WO2002013838A1 - Seal-oil-based pharmaceutical, cosmetic, dermo-cosmetic, hygiene, alimentary and para-alimentary (food-supplements) products; their methods of preparation; their uses as preventive and/or as therapeutic agents - Google Patents

Abstract

This invention concerns Pharmaceutical, Cosmetic Dermo-Cosmetic, Hygiene, Alimentary and Para-Alimentary (Food Supplements) Compositions (or Products or Compounds), characteristically containing Seal-Oil, its Components or Derivatives, associated with Active Ingredients (synergyzing them or compensating clinical or sub-clinical deficiencies) which said Compositions (Products or Compounds) deliver to the human organism; It also concerns the process(es) of preparation of said Compositions (Products or Compounds), which normally consist in mixing the necessary ingredients, eventually under heating and/or cooling, extraction of water, etc. An example of these processes is the following composition, involving : (a) Seal-Oil - with or without fish-oil; (b) Excipients : Distilled water; Glycerol; Emulgin; Myristol; Isopropyl-palmitate; Alcohol; Cutin; a Thickening Agent (modocoll); (c) Ubiquinone; (d) Liposomes - for a total of 100 %. This current invention also comprises the uses (utilisation) of these Compositions (or Products or Compounds) in the preparation of Pharmaceutical Products (whether Preventive or Therapeutic), which are useful in the Treatment of Illness and/or Deficiencies of the Active Ingredients and/or the consequences thereof (including signs and symptoms) elicited by said deficiencies), as well as the clinical and non-clinical uses of said Products.

Description

PATENT

PHARMACEUTICAL , COSMETIC, DERMO-COSMETIC, HYGIENE, ALIMENTARY AND PARA-ALIMENTARY

(FOOD-SUPPLEMENTS) PRODUCTS INCORPORATING SEAL-QLL AND/OR THE RESPECTIVE COMPONENTS THEREOF,

ENRICHED BY LLPOSOMES OR PHITOSOMES AND/OR ACTIVE INGREDIENTS REINFORCING THE EFFECTS OF SEAL-

OIL COMPONENTS OR THEIR DERIVATIVES. METHODS, PROCESSES AND PROCEDURES FOR PREPARING, SAID

PRODUCTS USES OF THE ABOΓE PRODUCTS, ACTING AS PREVENTIVE OR AS THERAPEUTIC AGENTS.

DESCRIPTION :

This current invention is related to Compositions (Compounds^', or Products) for topical and non-topical use, characteristically containing seal-oil and/or the respective essential fatty acids (EFA's) of the Omega- 3 (Ω-3) series and/or physiologically-and-therapeuticalfy-acceptable salts thereof; and/or any seal-oil-de- rived phospholipids and/ /or the respective derivatives; and/or other components of seal-oil and the derivatives thereof; these Compositions (Compounds) can be enriched with Liposomes or Phitosomes, and / or other ctive Ingredients (reinforcing the effects elicited by the Seal-Oil Ω-3EFA's or by other Components typical of Seal-oil; and/or compensating simultaneously existing cellular deficiencies); the usages of said Compositions or Products, as well as to their methods or processes of preparation.

In particular, this invention is also related to the use, either as preventive or as therapeutic agents, of said Compositions (Compounds, or Products)^', which make use of Ω-3EFA's and/or any seal-oil-derived phospholipids and/pr the respective derivatives; and/or other components typical of seal-oil) or their respective derivatives, which will be found useful and adequate in the perspective outlined here.

In this particular invention said Compositions (Compounds, of Products) can be used either isolated or in different combinations. The Ω-3EFA's and/or their acceptable salts, the phospholipids and/or their acceptable derivatives, and/or other seal-oil components and/or their acceptable derivatives can be obtained by extraction from seal-oil, but they can also be extracted from other natural sources or be obtained through chemical or bio-technological or bio-engineering synthesis.

ANTECEDENTS OF THIS INVENTION

Cosmetic products laboratories, enterprises and firms are particularly interested in formulating treatinent cosmetics and/of treatments endowed with beneficial effects upon the skin, the mucosal membranes and their associated, allied structures (phanerae) - such as hair and nails. It is widely known that animal-derived prq- ducts exert beneficial effects upon the skm_s the mucosal membranes and the associated, allied structures (phanerae) and this has rendered the incorporation of substances of this type in cosmetics and personal-care products, as well as in dermo-cosmetics.and pharmaceutical products, including those with a decidedly therapeutic vocation.

The Ω-3EFA's (aiid/or their physiologically acceptable Salts) are widely distributed in the vegetable and animal kingdoms, where they play ubiquitous, frequent and relevant roles, namely in the realms of cellular functions and the functional regulation of cellular and intra-cellular membranes. Phospholipids also are essential constituents of the cell structures (whether these are part of the different membranes or not) and they can be (or become) "denatured" ("denatured" ?) by the inclusion in their own molecular structure of elements having a structure very close (or similar) to that of the normal physiologic elements normally found in said cell structures but differing from them thϊough small changes as those, for instance, induced by the manipulations and treatments usually imposed by the western civilisation industries to industrially extracted or treated to foods and/or their ingredients - such as the rotation of asymmetric carbon atoms, and/or other subtle and little apparent changes which tender physiologically determinant molecules incapable of fully carrying out their physiological roles. Other ingredients (still unidentified or only partially identified) of seal oil may have important physiologic fimctions and be important to counter of substances which are the object of similar (or different) impacts (such as those inducing the appearance of isorhers and other altered rnόlecules acting as antagonists - either isosteric or allosteric) making their physiological functions impossible.

The administration (or use) of seal oil or of it!s elements (and/or of their respective derivatives) by oral or parenteral route, under formulations such as food supplements or pharmaceutical preparations, has been shown to be useful in the prevention or the reversion of dysfunctional and/or involutive (ageing) processes inciding in the cellular (and intra-cellular) membranes, since thøy carry out functions which are of great importance for the biochemical regulations in the cell-membrane, intra-cellular and inter-cellular spaces.

It has been shown that seal-oil (as well as its Ω-3EFA's and/or their acceptable salts, its phospholipids and / or their acceptable derivatives, and/ /or other seal-oil components and/or their acceptable derivatives are very well absorbed by the topical route when presented in ah adequate formulation, such absotption being . a valuable "exogenous" alternative for supplying them to epithelial and sub-epithelial cells via an endogenous (oral or parenteral) route.

Thu§, seal-oil (or, rather, Seal-Oils, since different compositions are known to exist for different species or even for different strains of seals), as well as its Ω-3EFA's and/or their acceptable salts, its phospholipids and/or their acceptable derivatives_? and/or other seal-oil components and/or their acceptable derivatives, possess properties and characteristics which are most interesting and useful to be exploited, once adequately formulated, in the domains of cosmetic, dermo-cosmetic and pharmaceutical prevention and therapy, as well as in Alimentary, Para-Alimentary.and Hygiene (Consumer) Products Said use and exploitation is based on the fact that the referred Compositions (or Compounds) have properties which induce humidifying, anti-dehydration, emollient, elastifying, restorative, and allied or similar effects.

The concentrations of seal-oil, its Ω-3EFA*s and/or their acceptable salts, its phospholipids and/or their acceptable derivatives, and/ /or other seal-oil components and or their acceptable derivatives, in this current invention may vary within very ample limits, according to the intended aims and goals and the fonnulation : for example, thøy can be used within the interval comprised between 0,01 % and 99,50 % weight/weight, preferably between 0,1 % and 40 % weight/weight.

Seal oil, its Ω-3EFA's and/or their acceptable salts, its phospholipids and/or their acceptable derivatives, and /or other seal-oil components and or their acceptable derivatives all have an extremely low systemic toxicity and a topical toxicity close to nihil, according to tests carried out in animals. Besides, it is important to state that seal oil has been shown to contain the Ω-3EFA's in proportions which match those of the human body - a characteristic which immediately makes seal-oil a preferential source of saidΩ-3EFA's for human use.

