Formulation comprising ozonized oil for the prevention of side effects of chemotherapy or radiotherapy

Abstract

The present invention relates to the use of a formulation comprising ozonized oil for the prevention or reduction of the side effects of chemotherapy or radiotherapy, in particular for the prevention of leukopenia, anaemia or thrombocytopenia caused by said anti-tumour treatments.

Description

[0001] FORMULATION COMPRISING OZONIZED OIL FOR THE PREVENTION OF SIDE EFFECTS OF CHEMOTHERAPY OR RADIOTHERAPY

[0002] Field of application

[0003] The present invention relates to the use of a formulation comprising ozonized oil for the prevention of side effects of chemotherapy or radiotherapy, in particular for the prevention of leukopenia caused by such anti-tumour treatments.

[0004] Prior art

[0005] One of the greatest limits to the continued use of chemotherapy in a cancer patient is represented by its adverse side effects. Many chemotherapies express a non-selective cytopathic and cytotoxic action, i.e. an action not only against the target neoplastic cells but also against healthy cells. This situation occurs above all in the case of non-targeted chemotherapies, i.e. the ones that kill neoplastic cells by means of nonspecific mechanisms such as DNA damage, blocking of mitosis, etc. By their nature, such mechanisms also involve healthy cells in an active replication phase. Therefore, chemotherapy side effects are observed above all in normal circulating cell populations, with particular reference to epithelia and to bone marrow and the haematopoietic system. Furthermore, chemotherapies have significant side effects also on the musculoskeletal system. Such effects are due to the genotoxic action exerted by chemotherapies against mitochondrial DNA, particularly abundant in skeletal muscle.

[0006] The suppression of haematopoiesis represents one of the main and most dangerous adverse effects of chemotherapy in the cancer patient. Genotoxic and cell duplication-inhibiting chemotherapeutics in fact induce a typical decrease in haematopoiesis, with particular reference to red blood cells and platelets. The reduction of haematocrit, i.e. of the percentage of the volume of red blood cells relative to the total blood volume, is often dramatic and requires the introduction of major support therapies, such as the administration of bone marrow growth factors or even the transfusion of whole blood or derivatives thereof. Thrombocytopenia is a typical side effect of some chemotherapeutic drugs, as for example typically occurs in the case of temozolomide used for the treatment of brain tumours such as grade IV glioblastoma. The reduction of platelets below the limit of 100,000 may result in vascular fragility and frequent haemorrhages, both external and internal, such as to induce the suspension of the chemotherapy treatment until sufficient platelet values have been restored.

[0007] There is thus a felt need in this sector to provide a formulation for the prevention or reduction of the side effects due to anti-tumour chemotherapy or radiotherapy, in particular for the prevention or reduction of the haematopoietic bone marrow suppression caused by such treatments.

[0008] Summary of the invention

[0009] A similar problem has been resolved according to the invention by a formulation comprising at least one ozonized oil for use for the prevention and / or reduction and / or treatment of one or more side effects due to an antitumour chemotherapy and / or radiotherapy.

[0010] This formulation resolves the above-described problem in an advantageously non-invasive manner, i.e. via the administration of ozonized oil according to the invention. In the context of the present invention, "prevention” means that the pathology, in particular the side effect due to chemotherapy and / or radiotherapy, does not occur or occurs to a reduced degree.

[0011] "Reduction of one or more side effects” means that the one or more side effects occur to a lesser degree than what would be the case if the formulation described herein were not used. Said reduction may be of any entity.

[0012] "T reatment” means that the one or more side effects occur to a lesser degree than what would be the case if the formulation described herein were not used.

[0013] "Side effect due to anti-tumour chemotherapy and / or radiotherapy” means any undesirable effect due to or in any way correlated with the pharmacological action of an anti-tumour chemotherapeutic or the action of a radiotherapy.

[0014] Said one or more side effects are preferably selected from: haematopoietic bone marrow suppression, alopecia and chemotherapy-induced chronic fatigue syndrome.

