Technical Field of the Invention

In general terms, the present invention concerns a new use of non-saponifiable fractions obtained from lipids of natural origin, both vegetable and animal, for the therapeutic treatment of imbalance, i.e. chronic permanent change, of the steroidal balance outside of the natural physiological equilibrium of its components in a patient suffering from this chronic pathological condition.

Specifically, the invention refers to the aforementioned fractions of non-saponifiable compounds for use in the treatment of permanent chronic pathological change of the steroidal balance in a person suffering from said pathological condition (and, consequently, also in the treatment of those chronic, relapsing or progressive pathologies, i.e. which are not cured apart from symptomatically and for relatively short time periods with known drugs, which are caused by it), inducing the re-balancing of the components within the natural physiological levels.

In particular, the invention also refers to a pharmaceutical composition of said non- saponifiable compounds for use in the treatment of permanent chronic pathological change of the steroidal balance in a person suffering from said pathological condition (and, consequently, also in the treatment of those chronic, relapsing or progressive pathologies, i.e. which are not cured apart from symptomatically and for relatively short time periods with known drugs, which are caused by it), inducing the re-balancing of the components within the natural physiological levels. Said pharmaceutical composition is particularly suitable for transdermal and/or transmucosal adminstration.

State of the art

Introduction - Definitions

1. Lipids

Lipids, or fats, are organic compounds found widely in nature and they represent one of the main classes of natural organic compounds of biological interest.

It is known that a lipid of natural origin, both vegetable and animal, whether in the form of fat, oil or wax, consists of a complex mixture of compounds not always clearly identified. Generally speaking, a lipid comprises mostly saponifiable esters (mainly triglycerides of fatty acids) and in smaller dose (variable from lipid to lipid) non-glyceride substances, including mainly a fraction made up of non-saponifiable compounds.

Only as a non-limiting example, among lipids of animal origin richest in non-saponifiable substances (hereinafter, "non-saponifiable compounds") are: sheep sebum (lanoline); shark oil; egg oil; whale oil; cod-liver oil; ox- foot oil: horse mane oil; sea-animals fat; wool wax; and so on.

Only as a non-limiting example, among lipids of vegetable origin richest in non-saponifiable substances (hereinafter, "non-saponifiable compounds") are: shea-tree butter; carob germ oil; avocado oil; wheat germ oil; triticum vulgaris oil (common wheat); maize germ oil; soya oil; soya glycine oil; sesame oil; safflower oil; almond oil; rice oil; linseed oil; carrot oil; olive oil (olea europaea); peanut oil; hazelnut oil; walnut oil; coconut (cocos nucifera) oil; castor oil; sunflower oil; pumpkin-seed oil; rapeseed oil; raw cotton oil; palm butter; palm-kernel butter; cocoa butter; vegetable waxes; carnauba wax; bee wax; and so on.

Only as an example, the vegetable oils from which the non-saponifiable fraction is extracted are usually selected from: avocado oil, wheat germ oil, triticum vulgaris oil, soya oil, olive oil.

2. Non-saponifiable compounds

Among the aforementioned non-glyceride substances, in lipids of natural origin there are also esters of fatty acids with sterols and with aliphatic or triterpene fatty alcohols. In normal saponification conditions of lipids, these esters are also divided like all the other esters and the resulting sterolic and alcohol component, which is no longer saponifiable, forms part of the non-saponifiable fraction.

The whole of the substances not transformed into salts of fatty acids (obviously excluding glycerine) after the saponification of the lipid is defined as "total non-saponifiable substances" (and reference will be made to total non-saponifiable substances hereinafter in the present document).

The whole of the substances not transformed into salts of fatty acids (also excluding glycerine) after saponification is defined as "total non-saponifiable substances".

3. Composition of non-saponifiable compounds

The composition of the non-saponifiable compounds changes, even substantially, from one lipid to another. In general, every lipid contains in its non-saponifiable fraction also more than thirty different substances.

In general and not for limiting purposes, among known non-saponifiable compounds, contained in the lipids of natural origin, are:

I) HYDROCARBONS; liquid or solid, like for example:

- Karitene (or Illipene), present in shea-tree butter or in Illipe,

- Laurane (or n-eicosane), present in Bryony oil, laurel oil, Parsley oil,

- Pristane (or tetramethylpentadecane), extracted from dogfish liver oil,

- Squalene (or hexamethyltetracosene), contained in human sebum, in shark, cod and herring liver oil and in some oils of vegetable origin (olive oil, rice husk oil, peanut oil, wheat germ oil, rapeseed oil and so on).

II) HYDROCARBON CAROTENOIDS; like, for example:

- α-, β-, γ-Carotene (the most common is β-carotene, present in palm oil, carrots, chestnut leaves, and so on),

- Lycopene (present in tomatoes, chili pepper, and so on).

III) OXYGENATED CAROTENOIDS (Xanthophylls);

- among the most common are Lutein, Zeaxanthin, Flavoxanthin, Capsorubin, Bixin, Azaphen.

IV) TOCOFEROLS α-, β-, γ-;

- they are particularly present in wheat germ oil, maize oil, carob oil, rice oil, soya oil, raw cotton oil, and in lard.

V) HIGHER FATTY ALCOHOLS; like for example:

- saturated alcohols from C12 to C26 and unsaturated alcohols from Ci6 to C20, like, for example,

a) saturated: for example, lauryl, myristic, cetyl, stearyl, aralkyl, carnauba, ceryl alcohols, b) unsaturated: for example, n-hexadecane, oleyl, n-eicosene, n-eicosanediene alcohols.