X

Olive Oil is, of all those which are known, the natural fat most suited for human consumption in what concerns the preparation of food at high temperatu-re. In fact, not only have scientific, modern, clinical studies demonstrated that Olive Oil lowers total cholesterolemia and raises HDL-cholesterol <the "good- colesterol"), but also Olive Oil has been shown to be the only edible fat which will go through heating to 200 ⁰ C without significant generation of products harming health. In fact, in receht investigations, carried out witlbdifferent edible fats easily found in supermarkets or food shops, all experimental animals (rats, mice and guinea-pigs) after a 6 months period of ingestion of said edible fats (after being heated to 200 ° C during sufficiently long periods of time), exhibi-ted cancerous lesions - the exception was the group of animals fed Olive Oil. With the exclusion of all other fats. Besides, Olive Oil is most probably the edible fat most generalizedly appreciated (liked) all over the world.

Urtfortunartely, Olive Oil is insufficiently rich in those AGE (or EFA's) - which the human organism is unable to synthesize Out of other fats (this being the reason for EFA's really being ESSENTTAI for human heath ..,). It would therefore be ideal if Olive Oil was endowed with said EFA's in proportions covering the daily needs of each Consumer. This being so, by adding hatural oils (or fats), rich in EFA's (or even the adding purified EFA's) to Olive Oil, it will be possible to obtain mixtures which are non-existing in Nature but which shall have great higher dietetic value p guarantee feedi g habits ensuring good, equilibrated health to those who adopt them.

The ingestion of said fats enriched with the EFA's needed to avoid all and every state of carency (in EFA's) of the organism shall be capable of doing tj p correcgao and, a fortiori, the prevention of many illnesses, among which the following deserve being mentioned : arteriosclerosis (and platelet hiperag- gregability and hiper-adhesiveness, hiper-coagulability and low blood thrombo-lyic activity); doencas de tipo rheumathόid; states of excessive dryness of the skin and/or the mucosai membranes, and skin diseases triggered or aggravated by said states of careήcy; illnesses (of the intestines and other organs, as it happens in the eyes and in feminine genital organs) involving mucosal inflammation and immunitary; neurologic and psychologic dysfunctional processes. Among the natural fats to be added to Olive Oil, the following inust be counted :

(a) vegetable oils rich in EFA's (also knowri as "fats rich in όmega-3") - Cold-pressed Oils EXTRACTED frombόrhage, gt&ps seeds, linnseed, cartharnus, sunflower, etc.;

(b) fish oils - mostly and preferably ; from fat fish (salmon, Sardine, halibut, shark, thunafish, etc, etc.);

(c) animal oils - ass much as possible they must be Cold-Pressed, preferably Seal-Oil, particularly rich in EFA's (inclunding DPA) in proportions closely mimmicking those foμnd in the human organism, a reason why such oils are the most adequate, in terms pf physiology, for human consumption!.

On the other hand, enriching Olive Oil as suggested above, not with complete natural fats, rather (only) with the essentials fatty acids of the όmega-3 series and/or the phisiologically acceptable salts thereof and/or otiier of their components and/or derivatives considered to be desirable, to say nothing of any other active ingredients referred to in this Patent and adequate for human feeding ingestion.

Thus alimentary products shall be prepared (through mixing Olive Oil with with other fats) capable of supplying to the human body healthier alimentary fats (exempt of toxicity), and being complete (through containing the Essential Fatty Acids or EFA's, whose want trigger states of carency). Said enriched fats are therefore preventive of phisiopatologically seroius carencies, which induce the loss of health and of immunity against illnesses) and superior to those usually proposed for sale to the public, avoiding carencies of serious consequences for the maintenance of a healthy state and of the capacity tp defend himself, (directly ou indirectly) of multiple diseases,.

X

Different phenomena and processes must be taken in consideration in the amplest context, within which only really self-sustainable decisions can be taken in the long run - that is, only biologically and ecologiςally sound decisions must be underwritten. In that perspective, a somewhat surprising phenomenon (or process) has beeri taking place and the public opinion which does not follow this specific field: has not been aware of its importance - the exponential increase of the seal population , after this¹ species was considered by the world ress to be an endangered one, after the campaigns that ecologi§ts and other well-intended entities prganised to stop the killing of baby-seals, whose skhϊs were used to make fur coats for women. The hunting restrictions thus elicited by these lejμtimate preoccupations (more "humanitarian", if such word can be used in t elation to non-human animals, than ecological) allowed for a significant shift of the then existing equilibrium and the consequent expansion of the number of existing seals. Significantly safe data are now available (from the Government of Canada) which demonstrate that this seal population is the largest wild mammal population in the world (provided that the human is not considered) - with over 6 (six) million seals in Canada alone. Some consequences of an equilibrium shift should have been exfiected - but they werέ not all anticipated or set in a perspective taking into account immediate human problems and priorities. One rather striking illustration pf this last statement pertains to the fact that each seal eats an average of 14 Kg of cod (and sinύlar) fish per d$y, a fact which, albeit not being probably not the sole factor responsible for the current scarcity of that fish species, .nevertheless probably contributed significantly to the "palmeta" (cod fish) war, which had as a consequence that Portuguese (and other) fishermen were forbidden from carrying out their traditional activity of fishing cod in Newfoundland.

The census carried out estimate that the current annual seal hunting kills 250.000 to 300.000 animals in Canada, and that it would be necessary to kill 600.000 animals per year to reach a zero-growth equilibrium in this mammal population (in Canada alone), The annual production of seal-oil - in Canada alone, which has about 80 % of the world production_; of seal-oil - 3,000 metric tons. It is therefore of importance (it urges) to find added value uses for a product which, otherwise, shall be discarded away and lost - or shall be indiscriminately used in purposes of no special interest, depriving populations (mainly Eskimo) of a compensation which is legitimately due to them and which shall be able to sustain themselves through them instead of having to resort to charity and welfare. Different potential uses have been studies and what follows should be considered as part of that perspective.

X

Essential Fatty Acid (EFA's) are dietery (or alimentary) factors whose ingestion is essential for the body to keep healthy. They were disςovered in 1929 by George and Mildred Burr (University of Minnesota, USA). There are two series of EFA's, the n-6 (or όmega-6), derived of cis-linoleic acid; and the n-3 (or όmega-3), derived of alfa-linolenic acid The digits indicate the position of the first double link (C=C) in the molecule counted from the omega terminal. As for certain vitamins, cis-linoleic and alfe-linplenic acids are devoid of activity (except that of serving as energy substrates - being "burnt" i cellular metabolism to generate energy for the cell) while they have not been specifically bio-transformed in the human body, as shown hereafter¹ :

Sέries n-6 Sέrise n-3 cis-linoleic acid alfa-linolέnic acid

^■ delta-6-desaturase (D6D) gama-linolenic acid (AGL) 18:4, n-θ i elongation - dihomo*gamma-hnplenic acid (DGLA) 20:4:, n-3

4 4- delta-5-desaturase (D5D) -

PG's series 1 arachidόnic acid eicosa-peήtaenoic acid (20:5, n-3)

I I i PG's serie 3

PG's serie s longer EFA's longer EFA's

The EFA's of these two series (n-6 and n-3) are not interchangeable in animals. It is. orthy noting the low activity of delta-5-desaturase no Man and the guinea-pig, while it is high in mice and rats.

EFA's are important for two foundamental reasons: (a) they are constituents of all membranes in all tissues of the body, playing a role which is vital for determining the characteristics and the biological capacities of their respective membranes - it is therefore logic that EFA's deficiencies trigger great dysfunctions in all body tissues; and (b) EFA's are the precursors of a group of highly reactjve and very efemerous substances - prostaglandins (PG's), leuco-trienes {LT's) and other related molecules, such as fhromboxaiies (TX's), which intervene in an infinity of cell and organ processes. More than 50 PG's, LT's and related molecules with biological importance have been identified, acting ai local messangers in the regulation of the activity of different tissues and organs where they are produced. Arachidonic acid (AA) has very different and varied effects through the products it generates. Thus, for pxample, i both originates PGI2 (prostaciclin), with desirable effects pf inhibition of platelet aggregation and vasodilatation, and thrpmboxane A2 (TXA2) and PGF2 , which promote vasospasm, thrombosis and inflammation. After AA, PG's and thromboxahes (TX's) are due to the intervention of a ciclo-oxigenase, while LT's are due to a completely different enzime - a lipo-oxigenase :

AAini mpmbrane deposit

10 (inhibited by NSAI's and PGE1) free AA

10 I

(inhibited by vit and and bt Lipooxigenasei ^Ciclooxigenase (inhibited by NSAI's and

AAS) a OH-acid derived I from DGLA) LT's PG's an TXA2

(After Horrobln, 1982)

NSAI's (noή-steroidal anti-inflammatorieS) and AAS (acetyl-sallicilic acid, or aspirin), do not interfere directly with the production of LT's, hile inhibiting tiie production of PG's and related products (TX's, etc.), make available a greater quantity of AA the lipo-oxigenase, a change which can exacerbate inflammatory processes regulated by LT's. This is what happens, apparently, in the cases of asthma induced or aggravated by AAS. Cortico-sterόids, far more potent than NSAI's and AAS, block the liberation of AA horn the membrane deposits and, therefore, the production of both LT's and PG's.