[0015] Preferably, said formulation comprising at least one ozonized oil is for the prevention or reduction of the haematopoietic bone marrow suppression due to an anti-tumour chemotherapy and / or radiotherapy.

[0016] "Haematopoietic bone marrow suppression” means a reduction in the normal haematopoietic function of bone marrow. "Myelosuppression” is a synonym. Said bone marrow suppression may lead to anaemia, leukopenia and / or thrombocytopenia.

[0017] Therefore, in a preferred embodiment, said formulation comprising ozonized oil is for use for the prevention or reduction or treatment of the anaemia and / or leukopenia and / or thrombocytopenia due to an anti-tumour chemotherapy and / or radiotherapy.

[0018] "Anti-tumour chemotherapy” means the administration of one or more anti-tumour drugs. "Chemotherapy” is used here as a synonym.

[0019] "Radiotherapy” or "anti-tumour radiotherapy” means a therapy that includes the use of ionising radiation. The radiation can be of any type, according to what is known regarding the use of radiotherapy for the treatment of tumours.

[0020] The formulation according to the invention is typically administered to an individual who has tumor. Said tumour may be solid or liquid; for example, it can be breast, pancreatic, lung, liver, colorectal or gastric tumor. Preferably, said individual is or has been under treatment with anti-tumour chemotherapy and / or radiotherapy. Said anti-tumour chemotherapy can comprise the administration of one or more known anti-tumour drugs, such as, for example, 5-fluorouracil, temozolomide, cisplatin, nitrosoureas, alkylating agents, antimetabolites, taxanes, biologic drugs, angiogenesis inhibitors, and PD1 (programmed cell death protein 1) inhibitors.

[0021] The formulation of the invention can be administered before or concurrently with or following chemotherapy and / or radiotherapy; preferably, it is administered concurrently with the administration of chemotherapy or radiotherapy.

[0022] In one embodiment, said formulation is for use together with an anti-tumour chemotherapeutic agent, for example a chemotherapeutic mentioned above.

[0023] Preferably, said formulation comprising at least one ozonized oil is for use by oral administration. Preferably, the ozonized oil has a content of ozonides from 500 to 1500 meq 02 / kg, more preferably from 600 to 1400 meq 02 / kg, even more preferably from 700 to 1300 meq 02 / kg, even more preferably from 1100 to 1300 meq 02 / kg, most preferably 1200 meq 02 / kg.

[0024] The content of ozonides can be measured according to techniques known in the art, for example by means of the method for the determination of the peroxide index described in Regulation (EEC) No 2568 / 91 of 11 July 1991 on the characteristics of olive oil and olive-residue oil and on the relevant methods of analysis (Annex III).

[0025] In accordance with the present invention and appended claims, the expression "ozonized oil” means: a vegetable oil that has undergone an ozonation process; an unsaturated fatty acid, preferably having a number of carbon atoms from 8 to 30, more preferably from 16 to 20, which has undergone an ozonation process; an ester of an unsaturated fatty acid, preferably having a number of carbon atoms from 8 to 30, more preferably from 16 to 20, which can be monoester, diester or triester, with an alcohol or a polyol, in particular glycerol, which has undergone an ozonation process; or mixtures thereof.

[0026] Preferably, the at least one ozonized oil is selected from: at least one vegetable oil that has undergone an ozonation process; at least one unsaturated fatty acid that has undergone an ozonation process; at least one monoester of an unsaturated fatty acid that has undergone an ozonation process; and mixtures thereof; more preferably at least one vegetable oil that has undergone an ozonation process.

[0027] Preferably, the at least one vegetable oil that has undergone an ozonation process is selected from: sunflower oil, peanut oil, argan oil, olive oil, grapeseed oil, jojoba oil, soybean oil, maize oil, palm oil, cottonseed oil, rapeseed oil, coconut oil, castor oil, linseed oil, borage oil, evening primrose oil, and mixtures thereof; more preferably sunflower oil, peanut oil, argan oil, grapeseed oil, jojoba oil, soybean oil, maize oil, palm oil, cottonseed oil, rapeseed oil, coconut oil, castor oil, linseed oil, borage oil, evening primrose oil, and mixtures thereof; even more preferably sunflower oil and / or peanut oil, most preferably sunflower oil.

