from natural sources, according to known techniques. Some preferred sugar acid stilbenes to which the present invention relates are represented by the general structural formula (I); they may be used in the compositions of the invention, alone or in admixture with one another.

Particularly preferred compounds are shown below.

Polydatin- (2S,3R,4S,5S,6R) -2- (4- ((E) -3, 5-dihydroxystyryl) phenoxy) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol- (CAS number 38963-95-0) having two hydroxyl groups (formula II) at the 3 and 5 positions of the benzene furthest from the glycoside group.

Polydatin- (2S,3R,4S,5S,6R) -2- (3-hydroxy-5- ((E) -4-hydroxystyryl) phenoxy) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol- (CAS number 27208-80-6) having two hydroxyl groups, one at the 3-position of the benzene adjacent to the glycoside group and the other at the 4-position of the benzene further from the glycoside group (formula III).

Piceatannol glucoside (Astringin) - (2S,3R,4S,5S,6R) -2- (4- ((E) -3, 5-dihydroxystyryl) -2-hydroxyphenoxy) -6- (hydroxymethyl) -tetrahydro-2H-pyran-3, 4, 5-triol- (CAS No. 29884-49-9) has three hydroxyl groups, one at the 2-position of the benzene adjacent to the glycoside group, one at the 3-position of the benzene further from the glycoside group, and the other at the 5-position of the benzene further from the glycoside group (formula IV).

(2S,3R,4S,5S,6R) -2- (hydroxymethyl) -6- (4- ((E) -3-hydroxystyryl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triol- (CAS not available) having a hydroxyl group (formula V) at the 3-position of the benzene further from the glycoside group.

Generally, the compound represented in formula (I) is present in various concentrations in natural extracts containing the compound, such as pine nut extract of Pinus (genus Pinus) and extract of polygonum cuspidatum (especially root).

According to the present invention, the terms curcuminoids and curcuminoids (curcuminoids) refer to purified compounds extracted from turmeric, its analogs, derivatives and metabolites, which are commonly traceable from turmeric rhizomes. The compounds, either individually or in admixture, are of natural and synthetic origin. In fact, curcumin is not a single substance, but a mixture of congeners. Hereinafter, the term curcuminoid also includes curcuminoids, including cyclocurcumin and hydrocurcumin, as defined below, and related mixtures.

Curcuminoids typically have a linear diarylheptane structure with 2 differently substituted phenolic groups connected by a chain of 7 carbon atoms (C6-C7-C6). The 2 phenolic groups are typically bonded by α, β -unsaturated β -diketones. The bond may also be an alpha, beta-unsaturated dihydropyrone group due to internal cyclization, such as in cyclocurcumin (2- (4-hydroxy-3-methoxyphenyl) -6- [ (E) -2- (4) -hydroxy-3-methoxyphenyl) acetylene]-3, 4-dihydro-2H-pyran-4-one), or those for hydrogenation, free of unsaturated bonds, such as in iderocurcins (extirpated from)https://it.wikipedia.org/wiki/Curcuminoidi). They may be used alone or in admixture thereof.

Hereinafter, the term "curcumin" refers to a combination of curcumin I, curcumin II and curcumin III, preferably used in the following ratios:

according to the present invention, the term "curcuminoid" refers to a curcuminoid in the strict sense, as well as curcuminoids, derivatives and metabolites thereof, as described above, which can be obtained by extraction from turmeric or by chemical synthesis.

According to the invention, curcuminoids can be used in the composition of the invention, alone or mixed with each other. They may be obtained by chemical synthesis or by extraction from natural sources, according to known techniques.

The extracts according to the invention can be prepared according to methods conventionally used in the field of natural product extraction, which are known to the person skilled in the art, or, for example, as described in EP1292319, or as described in "botanics, a phytochemical Desk Reference" Frank S.D' Amelio, CRC Press, pgs.39-48.

The inventors have now found that by a combination of piceid + curcuminoids, in particular polydatin + curcumin (a mixture of curcumin I, curcumin II and curcumin III), a surprising synergistic effect is shown in the treatment of tumours of the central nervous system, in particular in the treatment of GBL, when administered by the oral mucosa, in particular sublingually.