VI) TERPENES AND TERPENE ALCOHOLS (TETRA AND PENTACYCLIC TRITERPENOIDS); like, for example:

- Ambrein, Lanosterol, Dihydrolanosterol, Agnosterol, Dihydroagnosterol, a-Amirin, β- Amirin, Butyrospermol, Cycloartenol, Lupeol, Basseol, Parkeol, Cyclobranolol, Gramisterol, Tirucallol, Citrastadienol, Geranylgeraniol, Eiythrodiol; Uvaol, Phytol, Citrastadienol.

VII) STEROIDS (STEROLS);

- Zoosterols; extracts from mammal lipids, like, for example, Cholesterol, Dehydrocholesterol, Δ-7-Cholesterol, Desmosterol, Cerebrosterol, Cholestanol, 7- Dehydrocholesterol, 7-Cholestanol, Bombyxsterol, Stellasterol, Clionasterol, Spongisterol, Coprosterol,

- Phytosterols; extracts from lipids of vegetable origin, like for example, Stigmasterol, β- Sitosterol, Brassicasterol, Campesterol, a-Spinasterol, Fucasterol, Sargosterol, 24- Methylene-cycloartenol, Gramisterol, 24-Methylcholest-7-enol, Isofucosterol, Δ-5- Avenasterol, Δ-7-Avenasterol, A-5-C24-Stigmastadienol, Clerosterol, Δ-7-Stigmastenol cholesterol, Δ-5-Avenastenol, A-5-C23-Stigmastadienol, Campestanol, Sitostanol, and so on.

4. Preparation of non-saponifiable compounds

The total non-saponifiable fractions are isolated from the starting lipid(s) by using technologies well known and commonly used in the field. As a non-limiting example, the non-saponifiable compounds are separated from the alkaline salts of fatty acids, after saponification of the starting lipids carried out in basic hydrolysis conditions commonly known and used in the field, through extraction with suitable solvents or, preferably, through molecular distillation.

The non-saponifiable compounds are, for example, used in cosmetics for their properties that promote good skin health.

5. Steroidal balance

From the in-depth studies carried out by the Applicant it was found that the ability of any cell of the organism to effectively carry out its particular functions and to communicate depends on the situation of the endocrine environment of the district in which the cell itself is located. Substantially, the Applicant, after long, intense studies and covering extensive criteria, found that the correct operation of the cells depends on maintaining an equilibrium between the opposite and simultaneous action of anabolic steroid hormones (with agonist action, or for growth development) and of catabolic steroid hormones (with antagonist, metabolic action, or causing deterioration).

When in the cell environment, i.e. in the district, there is an equilibrium (typical and variable depending on age and sex) between anabolic drive (due mainly to androgynous hormones, oestrogens, DHEA, and also other growth hormones like GH, thyroxine and so on), which stimulates protein synthesis and, therefore, the cell proliferation and functionality, and catabolic drive (due mainly to the metabolic action of glucocorticoids, for example, Cortisol), which, on the other hand, inhibits protein synthesis and induces atrophy, it is possible to speak of a condition of equilibrium of the so-called steroidal balance and, consequently, there is a condition of homeostasis in which there is full functional and proliferation metabolic efficiency of the cells, relative to age and sex.

In the present document, the term "steroidal balance", or "equilibrium of the steroidal balance", is meant to indicate/designate, therefore, the physiological ratio, by weight or in mols, at the district level between the hormones intended for anabolism and those intended for catabolism (substantially, at least the ratio between androgens/oestrogens/DHEA and Cortisol). In more general terms, the aforementioned equilibrium is essentially regulated by the hormones that have receptors in the nucleus.

The equilibrium of the steroidal balance is defined by a number of values, or ranges of values, physiologically variable with age and sex, of the basic concentrations, and thus regional, of the aforementioned hormones.

Only as a non-limiting example, as far as testosterone is concerned, usually, in a male, the basic values on average progress as follows:

- they slowly increase up to about 1 mg/die by ten years of age;

they rapidly increase between ten and twenty years of age (male adolescence) until 5- 7 mg/die is reached, remaining at this level up to about thirty years of age;

after thirty years of age, the production of testosterone decreases by about 2% per year until it reaches levels of 3-4 mg/die at the age of about eighty years old.

In turn, in a female, the levels of estradiol reduces from 70-100 pg/dL, reached at fertile age, to 20 pg/dL in female menopause.

As far as Cortisol is concerned, the average values in the blood can, for example, be:

comprised between 50 and 100 μg/L in a child less than about 10 years old;

comprised between 100 and 200 μg/L or between 250 and 550 nmols/L in an adult (at 08:00);

about 100 μg/L in an adult (at 20:00).

As far as DHEA&DHEAS values are concerned, they can on average vary in the following way:

DHEA

Age Male Female

6-24 months less than 2500 ng/L less than 1990 ng/L

2-3 years less than 630 ng/L less than 850 ng/L 4-5 years less than 950 ng/L less than 1030 ng/L

6-7 years 60-1930 ng/L less than 1790 ng/L

7-9 years 100-2080 ng/L 140-2350 ng/L

10-11 years 320-3080 ng/L 430-3780 ng/L

12-13 years 570-4100 ng/L 890-6210 ng/L

14-15 years 930-6040 ng/L 1220-7010 ng/L

16-17 years 1170-6520 ng/L 1420-9000 ng/L

18-40 years 1330-7780 ng/L 1330-7780 ng/L

DHEAS

Male

18-29 years: 89-457 mcg/dL

30-39 years: 65-334 mcg/dL

40-49 years: 48-244 mcg/dL

50-59 years: 35-179 mcg/dL

60 years or over: 25-131 mcg/dL

Female

18-29 years: 44-332 mcg/dL

30-39 years: 31-228 mcg/dL

40-49 years: 18-244 mcg/dL

50-59 years: < 15-200 mcg/dL

60 years or over: <15-157 mcg/dL

Said values/ranges (of physiological equilibrium) change, as exemplified above, in a natural and gradual manner (i.e. physiologically) depending on age and sex. In any case, when the aforementioned values of the basic concentrations of hormones remain within these ranges, there is full efficiency (metabolic, function and proliferation) of the cells, which is the necessary and sufficient condition so that a pathology does not occur and become chronic. When, on the other hand, values above or below these ranges are encountered, an unbalanced situation of endocrine dystrophism is created that is the primary condition for the occurrence of any pathology.

