Granular formulation comprising ozonated oil, method for its preparation, pharmaceutical forms comprising said granular formulation and their uses

Abstract

The present invention relates to a granular formulation comprising at least one ozonated oil; at least one absorbing agent chosen from silicon dioxide, silica gel and mixtures thereof; at least one calcium phosphate; and at least one lubricating agent. The present invention also relates to a method for the preparation of the granular formulation of the invention. The present invention also relates to a pharmaceutical form for oral use comprising the granular formulation of the invention and its uses in the treatment of a tumour or leishmaniasis.

Description

[0001] GRANULAR FORMULATION COMPRIS ING OZONATED OIL, METHOD FOR

[0002] ITS PREPARATION, PHARMACEUTICAL FORMS COMPRIS ING SAID

[0003] GRANULAR FORMULATION AND THEIR USES

[0004] Field of application

[0005] The present invention relates to a granular formulation comprising ozonated oil and method for its preparation .

[0006] Furthermore , the present invention relates to pharmaceutical forms comprising said granular formulation, in particular gastro-resis tant pharmaceutical forms , e . g . gastro-resistant capsules , and their uses .

[0007] Prior art

[0008] Ozonated oils are oils whose molecule contains unsaturated fatty acids that have undergone the action of ozone . Ozone is added to carbon-carbon double bonds , forming molozonides . These molecules quickly rearrange themselves according to the Criegee mechanism to give trioxolans .

[0009] Ozonated oils have shown a high versatility of use in both the medical field and cosmetic field .

[0010] In the cosmetic field, o zonated oils are used, for example , to prevent skin ageing and to eliminate skin imperfections such as hyperpigmentation .

[0011] In the medical field, o zonated oils can be used for their known antimicrobial , immunological antiinflammatory and oxido-reductive balancing properties .

[0012] It has also been proven that ozonated oi l , particularly when it has a high ozonide content, is effective in treating various tumours. In this regard, reference is made to international patent application WO 2020 / 070623 Al, which discloses a formulation comprising ozonated oil in the prevention and / or treatment of a tumour for oral, topical and / or injection administration .

[0013] Ozonated oil is also effective in the treatment of leishmaniasis, as described in international patent application WO 2021 / 205303 Al, which discloses a formulation comprising ozonated oil in the prevention and / or treatment of leishmaniasis in a mammal for oral, topical and / or injection administration.

[0014] Referring in particular to the oral administration of ozonated oil, it has been observed that there are some drawbacks. Ozonated oil is in fact difficult to digest when taken orally in liquid form. This poor digestibility is due to the interaction of the ozonated oil with the gastric juices in the stomach, which operate an oxido-reductive neutralisation; and with the bile acids in the duodenum, through the emulsifying activity of the latter, with the formation of micelles. Both of these mechanisms lead to a decrease in the bioavailability of the oil.

[0015] Furthermore, side effects such as nausea, vomiting and intestinal meteorism are observed due to the intolerance of the intestinal mucosa to alkaline oxidising substances such as ozonated oil.

[0016] As mentioned above, a high ozonide content may be associated with certain therapeutic effects. However, the progressive formation o f ozonides in the oil increases the viscosity of the oil until it reaches a j elly-like consistency . Peroxides present in the oil also tend to hydrolyse , giving rise to aldehydes and ketones with a shorter chain than the original fatty acid, resulting in unpleasant odours .

[0017] Therefore , a high o zonide content in an ozonated oil is inevitably associated with an oil consistency and flavour that is particularly unpleasant for the user and therefore leads to a compliance problem .

[0018] In view of the above, the need is felt in the field to make available ozonated oil , even with a high ozonide content , in a form that does not give rise to s ide ef fects ( such as nausea and vomiting) , that is better assimilated than the liquid form, and that is pleasant and convenient to use .

[0019] The technical problem underlying the present invention is thus to make available a formulation comprising ozonated oil and a pharmaceutical form comprising ozonated oil that overcomes the aforementioned drawbacks of the prior art .