[0028] Preferably the at least one unsaturated fatty acid that has undergone an ozonation process has a number of carbon atoms from 8 to 30, more preferably from 16 to 20, even more preferably 18.

[0029] Preferably, the at least one unsaturated fatty acid has from one to six double bonds in the carbon chain, more preferably from one to three double bonds in the carbon chain.

[0030] Preferably, the at least one fatty acid is monounsaturated (and thus has a single double bond in the carbon chain) or diunsaturated (i.e. it has two double bonds in the carbon chain).

[0031] Preferably, the at least one fatty acid is oleic acid or linoleic acid.

[0032] Preferably, the at least one monoester of an unsaturated fatty acid that has undergone an ozonation process is obtained from the esterification of the aforesaid unsaturated fatty acid as described above, the monoester having undergone an ozonation process.

[0033] Preferably, the at least one monoester of an unsaturated fatty acid is obtained from the esterification of the aforesaid unsaturated fatty acid with an aliphatic primary alcohol having a single -OH group (monovalent), more preferably ethanol.

[0034] Preferably, the at least one monoester of an unsaturated fatty acid is ethyl oleate. Preferably, the at least one ozonized oil is substantially devoid of antioxidant agents.

[0035] Preferably, the at least one ozonized oil is obtained from an ozonation process that uses highly purified gaseous oxygen for the introduction of oxygen.

[0036] As regards oral administration, the at least one ozonized oil can be in the form of ozonized oil as such or in a formulation for oral administration comprising the at least one ozonized oil and at least one pharmaceutically acceptable excipient.

[0037] The formulation for oral administration can be in a form selected from oil, syrup, tablets and capsules, more preferably capsules.

[0038] Preferably, the capsules are gastro-resistant.

[0039] Preferably, the capsules are selected from soft gel-based capsules, and gastro-resistant capsules, more preferably gastro-resistant capsules.

[0040] Preferably, the composition of the gastro-resistant capsules comprises at least one coating agent, preferably hydroxypropyl methylcellulose, and at least one gelling agent, preferably selected from pectin, gellan gum, and mixtures thereof.

[0041] The formulation in capsules can be in liquid form or in solid form, preferably solid form, even more preferably in powder or granules.

[0042] Preferably, the capsules each contain from 200 to 700 mg, more preferably from 250 to 600 mg, even more preferably from 350 to 500 mg, most preferably 350 mg, of ozonized oil.

[0043] The at least one pharmaceutically acceptable excipient is selected from those commonly used in formulations for oral administration. It should be observed that such excipients preferably do not include any preservative or antioxidant agent. In fact, such agents interact with ozonized oil, as they are subject to oxidation by the ozonide groups.

[0044] As regards the dosage of oral administration, it varies according to the patient's conditions and the stage of the disease.

[0045] Preferably, the oral administration of the ozonized oil is carried out by administering a quantity of ozonized oil from 3000 to 6000 mg per day per 70 kg of body weight, more preferably from 3500 to 5300 mg per day per 70 kg of body weight, even more preferably from 4000 to 5000 mg per day per 70 kg of body weight.

[0046] Preferably, the oral administration is carried out once or twice or three times a day, more preferably twice a day.

[0047] Preferably, the oral administration of the ozonized oil is carried out for a period of at least one month, more preferably from one month to 3 years, even more preferably from 2 months to 14 months, most preferably from 5 months to 12 months.

[0048] In one embodiment, the ozonized oil is in the form of a dietary supplement or nutraceutical.

[0049] Additional features and advantages of the present invention will be apparent from the following detailed description.

[0050] Brief description of the Figures Figure 1. Two-dimensional culture of human keratinocytes: untreated control (left panel) or treated with ozonized oil (right panel).