Since delta-5-dέsaturase is very little active in the human species, diet may have an important impact in the (quantitative and qualitative) regulation of the equilibrium of the series of PG's referred above. Thus, for example, ljnoleic acid (whichh originates DGLA) is ingested mainly in vegetables (and in minor quantity in certain animal organs^ while AA is found nainly in meats and seafood (shrimos being particularly rich in AA).

¹ Horrobin, 1982 All that has been said implies that states of deficiency of EFA's cause dysfunctions more or less intense (depending largely on the intensity of the deficiency) in animals (human or not) where they occur. The main signs and symptoms to be found in (ACUTE & CRONIC) EFA's DEFICIENCIES were the following :

1. Hair loss; skin lesions pf eczematous type; hypertrophy pf sebaceous glands.

Dry, scaly skin, eczematous or soriatic, erifhematous, very sensitive and hyper-reactive.

2. Great general and cutaneous irritability, higher apetite and caloric consumption.

3. Delayed and deficient healing, mainly due to collagen deficiency.

4. Delayed or arrested growth.

5. Hyperpermeability of all body membranes to water. Excessive loss of water through the pele, causing paradpxal dehydration, with thirst and hyper-concentrated urine.

6. Loss pf reproductive activity, particularly in the male; females usually develop complicated pregnancies and miscarriages.

7. Kidney hypertrophy and haemorrhages, with rehal insufficiency.

8. Hepatic steatosis.

9. Atrophy of execrine salivary, lacrimal and pancreatic glands

10. Inhibition of immune system, with great susceptibilidty to infections.

In what concerns cronic EFA's deficiency states, alimentary supplementation in EFA's improved Patients with cardio-vascular problems, diabetes, breast problems and multiple sclerosis. Mosy relevant was the discovery by the Brenner group of the progressive disappearance of actividade of delta-6-desatυrase wi h ageing, which renders animals (humans included) functionally deficient in EFA's as age increases. The loss of activity of this enzyme occurs first in the gonads. EFA's administration has systematically been able to increase the concentration of EFA's in tissues -accompanied by clinical benefits widely documented in the medical literature during the l st years.

Nevertheless, ageing is not the sole cause of the loss of enzymatic activity of delta-6-desaturase. Other factors contribute to that effect : ^• 1. Saturated fats inhibit this enzyma.

2. "trans" fatty acids (v. infra), formed during industrial extraction and processing of alimentary fats, inhibit delta-6-desaturase.

3. Diabetes has low activity of delta-6-desaturase,

4. Alcohol (ethyl) inhibits the activity of delta-6-desaturase (D6D).

5. Adrenalin (and, therefore, stress) inhibit the activity of D6D, which beta-blockers antagonize

6. Fasting inhibits the activity a£D6D, but a hypocaloric diet increases its activity 3 fold.

7. Gluco-corticoids (high in long-lasting stress) inhibit the activity of D6D.

8. Hypoproteic diets inhibit the activity of D6D and hyperproteic diets raise it. 9s The ingestion of glucose inhibits the activity of D6D.

10. Oncogenicos viruses and ionizing radiation inhibit the activity of D6D. x

Seal Oil is particularly endowed with (Omega-3) Essential Fatty Acids (Omegar3 EFA's or simply Ω-3EFA 's) necessary (and, above all, well suited) to the human organism, particularly because it contains all Ω-3 EFA's which are known to exist in (and are needed by) the human species and because those same Ω-3 EFA 's are found in the same proportions in the tissues of the human body.

Now_* it has been shown that when these Ω-3EFA's (essential, as their name clearly indicates, to many metabolic processes - among which the synthesis and the renovation of different cellular membranes structures, because the body can not function well without said Ω-3EFA's, and is unable (and incapable) of synthesising them, if and when such Ω-3EF^'s are not present in sufficient quantity in the organism, the body replaces them with the most similar Fatty Acids (FA) it can find in its existing reserves. Such deficiency states normally involve serious cellular dysfunctions, affecting different organs, not only because said EFA intervene directly in metabolic chains as substracts or regulators (an example of that being the metabolism of prostaglandins)., but also because, inadequate FA overloads alter significantly the permeability and the selectivity of different cellular membranes, thus excessively impeding and/or facilitating the passage of substances across cell membranes. This causes ill functioning (with clinical symptoms ranging from light to intense) related with deficiency (relative or not) and/or overload (relative or not) of metabolites and products (which may be .essential as, for example, water) states which are detrimental for the good ftinotioning of cells. When this occurs, organs which are important for bodily equilibrium tend to suffer, as, for example, happens with the Central Nervous System (CNS), the Peripheral Nerves, the Blood Vessels, the Immune Cells, the Joints, the Mucosal Membranes (Opular, Nasal, Intestinal, Genito-Urinary, etc.) and the S n -to mention only some pf them. They display dysfunctions of varying intensity which are a function of the intensity of the Ω-3EF 's deficiencies^ on the one hand, and of deficiencies and/or excesses which it secondarily results in Or, at least, accompanies, such as those of certain non-essentiai FA which act as Ω-3EFA's antagonists. Therefore, one of the consequences systematically found in persons with prolonged and intense Ω-3EFA's deficiencies is the alteration of their cell membranes - in what concerns their macro and microscopic appearance and constitution, as well aέ in what concerns their functional capacities. Of these, one pf the most frequently affected has to do with the capacity of carrying out the amount normal regulation of the metabolism (or control) of water. The consequences appear easily, among which the following deserve mentioning : (a) edematous fluid collections, r very often "of lymphatic type"; and (b) the different types of the "inadequate secretion o anti-diuretic hormone syndrome", usually associated with "lymphatic edema" and "orange skin cellulitis".

The n-3 EFA's considered most beneficial for human health (specifically, in what concerns the

From 1980 onψapάs hundreds of experimental studios, mostly in rats (because humans are far more volmnmous and expensive for such studies), and some in Humans: Strangely,, most these studies reported EPA and DIJA levels but made no reference to DPA. Knowing that EPA and DHA are the main components offish-oils, and that they were initially considered to be responsible for the beneficial effects pf fish oils upon circulation, strangeness lessens. Then, as analytical technology improved, specially that of capillary columns for GLC, reference to DPA started to show up. ^■

O arachidonic acid (AA) is a n-6 series EF A biochemically importante (essential) in the human body economy. Its concentration serum phospholipids and in thp lipids of different organs is changed by n-3 EFA's. Administered $ an isolated preparation, EPA and DHA slightly and similarly dpcrea-sed the levels of AA. But their own concentrations increased sharply. EPA lpwered DHA circa 15 % Jjut raised DPA more than 100 %. On the contrary, DHA lowered DPA concentration by 1/3 while EPA levels increased :

Fish oils have DPA concentrations of only circa 1/10 of those of EPA and DHA - therefore it is not surprising that its supplementation had no great impact on circulating DPA concentrations, and-those which were observed probably were mediated by pelo EPA elongation to DPA, Benistant et a (1996) found that DPA can accumulate in endohtelial cells phospholipids and reduce AA's undesirable effects; and Kanayasu- Toyoda et al. (1996) found that DPA has no effect upon vascular smooth muscle cells migration but that it can, (trough phospholipidic-DPA) increase 20 fold (dose-dependently) the migration of vasculares endohtelial cells, while HogdSon et al. (1993) demonstrated that DPA concentration human blood platelets sanguineas is inyersely correlated with the rate of deposition of those platelets in the coronary arteries of women (it should be remembered that there are 10 times more deaths vascular causes among women than those due tobreast cancer).

