WO2018051294A2

WO2018051294A2 - Non—saponifiable compounds of natural lipids for use in the treatment of cardiac pathologies

Info

Publication number: WO2018051294A2
Application number: PCT/IB2017/055621
Authority: WO
Inventors: Chiara De Gregorio
Original assignee: Codex V Srl
Priority date: 2016-09-19
Filing date: 2017-09-18
Publication date: 2018-03-22
Also published as: IT201600093741A1; WO2018051294A3

Abstract

The present invention relates to the use of non-saponifiable moieties obtained from natural, plant and/or animal lipids, for the treatment of cardiac diseases caused by the permanent (or chronic) alteration (or imbalance) of the normal physiological equilibrium of the steroidal balance in a patient suffering from this chronic condition. In particular, the invention relates to a pharmaceutical composition of said non-saponifiable moieties for use in the treatment of those cardiac disorders, heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction or valvulopathies, which are caused by permanent, chronic, pathological alteration of the natural physiological equilibrium of the steroidal balance in a patient suffering from said disease, and of the chronic lesions, either peripheral or not, associated with the same that determine them. Said pharmaceutical composition is particularly adapted for transdermal topical administration.

Description

TITLE:

"NON—SAPONIFIABLE COMPOUNDS OF NATURAL LIPIDS FOR USE IN THE TREATMENT OF CARDIAC PATHOLOGIES"

DESCRIPTION

Technical field of the invention

The present invention relates to the use of non-saponifiable moieties obtained from natural, plant and/or animal lipids, for the treatment of cardiac diseases caused by the permanent (or chronic) alteration (or imbalance) of the normal physiological equilibrium of the steroidal balance in a patient suffering from this chronic condition.

In particular, the invention relates to the above non- saponifiables moieties for use in the treatment of heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction and/or valvulopathies , which are caused by permanent (or chronic) alteration (or unbalance) of the natural physiological equilibrium of the steroidal balance in a patient suffering from said chronic disease.

In particular, the invention relates to a topical transdermal pharmaceutical composition comprising said non-saponifiable moieties for use in the treatment of those cardiac diseases, such as in the treatment of heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction and/or valvulopathies, which are caused by permanent (or chronic) alteration (or unbalance) of the natural physiological equilibrium of the steroidal balance in a patient suffering from said chronic disease. Said pharmaceutical composition is particularly adapted for transdermal topical administration.

Prior art

Definitions

1. Lipids Lipids, or fats, are organic compounds widespread in nature and represent one of the major classes of natural organic compounds of biological interest.

It is known that a lipid of natural, plant and/or animal origin, either in the form of fat, oil or wax, consists of a complex mixture of compounds not all well identified. Generally speaking, a lipid mostly comprises saponifiable esters (mostly triglycerides of fatty acids) and non-glyceric substances in smaller dose (variable from lipid to lipid) , among which mainly a moiety consisting of non-saponifiable compounds .

By way of non-limiting example, among the animal lipids richer in non-saponifiable substances (hereinafter, "non- saponifiables ) , the following may be mentioned: sheep sebum (lanolin); shark oil; egg oil; whale oil; cod liver oil; neatsfoot oil; horse mane oil; the fat of marine animals; wool wax; and so on.

By way of non-limiting example, among the plant lipids richer in non-saponifiable substances (hereinafter, "non- saponifiables ) , the following may be mentioned: 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 seed 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.

2. Non-saponifiables

Among the above non-glyceric substances, fatty acid esters with sterols and with aliphatic or triterpene fatty alcohols are also present in naturally occurring lipids. Under normal conditions of saponification of lipids, also these esters are broken down as all other esters and the resulting sterol and alcohol component (obviously no longer saponifiable) becomes a part of the non-saponifiable moiety.

The set of all substances not converted into fatty acid salts (of course, also with the exclusion of glycerin) after saponification of the lipid is referred to as "total non- saponifiable" (and reference to the total non-saponifiables will be made hereinafter in the present document) .

3. Composition of non-saponifiables

The composition of non-saponifiables varies, even significantly, from lipid to lipid. Typically, each of them contains in its non-saponifiable moiety even more than thirty different substances; among them, many have a chemical structure still unidentified.