[0020] Summary of the invention

[0021] This problem has been solved according to the invention by a granular formulation comprising at least one ozonated oil ; at least one absorbing agent chosen from silicon dioxide , silica gel and mixtures thereof ; at least one calcium phosphate ; and at least one lubricating agent .

[0022] Preferably, the at least one ozonated oil is present in a quantity, in weight percentage based on the weight of the granular formulation, from 5 to 40%, more preferably from 10 to 30%, even more preferably from 15 to 20%. In some embodiments, this percentage is between 30 and 40%, in particular between 35 and 40%.

[0023] Preferably, the at least one ozonated oil has a content of ozonides from 500 to 1500 meg Cb / kg, more preferably from 900 to 1400 meq Cb / kg, even more preferably from 1100 to 1300 meq Cb / kg.

[0024] The content of ozonides can be measured according to techniques known in the field, for example by the method for determining the number of peroxides described in the Regulation (EEC) No. 2568 / 91 of 11 July 1991 concerning the characteristics of olive oils and olivepomace oils and their related methods, Annex III.

[0025] According to the present invention and appended claims, the term "ozonated oil" means: a vegetable oil that has undergone an ozonising process; an unsaturated fatty acid, preferably having a number of carbon atoms from 8 to 30, more preferably from 16 to 20, that has undergone an ozonising 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 may be a monoester, diester or triester, with an alcohol or a polyol, in particular glycerol, that has undergone an ozonising process; or mixtures thereof.

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

[0027] Preferably, at least one vegetable oil that has undergone an ozonising process is chosen from: peanut oil, sunflower oil, argan oil, olive oil, grapeseed oil, jojoba oil, soybean oil, corn oil, palm oil, cottonseed oil, rapeseed oil, coconut oil, castor oil, linseed oil, borage oil, evening primrose oil, and mixtures thereof, preferably peanut oil, sunflower oil, argan oil, grapeseed oil, jojoba oil, soybean oil, corn 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 and / or peanut oil.

[0028] Preferably the at least one unsaturated fatty acid that has undergone an ozonising process has a number of carbon atoms from 8 to 30, more preferably from 16 to 20, even more preferably of 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 (i.e. has only one double bond in the carbon chain) or diunsaturated (i.e. 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 said fatty acid is obtained by esteri fication of said unsaturated fatty acid as described above , the monoester having undergone an ozonising process .

[0033] Preferably, the at least one monoester is obtained by esteri fication of said unsaturated fatty acid with a primary aliphatic alcohol having only one -OH group (monovalent ) , more preferably ethanol .

[0034] Preferably, the at least one monoester is ethyl oleate .

[0035] Preferably, the at least one ozonated oil is substantially free of antioxidant agents .

[0036] Preferably, the at least one ozonated oil is obtained through an ozonising process which uses highly puri fied gaseous oxygen for the introduction of oxygen .

[0037] Preferably, the at least one absorbing agent i s silicon dioxide .

[0038] Silicon dioxide can be obtained by synthesis or by processing materials of natural origin . Among the synthetic silicas , particularly preferred forms are fumed silicas or precipitated silicas .

[0039] Preferably, silicon dioxide is in powder form .

[0040] Preferably, silicon dioxide has a density from 100 to 150 kg / m3, more preferably from 110 to 130 kg / m3, even more preferably from 115 to 125 kg / m3.

[0041] Preferably, silicon dioxide is precipitated silica in powder form, such as the commercial product Perkasil® SM 660 , distributed by Grace Materials Technology (USA) .

[0042] Preferably, the at least one calcium phosphate i s chosen from dihydrate dibasic calcium phosphate , anhydrous dibasic calcium phosphate , dihydrate calcium sulphate, hydroxyapatite and mixtures thereof, more preferably dihydrate dibasic calcium phosphate.

[0043] Preferably, the at least one calcium phosphate is in granular form.