[0051] Figure 2. Culture of human keratinocytes: untreated (top panel), treated with gamma radiation (middle panel), pretreated with ozonized oil and then with gamma radiation (bottom panel).

[0052] Figure 3. Evaluation of DNA fragmentation by means of the comet assay in a two-dimensional culture of human keratinocytes exposed to gamma radiation. The DNA maintains its high molecular weight and rounded shape and does not migrate in the electrophoretic field because not damaged in the untreated reference control (top panel). In contrast, it becomes very fragmented with a high degree of migration and the formation of bodies with an appearance similar to that of comets in the case of exposure to gamma radiation (middle panel). The pretreatment with ozonized oil reduces the gamma radiation-induced DNA fragmentation (clastogenic effect) by 50% (bottom panel).

[0053] Figure 4. Examples of the prevention of alopecia in cancer patients undergoing chemotherapy, before (left panels) and after co-treatment with orally administered ozonized oil (right panels).

[0054] Figure 5. Prevention of haematopoietic bone marrow suppression in cancer patients undergoing chemotherapy, before (left columns, CT) and after co-treatment with orally administered ozonized oil (right columns CT+HOO).

[0055] Detailed description of the invention

[0056] The present invention will now be further illustrated by means of some example embodiments as set forth below.

[0057] EXAMPLE 1

[0058] Physiological mechanisms of cytoprotection of healthy cells and their activation by ozonized oils

[0059] Ozonized oil produces a cytoprotective effect by increasing the level of the cell's endogenous antioxidant defences. This result is achieved by virtue of the adaptive phenomenon defined as hormesis (Izzotti A et al., "The molecular mechanisms of adaptive response related to environmental stress”. Int. J. Mol. Sci. 21 : 7053, 2020). In fact, the ozone released by the lipid at the intracellular level triggers an activation of antioxidant responsive elements with a consequent increase in intracellular antioxidants such as reduced glutathione.

[0060] The induction, by ozonized oil, of cytoprotective effects in healthy cells was demonstrated in an in vitro experimental model. A cell line of human keratinocytes, obtained from a cell bank of the IRCCS Policlinico Universitario San Martino in Genoa (Italy), was cultured in a two-dimensional culture and then underwent treatment with ozonized oil at a dose of 10% volume relative to the culture medium.

[0061] The microscopic analysis performed after 48 hours did not reveal the presence of any cytopathic effect compared to the untreated control sample. In fact, also in the sample treated with ozonized oil the cells remained adherent and viable and maintained their intracellular contacts intact. The treatment with ozonized oil thus does not in any way alter the morphology of the cell layer, intercellular adhesion interactions or cell viability, and no detachment of cells from each other or from the growth substrate is observed (Figure 1).

[0062] The cells thus treated were then exposed to genotoxic damage induced by ionising gamma radiation. A sample of untreated cells and a sample of cells pretreated with ozonized oil were exposed to gamma radiation at a dose of two grays in a cobalt irradiator.

[0063] The viability situation of the cells was then examined under a microscope. In the control sample not exposed to radiation, the keratinocytes remained adherent to the substrate and viable (CTRL). The sample exposed to two grays of gamma radiation suffered considerable damage, with the death of almost the totality of cells and their detachment from the growth substrate (2 Gy). In the sample pretreated with ozonized oil according to the previously described procedures, the gamma radiation did not induce any significant cytotoxic effects. The cells pretreated with ozonized oil in fact maintained their rounded shape, their intercellular contacts and above all their adhesion to the culture substrate without manifesting signs of cytopathic suffering despite the intense explosion of ionising radiation (OIL) (Figure 2). The pretreatment with ozonized oils thus protects cells from the cytotoxic effects of gamma radiation.

