FIELD OF THE INVENTION

The present invention relates to the field of anticancer treatments, and more specifically to the topical/local administration of inositol hexaphosphate as an adjuvant in anticancer treatments.

BACKGROUND ART

Despite continuous progress of scientific research, cancer is still the second leading cause of death. Cancer is a disease characterized by alterations or losses of the control mechanisms of cell proliferation and differentiation.

These alterations lead to transformations which are defined as neoplasms, i.e. new formations; in fact, neoplastic cells express surface antigens which are typical of embryonic cells.

Cancer is classified according to different features also determined as a function of the clinical aspects found, the main ones being:

1 ) the original histological type of proliferating cells (e.g. epithelial, mesenchymal, blood cell or nervous tissue tumors);

2) tumor staging, or TNM Classification, as regards malignant tumors.

The therapies currently available are of the surgical, radiological and pharmacological type.

In particular, the three therapies may be combined to identify the best therapeutic approach on a case-by-case basis.

In fact, surgical or radiotherapy procedures represent the primary approach to the disease, with which chemotherapy may further be associated.

In particular chemotherapy is used in three main situations:

1 ) primary induction chemotherapy, that is in patients with advanced disease, or suffering from neoplasms for which there are no viable treatment alternatives;

2) neoadjuvant chemotherapy, in patients with neoplasms at an early stage and whose treatment with surgery alone and/or radiotherapy would not be fully effective; 3) adjuvant chemotherapy, that is supplementary to surgery and/or radiotherapy [1 -3].

Primary induction chemotherapy

It is a first-line pharmacological therapy for those patients with advanced disease or neoplasms for which there are no alternative treatments. Historically this has been the therapeutic approach for patients with metastasized tumors, mostly with the purpose of controlling the symptoms of the disease, improving the quality of life and delaying the progression of cancer. Studies conducted on patients suffering from a wide variety of neoplasms have shown that, compared to simple adjuvant therapy, chemotherapy has significant benefits in terms of survival, thus strengthening the rationale for starting it as early as possible. In some cases, however, chemotherapy may have actual healing effects; this is especially true in adult patients with Hodgkin's and non-Hodgkin's lymphomas, acute myeloid leukemia, germ cell tumors, and choriocarcinoma etc. [1 ].

Neoadjuvant chemotherapy

This type of therapy is used in patients with localized neoplasms which cannot be fully controlled by surgery or other local therapies. This therapy aims to reduce the tumor mass volume prior to surgery.

Neoadjuvant chemotherapy is used in patients with anus, bladder, breast, esophagus and lung neoplasms, as well as osteogenic sarcoma [2].

Adjuvant chemotherapy

This is one of the most important applications of chemotherapy, especially when it is administered in addition to localized treatments such as radiotherapy or following surgical treatment. In this case, the purpose is to reduce local relapses and improve overall survival in patients. In principle, adjuvant therapy is capable of extending both disease-free survival (DFS) and overall survival (OS) in patients with breast, colon, stomach and lung cancer. Finally, the administration of anti-estrogens such as tamoxifen, anastrozole and letrozole as adjuvants is highly effective in patients with estrogen-receptor-positive breast cancer. It should, however, be noted that because of their cytostatic, rather than cytotoxic, effect, their use is to be extended to at least 5 years [3]. Although there are several types of chemotherapeutic drugs commonly used by the medical class (Table 1 ), due to their cytotoxic effect, they are connected by a plethora of side effects shared among the different types of drug and the different molecules [4]. Table 1. Most commonly used chemotherapeutic drugs.

Particularly, these undesirable effects cause acute and late toxicity.

Typical symptoms of acute toxicity are: nausea, vomiting, asthenia, headache, diarrhea, allergic reactions, fever, hypersensitivity etc. [5,6].

On the other hand, late toxicity is characterized, among other things, by cytopenia, leukopenia, alopecia, nephropathy, neuropathy, hepatic disease, myelopathy etc.

VI Both acute toxicity and late toxicity events adversely affect a patient's quality of life. A crucial aspect of late toxicity is its impact on the treatment plan. In fact, if the chemotherapy treatment induces significant late toxicity the physician will have to postpone or cancel the scheduled cycle of chemotherapy.

Particularly in the case of breast cancer, chemo- and/or radiotherapy can be used both before and after surgery.