[0044] In a preferred embodiment, said calcium phosphate is anhydrous dibasic calcium phosphate or anhydrous calcium hydrogen phosphate, preferably in granular form. In an embodiment, said anhydrous dibasic calcium phosphate in granular form is composed of granules with an average size of between 120 and 130 pm, typically about 120 pm; typically the granules have a spherical shape. Preferably, said anhydrous dibasic calcium phosphate has an oil absorption capacity between 1.0 and 1.2 ml / g, typically about 1.1 ml / g. An example of said anhydrous dibasic calcium phosphate is commercially available under the name Fujicalin® (Fuji Chemical Industries Co., Ltd, Japan) and has the following characteristics :

[0045] Carr value calculated by adding relevant index points (Carr, R. L., Chem. Eng., 1965; 72 (3) , 163-168) .

[0046] It has in fact been observed that, compared to the use of the absorbing agent alone, the combination of the absorbing agent according to the invention with calcium phosphate has the advantageous effect of resulting in a denser, and thus less voluminous, formulation. In addition, said combination improves the absorption of ozonated oil. The formulation is therefore relatively rich in ozonated oil, i.e. in the active ingredient, relative to the volume, with obvious advantages in the production of high-content active ingredient capsules, for example. In particular, the use of anhydrous dibasic calcium phosphate as described above allows to produce capsules containing high quantities of ozonated oil.

[0047] Preferably, the granular formulation has a weight ratio between the at least one ozonated oil and the sum of the at least one absorbing agent and the at least one calcium phosphate from 1:2 to 1:7, more preferably from 1:3 to 1:6, even more preferably from 1:4 to 1:5.

[0048] Preferably, the granular formulation has a weight ratio between the at least one absorbing agent and the at least one calcium phosphate from 1:1 to 1:6, more preferably from 1:2 to 1:5, even more preferably from 1:2.5 to 1:4. Preferably, the at least one absorbing agent is characterised by a specific surface area (BET) from 50 to 1000 m2 / g, preferably from 100 to 500 m2 / g, even more preferably from 150 to 300 m2 / g.

[0049] The specific surface area (BET) can be determined according to methods known in the field, e.g. according to the ISO 9277-2010.

[0050] Preferably, the at least one absorbing agent is characterised by an average particle diameter (size (MT50) ) from 2 to 100 pm, more preferably from 5 to 50 pm, even more preferably from 10 to 25 pm.

[0051] In the context of the present description and the attached claims, "average particle diameter" refers to, unless otherwise indicated, the diameter d50 (median value) , i.e. the value of the diameter below which there is 50% by weight of the particle population (see "A Guidebook to Particle Size Analysis" published by Horiba Instruments Inc. - 2016, available on eMag / PSA / Guidebook / pdf / PSA_Guidebook . pdf ) . It can be determined through a laser diffraction technique, according to ISO 13320:2009.

[0052] Preferably, the at least one calcium phosphate has a tapped density value as measured by Method 2 described in "European Pharmacopoeia 7.0 - 2.9.34" from 0.40 to 0.90 g / ml, more preferably from 0.50 to 0.85 g / ml, even more preferably from 0.75 to 0.85 g / ml, even more preferably from 0.80 to 0.83 g / ml. For example, the tapped density can be about 0.54 g / ml or about 0.85 g / ml.

[0053] Preferably, the at least one calcium phosphate has a particle size distribution such that: particles with a particle size greater than or equal to 500 pm are equal to or less than 0.50% by weight; particles with a particle size greater than or equal to 150 pm are equal to or greater than 60% by weight; particles with a particle size greater than or equal to 75 pm are equal to or greater than 90% by weight; particles with a particle size greater than or equal to 53 pm are equal to or greater than 98% by weight.

[0054] The particle size distribution can be determined according to methods known in the field, e.g. by means of a screen, e.g. a vibrating screen.