Indeed, the compositions of the invention are capable of inducing unexpected improvements in subjects with CNS tumors of grade 3 and 4. More particularly, through a five-year study carried out on humans, it was experimentally found that an improvement in the control of the progress of poor prognosis of neoplastic pathologies is achieved, with an increase in life expectancy that is at least doubled compared to subjects receiving traditional therapies (surgery and/or chemotherapy and/or radiotherapy), thus surprisingly obtaining an almost normal quality of life, with a significant reduction in the size of the tumor mass, as shown in the magnetic resonance images of the patients during the combined treatment according to the invention.

Accordingly, the present invention relates to pharmaceutical compositions comprising piceid and curcuminoids, in particular polydatin + curcumin in combination (mixture of curcumin I, curcumin II and curcumin III) for use in the treatment of CNS tumors in combination with each other. The effects of picroside are related to the effects of inhibiting proliferation, increasing apoptotic activity, or reducing malignant glial cell migration or invasion. The curcumin compound mainly relates to an important protein complex which can be used as a DNA transcription factor (NF-kB) controller or a cell factor for promoting cell survival. The main role of this factor occurs in inflammation, the "prime mover" (of proliferative activity). By maintaining this state, it is possible to create stimulation conditions for cell growth, new blood vessel growth and uncontrolled growth. NF-kB blockade refers to the elimination of the stimulus for edema, inflammation and growth stimuli. In the case of glioblastoma, especially after surgery or radiotherapy, the use of curcuminoids will lead to a reduction of inflammatory diseases, thus reducing angiogenesis and therefore stimulation of uncontrolled cell growth. The inventors have also surprisingly found that the synergy is further improved if a mixture of piceid and curcuminoids is used in combination with at least one anti-edema compound, in particular with a plant extract of mastic gum. In fact, the effect of such a combination is even more pronounced than the expected improvement effect of a simple superposition due to the mixture of piceid and curcuminoids.

The pharmaceutical composition according to the present invention can be administered in combination with surgical treatment and/or anticancer drugs and/or radiation/chemotherapy/Therapy to constitute Integrated Oncology Therapy (IOT) and can also be administered in a simultaneous, sequential or delayed manner compared to the traditional therapies mentioned previously.

The compositions of the present invention are administered sublingually or intranasally. The pharmaceutical form may be a capsule, tablet or pill formulated for absorption through the oral or nasal mucosa, in particular by sublingual means, or in an orally soluble gel, or in an aerosol formulation.

The administration of curcumin through the oral mucosa is further enhanced by a phospholipid complex (phytosomal) formulation, which consists of a combination of active ingredient with phospholipids and also makes it easy to penetrate at intestinal level, thus making the molecule bioavailable and having a high percentage of active ingredient in the blood.

In another aspect, the composition comprises (in weight%): (polydatin) from about 4.5% to about 7.5%, more preferably from about 5.5% to about 6.5%, by weight of polydatin; (curcuminoid) is about 5.5% to about 8.5%, more preferably about 6% to about 8%, by weight of curcumin.

It may be advantageous for the compositions of the present invention to be used in conjunction with the administration of an anti-edema compound, preferably, from about 0.0% to about 1.5%, more preferably, from about 1.2% to about 1.4% by weight.

The active agent is formulated in combination with at least one pharmaceutically acceptable carrier. Such carriers are well known in the art and are typically present in solid, liquid or gel form.

Solid form pharmaceutical formulations that can be formulated according to the invention include powders, tablets, dispersible granules, capsules and cachets. Typically, solid form formulations will generally include from about 5% to about 90% by weight of the active agent.

Solid carriers can be prepared from one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or disintegrating agents for the tablet; they may also be sealing materials. In tablets, the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. Suitable solid carriers include magnesium carbonate, magnesium stearate, pectin, starch, gelatin, tragacanth, methylcellulose, carboxymethylcellulose, waxes, cocoa butter, and the like. The term "formulation" includes preparations of the active compound with encapsulating materials which are known per se as carriers, which may provide a capsule containing the active ingredient, with or without other adjuvants.

Tablets, powders, capsules and soft capsules may be used as solid dosage forms suitable for oral administration, absorption through the oral mucosa, particularly sublingually.