The most commonly used chemotherapy protocols provide for the administration of treatment with a frequency which can be on a weekly or monthly basis for a number of cycles which can range from 3 to 8. Actually, it should be defined as polychemotherapy; in fact, most protocols involve the administration of multiple chemotherapeutic drugs possibly coupled to radio- or hormone therapy [1 -7] Table 2 shows the most used drugs in therapeutic protocols. In particular, there are anthracyclines (for example, epirubicin and doxorubicin), taxanes (docetaxel and paclitaxel), fluorine derivatives (5-fluorouracil and capecitabine), methotrexate, vinorelbine, gemcitabine, platinum derivatives (for example, cisplatin and carboplatin). Combination regimens are characterized by the association of multiple drugs, according to different schemes. The most used combinations in clinical practice are: AC (doxorubicin and cyclophosphamide), CMF (cyclophosphamide, methotrexate and 5-fluorouracil), FEC (5-fluorouracil, epirubicin and cyclophosphamide), CMF (doxorubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil), E-CMF (epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil), AT CMF (doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate and 5-fluorouracil), AC/T (doxorubicin and cyclophosphamide followed by paclitaxel or docetaxel).

Table 2. The following table shows the most commonly used chemotherapeutic protocols.

WO2005044278 describes compositions comprising myo-inositol hexaphosphate (2%, 0.5% and 1 .7%) in a form suitable for topical administration for use in treating or preventing a disease associated with the development of heterogeneous nucleating agents in a soft tissue, that is subepithelial, dystrophic, kidney, lung, brain, or blood vessel wall calcifications.

Further, the anticancer properties of inositol hexaphosphate [9,10], its oral administration [1 1 -13] and investigations about the uptake limits due to the oral uptake pathway are present in the literature [14,15].

The unsolved technical problem of the prior art is the reduction of late toxicity associated with chemo-or radiotherapy protocols.

It is the object of the present invention to provide a product which is effective in reducing acute and late toxicity of anticancer treatments or in improving patients' quality of life; it is the object of the present invention to provide a product for use as an adjuvant in anticancer treatments.

SUMMARY OF THE INVENTION

The applicant has surprisingly found that inositol hexaphosphate, also known as phytic acid, when administered topically/locally is capable of improving the quality of life of patients undergoing chemotherapy and radiotherapy, representing an excellent adjuvant in chemo- and/or radiotherapy treatments.

Therefore, the present invention relates to inositol hexaphosphate for use as an adjuvant in anticancer treatments, or for use in combination with anticancer treatments, said inositol hexaphosphate being characterized in that it is administered topically/locally.

The present invention further relates to a pharmaceutical composition comprising inositol hexaphosphate, said composition to be administered topically/locally for use as an adjuvant in anticancer treatments.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, the active ingredient inositol hexaphosphate is selected from the group consisting of phytic acid, sodium phytate, potassium phytate, calcium phytate, dipotassium phytate, calcium-magnesiujm phytate (phytin), magnesium phytate and sodium phytate dodecahydrate; preferably sodium phytate or sodium phytate dodecahydrate.

For the purposes of the present invention, topical administration means the cutaneous (skin) or mucous membrane (e.g. mucous membranes of nasal cavities, lung, gastrointestinal, anogenital) application at or near the cancer lesion. Topical application can take place by means of gels, creams or ointments but also by means of an intradermal implant or a patch.

For the purposes of the present invention, local administration means the local intraorgan (e.g. intrapulmonary, intracutaneous) or intramuscular application, in any case near the cancer lesion. The local application may be by in-situ injection.

In order for inositol hexaphosphate for use according to the present invention to be effective, it should be administered in amounts of 2.5-2500 mg per day in one or more doses. Inositol hexaphosphate for use according to the present invention is useful as an adjuvant in anticancer chemotherapy and/or radiotherapy treatments for the treatment of breast, prostate, colon, colorectal, lung cancer.

In the case of breast cancer, anticancer chemotherapy and/or radiotherapy treatments may also be in combination with antiestrogenic therapy.

Therefore, it is also the object of the present invention a pharmaceutical composition adapted for topical/local administration, said composition comprising inositol hexaphosphate in a % by weight with respect to the total of 0.5-50%, preferably 1 - 10%, more preferably 2-5%.

Preferably, it is the object of the present invention a pharmaceutical composition in the form of a gel which has the following percentage composition by weight with respect to the total weight:

Table 3 Example of possible qualitative-quantitative formulations of a gel related to the present invention

The preservative, if any, is preferably present at 0.1 -1 %, more preferably at 0.1 - 0.7%.