[0055] Preferably, the at least one lubricating agent is chosen from magnesium stearate, calcium stearate, stearic acid, zinc stearate and mixtures thereof, more preferably magnesium stearate.

[0056] Preferably magnesium stearate is of vegetable origin .

[0057] Preferably, the at least one lubricating agent is distributed on the surface of the granules of the formulation .

[0058] The at least one lubricating agent is preferably present in a quantity in weight percentage based on the weight of the formulation from 0.5 to 9%, more preferably from 1 to 6 %, even more preferably from 2 to 5%.

[0059] Preferably, the granular formulation also comprises at least one additional active ingredient, more preferably chosen from at least one vitamin, at least one mineral and mixtures thereof.

[0060] Preferably, said at least one vitamin is chosen from vitamins of group B, more preferably from B5, B6 and B9 and mixtures thereof; vitamins of group K, more preferably from K2, K3 and mixtures thereof; vitamins from group D, more preferably D3; and mixtures thereof.

[0061] Preferably, the at least one mineral is chosen from zinc, magnesium, iron, calcium and phosphorus, more preferably zinc.

[0062] Preferably, the at least one mineral is in salt form, e.g. gluconate.

[0063] Preferably, the at least one mineral is zinc gluconate .

[0064] The at least one additional active ingredient is preferably present in a quantity in weight percentage based on the weight of the formulation from 0.001 to 10%, more preferably from 0.0015 to 7%, even more preferably from 0.002 to 5%.

[0065] Preferably, the at least one additional active ingredient is distributed over the surface of the granules of the formulation.

[0066] The granular formulation according to the invention may further comprise one or more additional excipients chosen from, for example, sweeteners, flavourings, preservatives, colouring agents and mixtures thereof. Said one or more further excipients are preferably present in a quantity in weight percentage based on the weight of the formulation from 0.05 to 10 %, more preferably from 0.1 to 7 %, even more preferably from 0.2 to 5 % .

[0067] Preferably, the granular formulation has a granule size from 100 to 5000 pm, more preferably from 1500 to 2500 pm, even more preferably from 1800 to 2200 pm.

[0068] Granule size can be determined according to methods known in the field, e.g. by means of a screen, e.g. a vibrating screen.

[0069] In fact, the Applicant has found that by using a specific combination of ingredients, in particular by using at least one absorbing agent according to the present invention in combination with at least one calcium phosphate, it is possible to obtain a formulation that is particularly adapted to be used in the preparation of pharmaceutical forms, more particularly gastro-resistant forms (e.g. a capsule) , so that the formulation is released with sufficient delay, with respect to ingestion, to avoid the drawbacks of the prior art. The lubricating agent performs the function of improving granule sliding. This effect favours workability e.g. during encapsulation.

[0070] Unlike ozonated oil in liquid form, which would degrade the pharmaceutical form, e.g. a gastro-resistant capsule, the formulation according to the present invention is stable, non-reactive, and thus adapted to be incorporated into a pharmaceutical form, e.g. a gastro-resistant capsule.

[0071] The pharmaceutical form, e.g. gastro-resistant, comprising the ozonated oil in a formulation according to the invention significantly increases compliance, ensures optimal absorption of the active ingredient in the intestine and avoids side effects related to the interaction of gastric juices and bile acids with the oil . In another aspect, the present invention relates to a method for the preparation of a granular formulation comprising at least one ozonated oil; at least one absorbing agent chosen from silicon dioxide, silica gel and mixtures thereof; at least one calcium phosphate; and at least one lubricating agent, comprising the following steps: a) mixing said at least one absorbing agent, said at least one calcium phosphate and said at least one ozonated oil, resulting in a mixture; b) sifting said mixture obtained in step a) , obtaining a granular formulation; and c) dry-mixing said granular formulation obtained in step b) with said at least one lubricating agent.

[0072] The term "dry mixing" means that there is no addition of liquids during mixing.