Several studies suggest clearly that DHA may be the object of a shortening of its chain so as to generate EPA, hile EPA can be easily converted to DPA It bepame evident, througli tiie studies carried out : contraaily to what is usual for products alien to the human body (xenobiόtics, such as, for example, aspirine), linear dose-effect curves of correspondence are not easily established. DPA is a usual and phisiologial comonent of human blood (a biological, therefore) and, jn circulating phospholipids reaches in general concentrations circa half of those found for EPA, which for a long time was thought to be the active component in the cardio-vascular system essential to the eskimo dipt.²

Once Kanayasu-Toyoda et al. (199,6) and Benistant et al. (1996) and many other authors demonstrated that EPA, DHA and DPA induce significant effects upon the regulation of circulation and of diverse cellular behaviours, it was easy to understand that these EFA's, present in Seal Oil (particularly DPA), partipipate in the fine regulation of those mechanisms which help maintain healthy since they are ingredients of the eskimo (iniiit) diet, based in -seal fat* a foodstuff far richer in DPA than any other ever proposed as valuable througli the induction of cardio-vascular effects - preventive or curative (therapeutic)s of diverse damaging processes, such as coronary disease, thrombosis, vascular inflammatory processes, the production of tri-glycerides and of low density lipoproteins (LDL); it was also demonstrated that the seal fat and PPA are capable of reducing the conversion of AA to thromboxane A2 (TXA2, a fhrombogenic agent) and to give birth to prostaglandin D3 (PGD3, a platelet-anti-aggregant agent), a series of effects which can only be favorablp to health and the fight against disease³.

On the other hand, it has recently been recognised that natural oils (namely those of vegetable origin), if extracted under heat (between 160 and 200°C) and high pressure, can be found to be quite impoverished in or even deprived of said Ω-3EFA's as a consequence of Ω-3EFA's transformation into their stereo-isomers through the rotation of asymmetrical carbons, passing from cis (or cis-cis) form to trans (or cis-trans) form, as is the case, for example, of s-gamnra-lin leiiie acid, which af temperatures oscillating between 54 and 60°C transforms itself into trβrø-gamma-linolenic acid..

Such newly formed stereo-isomers are rqetabolically antagonists,to (against) the physiological metabolic use of the still existing Ω-3EFA's because they act as (isosteric and/or allosteric) biό-chemical competing antagonists -which extraordinarily aggrav te the scarce-ϊntake-of-Ω-3EFA's-deficiencies - extremely frequent today because almost all alimentary vegetable fats the public consmner (today) can buy are precisely extracted under high heat (160 to 300°C) and high pressure of circa 2,5 to 3 atmospheres (both resulting in much higher yields of those fats).

Thus, it happens that most persons suffer from more or less intense Ω-3EF^'s deficiencies - but the symptoms of such deficiencies still go unnoticed of both Patients and Physicians, since the referred discoveries are rather recent and have not yet been transferred into the public domain, And what has been shown to exist at systemic }evel in- the body, also exists at the level of different organs and systems, where certain particularities gain importance, as is the^' case of the skin ahd the mucosal membranes, which together form ah enormous system, of great importance for the total body economy.

²Ackman, 1997

³ Kanayasu-Toyoda et al; (1996); Dyerberg et al, (1978); Kromhout et al. (1985); Phillipson et al. (1985); Lee et al.

(1985); πiingworfh et aL (1984); Whitaker et al. (1979)^ Needleman et al. (1980); Benistant et al. (1996); etc... One of the symptoms of intense deficiency is the dryness of the sldn and it is easily confirmed that, in the modern western world, the vast majority of women over 35 feels the need to apply fat-containing creams (said to be "hydratihg ") to their legs because they feel they are excessively dry. On the other haiid, the alteration triggered by Skin deficiency in Ω-3EFA's, not only gives skin a rough and scaly aspect, it also implies one perturbation of prostaglandins (PG) metabolism. PG are recognised participants in the fine control of inflammatory prpcesses, as "second messengers". Thus, the skin of persons deficient in EFA is particularly prone to inflammatory, scaling, or pther types of processes - which can manifest themselves as important components of clinical entities, such as eczema, dermatitis (urticarious, erithematous, psoriatic), etc., etc..

It was therefore not, surprising that creams and ointments and ther (galenic forms)pf Seal-Oil-based Product!} - in which seal-oil was (pharmacologically) synergised and enriched by thp use of Liposomes (or Phito- somes) and of Active Ingredients which reinfoϊce the effects of characteristic seal-oil Ω-3EFA's - revealed themselves to be particularly active in the clinical essays we have carried out to treat problems - deπnatologic and of those afflicting other fields (gynecologic, ocular, ENT_? respiratory, digestive, urinary) - related to Skin ahd JVIucosal problems linked to clinically detectable Ω-3EFA's deficiencies. These Products were also found to be efficacious in homologous dysfunctions (of similar nature), striking structures deeper than the Skin and the Mucosae referred above (organs, tissues, etc.). The Products referred to will serve, therefore, to treat both topic and systemic problems. Oh the other hand, we verified that the addition of certain Products necessary to the organism - which was in a state of deficiency in relation to them -, as they were added to said Ω-3EFA's, triggered a prompter saturation of those cellular structures deficient in them. Thence the obtained effect of synergy resulting from the addition of said Products to Ω-3EFA's or to the Oils containing them - preferably those richer in Ω-3EFA's, most preferably Seal-Oil, in which the Q-3EFA,'s exist in proportions similar or even equal to those characteristic of the human body.

One should nevertheless stress that Seal Oil is endowed with a specific EFA - DRA, or Docosa-pentaenoic acid (22:5, n-3) which has been shown to induce (a) inhibition of vascular smooth muscle cells; and (b) the migration of endothelial cells and the endothelial repair of blood vessels, an effect confirming its usefulness in thp prevention of vascular diseases, namely, that of arteriosclerosis; besides, it has been shown that DPA is far more active that other EFA's; and that other EFA's, specifically those which exist in fish-oils, such as EPA (eicosa-pehtaenoic acid [20:5,n-3]) and DHA (docosa-hexaeηoic acid [22:6,n-3]), recognized as useful in the fight againstvascular diseases, act through their transformation into DPA, which has been shown to be 10 times more active than EPA in what concerns the migration of endothelial cells. That explains why Seal Oil and its derivatives (namely DPA and/or at least those containing DPA, such a phPspholipids andtriglyce- tides) are far more potent and useful in preparations hereinafter indicated than EFA's of other origin.⁴

The Products hereby described to correct at SMn and (various) Mucous Membrane levpl, as well as in the internal milieu of different organs (at which they are aimed, through the usp of more adequate galenic forms) the consequences of EFA deficiencies and/or deficiencies in other substances referred by this Patent assume (among other) the forms of : Creams, Ointments, Lotions, Solutes, Irrigations, Drops, Collyria, Sprays, Nebulizations, Aerpsols, Suppositories, Tablets, Capsules, Oragees, Gums (Chewing-Gums), etc., etc. - each One of them with or without liposomes or phitosomes.

Said Products (or the galenic forms thereof) shall contain the Active Ingredients in varying quantities and proportions (without necessarily going beyond, in Cosmetic and Dermo-Cosmetic Products, the concentrations of 30 % in terms of weight weight or weight /volume). A certain number of these Ingredients (hereinafter indicated, and meant to compensate deficiencies, or to synetgise the effects of Ω-3EFA'S or of any of other active Ingre-dients referred in this Patent) may not be present in some Products (and in the respective Formulations) :

(1)^' Seal Oil (mostly under filtered and deodorised fprm) - and/or the respective Ω-3EFA's; these should represent 0,5 % to 25 % (weight/weight) of the final product, more particularly 2,5% to 25 %, preferably 2,5 % to 15 %;

(2) Excipients, among which the following may be the chosen ones : Water (distilled or demineralized), which may amount to 40 to 75 % (W: W or weight : weight) of the final product; Glycerol, which will amount to 2,5 a 10 % (W : W) of the final product; Emulgin (product n° 7450 in Merck Index), which will amount to 1,5 a 5 % (W : W) of the final product; Myristol (product n° 6184 in Merck Index), which will amount to 2,5 a 10 % (W : W) of the final product; Isoprop'ylpalmitate, which will amount to 2,5 a 10 % (W : W) of the final product; Alcohol, which will amount to 1,5 a 5 % (W : W) of the final product;

⁴ T. KamayaSu-Toyoda et al - Prostaglandins, LeukotriPnes and Essential Fatty Acids (1996) 54(5), 319-325 Cutin (product n° 2610 in Merck Index), which will amount to 4,5 a 15 % (W : W) of the final product; a thickening agent (such as sodium bentoήite or modocoll), which will amount to 0,5 a 5 (W : W) of the final product; carb mer ,(940, etc.); waxes (bee wax, etc.); etc., etc..