Formulations in solid or liquid form may include, in addition to the active ingredient, flavoring agents, coloring agents, stabilizing agents, preservatives, buffering agents, sweetening and natural agents, dispersing agents, thickening agents, solubilizing agents, and the like. The pharmaceutical preparation may also be in unit dosage form. In this form, the preparation is subdivided into the appropriate quantities of active ingredient in unit dose.

Sublingual tablets are formulated to produce CO in the oral cavity₂. The production of carbon dioxide results from the reaction of a soluble organic acid with a base. The soluble organic acid may be: citric acid, malic acid, tartaric acid, and the like. The soluble base may be: sodium carbonate/bicarbonate, potassium carbonate/bicarbonate. The formulation is calibrated so that the tablet will start to dissolve with a very small amount of water (saliva), which will react due to the neutralization of the alkaline acid, the effect of which is to form more water. Therefore, contact with water and moisture should be avoided during production and storage.

Water soluble binders (sorbitol, dextrose xylitol, etc.) and anti-caking agents (vegetable magnesium stearate, benzoic acid, adipic acid, etc.) are used. Other excipients may be used to improve the taste of the tablet, to limit its bitter taste, and to improve the sweetness and mouth feel of the formulation.

Care should be taken to avoid that excipients (e.g., sugars) for cancer patients may be banned in the literature.

Sublingual tablets are produced in a manner similar to that of ordinary swallowable tablets, but further measures must be taken:

the raw materials already indicated must be placed away from moisture;

if necessary, the raw material with poor compressibility must be granulated.

The end result is the development of a stable immediate release formulation with a good taste and fast disintegration, resulting in a higher absorption of the active ingredient and a higher content in the systemic circulation.

Bioadhesive polymer-based delivery systems are particularly advantageous because they are suitable for administration in the oral cavity. The delivery system includes:

-an active ingredient;

bioadhesive polymers, for example selected from polyacrylic acid, polyvinyl alcohol, semisynthetic cellulose derivatives, hydrophilic derivatives of starch, alginates, pectins, chitosan, polysaccharides, natural rubber, polyethylene oxide, preferably polyethylene oxide with a molecular weight of more than 600kDa, more preferably mixed in equal proportions with polyethylene oxide with a molecular weight of more than 4000 kDa; and related mixtures; and

-Cyclodextrins (CD), preferably β -cyclodextrin and its derivatives, more preferably HP- β -CD and methyl- β -CD, the percentage by weight of Cyclodextrin (CD) with respect to the polymer being in the range of 0 to 70%, preferably about 50%.

The components are treated by known techniques, such as film casting or other techniques capable of obtaining a segmented film suitable for administration in the oral cavity, in particular by sublingual administration. The films thus obtained are particularly suitable for administration to animals, neonates, infants and elderly.

According to the invention, the composition can be achieved in a manner that allows the release of the different active ingredients in a simultaneous, sequential or delayed manner.

The compositions according to the invention can be formulated as liposome preparations with unilamellar and multilamellar liposomes, which are inserted into the graphene-based dextran matrix and bound to nanocarbon particles, so-called carbon quantum dots (CQD, C dots or CD) (less than 10nm)https://en.wikipedia.org/wiki/Carbon_quantum_dots。

Another advantageous method of administration is spraying or aerosol, which is particularly advantageous in the case of intranasal administration.

According to the invention, the composition can be used alone or in combination with other known active ingredients, which can be effective as an anticancer or antitumor and/or radioprotectant and/or other pre-or post-operative drug for reducing or eliminating tumors.

Among the antineoplastic agents, mention may be made of those belonging to the family of antineoplastic agents: temozolomide, dacarbazine, lomustine, cisplatin, or those belonging to the class of antiangiogenic agents: primarily trastuzumab.

Radiotherapy "whole brain" techniques or gamma knife radiosurgery or helical tomotherapy (tomotherapy), or hydrotherapy (hydrotherapy) or stereotactic radiosurgery (radioknife) may be used in combination with the compositions of the invention.

In a preferred embodiment, administration is carried out in daily doses (single or divided doses throughout the day) of at least a total of about 500mg of active product.