As already described above, the ranges compatible with the optimal state of health change with age in a practically continuous manner. However, big changes occur within these ranges. In particular, for example: 1) during puberty and post-puberty there is a movement towards the anabolic arm of the scale, as a consequence of greater secretion of anabolic hormones, until a new reference standard is obtained/reached (in other words the resultant of the anabolic and catabolic forces goes increasingly towards the anabolic quadrant making the androgenic and/or estrogenic concentration typical of the adult age of youth);

2) during ageing, with the passing of the years, the steroidal balance moves progressively towards the catabolic arm, as a consequence of the drop in production of oestrogens in women and androgens in men, in a very sudden manner in the first case (depletion and exhaustion of ovarian reserve and with it of oestrogen production of the gonads) and slower in the second. Also the suprarenal production of DHEA&DHEAS, after 40 years of age, undergoes a progressive decrease whereas there is a progressive increase in Cortisol secretion. Therefore, with the passing of time, the resultant of the anabolic and catabolic forces goes increasingly towards the catabolic quadrant. With chronological ageing, the range in which the resultant can fall without any change in homeostasis due to internal or external forces to the organism can determine the occurrence of a pathology, i.e. the range in which the organism and the districts are capable to react, becomes increasingly narrow until it almost disappears. The same conditions outside or inside the organism that previously were not capable of determining pathological scenarios able to be cured by the immune system can now cause the specific pathology or the different specific chronic pathologies that the elderly live with for a more or less long period (only as an example, sarcopenia, osteopenia with the reduction of muscle strength and the progressive increase in fatty mass, the progressive compromising of immunocompetence capacity, the deterioration of some behavioural functions as a consequence of neuro-modulation processes on the cerebral neurotransmitters, but also a series of chronic pathologies of an entirely different type, for example, cancerous).

In any case, irrespective of age, when for various causes (whether internal or external) there is a clear imbalance towards one of the two arms of the balance, outside of the physiologically natural range compatible with age, and this imbalance is prolonged in time, i.e. it becomes a chronic permanent change, then in the district hit by this chronic permanent change the pathology, organic or systemic, and, locally, the lesion occur. All of this occurs irrespective of the type of lesion (inflammatory, infective, neoplastic, vascular, cardiovascular). What type of lesion occurs depends on a series of factors, such as exposure, genetic predisposition and others, but the base cause is always chronic permanent change of the steroidal balance outside the physiologically natural range. When the period of time during which said change of the steroidal balance lasts becomes sufficiently long (becoming chronic), the pathology or pathologies occur, which in turn become(s) chronic, in particular in elderly subjects where it is easier for a substantially catabolic imbalance, i.e. destructive and no longer proliferative, to be present or form.

In this case, it is no longer possible to cure/resolve the pathology, because it is not possible to cure the basic pathological cause that causes it (i.e., chronic permanent change of the steroidal balance); at most, with conventional drugs, it is possible to treat the symptoms of the pathology, but usually only for more or less limited time periods.

On the other hand, by supplying the region suffering from the lesion caused by the chronic permanent change of steroidal balance in the district with a suitable drug, or a metabolic precursor, this, suitably metabolised according to the requirements of the region itself, would induce the rebalancing of the steroidal balance taking it back within the physiologically natural range. This fact would lead to the restoration of trophism in the district. In this new balanced endocrine environment (homeostasis) every single cell still subject to trophic stimulation would regain functional and intercellular communication efficiency, whereas the cells now below a responsivity threshold, together with the damaged tissues, would be progressively eliminated and replaced with new healthy cells and with new efficient tissues, thus managing to definitively solve the situation of chronic pathological functional dystrophy of the steroidal balance and, as a consequence, also of pathologies and of chronic lesions (incurable) linked to it, in other words caused by it.

Technical Problem

In light of what is outlined above, there is therefore a great need to have a suitable drug, or a suitable pro-drug, which are capable, in accordance with the age and sex of the patient and irrespective of the type and seriousness of the specific pathology caused by the permanent chronic pathological change of the steroidal balance, of restoring the natural physiological equilibrium of the steroidal balance, thus managing to obtain, as a consequence, also the definitive cure of possible chronic pathologies deriving from/caused by the change thereof. As far as the Applicant is aware, no satisfactory response to the problem outlined above has yet been identified or described, nor have natural products been described that are capable of giving the aforementioned response. The purpose of the present invention is to provide an adequate response to the technical problem described above.

Context of the invention

As already mentioned earlier, non-saponifiable compounds are generally used in cosmetics for their properties promoting healthy skin. Suitably formulated with other possible active ingredients, both of natural or synthetic origin and/or in association with suitable well-known co-formulants and widely used in pharmaceutical formulation technology of the field, they can be used, in particular for topical administration, for eutrophicating treatment of the skin, as well as for the pharmaceutical treatment of some superficial inflammatory cutaneous pathologies (for example, sunburn erythemas and so on).