In principle, among the known non-saponifiables known contained in naturally occurring lipids, the following may in particular be mentioned:

I) HYDROCARBONS; liquids or solids, such as:

- Karitene (or Illipene) , present in shea butter or Illipe, - Icosane (n-eicosane) , present in Bryonia, bay leaf, parsley oil ,

Pristane ( tetramethylpentadecane ) , extracted from shark liver oil,

- Squalene (hexamethyltetracosene ) , contained in human sebum, in shark, cod and herring liver oil, and in certain vegetable oils (olive, rice bran, wheat germ, peanut, rapeseed oil, etc . ) .

II) HYDROCARBON CAROTENOIDS; such as, for example:

- -, β-, γ-carotene, (the most common one is β-carotene found in palm oil, carrots, chestnut leaves, etc.),

- Lycopene (found in tomatoes, red pepper, and so on) .

III) OXYGENATED CAROTENOIDS (Xanthophylls ) ; in nature, they are often found in the form of fatty acid esters: among the most popular ones are lutein, zeaxanthin, flavoxanthin, capsorubin, crocetin, azafrene.

IV) α-, β-, γ-TOCOPHEROLS;

- they are particularly present in wheat germ, corn, rice, soybean, carob, raw cotton oil, in lard.

V) HIGHER FATTY ALCOHOLS; such as:

- saturated alcohols from C12 to C26 and unsaturated ones from Ci₆ C₂O_A such as, for example,

a) saturated alcohols: for example, lauryl, myristyl, cetyl, stearyl, aralkyl, carnaubilic, cerylic alcohol;

b) unsaturated alcohols: for example, n-hexadecenyl , oleyl, n- eicosenyl, n-eicosandienyl alcohol.

VI) TERPENES AND TERPENIC ALCOHOLS (PENTACYCLIC AND TETRA TRITERPENOIDS) ; such as, for example:

- ambrein, lanosterol, dehydrolanosterol , agnosterol, dehydroagnosterol , -amyrin, β-amyrin, butyrospermol , cycloartenol , lupeol, basseol, parkeol, cyclobranolol , tirucallol, citrastadienol , geranylgeraniol , erythrodiol; uvaol, phytol, citrastadienol.

VII) STEROIDS (STEROLS); natural derivatives of perhydropentanophenantrene are not considered, at least from a formal point of view, among steroids, which have a backbone of 30 carbon atoms and which fall within the group of triterpenoids .

Steroids are of animal (zoosterols) or vegetable (phytosterols ) origin, for example:

- zoosterols; mainly extracted from mammalian lipids such as, for example, cholesterol, dehydrocholesterol , Δ-7-cholesterol , desmosterol, cerebrosterol , cholestanol, 7-dehydrocholesterol , 7-cholestanol , bombicesterol , stellasterol , clionasterol , spongisterol , coprosterol;

- phytosterols; extracted from lipids of plant origin such as, for example, stigmasterol , β-sitosterol , brassicasterol , campesterol, -spinasterol , fucasterol, sargosterol, 24- methylene-cycloartenol , gramisterol , 24-methylcolest-7-enol, isofucosterol , Δ-5-avenasterol , Δ-7-avenasterol , Δ-5-024- stigmastadienol , clerosterol, Δ-7-stigmastenol cholesterol, Δ- 5-avenastenol , A-5-C23-stigmastadienol, campestanol, sitostanol, and so on.

4. Preparation of the non-saponifiables

The total non-saponifiable moieties are isolated from the starting lipid (s) by using well-known technologies commonly used in the industry. By way of non-limiting example, the non- saponifiables are separated from the alkali salts of fatty acids after the saponification of the starting lipids under basic hydrolysis conditions commonly known and used in the industry, through the extraction with suitable solvents or, preferably, through molecular distillation.

Prior art

Non-saponifiables are generally used in cosmetics for their beneficial properties to maintain good skin health. Properly formulated with other possible active ingredients, either natural or synthetic, and in combination with suitable co- formulants well-known in the pharmaceutical formulation technology of the field can be used, in particular by topical administration, for the skin eutrophying treatment, as well as for the pharmaceutical treatment of superficial inflammatory skin diseases.

The Applicant has devoted extensive studies on the properties of non-saponifiables derived, in particular, from naturally occurring lipids.