Typically, the effective daily amount comprises about 2mg to about 4mg polydatin, and about 2mg to about 5mg curcumin per kg body weight of the patient. The effective amount may vary depending on the physical condition of the patient and other factors known in the art. In addition, the dose of active agent may be administered in a single unit or in multiple dosage units to provide the desired therapeutic effect.

In another aspect, the composition is administered daily for at least 6 weeks (during the radiation therapy administration period), preferably daily for the remainder of the patient's life. It is preferred to determine the dosing to be performed in two dosing cycles, a cycle relative to the acute phase and a cycle relative to the maintenance phase. In the acute phase, the composition is administered in an amount of at least 500mg, which lasts for up to 1 year. The composition is administered in an amount of 300mg during the maintenance phase, which may last for the remainder of the patient's life.

The acute phase typically involves a treatment phase of radiotherapy (15 to 30 administrations total) and a chemotherapy cycle (using the above drugs), with a maximum period of 1 year (temozolomide 6-12 cycles).

Typically, the maintenance phase involves an observation (follow-up) phase in which no dosing is performed with conventional therapy.

The medicine is taken 1 bag x2 times per day. The amount of active ingredient and dosage will depend upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, time of administration, and the like; the rate of excretion; combinations of drugs administered, the severity of the particular disease to be treated, and the form of administration.

The inventors have investigated the effect of a pharmaceutical composition comprising the following ingredients on more than 70 patients with glioblastoma:

polydatin + curcumin according to the invention, plus excipients, in a mode of administration other than sublingual administration

Polydatin + curcumin according to the invention, plus excipients, in a sublingual administration.

The combination was also tested on pediatric subjects between 4 and 15 years of age, in which case there was also a positive result.

The results of the simultaneous administration of the two molecules, even after radiochemical therapy, led to a reduction in the tumour area of the patient (confirmed by radiology) due to the synergistic effect of the antitumor activity of polydatin (induced apoptosis of GBL cells) and the anti-inflammatory effect of curcumin by sublingual antiangiogenesis, as shown in the figures.

The sublingual route, together with the intranasal route, is one of the enteral routes by which the drug can be administered; instead of being swallowed, the drug may be placed under the tongue or between the gums and cheeks for absorption into the mouth, or sprayed into the interior of the nose. The sublingual venous circulation is a branch of the superior vena cava, which ensures that the drug reaches the systemic circulation (including the brain ring) more quickly; in this way, the drug can bypass hepatic metabolism and enter the systemic circulation. Since the absorption surface is thinner than the intestinal tract, the absorption is very fast, and the lipid solubility of the drug is higher than the lipid solubility of the surface of the drug absorbed in the intestinal tract (it must be considered that the extent of the absorption surface is much smaller), whereby the effect can be produced quickly.

The data provided by the inventors are clinical data certified by the public health administration, so they can be used in the international agreement on GBL of the therapist.

For comparison, experimental data in animals in the literature relate to transplanted tumors, which are completely different from spontaneous tumors in humans due to chronic inflammation and/or immunodeficiency; however, as already discussed in the part of the description relating to the known technology, the experimental data of tumors in mice cannot be transferred in any way to the therapeutic practice in humans.

The present invention relates to a method of sublingual administration and utilizes the natural lipid affinity of molecules selected with respect to the buccal/sublingual mucosa, wherein specific vascularization enables rapid diffusion in the blood circulation in the vicinity of the cerebral circulation; thus by skipping the enterohepatic circulation, the drug can reach systemic circulation, including the brain, more rapidly, whereas in the enterohepatic circulation the molecule undergoes metabolic conversion, such as occurs upon oral or intraperitoneal administration.

Given the intrinsic characteristics of curcumin and polydatin (resveratrol is not absorbed by the mucosa-even by the intestinal tract, in contrast to the more widely known resveratrol) -this allows the mixture of ingredients to be advantageously emulsified locally in contact with saliva, which is rapidly absorbed by diffusion in the oral mucosal capillary microcirculation.

In addition, still according to the authors' hypothesis, the action of the molecule is not only anticancer but may also be linked to factors that have demonstrated natural immunity to polydatin, in addition to the demonstrated antitumor action, due to the inhibition of lipid peroxidation (the generation of ROS during radiotherapy), also anti-inflammatory.

The following examples are to be considered as illustrative and not limiting the scope of the invention. All percentages are by weight unless otherwise indicated.