(3) lϊsh Oils (mostly of halibut, salmon, tunna, sardine, shark, cod, etc.) rich in Ω-3EFA's - and/or the respective Ω-3EFA's; such Ωτ3EFA's (as any other Ω-3EFA's mentioned in this Patent) may eventually be produced by chemical synthesis and or through techniques of genetip engineering; they will represent 7,5 to 15 % (W;W) of the final product;

(4) Vegetablee Oils (namelly those of evening primrose or field borage, of grape seeds, etc.) rich in Ω- 3EFA's - or the respective Ω-3EFAY, they will represent 7,5 to 15 % (W: W) of the final product;

(5) De-acylated glycerophospholipids (glycero-phosphoryl-choline; glycero-phosphoryl-inositol; glycero- phosphoryl-serine; glycero-phosphoryl-ethanolamine; etc.) and/or their respective physiologically accp- ptable salts, ih concentrations ranging from 0,1 % to 10 % (W:W);

(6) Silicotte(s) (cyclomethicone, dimethicone coliopol, cyclomethicpne, etc.).

(7) Ubiquinone (or ubidecarenone or Co-enzyme Q-10) - a natural product acting as a potent and physiologic anti-oxidant which our experiments have revealed is capable of completely reverting inflammatory skin processes due to physical, chemical agents (burns, etc.) or biologipal agents.

(8) Liposomes or Phitosomes made so as to contain and/or help deposit said Ω-3EFA's and or Q-i0 and/or Ingredients such as those in this list on the surface of cell membranes of those cell we aim at enriching With these Active Ingredients. We aim at enriching the Liposomes or Phitosomes in question in tliose Ingredients referred to; they may eventually contain Seal Oil itself inside their membranes, but even in such eventuality they shall in principle contain other Ingredients; they shall represent 5 to 15 % (W:W) of the final product;

(9) Silver Salts (tliose metabolically more active and directed at cell fractions more specifically mvolved ih cellular respiration and in energy production and control) -because we confirmed that silver is one oligo- element capable of augmenting the efficacy of Q-10; said salts are, for examplpj, orotate, gluponate, picoli- nate, and all those capable of easy penetration into cell structures - butyrate and its immediate derivatives and other salts of amino or fatty acids of low molecular weight - can be used to alter energy metabolism at cellular mitochondrial and nuclear level;

(10) vitamina Bl (cocarboxylase, if possible under stabilised form) a d/ r ATP (Adenosine-tri-phosphate - dissodic or other) under a form capable of promoting and activating energy production and/or liberation even in visibly deficient cells o_r those under aggression or intoxication decreasing such processes significantly;

(11) other vitamins of B complex, and above all B5 (Panthenol), B6, B12 and Folic Acid, which are implicated in cell respiration processes and in those pontrolling cellular energy;

(12) other Anti-oxidants - such as vit. A, C and E, glutathion and glutathion reductase, catalase, supero- xyde-dismuthase. poliphehols (including picnogenot) and catechines and their elements and polimers;

(13) Anti-Ageing Products and antagonists of collagen and elastiή cross-linMng, such as anti-oxidants, or liphenols and catechines, and their elements and polimers, as well as Products rich in silicium (such as the garlic derivatives and extracts of plants with similar properties); glucosaminόglycans; hyaluronic acid; amino-aeids and or bio-stimulins; collagen, elastin and placental hydrolysates and extracts; and/or the extensible proteins;

(14) certain oligo-saccharides of vegetable origin, namely those extracted from algae and/or DMSO (of vegetable and non-vegetable origin), inducing membrane de-stabilisation and, therefore, increased membrane permeability to the chosen Active Ingredients used in the Products contemplated in this Patent;

(15) solublfe calcium carbonate and, other soluble salts of (mostly soluble calcium carbonate known as "coral- calcium" (CC, extracted in QMnawa and Tokunoshimo Islands, in Japan, and marketed, outside Japan, by the Swedish firm PMG - Preventive lytedical Group); other oligo-elements, including chromium and/ or selenium and/or germanium and/or zinc (as salts - orptate, picolinate, gluconate and other salts derived of fatty- and amiήo-acids) with great importance in the processes related to tissue healing and cellular reparation (systemic, epithelial and/or occurring in other structures related to the Skin and the Mucous Membranes, etc).

(16) Chelanting agents and ion-exchange substances (as, for example, calcium-EDTA); .

(17) Chromoglycate (disodic or not) and/or other anti-allergic and/or membrane-stabilising products.

(18) Different Vegetable or Animal Products, capable of inducing metabolic recovery in cells, such as cen- trophenoxine and certain Vegetable Extracts (as, for example, tepescohuite or mimosa tenuflora pair, tabernanthine, gingko biloba, aloe vera, and other extracts, such as those rich in Vegetable Auxins).

(19) Epidermal Growth Factor (EG?);

(20) Interferon - alpha, beta and / or gamma;

(21) Enzymes, specially enzymes capable of digesting and mobilising blood components (a good example is hirudin) or components of connective pr elastic tissue (for example, cbllagenase and elastase);

The Products must be produced (fabricated) in agreeihent with the well known rules of the Pharma- cetitical^rt. As the different, relevant methods of galenic preparation are perfectiy known in the Pharmaceutical world, it does not seem necessary to describe them in this document. It suffices to say that in certain formulations some of the Active Ingredients shall be inside the Liposome or inside the Liposome membranes and the other outside them (that is, in the vehicle in which the Liposomes are dispersed; ahd that in other formulations the relative positions (or distributions) in relation to the Liposome membranes will be inverted when compared to the first. On the other hand, it should be said that it is intended not to exclude from this Patent any possible combinations and permutations of the above Ingredients, including Seal Oil and the respective Ω-3EFA's, whiph may similarly be jinside or outside the Liposomes), The proposed trademarks, indi cations and uses of the different formulations may be totally and/or partially coincident or overlapping - but it is opportune to declare that substantial differpnces between thpni will be found by the Specialists who evaluate them clinically.

The follwoing examples illustrate this current invention, without limiting it in any way whatsoever :

Example # 1 NUTRITIVE CREAM (I) weight / weight

(a) seal-oil - 10 %; ou seal-oil - 5 % + fjsh-oil - 5 %; total : 10 %

(b) Glycerol 04 %

(c) Emulgin 03 %

(d) Myristol 05>o

(e) Isopropyl- Palmitate 04 %

(f) Alcohol 03 %

(g) Cutin 06 %

(l ) Thickening Agent ( iodocoll) 02 %

(i) Ubiquinone 05 % .

(j) Liposomes 10 %

(k) Distilled Water 48 % for a total of 100 %.

Preparation : Mix the indicated ingredients at 40 °C temperature, under stirring and allow cooling.

Example 2 NUTRITIVE CREAM (II) ip)

(I) a Seal-oil 10,0 % or Seal-oil (5,0 %) f Fish-oil (3,0 %) + Vegetable Oil (2,0 %) 10.0 % b Gliyerol Monoestearate emulsified with Poliethilene-glycol 05,0 % c Stearic Acid of origin vegetable 08,0 % d Sweet almonds Oil 07₅0 % e Miristyl Ethpxi-iniristate 06,0 % f Cetyl Alcohol .01,0 % g Lauryl Pyroglutamate 01,0% h Silicohe 00,5 % i Demineralized Water q.s.