The chelator, if any, is preferably present at 0.01 -0.6%, more preferably at 0.05- 0.3%, even more preferably 0.1 -0.2%.

Moisturizing component means a mixture or a single component selected from: phospholipids, sphingolipids, ceramide, cyclodextrins, diols, ethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tripropylene glycol, butylene glycol, polyethylene glycol sorbitol, xylene, collagen, lactic acid, nanolipidgels, glycerin; methyl gluceth-20, methyl gluceth-10, betaine and polyethylene glycols. Preferably the moisturizing system consists of propylene glycol, glycerin and lactic acid; more preferably it consists of 3-4 parts of propylene glycol, 3-5 parts of glycerine and 2-3 parts of lactic acid; where parts means parts by weight compared to the total of the moisturizing mixture.

The preservative system may consist of one or more components to be selected from: quaternary ammonium compounds, PHMB, EDTA, silver and its salts, chlorhexidine, essential oils, potassium sorbate, nitrates and nitrites, chlorophenols, sodium benzoate, imidazolidin urea, diametazolidin urea, parabens, ethyl paraben, isobutyl paraben, ethyl paraben, O-Cymen-5-ol, phenoxyethanol propyl paraben, butyl paraben, potassium sorbate, sodium benzoate, benzyl alcohol, sodium dehydroacetate, diazolidinyl urea, imidazolidinyl urea, ethylhexylglycerin dehydroacetic acid, iodopropynyl butylcarbamate, benzoic acid, polyaminopropyl biguanide, DMDM hydantoin, methylisothiazolone, sorbic acid, triclosan sodium hydroxymethylglycinate, and methylisothiazolone. The preservative system preferably consists of O-Cymen-5-ol, potassium sorbate, sodium benzoate; more preferably 0.5-1 .5 parts of O-Cymen-5-OI, 2-4.5 parts of potassium sorbate, 2-4.5 parts of sodium benzoate.

The emulsifier is selected from: potassium cetyl phosphate, cetyl alcohol, polyglyceryl-3 methylglucose distearate, PEG-30, dipolyhydroxystearate, cetearyl glucoside, arachidyl glucoside, PEG-20, C12-13, pareth-3, PEG-100 stearate, sucrose polystearate, sodium steatoryl glutamate, PEG-20 stearate, polysorbate 80, polysorbate 60, cetyl phosphate, polyoxyethylene 20 cetyl stearyl ether (ceteareth- 20), polyoxyethylene 12 cetyl stearyl ether (ceteareth-12), polysorbate-85, C12-20 acid PEG-8 ester, myristyl glucoside, C12-20 alkyl glucoside, sorbitan stearate, beheneth-20, hydrogenated vegetable glycerides, PEG-40 citrate, PEG-8 stearate, beeswax, sorbitan olivate, steareth-2, ethoxydiglycol alcohol, diethylhexyl 2,6- naphthalate, triglycerides, cetyl stearyl alcohol, ceteth-1 , -2, -3, -4, -5, -6, -10, -12, - 14, -15, -16, -20, -24, -25, -30 and -45, glyceryl stearate; preferably ethoxy diglycol. The chelating agent may be one or a mixture of the following components: Disodium EDTA, Trisodium EDTA, Tetrasodium EDTA, EDTA; preferably Disodium EDTA. The agent which modifies the rheological properties may be one or a mixture of the following components: gum arabic, tragacanth gum, karaya gum, hydroxypropylguar, ghatti gum, guar gum, C12-22 alkyl hydroxypropylguar, carob bean gum, alginates, carrageenans, agar agar, pectins, starches, xanthan gum, gellan gum, cellulose derivatives, guar derivatives, hydrogenated castor oil, alginic acid derivatives, starch derivatives, acrylic polymers, polyethylene derivatives, fatty acid derivatives, hydrophilic and organophilic clays, hydrated silica, pyogenic silica and precipitated cellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium magnesium silicate, bentonite, silica gel, salts of fatty acids, butylene, ethylene, styrene copolymer. The agent which modifies the rheological properties is preferably hydroxyethylcellulose. It is preferably the object of the present invention a gel comprising:

Table 4 Example of possible qualitative-quantitative formulations of a gel related to the present invention

As an alternative to gel, the composition of the invention may be in the form of a cream or ointment.