Examples

Examples of compositions comprising polydatin + curcumin.

Method for preparing polydatin and curcumin sublingual tablet

Sublingual tablets are formulated to produce CO in the oral cavity₂. The production of carbon dioxide results from the reaction of a soluble organic acid with a base. The soluble organic acid may be: citric acid, malic acid, tartaric acid, and the like. The soluble base may be: sodium carbonate/bicarbonate, potassium carbonate/bicarbonate. The formulation is calibrated so that the tablet will start to dissolve with a very small amount of water (saliva), which will react due to the neutralization of the alkaline acid, the effect of which will be the formation of additional water. Therefore, contact with water and moisture must be avoided during production and storage.

Water soluble binders (sorbitol, dextrose xylitol, etc.) and anti-caking agents (vegetable magnesium stearate, benzoic acid, adipic acid, etc.) are used. Other excipients may be used to improve the taste of the tablet, to limit its bitter taste, and to improve the sweetness and mouth feel of the formulation.

Care should be taken to avoid that excipients (e.g., sugars) for cancer patients may be banned in the literature.

Sublingual tablets are produced in a manner similar to that of ordinary swallowable tablets, but further measures must be taken:

the raw materials already indicated must be placed away from moisture;

if necessary, the raw material with poor compressibility must be granulated.

The end result is the development of a stable immediate release formulation with a good mouth feel and fast disintegration, resulting in a higher absorption of the active ingredient and a higher content in the systemic circulation.

Examples of sublingual polydatin-curcumin formulations:

sublingual polydatin-curcumin 30 tablets for sublingual administration of 400mg D.10

The phases of the composition of the formulation constitute:

example 2 (effervescent tablet):

amount of characteristic elements:

polydatin 60mg

Curcumin 200mg

Preparing materials:

acidifying agent: anhydrous citric acid; acidity correcting agent: sodium bicarbonate; maltodextrin; a fragrance; a sweetening agent: steviol glycosides and sorbitol; dye: beta-carotene.

Example 3 (drinkable stick pack gel):

amount of characteristic elements:

polydatin 60mg

Curcumin 200mg

Preparing materials:

polydatin (e.g. from plants of giant knotweed (Fallopia Japonica)), curcumin (from curcumin, e.g. rhizomes), emulsifiers: beta-cyclodextrin, thickener: xanthan gum, orange flavor, acidulant: citric acid; preservative: potassium sorbate, sweetener: erythritol and water.

Clinical researchIs especially suitable for the treatment of diabetes

Improvement of the quality of life and survival of patients with glioblastoma using conventional therapeutic combinations of natural substances

Introduction to

High grade gliomas are considered to be one of the worst, most aggressive diseases for prognosis. The mean survival time for patients with glioblastoma (the most aggressive malignant glioma) is 9 to 12 months, whereas for patients with malignant oligodendroglioma the mean survival time is about 2 years. Even in the case of chemotherapy and radiotherapy treatment, recurrence after surgical treatment is very common. This study was aimed at exploring the efficacy of the natural substances that are the subject of the present invention in selected glioblastoma patients and to investigate the utility of a combination therapy comprising a combination of natural curcumin, polydatin and mastic in combination with the conventional treatment of glioblastoma.

Materials and methods

GBL has an incidence of 3-4 cases per 100,000 cases, so the sample studied is highly representative, as it concerns about 200 million people.

We conducted a retrospective study of 72 patients with glioblastoma cancer in roman hospitals between 9 months 2012 and 3 months 2017. We derive patient data from a review of patient clinical and outpatient records and direct follow-up of patients. The main inclusion criteria are as follows: 18 years old or older; histological evidence of glioblastoma, and clinical and imaging evidence of brain cancer.

All patients who were radioactively diagnosed as possibly having brain-derived tumor lesions received a surgical biopsy for histological diagnosis and, where possible, surgery for removal of the tumor. Subsequently, all patients received 30 radiation treatments (whole brain radiotherapy) in combination with first-line pharmacotherapy: temozolomide (dose: 80 mg/m)²Body surface). Temozolomide, where possible, was continued 1 month after the end of treatment for 5 consecutive days every 28 days, 1 time a day.