01) a Glycerol 02,0 % . b dlycprpphosphorylcholinae 03,0 % c Zinc Pyroglutamate 0O,2 % d Pyroglutamate of crhomium 00,2 % e Pyroglutamate of copper 00,2 % f Demineralized Water q s. Preparation :

Mix the components of phase (I) with water and heat up to 54 °C;

Mix the components of phase (ll) with water and heat up to 54 °C;

Add as phases (I) and (II) stirring slowly;

Add the products of this phase

(IH) to Triethanolamine q.s. up to pH 6,4 - 6,6

Add b Perfume q.s. c Demineralized Water (diluting) q.s. up to 100,0 %

Allow cooling up to 35 °C, stirring slowly.

Example 3 DERMO-COSMEΗC HYDRATING¹ LOTION (I) (P/P) a Seal-oil 10,0 % ou Seal-oil (5,0 %) + Fish-oil (3,0 %) + όleo vegetable (2,0 %) 10.0 % b methyl p-oxybenzoate 00,7% c propyl p-oxybenzoate 00,3 % d Glycerylphosphorylchpline 35,0 % e Demineralized Watef (diluting) q.s, up to 100,0 %

Preparat ion :

Dissolve Seal-oil (or a mixture of oils indicated above) and os conservantes in water tepid de-ionized; Add a Glycerylphosphorylcholine, stirring slowly.

Example 4 LQTIONHYDRATINGDERMO-COSMETIC (H) (p/p) a Seal-oil 07,0 % or Seal-oil (5,0 %) + Fish-oil (3,0 %) + Vegetable Oil (2,0 %) 07.0 % b Glyceryl Stearate 00,5 % c Isocethyl Stearate 10,0 % d Lanolinic Ether PPG-10 00,3 % e Lanolinic Alcohol 00,7 %, f Acido oleic 02,0 % g Triethanolamine 01,3 % h Carbomer 941 00,1 % i Glycerol 04,0 % j Conservative Agent(s) 00,4 % k 5 % Solution of carrot extensin 05,0 % 1 Polipeptides of 5 % extensina hydrolisate ("Vegagen" Centerchem⁵) 05,0 % e Demineralized Water (diluting) q.s. up to 100,0 % Preparation :

Dissolve Seal-oil (or the mixture of oils indicated above) and the conservative agents in tepid de-ionized water; Add the ofhpr elements, under stirring.

Example 5 MAKE-UP CREAM (A) : ⁽ ip) ω Seal-oil 10,0 % or Seal-oil (5,0 %) + Fish-oil (3,0 %) + Vegetable OIL (2,0 %) 10.0 % b Bees Wax 03,0 % c Polyglyceryl-4-oleate 02,0 % d Silicones (ciclomethicone and dimethicone coliopol) 08,0 % e Silicone (cyclomethipone) 08,0 % f Glycerylphosphorylethanolamine 01,0 % g !pigments 15,0 %

(H) a Sodium Citrate 03,0 % b Conservative agents q.s. e Demineralized Water (diluting) q.s. up to 100,0 %

Preparation :

Mix Seal-oil (o the mixture of oils i^ήdicada above), silicones, PolyglyCeryl-4-oleate and

Centerchem Inc. - Stamford, CT₅ USA Bees Wax and conservative agents, heating up to 54 °C; Add the other elements of phase d), dissolving them in de-ionized water, adding. Glycerylphosphorylethanolamine last, under slow stirring;

Mix phase (II) in de-ionized water ;

Mix phases (I) and (II) under slow stirring ; allow cooling;

Homogenise the resulting CREAM.

Example 6 CREAM of MAKE-UP (B) : (I) (P/P) a . Seal-oil 10,0 % or Seal-oil (5,0 %) + Fi?h-oil (3,0 %) + Olep vegetable (2,0 %) 1Q.0 % b Bees Wax 03,0 % c Polyglyceryl-4-oleate 02,0 % d Silicones (cyclomethicone and coliopol of Dimethicone) 08,0 % e Silicone (cyclomethicone) 08,0 % f Glycerylphosphorylethanolairiine 01,0 % g Pigments 15,0 %

(π) a Citrate of sodium 03,0 % b Conservative agents q.s. e Demineralized Water (diluting) q.s. up to 100,0 %

Preparation : Mix Seal-oil (or the mixture of oils indicated above), silicones, Polyglyperyl -4-oleate i

Pees Wax and the conservative agent^, heating up to 54 °C; Add the other elements of phase (1), disolving them in de-ionized water, adding Glycerylphosphorylethanolamine last under slow stirring ;

Mix phase (II) in de-ionized water; Mix phases (I) and (II) under slow stirring ; allow cooling; Homogenise tlie resulting CREAM.

Example 7 HYDRATING CREAM (I): ( ip) a Seal-oil 10,0 % or Seal-Oil (5,0 %) + Fish-oil (3,0 %) + Olep vegetable (2,0 %) 10.0 %

_, + Mineral Oil 02,0 % b Stearate of glyceryl 05,0 % c Stearate of isopropyl 04,0 % d Cethylic Alcohol 02,0 % e Stearylic Alcohol 02,0 % f Polysorbate 60 01,0 % g Gum of xantane 00^;,3 % , h Glycerol 08,0 % i Conservative Agent(s) 00,6 % j 5 % Solution of carrot extensin 05,0 % k Polipeptides of 5 % extensina hydrolisate ("Vegagen" Cpnterchein⁶) 05,0 %

1 Demineralized Water (diluting) q.s, up to 100,0 %

Preparation :

Dissolve Seal-oil (or a mixture of oils indicated above) and the conservative agents in tepid, de_^ionized water; Add the other elements, under stirring.

Example 8 MAKE-UP C_REAM (C) : (p/p) a Seal-oil (5%) or or Seal-oil (2,5 %) + Fish-oil (1,5 %) + Vegetable Oil (1,0 %) 05,0 % b Octildodecyl-stearyl Stearate 04,0 % c Isόcetyl Stearate 01,0 % d Propilene-glycol 03,0 % e Iron Oxydp 02,0 % f Titanium Dioxyde 08,0 % g Tensioactive Agents⁷ (lecithin, polisorbate 20, sorbitane laurate) 01,0 % h Trietiianolamine 01,5 % i Conservative agents 00,6 % j Aglutinating and Thickening Agents 01,8 %

⁶ Centerchem Inc. Stamford, CT, USA

⁷ Aniόnicos k 1,5 % Solution of tomato extensine 01,0 % 1 Demineralized Water (diluting) q.s. up to 100,0 % Preparation :

Dissolve Seal-oil (or the mixture of oils mdicated above) and the conservative agents in tepid de-ionized water; Add the other plements, under stirring. .

Examples 9 and 10 MAKE-UP CREAMS (D) and (E) ; (pip) ⁽pip a Seal-oil 05,0 % 05,0 % or Seal-oil (2,5 %) + Fish-oil (1,5 %) + Vegetable Oils (1,0 %) 05.0 % 05,0 % b Bentone Gelllyfying Agente 05,0 % c "Laureth 7" 00,5 % d Propylene-glyeol 06,0 % 08,0 % e Iron Oxyde 03,1 % 02.4 % f Titanium DiOxyde 12,0 % 08.5 % g Teηsioactive Agent(s) 16,0 % 20,0 % h Cyclometliicone 22,5 % 12,0 % i Dimethicone 05,0 % j Conservative agent ) 00,5 % 00,5 % k Talcum powder 04,5 % 03,3 %

1 Sodium Chloride 02,0 % 02,0 % m 1,5 % Solution of potato extensine 00,5 % 00,5 % . n Demineralized Water (diluting) q.s. up to 100,0 % 100,0 %

Preparation :

Dissolve Seal-oil (or the mixture of oils indicated above) and the conservative agdnts in tepid de- ionized water. Add the other elements, under stirring.