[0064] The genotoxic damage was assessed under the three experimental conditions described through an evaluation of DNA fragmentation in an electrophoretic field, or a comet assay. This test entails detecting the macromolecular state of DNA marked with a red fluorescent stain. The untreated control sample shows the presence of intact, high molecular weight DNA enclosed in the round-shaped nucleus (CTRL). Exposure to gamma radiation at a dose of two grays induces a major fragmentation of the DNA, with its consequent reduction into low molecular weight fragments that easily migrate in the electrophoretic field. Therefore, the DNA of cells exposed to gamma radiation appears in the form of typical "comets” characterised by a head of reduced dimensions which represents the residue of the nucleus containing the fragmented DNA and a long tail which migrates towards the right in the electrophoretic field and consists of fragments of DNA destroyed by the radiation (2Gy). The pretreatment with ozonized oil protects the keratinocytes considerably from the clastogenic effects (i.e. DNA fragmentation) of ionising radiation. In fact, despite the exposure to ionising radiation, keratinocytes pretreated with ozonized oil maintain the integrity of their nucleic acid, as demonstrated by the presence of still rounded nuclei and the minimal quantity of fragmented DNA that migrates towards the right in the electrophoretic field (OIL). (Figure 3).

[0065] These results demonstrate that the pretreatment with ozonized oil is capable of inducing cytoprotective and radioprotective effects in healthy cells.

[0066] EXAMPLE 2

[0067] Prevention of haematopoietic bone marrow suppression

[0068] The administration of ozonized oil was surprisingly demonstrated to be able to attenuate the effects of haematopoietic bone marrow suppression due to chemotherapy.

[0069] In particular, the ability of ozonized oil, orally administered twice a day for 2 months, to attenuate side effects was examined in 5 cancer patients treated with temozolomide-based chemotherapy compared to 5 patients treated with temozolomide in the absence of treatment with ozonized oil.

[0070] The gastro-resistant capsule administered contained a solid formulation in granules comprising 350 mg of ozonized oleic acid having a content of ozonides of 1200 meq 02 / kg and pharmaceutically acceptable excipients. The gastro-resistant capsule was a conventional gastro-resistant capsule based on hydroxypropyl methylcellulose, pectin and gellan gum.

[0071] The quantity of platelets and red blood cells present in the blood of the subjects after treatment with temozolomide was then evaluated. The results obtained are shown in Figure 5. In the patients treated with temozolomide, the reduction in platelets was marked, with values decreasing from the normal reference value of 260,000 platelets per cubic millimetre to values of around 90,000 (left column, CT). In contrast, in the 5 patients similarly treated with temozolomide who also received treatment with ozonized oil administered orally for at least two months, a maintenance of platelet values close to normal values was observed, with a mean value of 240,000 platelets (right column, CT+HOO). Of particular interest is the fact that in patients undergoing co-treatment with ozonized oil it was thus possible to continuously prolong the treatment with temozolomide without variations, unlike what occurred in patients who received temozolomide alone.

[0072] Similar results were observed in relation to the erythropoietic series. The patients treated with temozolomide alone experienced a reduction in the number of red blood cells to 60,000 per cubic millimetre, compared to the normal value of four million, with a decrease of up to 3, 100,000 per cubic millimetre (left column, CT). In contrast, in the patients treated with temozolomide and simultaneously with ozonized oil, there was no observed reduction in the number of red blood cells, the level of which remained at around the normal reference value (right column, CT+HOO).

[0073] These results indicate that the oral treatment with ozonized oil is able to attenuate the cytotoxicity of chemotherapy.

[0074] Patients gave their express free and informed consent to the collection and use of the collected blood.

[0075] EXAMPLE 3

[0076] Prevention of alopecia due to chemotherapy

[0077] Alopecia represents one of the most common adverse chemotherapy side effects in cancer patients. The ability of ozonized oil to prevent or attenuate this side effect was thus evaluated. Two cancer patients undergoing chemotherapy were observed and evaluated in relation to their trichological situation, with particular reference to the state of hair growth and trophism of the hair bulb. In the first patient, the chemotherapy treatment induced nearly total alopecia after the first chemotherapy treatment. In the second patient a marked hypotrichosis with partial alopecia was observed (photos on the left in Figure 4). Therefore, during the subsequent chemotherapy cycle, in addition to the chemotherapeutic treatment, ozonized oil was orally co-administered in the same manner as described in example 2. This administration significantly attenuated the chemotherapy-induced alopecia. In fact, both in the first patient and in the second one a nearly total maintenance of hair density was observed, in the absence of hypotrichosis or alopecia (photos on the right in Figure 4). This protective effect is likely to be attributable to the cytoprotection exerted by the ozonized oil at the level of the cells of the hair bulb and the increased availability of oxygen for their metabolism in this site.