Since the patient received integrated treatment (IOT), we began monitoring all important parameters (hematology and urinalysis) and their progress from the point of view of instrumental examination (CT and MRI). From diagnosis, many of them begin treatment with the composition of the present invention. Some people begin IOT at a different stage of conventional therapy.

The dosage range is 3 mg/day/kg body weight of polydatin, and 200mg of curcumin, and single pharmaceutical preparation (gel and/or oral soluble tablet, adhesive film agent) of 80mg polydatin and 200mg curcumin is administered for single or divided administration.

Results

The clinical data obtained were statistically significant and based on a survival assessment method established by evidence-based medicine, which is an unexpected on-off result (on-off result) in GBL epidemiology supported by the ethical committee in oncology in the lazyo region (unpublished data).

As a surprising result, the undesirable effects of radiation therapy are reduced (reduced post-actin edema); reduces fatigue after radiation therapy. Also noted are the small magnitude of the decrease in platelet count (which often occurs in the use of temozolomide) and the decrease in white and red blood cell counts. These results make it possible to continue chemotherapy treatment without interruption and maintaining all the required cycles.

A total of 72 patients with glioblastoma cancer were enrolled in this study. The mean age was 57 years (between 12-79 years). More men (43; 59%) than women (30; 41%). Of these patients, 66 (91.7%) had undergone surgery, of which 28 (42.4%) had total resection. 69 patients (95.8%) received radiation therapy. 6 patients (8.3%) did not receive any chemotherapy, 53 patients (73.6%) received chemotherapy, of which 52 received temozolomide treatment, only 1 received nimotuzumab plus vinorelbine treatment, 11 (15.3%) received a second treatment consisting primarily of fotemustine, and 2 (2.8%) received a third treatment (1 BCNU carmustine plus PCV combined pneumococcal vaccine, 1 rituximab). The average time from diagnosis to first visit at our center was 3.9 months, varying from 10 days to 14 months. At the first visit, 31 (43.1%) patients had corticosteroids.

Of these 72 patients, 7 (9.7%) never started treatment, and 5 (6.9%) had poor compliance with the IOT regimen (in a sense that they did not follow the medical prescription regularly).

Univariate analysis and multivariate analysis

The overall survival (overall survival-OS) of the entire series was 13.3 months (95% confidence interval CI: 7.3-19.3), while the overall survival of 65 patients receiving treatment was 16.3 months (95% CI: 0.2-32.4). The mean OS for the 60 patient series that truly adhered to treatment was 25.4 months (95% CI: 8.3-42.5). The one-year survival rate for the entire series was 53.1%, and 55.4% of 65 patients receiving treatment.

The one-year survival rate of the true adherence to treatment 60 patient series reaches 59.0%. No difference in survival was observed in sex, age, number of previous chemotherapy treatments. In fact, the one-year survival rate is 51.9% for men and 59.1% for women. One-year survival rates were 53.8% for young patients (<57 years) and 57.0% for elderly patients. The one-year survival rate for patients receiving chemotherapy alone was 58.0%, while the one-year survival rate for patients receiving two or three treatments was 56.3%. The one-year survival rate for patients taking corticosteroids was 58.7%, while for patients not taking corticosteroids was 50.6%.

Overall average survival varied across the series: patients who did not receive surgery (18.3% survival one year), patients who received total surgery (74.0% survival one year), and patients who received biopsy only (56.4% survival one year). The mean OS after diagnosis was 34.4 months (95% CI: 18.1-40.8), with an one-year survival rate of 82.4% and a two-year survival rate of 54.2%.

Data update

The survivor samples are of great significance, with the median survival time now being higher than 55 months.

If we consider the group to adhere strictly to the protocol, the current survival results will exceed 25% (60 out of 72 patients), otherwise the total number of studies is 11%. In contrast, the international 5-year figure is only 3%.

Conclusion

Brain tumors, such as glioblastoma, have a poor prognosis and unfortunately patients rarely survive long-term even when treated with chemotherapy and radiation. The use of conventional multimodal treatment in combination with the present invention usefully helps to prolong the survival of brain tumor patients and ensures a good quality of life.

From the data presented herein, the inventors have discovered that patients receiving glioblastoma treatment have a surprising increase in survival and improved symptoms.