The Applicant has dedicated in-depth studies to the properties of non-saponifiable compounds derived, in particular, from lipids of natural origin.

After these studies, the Applicant has unexpectedly found that said non-saponifiable compounds, as well as by their other already known activities, are also characterised by a powerful pharmacological-therapeutic activity against a series of pathologies of the human and animal organism.

In other words, the non-saponifiable compounds object of the Applicant' s research, unlike many conventional synthesis drugs, proved capable of completely eliminating the causes forming the basis of the occurrence of the illness, thus restoring the natural state of well- being and good functioning of the unwell organism, tissue, or organ and, therefore, definitively curing the illness itself and not only dealing with its symptoms or its effects.

For example, patents IT 1382016 B, EP 2139493 B l, US 8, 1 14,861 and international application WO 2008/1 14125, to the Applicant, describe and claim the topical use of a suitable, specific mixture of phytosterols in the curative treatment of pathological conditions in which it is required to activate and differentiation") adult stem cells to obtain the regeneration of vessels or tissues that are sick or damaged by said pathologies and/or the activation and re-balancing of the immune response. These documents therefore describe a new medical use (i.e. a so-called "second medical use") of a number of known products derived/obtainable from vegetable non-saponifiable compounds.

Said documents, however, do not describe, nor even vaguely suggest the possibility of using the products quoted in them in the treatment of the permanent chronic pathological change of the steroidal balance, restoring the natural physiological equilibrium and thus obtaining, as a consequence, also the definitive cure of the possible chronic pathologies caused by said change of the steroidal balance.

Summary of the Invention

Through its research, the Applicant has now totally unexpectedly found that a suitable mixture of non-saponifiable compounds of natural origin, vegetable and/or animal, suitably formulated and applied transdermally and/or transmucosally, is capable of providing the desired response to the technical problem described above.

Therefore, an object of the present invention is a mixture of non-saponifiable compounds deriving from at least one lipid of natural origin, vegetable and/or animal, for use in the treatment of permanent chronic pathological change of the steroidal balance, as shown in the attached independent claim.

Another object of the present invention is a topical composition, for transdermal and/or transmucosal adminstration, comprising the mixture of the aforementioned non-saponifiable compounds, for use in the treatment of permanent chronic pathological change of the steroidal balance, as shown in the attached independent claim.

A further object of the present invention is also a process for preparing the aforementioned composition, as described hereinafter.

Preferred embodiments of the present invention are shown in the attached dependent claims. The preferred embodiments of the present invention shown in the following description are given here only as an example and absolutely not limiting the wide field of application of the present invention, which will become immediately clear to those skilled in the art.

Detailed description of the invention

In light of what is outlined above, the present invention is aimed at a new, further medical use of products already pharmaceutically known, and of their topical pharmaceutical compositions, in accordance with Community patent standards (see "Guidelines for Examination in the EPO" of November 2014; Part G - Chapter VI: Paragraph 7.1 Second or further medical use of known pharmaceutical products").

The object of the present invention is, therefore, a mixture of non-saponifiable compounds obtained from at least one lipid of natural origin, both vegetable and animal, for use in the treatment of permanent chronic pathological change of the steroidal balance outside its physiological equilibrium values in an individual suffering from said pathological condition, inducing the restoration of the natural physiological equilibrium of the anabolic and catabolic components thereof and, as a consequence, also inducing the definitive resolution (non- symptomatic, as normally happens with conventional drugs) of pathologies and of chronic lesions, peripheral or not, caused by the aforementioned permanent chronic pathological change of the steroidal balance.

In a preferred embodiment, the object of the present invention is also a topical pharmaceutical composition, the active portion of which comprises and/or consists of a mixture of the aforementioned non-saponifiable compounds, for use in the treatment of permanent chronic pathological change of the steroidal balance outside its physiological equilibrium values in an individual suffering from said pathological condition, inducing the restoration of the natural physiological equilibrium of the anabolic and catabolic components thereof and, as a consequence, also inducing the definitive resolution (non- symptomatic, as normally happens with conventional drugs) of pathologies and of chronic lesions, peripheral or not, caused by the aforementioned permanent chronic pathological change of the steroidal balance.

The non-saponifiable compounds of the present invention are obtained from at least one lipid of natural origin, animal and/or vegetable, selected from the group consisting of: sheep sebum (lanoline); shark oil; egg oil; whale oil; cod-liver oil; ox-foot oil: horse mane oil; sea- animals fat; wool wax; shea-tree butter; carob germ oil; avocado oil; shea-tree butter; carob germ oil; avocado oil; wheat germ oil; triticum vulgaris oil; maize germ oil; soya oil; soya glycine oil; sesame oil; safflower oil; almond oil; rice oil; linseed oil; carrot oil; olive oil(olea europaea); peanut oil; hazelnut oil; walnut oil; coconut(cocos nucifera) oil; castor oil; sunflower oil; pumpkin-seed oil; rapeseed oil; raw cotton oil; palm butter; palm-kernel butter; cocoa butter; vegetable waxes; carnauba wax; bee wax; and/or, preferably, from suitable mixtures thereof.

Preferably, said non-saponifiable compounds are obtained from at least one lipid of natural vegetable origin selected from the group consisting of: shea-tree butter and/or carob germ oil and/or avocado oil and/or wheat germ oil and/or triticum vulgaris oil (common wheat) and/or maize germ oil and/or soya oil and/or soya glycine oil and/or sesame oil and/or safflower oil and/or almond oil and/or rice oil and/or linseed oil and/or carrot oil and/or olive oil(olea europaea) and/or peanut oil and/or hazelnut oil and/or walnut oil and/or coconut oil(cocos nucifera) and/or castor oil and/or sunflower oil and/or pumpkin-seed oil and/or rapeseed oil and/or raw cotton oil and/or palm butter and/or palm-kernel butter and/or cocoa butter and/or vegetable waxes and/or carnauba wax and/or bee wax and/or, more preferably, from suitable mixtures thereof.