As a result of these studies, the same has, over the years, unexpectedly found that said non-saponifiables are characterized by a powerful pharmacological-therapeutic activity against chronic disease conditions of the human and animal organism, namely, those diseases that can no longer be treated or solved because the deep pathological cause that causes the same cannot be cured. At most, with traditional drugs, the symptoms of the disease are usually treated but only for periods of time more or less limited and subject to relapse.

In other words, the non-saponifiables object of the Applicant's research, unlike many traditional synthesis drugs, have proved to be able to completely eliminate the deep organic causes of onset and of becoming chronic of the disease, thus restoring the natural state of well-being/good functioning of the diseased organism, tissue or organ and thus solving upstream the disease itself and not just temporarily fixing the symptoms or effects thereof.

For example, patents IT 1382016 B, EP 2139493 Bl, US 8,114,861 and the international application WO 2008/114125 by the Applicant describe the use of a suitable mixture of phytosterols for treating all those medical conditions in which the activation of stem cells is required/useful to induce the regeneration of diseased vessels or tissues no longer or poorly functioning and/or the activation and the rebalancing of the immune response. A new pharmaceutical use of a number of products derived from non-saponifiables is, therefore, described.

Recently, patent application GB 102015000063163, also by the Applicant, describes the use of a mixture of non-saponifiables derived from naturally occurring lipids for treating the permanent alteration of the steroidal balance outside its natural range of physiological balance in a patient suffering from this chronic basic pathological condition. Said treatment restores the natural physiological equilibrium of the steroidal balance, thus restoring the situation of functional well-being of the organism. A further pharmaceutical use of said non-saponifiables is, therefore, described. However, IT102015000063163 does not describe the treatment of any specific disease caused by the permanent, i.e. chronic, alteration, of the steroidal balance outside its natural physiological range.

Technical task

In the light of the foregoing, the need to have a drug able to definitively treat/solve a specific chronic disease (or more diseases) that is (are) caused by the permanent/chronic alteration of the natural physiological equilibrium of the steroidal balance in a patient suffering from this chronic pathological condition is still very much felt.

The object of the present invention is to provide an adequate response to the technical task described above.

Summary of the invention

Considering that the present invention represents a further development of the subject matter of the patent application IT102015000063163 mentioned above, the content of which is included herein in its entirety as a reference, the Applicant has now found that a suitable mixture of non-saponifiables derived from natural, plant and/or animal lipids, transdermally applied, is able to give an adequate response to the technical problem above.

Therefore, an object of the present invention is a mixture of non-saponifiables derived from natural, plant and/or animal lipids, for use in the treatment of those cardiac disorders, such as heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction or valvulopathies , which are caused by permanent, chronic, pathological alteration of the natural physiological equilibrium of the steroidal balance in a patient suffering from said chronic pathology, as well as of the local or peripheral effects caused by the same, as described in the appended independent claim. It is another object of the present invention to provide a topical composition for transdermal administration, comprising the above mixture of non-saponifiables, for use in the treatment of those cardiac disorders, such as heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction or valvulopathies , which are caused by permanent, chronic, pathological alteration of the natural physiological equilibrium of the steroidal balance in a patient suffering from said chronic pathology, as well as of the local or peripheral effects caused by the same, as described in the appended independent claim.

A further object of the present invention is also a process for preparing the above composition, as described in the appended description.

Preferred embodiments of the present invention are set forth in the accompanying dependent claims.

The preferred embodiments the present invention shown in the following description are described herein only by way of non- limiting example of the broad application scope of the invention, which will be apparent to the man skilled in the art .

Detailed description of the invention

The present invention therefore relates to a mixture of non- saponifiables derived from natural, plant and/or animal lipids, for use in the treatment of those cardiac disorders, heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction or valvulopathies, which are caused by permanent, chronic, pathological alteration of the natural physiological equilibrium of the steroidal balance in a patient suffering from said pathology.

Said mixture, by inducing the restoration of the natural physiological balance of the anabolic and catabolic components of the steroidal balance both at a local/district and central level, produces the final resolution (not only symptomatic, as normally occurs with traditional drugs) of those cardiac disorders, heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction or valvulopathies , which are caused by permanent, chronic, pathological alteration of the natural physiological equilibrium of the steroidal balance in a patient suffering from said disease, and of the chronic lesions, either peripheral or not, associated with the same that determine them.