Example 11 MASCARA GEL : ⁽pip) a Seal-oil 10,0 % or Seal-oil (5,0 %) + Fish-oil (3,0 %) + Vegetable Oils (2,0 %) 10.0 % b 1,2-propanodiol 02,0 % c , Glyceryiphosphorylcholine (at 85 ° in Demineralized Water) 00,2 % d Carbomer 940 00,2 % e Triethanolamine 00,2 % f 95 "Ethyl Alcohol 10,0% g PVP (polivinyϊpyrrolidone K 30) 01,0 % h Conservative agents q.s. i Pigments q.s. e Deminetfalked Water (diluting) q.s. up to 100,0 %

Preparation :

Mix Seal-oil (or the mixture of oils indicated above), 1,2-propanodiol, Glyceryiphosphorylcholine in Demineralized Water; Add, under strong stirring, Pigments and carbomer; Neutralize with Triethanolamine in aquous solution; Add 95 ° Ethyl Alcohol and PVP (polivinylpyrrolidone K 30) uhder.stirring.

Example 12 CAPILLARY TONIC in CREAM FOR WASHING : (pip) a Seal-oil 05,0 % or Seal-oil (2,5 %) + Fish-ofl (1,5 %) + Vegetable Oils (1,0 %) 05.Q % b Stearalconium Cloride 02,0 % c "Ceteareth 20" 02,0 % d Citric Acid 00,3 % e Dimethicone 00,2 % f Gum of antano 00,5 % g Cethyl Alcohol 01,0 % h Stearilic Alcohol 00,5 % i 1 % Solutio of maize extensine 00,2 % j Demineralized Water (diluting) q.s. up to 100,0 %

Preparation :

Dissolve Seal-oil (or the mixture of oils indicated above) and the conservative agents in tefrd de-ionised water; Add the other elements, under stirring.

Claims

1. PHARMACEUTICAL, COSMETIC, DERMO-COSMETIC, HYGIENE, ALIMENTARY ANfl PARA-ALIMENTARY (FOOD STJPPLEMENTS> COMPOSITIONS (OR COMPOUNDS* OR PRODUCT^) characterised by the fact that they incorporate as active ingredient Seal-Oil and/or the respective Ω-3EFA's (Whether extracted from seal-oil or of any other origin) and/or their physiologically acceptable salts, and/or the respective (seal-oil) phospholipids and or Othpr (seal-oil) components isolated thereof for TOPICAL and NON-TOPICAL USE, eventually enriched and pharmacologically synergized through (by) the use of Liposomes or Phitosomes and/pt of (other) Active Ingredients (reinforcing the effects elicited by the Ω-3EFA's and/or the other constituents of Seal-Oil and/or compensa-. ting simultaneous cellular deficiencies), in association with adequate, pharmaceutically acceptable excipients.

2. COMPOSITIONS (OR COMPOUNDS, OR PRODUCTS) as per Revindication (1), characterised by the fact that they incorporate as active ingredient Seal-Oil and/or the respective Ω-3EFA's and/or their physiologically acceptable salts, eventually ih association with other ingrρd|ients actjve in this field.

3. COMPOSITIONS (OR COMPOUNDS, OR PRODUCTS) as per Reivindications (1) and (2), characterised by the fact that they incorporate as active ingredient Seal-Oil under the final forms of creams to counter (or prevent, or treat, or compensate) dty, squamous sMn, nutritive creams, make-up creams, dermatolόgical hydrating lotions, dermatological hydrating sprays, hydrating restojrative gels, mascara gels, lip products (whether shining or dull, in terms of light reflection), eye pow rs, shampoos, capillary gels, etc..

4. COMPOSITIONS (OR COMPOUNDS, OR PRODUCTS) as per keivindications (1) (2) and (3), characterised by the fact that thpy incorporate as aptive ingredients two or more of the following substances (or groups of substances) hereinafter indicated, one of them being Seal-Oil :

(1) Seal Oil (mostly under filtered and deodorised form) - and or the respective Ω-3EFA's; these should represent 0,5 % to 25 % (weight/weight) of the final product, more particularly 2,5% to 15 %, preferably 5 % to 10 %;

(2) Excipients, among which the following may be the' chosen ones : Water (distilled or demineralized), which may amount to 40 to 75 % (W:W or weight : weight) of the final product; Glycerol, which will amount to 2,5 a 10 % (W : W) of the final product; Emulgin (prpduct n° 7450 in Merck Index), which will amount to 1,5 a 5 % (W : W) of the final product; Myristol (product n° 6184 n Ivferck Index), hich will amount to 2,5 a 10 % (W : W) of the final product; Isopropylpalinitate, which will amount to 2,5 a 10 % (W : W) of the final product; Alcohol, which will amount to 1,5 a 5 % (W : W) of the final product; Cutin (product ή° 2610 in Merck Index), which will amount to 4,5 a 15 % (W : W) of the final product; a thickening agent (such as sodium bpntonite or modocoll), which will amount to 0,5 a 5 (W : W) of the final product; carbomer (940, etc.); waxes (bee wax, etc.); etc., etc..

(3) Fϊsh ils (mostly of halibut, salmon, tunna, sardin , shark, cod, etc.) rich in Ω-3EFA's - and/or the respective Ω-3EFA's; such Ω-3EFA's ,(as any other Ω-3EFA's mentioned in this Paitent) may eventually be produced by chemical synthesis and/or througli techniqupS of genetic engineering; they will represent 7,5to 15 % (W:W) of the final product;

(4) Vegetable Oils (namelly those of evening primrose or field borage, of grape seeds, ptp.) rich in Ω- 3EFA's - or the respective Ω-3EFA's; they will represent 7,5 to 15 % (W.'W) of the final product;

(5) De-acylated glycerophosphqlipids (glycero-phosphoryl-choline; glyeerorphosphoryl-inositol; glycero- phosphoiyl-serine; glyceto-phosphoryl-ethanolamine; etc.) and or their respective physiologically acceptable salts, in concentrations ranging from 0,1 % to 10 % (W:W);

(6) Silicone(s) (cyclomethicone, dimethicone cpliopol, cyclomethicone, etc,).

(7) Ubiquinone(or ubidecarenone or Cό-enzyme Q-10) - a natural product acting as a potent and physiologic anti-oxidant which our experiments have revealed is capable of completely reverting inflammatory sMn processes due to physical and chemical agents (burns, etc.).

(8) Lippsomes or Phitosomes made so as to contain and/or help deposit said Ω-3EFA's and/or Q-10 and/or Ingredients such as those in tins list on the surface of cell membranes of those cell we aim at enriching with these Active Ingredients. We aim at enriching the Liposomes or Phitosomes in question in those Ingredients referred to; they may eventually contain Seal Oil itself insidp their membranes, but even in such eventuality they shall in principle contain other Ingredients;

(9) Silver Salts (those metabolically more active and directed at cell fractions more specifically mvolved in cellular respiration and in energy production and control) - because we confirmed that silver is one oligo-element capable of augmenting, the efficacy of Q 0; said salts are, for example, orqtate, gluconate, picoli-ήate, and all those capable of easy penetr&tion into cell structures - bύtyrate and its immediate derivatives ahd other salts of amino or fatty acids of low molecular weight - can be used to alter energy metabolism at cellular mitoehondrial and nuclear level; (lθ)vitamina Bl (cocarbpxylase, if possible under stabilised form) and/or ATP (Adenosine-tri-phosphate - dissodic or other) under a form capable of promoting and activating energy production and/or liberation even in visibly deficient cells or those under aggression or intoxication decreasing such processes significantly;

(11) other vitamins of B complex, and above all B5 (Panthenol), B6, B12 and Folic Acid, which are implicated in cell respiration processes and in those controlling cellular energy;

(12) other Anti-oxidants - such as vit. A, C and E. glutathion and glutathion reductase, catalase, supero- xyde-dismuthase, poliphenols (including picnogenol) an catechines and their elements and polimers;

(13) Anti-Ageing Products and antagonists of collagen and elastin CToss-lin ng, such as anti-oxidants, poliphenols and catechines, and their elements and polimers, as well as Products rich in siticium (such as the garlic derivatives and extracts of plants with similar properties); glucosaminoglycans; hyaluronic acid; amiuo-acids and or bio-stiπwlins: collagen, elastin and placental hydrolysates nd extracts; and/or the extensine proteins;

(14) certain oligo-saccharides of vegetable origin, namely those extracted from algae and or DMSO (of vegetable and non-vegetable origin), inducing membrane de-stabilisation and, therefore, increased membrane permeability to the chosen Active Ingredients used in the Products contemplated in this Patent;

(15) soluble calcium carbonate and other soluble salts of (mostly soluble calcium carbonate known a? "coral- calcium" (CC, extracteα- in OMnawa and Tokunoshimo islands, in Japan, and marketed, outside Japan, by the Swedish firm PMJG - Preventive-Medical Group); other oligo-elements, including chromium and / or selenium and or germanium and/or zinc (as salts - orotate, picolinate, gluconate and other salts derived of fatty- and amino^acids) with great importance in the processes related to tissue healing and cellular reparation (systemic, epithelial andor occurring in other structures related to the SMn and the Mucous Membranes, etc).