[0073] Preferably the mixing step a) is carried out over a period of time longer than 15 minutes, more preferably from 20 to 60 minutes, even more preferably from 30 to 50 minutes, even more preferably from 35 to 45 minutes, most preferably 40 minutes.

[0074] In a particularly preferred embodiment, the device used to carry out step a) is a four-way mixer.

[0075] Preferably, the mixing speed is from 30 to 60 revolutions per minute (rpm) , more preferably from 35 to 50 revolutions per minute, even more preferably from 40 to 45 revolutions per minute.

[0076] Preferably, in step a) , the at least one oil is added to the at least one absorbing agent and to the at least one calcium phosphate, preferably to a mixture thereof .

[0077] Preferably, in step a ) , the at least one oil is slowly added to the at least one absorbing agent and to the at least one calcium phosphate during mixing, more preferably continuously .

[0078] Preferably, step a ) is performed until at least one ozonated oil is completely absorbed .

[0079] Preferably, the mixture obtained in step a ) is le ft to rest for a time from 6 hours to 4 days , more preferably from 10 hours to 48 hours , even more preferably from 20 hours to 30 hours .

[0080] Preferably, step b ) is carried out using a vibrating screen, whose screen has a mesh, more preferably a square mesh, having a side dimension from 500 to 5000 pm, more preferably from 1500 to 2500 pm, even more preferably from 1800 to 2200 pm .

[0081] Preferably, the dry mixing step c ) of the granular formulation comprises at least one additional active ingredient .

[0082] Preferably, step c ) i s carried out in a biconical mixer .

[0083] Preferably, in step c ) the granular formulation obtained in step b) i s added to the at least one lubricating agent or to a mixture of the at least one lubricating agent and the at least one additional active ingredient .

[0084] Step c ) is preferably carried out for a time from 20 to 60 minutes , even more preferably from 25 to 50 minutes , even more preferably from 30 to 40 minutes .

[0085] Preferably, in step c ) the mixing speed is from 5 to 40 revolutions per minute , more preferably from 10 to 30 revolutions per minute , even more preferably from 15 to 25 revolutions per minute .

[0086] Any additional active ingredients in liquid form, preferably lipophilic active ingredients , can be added during mixing step a ) .

[0087] The granular formulation thus obtained can be submitted to further processes aimed at producing a pharmaceutical form, preferably gastro-resistant , that comprises said granular formulation .

[0088] For instance , the granular formulation can be encapsulated in a capsule , or it can be compressed in order to obtain a tablet .

[0089] In particular, the granular formulation, the ozonated oil , the absorbing agent , the calcium phosphate and the lubricating agent are as defined above . For example , calcium phosphate is preferably anhydrous dibasic calcium phosphate in granular form, particularly as described above .

[0090] According to a further aspect , the present invention relates to a pharmaceutical form, preferably a gastro-resistant pharmaceutical form for oral use comprising the granular formulation of the present invention, more preferably a capsule or tablet , even more preferably a capsule .

[0091] Examples of pharmaceutical forms suitable for the invention are soft gel capsule , ( soft or hard) gastro- resistant capsule and gastro-resistant tablet .

[0092] According to a further aspect , the present invention relates to a pharmaceutical form, preferably a gastro-resistant pharmaceutical form, for oral use comprising the formulation of the present invention for use in the treatment of a tumour.

[0093] Preferably, said tumour is a malignant tumour, more preferably chosen from a solid tumour (e.g. prostate, liver, lung, breast, colorectal, pancreas, encephalic) , a skin tumour, a mucous membrane tumour (e.g. mouth, nose, anus, vulva or vagina) and a liquid tumour (e.g. a haematopoietic tumour) .

[0094] According to a further aspect, the present invention relates to a pharmaceutical form, preferably a gastro-resistant pharmaceutical form, for oral use comprising the formulation of the present invention for use in the treatment of leishmaniasis in a mammal.