In a preferred embodiment, particular, the present invention also relates to a topical pharmaceutical composition whose active portion consists of the above mixture of non- saponifiables, for use in the treatment of those cardiac disorders, heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction or valvulopathies, which are caused by permanent, chronic, pathological alteration of the natural physiological equilibrium of the steroidal balance in a patient suffering from said disease, and of the chronic lesions, either peripheral or not, associated with the same that determine them.

Said composition, by inducing the restoration of the natural physiological balance of the anabolic and catabolic components of the steroidal balance both at a local/district and central level, produces the final resolution (not only symptomatic, as normally occurs with traditional drugs) of those cardiac disorders, heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction or valvulopathies, which are caused by permanent, chronic, pathological alteration of the natural physiological equilibrium of the steroidal balance in a patient suffering from said disease, and of the chronic lesions, either peripheral or not, associated with the same that determine them.

The non-saponifiables of the present invention are obtained from at least one lipid of natural, animal and/or vegetable origin, selected from the group consisting of: sheep sebum

(lanolin); shark oil; egg oil; whale oil; cod liver oil; neat's foot oil; horse mane oil; fat of marine animals; wool wax; 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 seed 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, of suitable mixtures thereof.

Preferably, said non-saponifiables 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 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 {cocos nucifera) oil and/or castor oil and/or sunflower seed 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, of suitable mixtures thereof.

Preferably, said non-saponifiables 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 germ oil 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 ( cocos nucifera) oil and/or castor oil and/or sunflower seed oil and/or, more preferably, of suitable mixtures thereof.

Preferably, said non-saponifiables 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 germ oil 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 (cocos nucifera) oil and/or sunflower seed oil and/or, more preferably, of suitable mixtures thereof.

Preferably, said non-saponifiables 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 germ oil and/or maize germ oil and/or soya oil and/or soya glycine oil and/or olive oil (olea europaea) and/or coconut (cocos nucifera) oil and/or, more preferably, of suitable mixtures thereof.

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

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

In the composition of the present invention, the non- saponifiable mixture derived from the above lipids of a natural origin is preferably selected from the group consisting of: liquid or solid hydrocarbons, such as karitene, icosane, pristane, squalene; hydrocarbon carotenoids, such as -, β-, γ-carotene, lycopene; oxygenated carotenoids, such as Xanthophylls , such as lutein, zeaxanthin, flavoxanthin, capsorubin, crocetin, azafrene; -, β-, γ-tocopherols ; terpenes and terpenic alcohols, such as ambrein, lanosterol, dehydrolanosterol , agnosterol, dehydroagnosterol , -amyrin, β- amyrin, butyrospermol , cycloartenol , lupeol, basseol, parkeol, cyclobranolol , tirucallol, citrastadienol , geranylgeraniol , erythrodiol ; uvaol, phytol, citrastadienol; steroids (sterols), such as zoosterols such as cholesterol, dehydrocholesterol , Δ-7-cholesterol , desmosterol, cerebrosterol , cholestanol, 7-dehydrocholesterol, 7- cholestanol, bombicesterol , stellasterol , clionasterol , spongisterol , coprosterol, phytosterols , such as stigmasterol , β-sitosterol , brassicasterol , campesterol, -spinasterol , fucasterol, sargosterol, 24-methylene-cycloartenol, gramisterol, 24-methylcolest-7-enol, isofucosterol , Δ-5- avenasterol, Δ-7-avenasterol , A-5-C24-stigmastadienol, clerosterol, Δ-7-stigmastenol cholesterol, Δ-5-avenastenol , Δ- 5-C23-stigmastadienol, campestanol, sitostanol, il β- sitosterol and so on; and/or mixtures thereof.

In a further preferred embodiment, in the composition of the present invention, said non-saponifiables are selected from the group mentioned above with the exclusion of animal origin steroids (zoosterols) and of vegetable origin steroids (phytosterols ) . That is to say, in this case, in the preparation of the composition of the present invention, the mixture of non-saponifiables obtained from the previously described preferred lipids is first deprived of the non- saponifiable components with steroidal structure (zoosterols and phytosterols) .

By way of non-limiting example of the invention, the weight percentage compositions of the non-saponifiables of some of the lipids of vegetable origin particularly preferred for the purposes of the present invention are shown hereinafter. The marked difference in the composition of the non-saponifiables is apparent.