Preferably, said non-saponifiable compounds are obtained from at least one lipid of natural vegetable origin selected from the group consisting of: shea-tree butter and/or carob germ oil and/or avocado oil and/or wheat germ oil and/or triticum vulgaris oil (common wheat) and/or maize germ oil and/or soya oil and/or soya glycine oil and/or sesame oil and/or safflower oil and/or almond oil and/or rice oil and/or linseed oil and/or carrot oil and/or olive oil(olea europaea) and/or peanut oil and/or hazelnut oil and/or walnut oil and/or coconut oil(cocos nucifera) and/or castor oil and/or sunflower oil and/or, more preferably, from suitable mixtures thereof.

Preferably, said non-saponifiable compounds are obtained from at least one lipid of natural vegetable origin selected from the group consisting of: shea-tree butter and/or avocado oil and/or wheat germ oil and/or triticum vulgaris oil (common wheat) and/or maize germ oil and/or soya oil and/or soya glycine oil and/or almond oil and/or rice oil and/or linseed oil and/or carrot oil and/or olive oil(olea europaea) and/or peanut oil and/or coconut oil(cocos nucifera) and/or sunflower oil and/or, more preferably, from suitable mixtures thereof.

Preferably, said non-saponifiable compounds are obtained from at least one lipid of natural vegetable origin selected from the group consisting of: shea-tree butter, locust oil, avocado oil, soybean oil, olive oil, seed oil, palm oil, wheat germ oil, sunflower oil, coconut oil, peanut oil, linseed oil, rapeseed oil, tea tree oil, cotton oil, maize oil and mixtures thereof; more preferably, from olive oil, avocado oil, soya oil, shea-tree butter; even more preferably, from olive oil.

Preferably, said non-saponifiable compounds are obtained from at least one lipid of natural vegetable origin selected from the group consisting of: avocado oil and/or wheat germ oil and/or triticum vulgaris oil (common wheat) and/or maize germ oil and/or soya oil and/or soya glycine oil and/or olive oil(olea europaea) and/or coconut oil(cocos nucifera) and/or, more preferably, from suitable mixtures thereof.

In a preferred embodiment, said non-saponifiable compounds are obtained from a mixture of: avocado oil, wheat germ oil and/or triticum vulgaris oil (common wheat), soya oil, soya glycine oil, olive oil(olea europaea), coconut oil(cocos nucifera).

In a more preferred embodiment, said non-saponifiable compounds are obtained from a mixture of: avocado oil, triticum vulgaris oil (common wheat), soya glycine oil, olive oil(olea europaea), coconut oil(cocos nucifera). In a particularly preferred embodiment, the non-saponifiable compounds are obtained from a mixture of: triticum vulgaris oil (common wheat), soya glycine oil, olive oil(olea europaea) and/or coconut oil(cocos nucifera).

In the composition of the present invention the non-saponifiable compounds deriving from lipids of natural origin, both vegetable and animal, mentioned above are preferably selected from the group consisting of: hydrocarbons, liquid or solid, like Karitene, Laurane, Pristane, Squalene; hydrocarbon carotenoids like α-, β-, γ-Carotene, Lycopene; oxygenated carotenoids like Xanthophylls, Lutein, Zeaxanthin, Flavoxanthin, Capsorubin, Bixin, Azaphen; α-, β-, γ-Tocoferols; terpenes and terpene alcohols like Ambrein, Lanosterol, Dihydrolanosterol, Agnosterol, Dihydro-agnosterol, a-Amirin, β-Amirin, Butyrospermol, Cycloartenol, Lupeol, Basseol, Parkeol, Cyclobranolol, Gramisterol, Tirucallol, Citrastadienol, Geranylgeraniol, Erythrodiol; Uvaol, Phytol, Citrastadienol; steroids (sterols) like Zoosterols: Cholesterol, Dehydrocholesterol, Δ-7-Cholesterol, Desmosterol, Cerebrosterol, Cholestanol, 7-Dehydrocholesterol, 7-Cholestanol, Bombyxsterol, Stellasterol, Clionasterol, Spongisterol, Coprosterol; Phytosterols: Stigmasterol, β-Sitosterol, Brassicasterol, Campesterol, a-Spinasterol, Fucasterol, Sargosterol, 24-Methylene- cycloartenol, Gramisterol, 24-Methylcholest-7-enol, Isofucosterol, Δ-5-Avenasterol, Δ-7- Avenasterol, A-5-C24-Stigmastadienol, Clerosterol, Δ-7-Stigmastenol cholesterol, Δ-5- Avenastenol, A-5-C23-Stigmastadienol, Campestanol, Sitostanol, β-Sitosterol and so on; and mixtures thereof.

Preferably, said non-saponifiable compounds are selected from the group consisting of: Cholesterol; Brassicasterol (unsaturated A-5-C22); 24-Methylene-cholesterol; Campesterol; Campestanol; Stigmasterol (unsaturated A-5-C22); A-5-C23-Stigmastadienol; Clerosterol (unsaturated A-8-C25); β-Sitosterol; Sitostanol; Δ-5-Avenasterol (unsaturated A-5-C24); Δ- 5-C24-Stigmastadienol (unsaturated A-5-C24 diene); Δ-7-Stigmastenol; one or more of terpenes and terpene alcohols selected from Ambrein, Lanosterol, Dihydrolanosterol, Agnosterol, Dihydroagnosterol, a-Amirin, β-Amirin, Butyrospermol, Cycloartenol, Lupeol, Basseol, Parkeol, Cyclobranolol, Gramisterol, Tirucallol, Citrastadienol, Geranylgeraniol, Erythrodiol, Uvaol, Phytol, Citrastadienol.