Preferably, in the case of a cream, the composition by weight is: Table 5 Example of qualitative-quantitative formulations of a cream related to the present invention

Preferably, in the case of an ointment, the composition by weight is: Table 6 Example of qualitative-quantitative formulations of an ointment related to the present invention

For creams or ointments, the emulsifier may be one or a mixture of the following: potassium cetyl phosphate, cetyl alcohol, polyglyceryl-3 methylglucose distearate, PEG-30, dipolyhydroxystearate, cetearyl glucoside, arachidyl glucoside, PEG-20, C12-13, pareth-3, PEG-100 stearate, sucrose polystearate, sodium steatoryl glutamate, PEG-20 stearate, polysorbate 80, polysorbate 60, cetyl phosphate, polyoxyethylene 20 cetyl stearyl ether (ceteareth-20), polyoxyethylene 12 cetyl stearyl ether (ceteareth-12), polysorbate-85, C12-20 acid PEG-8 ester, myristyl glucoside, C12-20 alkyl glucoside, sorbitan stearate, beheneth-20, hydrogenated vegetable glycerides, PEG-40 citrate, PEG-8 stearate, beeswax, sorbitan olivate, steareth-2, ethoxydiglycol alcohol, diethylhexyl 2,6-naphthalate, triglycerides, cetyl stearyl alcohol, ceteth-1 , -2, -3, -4, -5, -6, -10, -12, -14, -15, -16, -20, -24, -25, -30 and -45, glyceryl stearate.

For creams or ointments, the moisturizing agent may be one or a mixture of the following: phospholipids, sphingolipids, ceramide, cyclodextrins, diols, ethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tripropylene glycol, butylene glycol, polyethylene glycol sorbitol, xylene, collagen, lactic acid and nanolipidgels, glycerin, methyl gluceth-20, methyl gluceth-10, betaine and polyethylene glycols.

For creams or ointments the surfactant may be one or a mixture of the following: hetero soaps, lipoproteins, amino acid derivatives (acyl glutamates and acyl sarcosinates), sulfuric esters, sulfone succinates, sulfonates (BABS and LABS), benzalkonium chloride, cetyltrimethylammonium bromide, betaines, sulfobetaines, alkyl betaines, PEG, alkyl glucosides, bis-diglyceryl polyacyladipate-2, glyceryl arachidonate monoester, glyceryl caprylate, glyceryl laurate, glyceryl linoleate, glyceryl linolenate, glyceryl octanoate/stearate/adipate, glyceryl oleate, glyceryl stearate, glyceryl stearate citrate, glyceryl stearate SE, PEG-7 glyceryl cocoate and polyglyceryl-3 methylglucose distearate.

The emollient agent can be one or a mixture of the following: octyl palmitate; C12- 15 Alkyl Benzoate; Dimethicone; Caprylic/capric triglyceride; Ethyl hexyl isononanoate; Simmondsia Chinensis oil; Argania Spinosa oil; Glycine Soja oil; Myristyl Myristate; Isononyl isononanoate; Cetearyl ethylhexanoate; Butylene glycol dicaprylate/dicaprate; Cetearyl isononanoate; Dicaprylyl carbonate; Vaseline oil; Arachidyl propionate; Squalene; Almond oil (Prunus Amygdalus Dulcis); Olive Oil (Olea Europaea); Cyclopentasiloxane; Diethyl hexyl adipate; Cocoglycerides; Diethyl hexyl carbonate; Sesame oil; Coco-Caprylate; Ethyl hexyl cocoate; Coconut oil; Glyceryl arachidonate; Hydrogenated polyisobutene; Coco caprylate/caprate; Dicaprylic ether; Avocado oil; Oleic/linoleic/linolenic Polyglycerides; isostearylic alcohol; Butylene glycol cocoate; Phenyl trimethicone; Isohexadecane; Isopropyl isostearate; Cyclohexasiloxane; Isocetyl stearate; Caprylic/capric/stearic triglycerides; Red grape seed oil; Ethyl hexyl stearate; Acai oil; Bis-PEG-18 Methyl Ether Dimethyl Silane; Babassu nut oil: Bis-Diglyceryl Polyacyl adipate-2; Isopropyl palmitate; Hexyldecanol; Glyceryl octanoate/stearate/adipate; Cetyl palmitate; Wheat germ oil; Diisopropyl Sebacate; Isopropyl Myristate; Cetyl Ethyl hexanoate; Peanut oil (Arachis Hypogeae); Olus Oil; hydrogenated vegetable oil; Blackcurrant; Rice oil; Cetyl Babassuate; apricot kernel oil; Corn oil; Isododecane; hydrogenated Polydecene; Petrolatum; C12-13 Alkyl lactate; Rosa moschata oil; Elaeis Guineensis Kernel Oil; Elaeis Guineensis Oil; Oenothera Biennis Oil; Isoamyl laurate; Triethylhexanoin; Behenic acid; Macadamia Ternifolia Seed Oil; Vaseline. The composition object of the present invention preferably further comprises a mixture of antioxidants and micronutrients selected from: Vitamin A, Vitamin B1 , Vitamin B2, Vitamin B3, Vitamin B5, Vitamin B6, Vitamin B7, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, Vitamin E, Vitamin K, lipoic acid, uric acid, carotenes, ubiquinol, polyphenol antioxidants, calcium; phosphorus, potassium, sodium, chlorine, magnesium, iron, zinc, copper, cobalt, iodine, fluorine, chromium, manganese, molybdenum, selenium, vanadium, silicon, lithium, nickel, arsenic. The present invention will be better understood in the light of the following embodiments.