Avocado oil

Soybean oil

- Phytosterols 35%

Sitosterol 50%

Campesterol 25%

Stigmasterol 25%

Olive oil {olea europaea)

The compositions of the present invention may be preferably prepared with the use of preparative technologies commonly known and used in the field of the pharmaceutical formulation technique. In particular, in this case, techniques and equipment employed commonly used for the preparation of compositions for topical, transdermal, transmucosal application (only by way of non-limiting example, for the preparation of creams, pastes, ointments, emulsions, transdermal patches, and so on) will be preferably used.

By way of non-limiting example only of the possible types of preparation of the various preferred formulations, the active components and any co-formulants which will form the non-fat phase of the final composition (A) are sequentially added (or also already premixed) to a fuser, provided with heating and stirring means (e.g. rotating blades) . The mixture temperature is brought to 65 °C, after which the other active components and any co-formulants which will form the fat phase of the final composition (B) are added to the fuser. The temperature of the mixture is gradually brought to 70 °C and is maintained under moderate stirring (speed 1 of the rotating blades) and under vacuum at 0.5-0.6 mm Hg.

The temperature is made to decrease to about 50 °C, the blades are stopped, the vacuum is removed and any other active and non-active components which do not belong to the previous two phases (A and B) are added. The fuser is then brought under vacuum at 0.5-0.6 mm Hg and, by operating the blades at speed 1, it is mixed to obtain a homogeneous product.

The compositions described above will be administered topically, transdermally, on the skin surface that concerns the district affected by the disease (in the present case, cardiac disorders, heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction or valvulopathies , which are caused by the permanent/chronic alteration of the steroidal balance) and on the chronic lesion (s) associated to this pathology that determine them, at doses which may range within wide limits due to the known substantial absence of toxicity of the active ingredients used in the compositions.

In general, for said types of administration, the total weight of the active ingredients in the formulations (i.e., the total percentage weight of the non-saponifiables, with or without the steroidal moiety) , expressed as a percentage by weight on the total weight of the formulation, may range from 0.001% to 40% by weight; preferably, from 0.01% to 20% by weight; more preferably, from 0.1% to 15% by weight. In a particularly preferred embodiment, the concentration of the mixture of the active ingredients is in the range from about 5% to about 11% by weight, with respect to the total weight of the formulation. In a further particularly preferred embodiment, said concentration ranges from 8% to 10% by weight, preferably, 8% or 10%.

Preferably, the compositions of the present invention will be suitably formulated in combination with excipients and/or conventional carriers and in reciprocal ratios which are well known and used by the man skilled in the art. Optionally, the compositions may further contain other active ingredients having a complementary or otherwise useful activity .

By way of non-limiting example only, said compositions may further contain products with a soothing/anti-inflammatory activity, such as zinc oxide (for example, they may contain zinc oxide in an amount ranging from 8% to 12% by weight with respect to the total weight of the composition; preferably, about 10% by weight) . In particular, said compositions may further contain suitable, well-known absorption promoters, of common use in the cosmetic and/or pharmacological field.

The following experimental examples are only intended to illustrate some significant aspects of the invention, without thereby limiting the broad application potential thereof.

Example 1

A topical pharmaceutical composition was prepared in the form of oleogel, comprising about 10% by weight (in comparison with the total weight of the composition) of a mixture of non- saponifiable compounds obtained from a mixture of avocado oil, triticum vulgaris germ oil, soya glycine oil, olive oil (olea europaea) , coconut (cocos nucifera) oil in a ponderal reciprocal ratio of about 1:1:1:1:1 (other ratios may optionally be used) .

The 100% missing residual percentage part is formed by a suitable, known mixture of excipients, carriers, absorption promoters, which are conventionally used in the field, comprising isodecyl-laurate, isodecyl citrate, Ci₀-Ci₈ triglycerides, isodecyl salicylate, silica, wherein said co- formulants have a reciprocal weight ratio selected from those known, such as to provide an oleogel with a high skin penetrability .

Example 2

A topical pharmaceutical composition was prepared in the form of oleogel, comprising about 10% by weight (in comparison with the total weight of the composition) of a mixture of non- saponifiable compounds obtained from a mixture of triticum vulgaris germ oil, soya glycine oil, olive oil (olea europaea) , coconut (cocos nucifera) oil in a ponderal reciprocal ratio of about 1:1:1:1 (other ratios may optionally be used) .