More preferably, said non-saponifiable compounds are selected from the group consisting of:

Cholesterol; Brassicasterol (unsaturated A-5-C22); 24-Methylene-cholesterol; Campesterol; Campestanol; Stigmasterol (unsaturated A-5-C22); A-5-C23-Stigmastadienol; Clerosterol (unsaturated A-8-C25); β-Sitosterol; Sitostanol; Δ-5-Avenasterol (unsaturated A-5-C24); Δ- 5-C24-Stigmastadienol (unsaturated A-5-C24 diene); Δ-7-Stigmastenol; one or more terpene alcohols selected from Lanosterol, Dihydrolanosterol, Agnosterol, Dihydroagnosterol, Butyrospermol, Cycloartenol, Lupeol, Basseol, Parkeol, Cyclobranolol, Grami sterol, Tirucallol, Citrastadienol, Geranylgeraniol, Erythrodiol, Uvaol, Phytol, Citrastadienol.

Even more preferably, said non-saponifiable compounds are selected from the group consisting of: Cholesterol; Brassicasterol (unsaturated A-5-C22); 24-Methylene-cholesterol; Campesterol; Campestanol; Stigmasterol (unsaturated A-5-C22); A-5-C23-Stigmastadienol; Clerosterol (unsaturated A-8-C25); β-Sitosterol; Sitostanol; Δ-5-Avenasterol (unsaturated Δ- 5-C24); A-5-C24-Stigmastadienol (unsaturated A-5-C24 diene); Δ-7-Stigmastenol.

In a further particularly preferred embodiment, in the composition of the present invention, said non-saponifiable compounds are selected from the aforementioned groups excluding steroids of animal origin (zoosterols) and steroids of vegetable origin (phytosterols). In other words, in this case, in the preparation of the composition of the present invention the mixture of non-saponifiable compounds obtained from the preferred lipids described earlier is preliminarily removed of the non-saponifiable components with steroidal structure (zoosterols and phytosterols) using purification techniques well known in the field.

Only as an illustrative example, absolutely not limiting the invention, hereinafter the ponderal percentage compositions of the most important non-saponifiable compounds of some from the lipids of vegetable origin particularly preferred for the purposes of the present invention are shown hereinafter. The marked difference in the composition of said non- saponifiable compounds is clear.

Avocado oil

Soya oil

Olive oil (olea europaea)

The compositions of the present invention can preferably be formulated/prepared using preparation technologies commonly known and used in the field of pharmaceutical formulation technology). In particular, in the present case, techniques and apparatuses are preferably used that are commonly used for preparing compositions for topical, transdermal, transmucosal application (as a non-limiting example, for preparing creams, pastes, ointments, emulsions, transdermal patches, and so on).

Only as an example, absolutely not limiting the possible types of preparation of the various preferred formulations, in a melter, equipped with heating and agitation means (for example with rotating blades), the active components and the possible co-formulants that will constitute the non-fatty phase of the final composition (A) are added in sequence (or even already pre-mixed). The temperature of the mixture is brought to 65°C, after which, in the melter the other active components and the possible co-formulants that will constitute the fatty phase of the final composition (B) are added. The temperature of the mixture is gradually brought to 70°C and it is kept under moderate agitation (speed 1 of the rotating blades) and under vacuum at 0,5-0,6 mm Hg.

The temperature is allowed to drop to about 50°C, the blades are stopped, the vacuum is removed and the possible other components, active and not, which do not belong to the two previous phases (A and B) are added. The melter is then brought back under vacuum at 0,5- 0,6 mm Hg and, by actuating the blades at speed 1, it is mixed until a homogeneous product is obtained.

The compositions described above are administered topically, transdermally, transmucosally, depending on the location/region suffering from the permanent change of the steroidal balance and from the lesion(s)/from the chronic pathology(-ies) caused by this change, at doses that can change within wide limits given the substantial absence of toxicity of the active ingredients of the invention used in the compositions.

In general, for said types of administration, the total weight of the active ingredients in the formulations, expressed as a percentage by weight of the total weight of the formulation, can vary between 0,001% and 40% by weight; preferably, between 0,01% and 20% by weight; more preferably, between 0,1 %> and 15% by weight. In a particularly preferred embodiment, the concentration of the mixture of active ingredients is comprised between about 5 %> and about 11%) by weight, with respect to the total weight of the formulation. In a further particularly preferred embodiment, said concentration is comprised between 8%> and 10%> by weight.

Preferably, the compositions of the present invention will be suitably formulated in combination with excipients and/or conventional carriers and in ratios that are well known and used by those skilled in the art.

Optionally, the compositions can further contain other active ingredients having a complementary or otherwise useful activity.

As an absolutely not limiting example, said compositions can further contain products with soothing/anti-inflammation action like methyl salicylate or zinc oxide (for example, they can contain zinc oxide in an amount comprised between 8%> and 12% by weight with reference to the total weight of the composition). In particular, the transdermal compositions can further contain suitable well-known absorption promoters, commonly used in the cosmetic and/or pharmacological field.

The following experimental examples have the sole purpose of illustrating some significant aspects of the invention, without for this reason limiting the wide application potential.