[0095] Preferably, said leishmaniasis is caused by one or more of Leishmania infantum, Leishmania donovani, tropica, Leishmania braziliensis , Leishmania chagasi, Leishmania mexicana , Leishmania amazonensis , Leishmania venezuelensis , major, Leishmania guyanensis , Leishmania panamensis , Leishmania peruviana , more preferably Leishmania donovani, Leishmania donovani, Leishmania tropica , Leishmania braziliensis, even more preferably Leishmania infantum.

[0096] The gastro-resistant capsule can be produced according to known techniques, e.g. using one or more of: hydroxypropyl methyl cellulose (HPMC) , gellan gum, and pectin.

[0097] Preferably, the gastro-resistant capsule also comprises a dye agent.

[0098] Preferably the dye is an iron oxide or iron hydroxide .

[0099] Preferably, the gastro-resistant capsule comprises gellan gum in a quantity, in weight percentage based on the weight of the capsule , from 2 to 8 % , more preferably from 4 to 6% , even more preferably about 5% .

[0100] Preferably, the gastro-resistant capsule is a hard capsule .

[0101] As mentioned above , the ozonated oil has been shown to be ef fective in the treatment of a tumour and leishmaniasis . By combining the granular formulation o f the invention with a pharmaceutical form, preferably a gastro-resistant one , an even more ef fective ozonated oil can be made available for this purpose .

[0102] The following examples are provided by way o f example and not limitation of the present invention . Examples

[0103] Example 1 : Pharmaceutical forms comprising granular formulations with ozonated oil

[0104] Various granular formulations comprising ozonated vegetable oil according to the present invention in the pharmaceutical form of a gastro-resistant capsule are reported below .

[0105] Table 1 : Gastro-resistant capsule with Granular formulation 1

[0106]

[0107] Table 2 : Gastro-resistant capsule with Granular formulation 2

[0108] Table 3 : Gastro-resistant capsule with Granular formulation 3 Table 4 : Gastro-resistant capsule with Granular formulation 4

[0109]

[0110] Table 5 : Gastro-resistant capsule with Granular formulation 5 Example 2 : Preparation of the pharmaceutical forms listed in Example 1 .

[0111] After the raw materials were weighed, the dihydrate dibasic calcium phosphate and precipitated silica were mixed in a four-way mixer manufactured by Tecnomaco Italia S . r . l . , with the model name 4-way Mixer, while the ozonated sunflower oil was added to them by being poured in slowly throughout the mixing process . The mixing was performed at a speed of 42 rpm for a duration of 40 minutes and, once ended, the oil had been perfectly absorbed .

[0112] The resulting mixture was left to rest for 24 hours and was then si fted through a vibrating screen manufactured by VibroWest Italians S . r . l . , Solaro (MI ) , Italy) having a screen whose square mesh has a si ze o f 2000 pm, resulting in a granular formulation compri sing ozonated oil .

[0113] Separately, the vitamins / minerals were mixed with magnesium stearate in a biconical mixer for 5 minutes and then the si fted formulation was added . This second mixing step was carried out for 35 minutes at a speed of 20 rpm .

[0114] The resulting formulation was encapsulated in gastro-resistant capsules according to methods well known in the field, and then the capsules were packaged in blister packs and boxes .

Claims

CLAIMS1. Granular formulation comprising at least one ozonated oil; at least one absorbing agent selected from silicon dioxide, silica gel and mixtures thereof; at least one calcium phosphate; and at least one lubricating agent .

2. Granular formulation according to claim 1, wherein said at least one ozonated oil is present in a quantity, in weight percentage based on the weight of the granular formulation, from 5 to 40%, preferably from 10 to 30%, more preferably from 15 to 20% or from 30 to 40% .

3. Granular formulation according to claim 1 or 2, wherein said at least one ozonated oil has a content of ozonides from 500 to 1500 meq Ch / kg, preferably from 900 to 1400 meq Ch / kg, more preferably from 1100 to 1300 meq O2 / kg.