[0078] EXAMPLE 4

[0079] Prevention of chemotherapy-induced chronic fatigue syndrome Chemotherapy-induced chronic fatigue syndrome is one of the major side effects that worsen the quality of life of a cancer patient. This syndrome further manifests itself in a significant worsening in mood, with the induction of states of anxiety and depression. We therefore evaluated whether the cytoprotective mechanisms activated in skeletal muscle by the administration of ozonized oil were capable of preventing fatigue induced by chemotherapy treatment in women with breast cancer. For this purpose, subjects undergoing treatment with chemotherapy or following chemotherapy treatment were made to follow a programme based on low-intensity physical activity engaged in twice a week combined with the administration of ozonized oil for two months twice daily, in the morning and evening. The ozonized oil was administered in the same manner as defined in example 2.

[0080] Data relating to the subjective state of mental and physical well-being of 50 subjects were then collected by means of the well-known SF 36 questionnaire (Ware JE Jr, Sherbourne CD. "The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection”. Med Care. 1992 Jun;30(6):473-83. PMID: 1593914). The results obtained are shown in Table 1 below:

[0081] Table 1 . APA = adapted physical activity; HOC = ozonized oil. The values in brackets indicate the projected percentage values at 6 months.

[0082] The left column (APA) shows the effect of physical activity alone on this type of patient according to what is reported in the scientific literature (Paulo TRS, Rossi FE, Viezel J, Tosello GT, Seidinger SC, Simbes RR, de Freitas R Jr, Freitas IF Jr., "The impact of an exercise program on quality of life in older breast cancer survivors undergoing aromatase inhibitor therapy: a randomized controlled trial”. Health Qual Life Outcomes. 2019 Jan 18;17(1):17. doi: 10.1186 / s12955-019-1090-4. PMID: 30658629; PMCID: PMC6339353). The right column shows by way of comparison the effect on the analysed parameters of physical activity (APA) combined with the administration of ozonized oil (HOC) as carried out in our assessment. It may be noted that the treatment with ozonized oil significantly improves the state of mental and physical well-being of a cancer patient previously undergoing chemotherapy. In particular, an increase in the quality of the items relating to physical health and emotional state was observed, with increases up to 8-10 times greater than was obtained in the absence of the treatment with ozonized oil. These results demonstrate that orally administered ozonized is a useful aid for the prevention of chemotherapy-induced fatigue.

[0083] Conclusions

[0084] In conclusion, the pre-clinical and clinical evaluations carried out indicate that oral treatment with ozonized oil represents an innovative tool for attenuating and preventing chemotherapy side effects in cancer patients. This treatment has been demonstrated to be capable of significantly improving the quality of life of these persons.

Claims

CLAIMS1 . A formulation comprising at least one ozonized oil for use in a method for the prevention and / or reduction and / or treatment of one or more side effects due to an anti-tumour chemotherapy and / or radiotherapy, wherein said one or more side effects are selected from the group comprising or, alternatively, consisting of: haematopoietic bone marrow suppression, alopecia and chemotherapy-induced chronic fatigue syndrome.

2. The formulation for use according to claim 1 , wherein said formulation comprising at least one ozonized oil is for use in a method for the prevention and / or reduction and / or treatment of the haematopoietic bone marrow suppression due to an anti-tumour chemotherapy and / or radiotherapy.

3. The formulation for use according to claim 1 , wherein said formulation comprising at least one ozonized oil is for use for the prevention and / or reduction and / or treatment of anaemia and / or leukopenia and / or thrombocytopenia due to anti-tumour chemotherapy and / or radiotherapy.