EXPERIMENTAL PART

A clinical study was conducted which involved 24 women with breast cancer who received chemotherapy and/or radiotherapy. In particular, 8 women were treated according to the standard protocols of chemo- and/or radiotherapy (control group), 8 according to the standard protocols of chemo- and/or radiotherapy and with 1 .6g of IP6 in capsules twice daily, and 8 women were treated according to the standard protocols of chemo- and/or radiotherapy and 5g of a 4% gel, the composition of which is specified hereinafter in Table 3, administered topically (applied to the breasts) once daily.

Table 7 - Composition of the gel used for the clinical study

rheology modifiers Hydroxyethyl cellulose 2.50

preservative O-Cymen-5-OI (1 part) 0.10

Potassium sorbate (3 0.30

parts) 0.30

Sodium benzoate (3 parts)

chelator Disodium EDTA 0.15

water q.s. to 100%

The treatments were carried out for the whole duration of chemotherapy. At the end of treatment, quality of life was assessed using two standardized questionnaires, i.e. EORTC QLQ-C30 (Tab. 5) EORTC QLQ-BR23 (Tab. 6), both tests were studied to obtain information on the patient's subjective feelings, a functional and a symptomatic assessment scale. Examples of these parameters are tiredness during daily activities or during physical activity, nausea, constipation, mood changes.

Table 8. Scales of the questionnaire on quality of life in subjects with cancer (EORTC QLQ-C30)

Table 6 shows the results of the study:

Table 10. Major results obtained

^# P<0.05, vs control ^## P<0.01 , IP6 oral vs control; ^*** P<0.001 IP6 topical vs control In addition, blood count parameters were tested (Table 7).

Table 11. Hemochrome parameters

In addition, following the same clinical protocol, the efficacy of formulations with different % of inositol hexaphosphate was tested

Table 12. Major results obtained (1 % gel)

^# P<0.05, vs control ^## P<0.01 ,

In addition, blood count parameters were tested (Table 13). Table 13. Hemochrome parameters

Table 14. Major results obtained (10% gel)

#P<0.05, vs control ^## P<0.01 ,

In addition, blood count parameters were tested (Table 7).

Table 15. Hemochrome parameters

The results obtained show that the local/topical administration of IP6 is capable of improving the quality of life, as measured by the two reference questionnaires used, QLQ-30 and QLQ-BR23, of patients undergoing chemotherapy treatment (Table 6). Furthermore, treatment with IP6 prevents excessive reduction in white blood cells and platelets allowing patients to fully comply with the chemotherapy protocols with no need to postpone certain cycles (Table 7).

Ultimately, taking into account the number of delayed cycles, it is possible to state that the topical/local administration of IP6 increases the effectiveness of chemotherapy.

By further analyzing the blood concentrations of some microelements known to be depleted during chemotherapy, it has been surprisingly found that the topical/local administration of inositol hexaphosphate is capable of preventing the drop thereof.

Effectiveness of the product is only achieved if the product can be administered in an amount between 2.5 and 2,500 mg of IP6 per dose regardless of the type of topical/local administration of the dosage form being used.

In addition, the topical administration of an IP6-based product showed the same beneficial effects, described merely by way of example with reference to breast cancer, on other diseases such as colorectal cancer, liver cancer, prostate cancer and lung cancer.

In two specific cases, namely those of colon and lung cancer, the oral administration of a dose of IP6 in the range of 1 g-20g has also shown to be effective. References

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