4. Granular formulation according to any one of the previous claims, wherein said at least one ozonated oil is selected from: at least one vegetable oil that has undergone an ozonising process; at least one unsaturated fatty acid that has undergone an ozonising process; at least one monoester of an unsaturated fatty acid, that has undergone an ozonising process; and mixtures thereof; preferably at least one vegetable oil that has undergone an ozonising process.

5. Granular formulation according to claim 4, wherein said vegetable oil that has undergone an ozonising process is selected from: peanut oil, sunflower oil, argan oil, olive oil, grapeseed oil,jojoba oil, soybean oil, corn oil, palm oil, cottonseed oil, rapeseed oil, coconut oil, castor oil, linseed oil, borage oil, evening primrose oil, and mixtures thereof, preferably peanut oil, sunflower oil, argan oil, grapeseed oil, jojoba oil, soybean oil, corn 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 and / or peanut oil.

6. Granular formulation according to claim 4 wherein said at least one ozonated oil is an unsaturated fatty acid that has undergone an ozonising process, wherein said unsaturated fatty acid is selected from oleic acid and linoleic acid or combinations thereof.

7. Granular formulation according to any one of the previous claims, wherein said at least one absorbing agent is silicon dioxide, preferably precipitated silica, more preferably in powder form.

8. Granular formulation according to any one of the previous claims, wherein said at least one calcium phosphate is chosen from dihydrate dibasic calcium phosphate, anhydrous dibasic calcium phosphate, dihydrate calcium sulphate, hydroxyapatite and mixtures thereof, preferably dihydrate dibasic calcium phosphate.

9. Granular formulation according to claim 8, wherein said calcium phosphate is anhydrous dibasic calcium phosphate in granular form.

10. Granular formulation according to claim 9 wherein said anhydrous dibasic calcium phosphate in granular form comprises granules having an average sizefrom 120 to 130 pm, preferably about 120 pm, and / or having a capacity of absorbing said ozonated oil from 1.0 to 1.2 ml / g, typically about 1.1 ml / g.

11. Granular formulation according to any one of the previous claims, wherein said at least one lubricating agent is chosen from magnesium stearate, calcium stearate, stearic acid, zinc stearate and mixtures thereof, preferably magnesium stearate.

12. Granular formulation according to any one of the previous claims, having a granule size from 100 to 5000 pm, preferably from 1500 to 2500 pm, more preferably from 1800 to 2200 pm.

13. Method for the preparation of a granular formulation comprising at least one ozonated oil; at least one absorbing agent chosen from silicon dioxide, silica gel and mixtures thereof; at least one calcium phosphate; and at least one lubricating agent, preferably as defined in claims 2-12, comprising the following steps: a) mixing said at least one absorbing agent, said at least one calcium phosphate and said at least one ozonated oil, resulting in a mixture; b) sifting said mixture obtained in step a) obtaining a granular formulation; and c) dry-mixing said granular formulation obtained in step b) with said at least one lubricating agent.

14. Method according to claim 13, wherein said mixture obtained in step a) is left to rest for a time from 6 hours to 4 days, preferably from 10 hours to 48 hours, more preferably from 20 hours to 30 hours.15 . Method according to claim 13 or 14 , wherein step b ) is carried out using a vibrating screen, whose screen has a mesh, preferably a square mesh, having a side si ze from 500 to 5000 pm, pre ferably from 1500 to 2500 pm, more preferably from 1800 to 2200 pm .16 . Pharmaceutical form, preferably gastro- resistant pharmaceutical form, for oral use comprising the granular formulation according to any one of claims 1 to 12 , more preferably a capsule or a tablet , even more preferably a capsule .17 . Pharmaceutical form according to claim 16 for use in the treatment of a tumour, preferably a malignant tumour, more preferably chosen from a solid tumour, a cutaneous tumour, a mucosal tumour and a liquid tumour . 18 . Pharmaceutical form according to claim 16 for use in the treatment of leishmaniasis in a mammal .

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