Example 1

A topical pharmaceutical composition was prepared in the form of oleogel comprising about 10%) by weight (with reference to the total weight of the composition) of a mixture of non- saponifiable compounds obtained from a mixture of avocado oil, triticum vulgaris oil (common wheat), soya glycine oil, olive oil(olea europaea), coconut oil(cocos nucifera) in a ponderal ratio of about 1 : 1 : 1 : 1 : 1 (other ratios can in any case possibly be used according to requirements).

The residual percentage amount up to 100% is formed from a suitable, known mixture of excipients, carriers, absorption promoters, which are used conventionally in the field, comprising isodecyl-laurate, isodecyl citrate, triglycerides C 10-C 18, isodecyl salicylate, silica, wherein said co-formulants have a ponderal ratio selected from those known, such as to provide an oleogel with high skin penetration.

Example 2

A topical pharmaceutical composition was prepared in the form of oleogel comprising about 10%) by weight (with reference to the total weight of the composition) of a mixture of non- saponifiable compounds obtained from a mixture of triticum vulgaris oil (common wheat), soya glycine oil, olive oil(olea europaea), coconut oil(cocos nucifera) in a ponderal ratio of about 1 : 1 : 1 : 1 (other ratios can in any case possibly be used, according to requirements).

The residual percentage amount up to 100%> is formed from a suitable, known mixture of excipients, carriers, absorption promoters, which are used conventionally in the field, comprising isodecyl-laurate, isodecyl citrate, triglycerides C 10-C 18, isodecyl salicylate, silica, wherein said co-formulants have a ponderal ratio selected from those known, such as to provide an oleogel with high skin penetration.

Example 3

A topical pharmaceutical composition was prepared in the form of paste or cream comprising about 8%) or 6%> by weight (with reference to the total weight of the composition) of a mixture of non-saponifiable compounds obtained from a mixture of avocado oil, triticum vulgaris oil (common wheat), soya glycine oil, olive oil(olea europaea), coconut oil(cocos nucifera) in a ponderal ratio of about 1 : 1 : 1 : 1 : 1 (other ratios can in any case possibly be used, according to requirements).

The percentage part of the composition to bring it to 100% includes a known conventional mixture comprising poly-isoprene, liquid paraffin, silica, wherein said co-formulants have a ponderal ratio such as to provide a paste or a cream with high skin penetration.

Example 4

A topical pharmaceutical composition was prepared in the form of paste or cream comprising about 8% or 6% by weight (with reference to the total weight of the composition) of a mixture of non-saponifiable compounds obtained from a mixture of triticum vulgaris oil (common wheat), soya glycine oil, olive oil(olea europaea), coconut oil(cocos nucifera) in a ponderal ratio of about 1 : 1 : 1 : 1 (other ratios can in any case possibly be used, according to requirements).

The percentage part of the composition to bring it to 100% includes a known conventional mixture comprising poly-isoprene, liquid paraffin, silica, wherein said co-formulants have a ponderal ratio such as to provide a paste or a cream with high skin penetration.

Examples 5 and 6

The compositions, respectively, of the aforementioned Examples 3 and 4 were prepared, wherein the mixture of non-saponifiable compounds is present at 8% by weight (with reference to the total weight of the composition), said compositions further comprising a percentage amount of zinc oxide of about 10% by weight, with reference to the total weight of the composition, to give a soothing paste (also provided with the known soothing/anti- inflammatory properties of zinc oxide).

Examples 7-12

The same compositions of the aforementioned Examples 1-6 were respectively prepared, with the difference that the non-saponifiable fractions used were previously removed of their steroidal component as described earlier.

Said purification was carried out with methods, for example chromatographic, commonly known and used in isolation and purification techniques of steroids.

Example 13

As further examples of non-limiting formulations of the invention, other possible pharmaceutical compositions of the invention are given hereinafter that comprise 10% by weight (with reference to the total weight of the composition) of a mixture of non- saponifiable compounds consisting (percentage by weight) of:

Cholesterol; 0,4-0,6%

Brassicasterol (unsaturated A-5-C22); 3,5-3,7%

24-Methylene-cholesterol; 0,2-0,4%

Campesterol; 24,7-25, 1%

Campestanol; 1,0-1,2%

Stigmasterol (unsaturated A-5-C22); 22,5-22,9% A-5-C23-Stigmastadienol; 0,4-0,6%

Clerosterol (unsaturated A-8-C25); 0,3-0,5%

β-Sitosterol; 42,9-43,2%

Sitostanol; 1,6-1,8%

Δ-5-Avenasterol (unsaturated A-5-C24); 0,4-0,6%

A-5-C24-Stigmastadienol (unsaturated A-5-C24 diene); 0,2-0,4%

Δ-7-Stigmastenol 0,3-0,5%.

The residual percentage amount up to 100% is formed from a suitable mixture of excipients, carriers, absorption promoters, which are used conventionally in the field and formulated in known ratios, such as to provide an oleogel provided with high dermal/cutaneous penetration.

Example 14

Other preferred topical pharmaceutical compositions of the invention comprise 8% by weight (with reference to the total weight of the composition) of a mixture of non-saponifiable compounds consisting (percentage by weight) of:

Cholesterol; 0,4-0,6%

Brassicasterol (unsaturated A-5-C22); 3,5-3,7%)

24-Methylene-cholesterol; 0,2-0,4%

Campesterol; 24,7-25, 1%

Campestanol; 1,0-1,2%

Stigmasterol (unsaturated A-5-C22); 22,5-22,9%

A-5-C23-Stigmastadienol; 0,4-0,6%

Clerosterol (unsaturated A-8-C25); 0,3-0,5%

β-Sitosterol; 42,9-43,2%

Sitostanol; 1,6-1,8%

Δ-5-Avenasterol (unsaturated A-5-C24); 0,4-0,6%

A-5-C24-Stigmastadienol (unsaturated A-5-C24 diene); 0,2-0,4%

Δ-7-Stigmastenol 0,3-0,5%.