The 100% missing residual percentage part is formed by a suitable, known mixture of excipients, carriers, absorption promoters, which are conventionally used in the field, comprising isodecyl-laurate, isodecyl citrate, Ci₀-Ci₈ triglycerides, isodecyl salicylate, silica, wherein said co- formulants have a reciprocal weight ratio selected from those known, such as to provide an oleogel with a high skin penetrability.

Example 3

A topical pharmaceutical composition was prepared in the form of paste or cream, comprising about 8% or 6% by weight (in comparison with the total weight of the composition) of a mixture of non-saponifiable compounds obtained from a mixture of avocado oil, triticum vulgaris germ oil, soya glycine oil, olive oil (olea europaea) , coconut (cocos nucifera) oil in a ponderal reciprocal ratio of about 1:1:1:1:1 (other ratios may optionally be used) .

The 100% missing percentage part of the composition includes a known traditional mixture comprising poly-isoprene, liquid paraffin, silica, wherein said co-formulants have a reciprocal weight ratio such as to provide a paste or a cream with high skin penetrability.

Example 4

A topical pharmaceutical composition was prepared in the form of paste or cream, comprising about 8% or 6% by weight (in comparison with the total weight of the composition) of a mixture of non-saponifiable compounds obtained from a mixture of triticum vulgaris germ oil, soya glycine oil, olive oil (olea europaea) , coconut (cocos nucifera) oil in a ponderal reciprocal ratio of about 1:1:1:1 (other ratios may optionally be used) .

Examples 5 and 6

The compositions of the above Examples 3 and 4 were prepared, in which the mixture of the non-saponifiables is present at 8% by weight (with respect to the total weight of the composition) , said compositions further comprising a percentage amount of zinc oxide of about 10% by weight, with respect to the total weight of the composition, to yield a soothing paste (also provided with the known soothing/anti- inflammatory properties of zinc oxide) .

Examples 7-12

The same compositions of the above examples 1-6 were prepared, with the difference that the non-saponifiable moieties used were first deprived of their steroidal component.

Said purification was carried out using methods, such as chromatographic, commonly known and used in the techniques of isolation and purification of steroids.

Example 13

Methods of treating patients with heart failure due to the permanent alteration of the normal physiological balance of the steroidal balance.

The patients (4 male patients, aged 70, 75, 80 and 89, respectively, already treated symptomatically and not satisfactorily with traditional diuretic-based drugs and ACE- inhibitors) were treated respectively with the oleogel of Examples 1, 2, 7 and 8 with the AITAC mode (application on Armpits Groin-Trunk-Abdomen-Neck) with massage on the interested parts to optimize the absorption, with two daily applications. Treatment lasted for a period of 30 days, after which heart failure was found completely cured. No recurrences were observed.

The following Table 1 shows the average systemic values measured at the beginning and end of treatment

Table 1

Example 14

Treatment of a patient suffering from cardiogenic edema with rupture of blisters (on the right leg) post traumatic in congestive heart failure (caused by the permanent alteration of the normal physiological equilibrium of the steroidal balance) .

The patient (male and aged 89, suffering from high blood pressure and congestive heart failure and under unsatisfactory treatment with oral anticoagulants and beta-blockers) was treated with local application on the wound (and on the whole area from the right ankle to the knee) of the soothing paste of Example 6 twice a day, applying the product with gentle massage to promote the absorption. Treatment lasted for a period of 22 days and allowed the restoration of tissue integrity and the limb functional recovery. Moreover, heart failure was also found completely cured and did not give rise to recurrences. The following Table 2 shows the systemic values measured at the beginning and end of treatment

Table 2

Results equal/similar to the previous ones were also obtained in the treatment of other diseases described in the present document .

Industrial applicability

The non-saponifiables of natural origin derived from the lipids of the present invention, either deprived or not of their steroidal moiety, have proved able to induce the definitive healing of those cardiac disorders, heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction or valvulopathies , which are caused by the permanent/chronic alteration of the natural physiological equilibrium of the steroidal balance in a patient suffering from these chronic pathologies.