4. The formulation for use according to any one of claims 1-3, wherein said formulation is administered to an individual having a tumor, wherein said individual is or has been under treatment with anti-tumour chemotherapy and / or radiotherapy.

5. The formulation for use according to any one of the preceding claims, wherein said anti-tumour chemotherapy comprises the administration of one or more anti-tumour drugs selected from the group comprising or, alternatively, consisting of 5-fluorouracil, temozolomide, cisplatin, nitrosoureas, alkylating agents, antimetabolites, taxanes, biologic drugs, angiogenesis inhibitors and PD1 (programmed cell death protein 1) inhibitors.

6. The formulation for use according to any one of the preceding claims, wherein said formulation is administered before or concurrently with or following said anti-tumour chemotherapy or radiotherapy preferably, it is administered concurrently with the administration of chemotherapy.

7. The formulation for use according to any one of the preceding claims, wherein said ozonized oil is administered orally.

8. The formulation for use according to any one of the preceding claims, wherein said ozonized oil has a content of ozonides from 500 to 1500 meq 02 / kg, preferably from 600 to 1400 meq 02 / kg, more preferably from 700 to 1300 meq 02 / kg, even more preferably from 1100 to 1300 meq 02 / kg, most preferably 1200 meq 02 / kg.

9. The formulation for use according to any one of the preceding claims, wherein said at least one ozonized oil is selected from: at least one vegetable oil that has undergone an ozonation process; at least one unsaturated fatty acid that has undergone an ozonation process; at least one monoester of an unsaturated fatty acid that has undergone an ozonation process; and mixtures thereof; preferably at least one vegetable oil that has undergone an ozonation process.

10. the formulation for use according to claim 9, wherein said at least one vegetable oil that has undergone an ozonation process is selected from: sunflower oil, peanut oil, argan oil, olive oil, grapeseed oil, jojoba oil, soybean oil, maize oil, palm oil, cottonseed oil, rapeseed oil, coconut oil, castor oil, linseed oil, borage oil, evening primrose oil, and mixtures thereof; preferably sunflower oil, peanut oil, argan oil, grapeseed oil, jojoba oil, soybean oil, maizeoil, palm oil, cottonseed oil, rapeseed oil, coconut oil, castor oil, linseed oil, borage oil, evening primrose oil, and mixtures thereof; more preferably sunflower oil and / or peanut oil, most preferably sunflower oil.11 . The formulation for use according to claim 9 wherein said at least one ozonized oil is an unsaturated fatty acid that has undergone an ozonation process, wherein said unsaturated fatty acid is selected from oleic acid and linoleic acid or combinations thereof.

12. The formulation for use according to any one of the preceding claims, wherein said at least one ozonized oil is in the form of ozonized oil as such or in a formulation for oral administration comprising said at least one ozonized oil and at least one pharmaceutically acceptable excipient.

13. The formulation for use according to claim 12, wherein said formulation for oral administration is in a form selected from oil, syrup, a tablet and a capsule, preferably a capsule, even more preferably a gastro-resistant capsule.

14. The formulation for use according to claim 13, wherein said capsule contains from 200 to 700 mg, more preferably from 250 to 600 mg, even more preferably from 350 to 500 mg, most preferably 350 mg, of ozonized oil.

15. The formulation for use according to any one of the preceding claims, wherein a quantity of ozonized oil from 3000 to 6000 mg per day per 70 kg of body weight is administered, more preferably from 3500 to 5300 mg per day per 70 kg of body weight, even more preferably from 4000 to 5000 mg per day per 70 kg of body weight.

16. The formulation for use according to any one of the preceding claims, wherein the administration of the ozonized oil is carried out once or twice or three times a day, and / or wherein the administration of the ozonized oil is carried out for a period of at least one month, preferably from one month to 3 years, more preferably from 2 months to 14 months, most preferably from 5 months to 12 months.

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