In this case, the residual percentage amount up to 100% is formed by a suitable mixture of excipients, carriers, absorption promoters, which are used conventionally in the field and formulated in known ratios, such as to provide a paste provided with high dermal/cutaneous penetration. Preferably, the aforementioned compositions, in which the mixture of non-saponifiable compounds is present at 8% by weight (with reference to the total weight of the composition), also comprise a percentage amount of zinc oxide of about 10% by weight, with reference to the total weight of the composition, to give a soothing paste (also provided with the known soothing/anti-inflammatory properties of zinc oxide).

Example 15

In a particularly preferred embodiment of the present invention, the preferred mixture of non- saponifiable compounds described above has the following composition by weight:

Cholesterol; 0,5%

Brassicasterol (unsaturated A-5-C22); 3,6%

24-Methylene-cholesterol; 0,3%

Campesterol; 24,9%

Campestanol; 1, 1%

Stigmasterol (unsaturated A-5-C22); 22,7%

A-5-C23-Stigmastadienol; 0,5%

Clerosterol (unsaturated A-8-C25); 0,4%

β-Sitosterol; 43, 1%

Sitostanol; 1,7%

Δ-5-Avenasterol (unsaturated A-5-C24); 0,5%

A-5-C24-Stigmastadienol (unsaturated A-5-C24 diene); 0,3%

Δ-7-Stigmastenol 0,4%

Example 16

The formulation of Example 13 was prepared further comprising between 3% and 15% by weight (with respect to the total weight of the formulation) of one or more terpenes and/or terpene alcohols selected from Ambrein, Lanosterol, Dihydrolanosterol, Agnosterol,

Dihydroagnosterol, a-Amirin, β-Amirin, Butyrospermol, Cycloartenol, Lupeol, Basseol, Parkeol, Cyclobranolol, Gramisterol, Tirucallol, Citrastadienol, Geranylgeraniol, Erythrodiol, Uvaol, Phytol, Citrastadienol, and/or mixtures thereof.

The percentage part of the composition to bring it to 100% includes a known conventional mixture comprising isodecyl-laurate, isodecyl citrate, triglycerides Cio-Cis, isodecyl salicylate, silica, wherein said co-formulants have a known ponderal ratio such as to provide an oleogel with high skin penetration. Example 17

The formulation of Example 13 was prepared further comprising between 3% and 15% by weight (with respect to the total weight of the formulation) of one or more terpene alcohols selected from Lanosterol, Dihydrolanosterol, Agnosterol, Dihydroagnosterol, Butyrospermol, Cycloartenol, Lupeol, Basseol, Parkeol, Cyclobranolol, Gramisterol, Tirucallol, Citrastadienol, Geranylgeraniol, Erythrodiol, Uvaol, Phytol, Citrastadienol and/or mixtures thereof.

The percentage part of the composition to bring it to 100% includes a known conventional mixture comprising isodecyl-laurate, isodecyl citrate, triglycerides Cio-Cis, isodecyl salicylate, silica, wherein said co-formulants have a ponderal ratio such as to provide an oleogel with high skin penetration.

Examples 18-19

The formulations of examples 16 and 17 were prepared, respectively without their phytosterolic component.

In a completely unexpected manner, the pharmaceutical composition of the present invention proved capable of inducing an appropriate preferred production of anabolic or catabolic hormones lacking in a specific district suffering from a chronic alteration thereof outside of the natural physiological range, relative to age and/or sex, thus restoring the aforementioned range of natural physiological values, in accordance with the need of the district itself. In other words, by topically providing the district suffering from the lesion (caused by the chronic pathology resulting from the permanent chronic pathological change of the metabolic balance) the aforementioned pharmaceutical composition, it has been unexpectedly found that it behaved like a suitable precursor, or pro-drug, which, metabolized according to the requirements of the district itself, induced the rebalancing in the region of the altered steroidal balance taking it stably back to its natural physiological range, relative to age or sex. All of this has led to the restoration of the trophism of the region so that each single cell subject to trophic stimulation has reacquired a sufficient functional and intercellular communication efficiency, whereas the cells below the responsivity threshold (those that are sick and cannot be cured), together with the damaged tissues, were eliminated and replaced with new cells and tissues that are once again efficient and functional. All of this has unexpectedly made it possible to obtain ex-novo a new healthy tissue, consisting of new healthy and functional cells, which has progressively replaced the old sick tissue (no longer curable, except for, possibly, for a limited time period and only from the symptomological point of view) stably recreating the state of health of the district before the chronic pathological alteration of the steroidal balance occurred with the consequent occurrence of various pathological conditions and the respective lesions.

Industrial application

The non-saponifiable compounds of natural origin, vegetable and/or animal, of the present invention, have proven capable of inducing the stable rebalancing of the steroidal balance within its natural physiological values, during the course of chronic pathologies caused by the permanent chronic pathological change thereof, irrespective of the causes that caused it. Specifically, the topical formulations of said non-saponifiable compounds of the present invention, with or without their component of zoosterols and/or of phytosterols, proved usable in the treatment of permanent chronic pathological change of the steroidal balance (with this also definitively resolving the further chronic, relapsing or progressive pathologies, not resolvable with conventional drugs, caused by the same), stably inducing the natural physiological rebalancing thereof.