Specifically, the pharmaceutical topical composition of said non-saponifiables have proved to be usable in the treatment of those cardiac disorders, heart failure and/or cardiac arrhythmias and/or myocardial ischemic disease and/or atrioventricular dysfunction or valvulopathies, which are caused by permanent, chronic, pathological alteration of the natural physiological equilibrium of the steroidal balance in a patient suffering from said disease, and of the chronic lesions, either peripheral or not, associated with the same that determine them.

Claims

1. A topical, transdermal pharmaceutical composition, containing as the active portion a mixture of non-saponifiable compounds obtained from at least one lipid of natural vegetal origin, for use in the treatment of those cardiac pathologies that are caused by the permanent, chronic, pathological alteration of the natural physiological equilibrium of the steroidal balance in an individual suffering from said pathology, in which:

- said at least one lipid of vegetal origin is selected from the group consisting of: 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 seed oil; pumpkin-seed oil; rapeseed oil; raw cotton oil; palm butter; palm-kernel butter; cocoa butter; vegetable waxes; carnauba wax; bee wax; or a mixture thereof;

- said cardiac pathologies that are caused by the permanent, chronic, pathological alteration of the natural physiological equilibrium of the steroidal balance are selected from the group consisting of: cardiac decompensation and/or myocardium ischemic disease and/or valvulopathies and/or atrioventricular disorder and/or cardiac arrhythmias;

- said mixture of non-saponifiable compounds is present in an amount from 0,001% to 40% by weight, in comparison with the total weight of the composition.

2. The composition according to claim 1, for use in the treatment according to claim 1, in which said at least one lipid is 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 germ oil 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 ( cocos nucifera) oil and/or castor oil and/or sunflower seed oil and/or a mixture thereof.

3. The composition according to claim 1, for use in the treatment according to claim 1, in which said at least one lipid is selected from the group consisting of: avocado oil, triticum vulgaris germ oil, soya glycine oil, olive oil (olea europaea) , coconut (cocos nucifera) oil and/or a mixture thereof .

4. The composition according to claim 1, for use in the treatment according to claim 1, in which said at least one lipid is selected from the group consisting of: triticum vulgaris germ oil, soya glycine oil, olive oil (olea europaea) and/or coconut (cocos nucifera) oil.

5. The composition according to anyone of claims from 1 to 4 for use in the treatment according to claim 1, in which said mixture of non-saponifiable compounds is free from the steroids of vegetable origin, the phytosterols .

6. The composition according to anyone of claims from 1 to

5, for use in the treatment according to claim 1, in which said mixture of non-saponifiable compounds is present in an amount from 0,01% to 20% by weight, in comparison with the total weight of the composition.

7. The composition according to anyone of claims from 1 to

6, for use in the treatment according to claim 1, further comprising an effective amount of one or more additional active ingredients having a complementary and/or soothing and/or anti-inflammatory action, selected from the group consisting of zinc oxide, in which zinc oxide is present in an amount comprised from 8% to 12% by weight, in comparison with the total weight of the composition, preferably, of 10% by weight, in comparison with the total weight of the composition .

8. The composition according to claim 7, for use in the treatment according to claim 1, in which zinc oxide is present in an amount of 10% by weight, in comparison with the total weight of the composition.

9. A topical pharmaceutical composition according to claim 4, for use in the treatment according to claim 1, comprising about 10% by weight (in comparison with the total weight of the composition) of a mixture of non-saponifiable compounds obtained from a mixture of triticum vulgaris germ oil, soya glycine oil, olive oil (olea europaea) , coconut ( cocos nucifera) oil in a ponderal reciprocal ratio of about 1:1:1:1: in which - said non-saponifiable compounds are free or not from their initial steroid phytosterol components; and

- said composition is under the form of an oleogel.

10. A topical pharmaceutical composition according to claim 4, for use in the treatment according to claim 1, comprising about 8% by weight (in comparison with the total weight of the composition) of a mixture of non-saponifiable compounds obtained from a mixture of triticum vulgaris germ oil, soya glycine oil, olive oil (olea europaea) , coconut (cocos nucifera) oil in a ponderal reciprocal ratio of about 1:1:1:1, and comprising about 10% by weight (in comparison with the total weight of the composition) of zinc oxide; in which

- said non-saponifiable compounds are free or not from their initial steroid phytosterol components; and

- said composition is under the form of a soothing paste.