(16)Chelanting agents and ion-exchange substances (as, for example, calcium-EDTA);

(17)Chromoglycate (diso ic or not) and/or other anti-allergic and/or membrane-stabilising products.

(18)Different Vegetable or AnimaLPrøducts, capable of inducing metabolic recovery in cells, such as cen- trophenoxine and certain Vegetable Extracts (as, for example, tepescoliuite or mimosa tenuflorapoir, tabernanthine, gingko biloba, aloe vera, and other extracts, such as those rich in Vegetable Auxins),

(19) Epidermal Growth Factor (EGF);

(20) Interferon - alpha, beta and / or gamma;

(21) Enzymes, specially enzymes capable of digesting and mobilising blood components (a good example is hirudin) or components of connective or elastic tissue (for example, collagenase and elast se);

(22)Xanthine derivatives (including caffeine) and vegetable extracts containing them (as is the case of guarana); iodo-thyrosine and/ox trj-iodo-thyro-acetic or tri-ioαo-thyro-propionic acids;

(23) To these Active Ingredients other may be added, such as certain Active Vegetable, or Animal, principles, allowing for Formulations & Preparations (mixtures) endowed with specially desired effects, such as (a) Vegetable or Animal Products active against penile ageing and the loss of male erectile potency due to local vascular and/or muscular deficits (as those related to muscles which compress veins draining the urethral corpus cavernosus);

(b) certain substances and certain animal extracts, namely male-seal penile extract, which may be obtained (for example) by sonic & mechanical destruction of the organ at stake, followed by differential centrifugation to separate the respective constituents; one of the objectives involves the use total extract having as Ingredients all elements with MW not superior the 200.000 D (therefore including hormone receptors and/or ADN and ARN of cells of this organ reputed for its permanent growth until the seal's death - these substances pTobably corresponding to nucleic acids and/or their precursors (DNA, RNA, puric and pyrimidic bases).

5. COMPOSITIONS (OR COMPOUNDS, OR PRODUCTS) as per Reivindications (1) through (4), characterised by the fact that they incorporate as active ingredients three or more pf the mdicated substances (or groups of substances), one _of them being Ubiquinone (Co-Enzyme Q10);

6. PHARMACEUTICAL PREPARATIONS, COMPOSITIONS (OR COMPOUNDS, OR PRODUCTS) for (lyiedical-and Npn-Medical) Dermatological, Cosmetic, Dermo-Cosmetic Use, Characterised by the fact that they incorporate mixtures with the compositions indicated in any of Reivindications (1) through (5);

7. The use of PHARMACEUTICAL PREPARATIONS, COMPOSITIONS (OR COMPOUNDS, OR

PRODUCTS) as per Reivindications (1) through (6), characterised by the fact that they contain pharma- ceutic products meant to treat deficiencies in Ω-3EFA's and other dysfunctional or deficiency states and or diseases and/or lesions associated with them at topic (cutaneous, dermic, mucous or submucous) . level or at a deeper level in the human body, with a preventive or therapeutic purpose in dermatology, and the cosmetic or dermo-cosmetic fields;

8. Proόess(es) for the preparation of pharmaceutical compositions (or compounds or products) as per reivindications (1) through (5), characterised by the fact that they contain mixtures of (all percentages represent W:W proportions of the finώ product) : a) Seal-oil - 0,10 to 50,0 ■%; or seal-oil - 0,10 to 30,0 % + fish-oil 0,10 to 25,0 %; b) Excipients : Distilled water 30,0 to 90,0 %; Glycerol 0-4 %; Einulgin 0-3 %; Myristol 0-5 %; Isopropyl-palmitate 0-4 %; Alcohol 0-3%; Cutin 0-6 %; a thickening agent (niodocoll) 0-2 %; c) Ubiquinone - 0, 10 to 55,0 %; d)- Liposomes or Phitosomes 0,10 to 30,0 % ; for a total of 100 %. or characterised by the fact that they contain mixtures of the substances indicated ill the following examples (already referred to illustrate this current invention, which they nevertheless do not limit in any way whatsoever the scope of application and use of this invention) :

Example #1 NUTRITIVE CREAM (I) weight / weight

(a) seal-pil - 10 %; ou seal-oil - 5 % + fish-oil, - 5 %; total : 10 %

(b) .Glycerol 04 %

(c) Emulgin 03 %

(d) Myristol 05 %

(e) Isopropyl- Palmitate 04 %

(f) Alcohol 03 %

(g) Cutin 06 %

(h) Thickening Agent (niodocoll) 02 %

(i) Ubiquinone 05 %

(j) Liposomes 10 %

(k) Distilled Water 48 %

^; for a total of 100 %.

Preparation : Mix the indicated ingredients at 40 °C temperature, under stirring ; and allow cooling.

Example 2 NUTRITIVE CREAM (II) (p/p)

(I) ^' a Seal-oil 10,0 %.

. or Seal-oil (5,0 %) + Fish-oil (3,0 %) + Vegetable Oil (2,0 %) 10.0 % b Gliyerol Monoestearate emulsified with Poliethilene-glycol 05,0 % c Stearic Acid of origin vegetable 08,0 % d . Sweet almonds oil 07,0 % e ristyl Ethoxi-miristate 06,0 % f Cetyl Alcohol 01,0 % g Lauryl Pyroglutamate 01,0 % h Silicone 00,5 % i Demineralized Water q.s.

(II) a Glycerol 02,0 % b Glycerόphosphorylcholinae 03,0 % c Zinc Pyroglutamate 00,2 % d Pyroglutamate of crhomiuin 00,2 % e Pyroglutamate of copper 00,2 % f Demineralized Water q.s.

Preparation :

Mix the components of phase (I) with water and heat up to 54 °C;

Mix the components of phase (II) with water and heat up to 54 °C;-

Add as phases (I) and (II) stirring slowly;

Add the products of this phase (III) to Triethanolamine q.s. up to pH 6,4 - 6,6

Add b Perfume q.s. Demineralized Water (diluting) q.s. up to 100,0 %

Allow cooling up to 35 °C, stirring slowly.

Example 3 DERMO-COSMETIC HYDRATING LOTION (I) ( 'P) a Seal-oil 10,0 % ou Seal-oil (5,0 %) + Fish-oil (3,0 %) + όleo vegetable (2,0 %) 10.0 % b methyl p-oxybenzoate 00,7 % c propyl p-oxybenzoate 00,3 % d Glycerylphosphorylcholine 35,0 % e Demineralized Water (diluting) q.s. up to 100,0 % Preparation :

Dissolve Seal-oil (or a mixture of oils indicated above) and os conservantes in water tepid de-ionized; Add a Glycerylphosphorylcholine, stirring slowly:

Example 4 LOTION HYDRATING DERMO-COSMETIC (H) (pip) a Seal-oil 07,0 % or Seal-oil (5,0 %) + FishrOil (3,0 %) + Vegetable Oil (2,0 %) 07.0 % b Glyceryl Stearate 00,5 % c Isocethyl Stearate 10,0 % d Lanolinic Ether PPG-10 00,3 % e Lanolinic Alcohol 00,7 % f Acido oleic 02,0 % g Triethanolamine 01,3 % h Carbomer 941 00,1 % i Glycerol 04,0 % j Conservative Agent(s) 00,4 % k 5 % Solution of carrot extensin 05,0 % 1 Polipeptides of 5 % extensina hydrolisate ("Vegagen" Centerchem⁸) 05,0 % e Demineralized Water (diluting) q.s. up to 100,0 % Preparation ;

Dissolve Seal-oil (or the mixture of oils indicated above) and the conservative agents in tepid de-ionized water; Add the other elements, under stirring.

Example £ MAKE-UP CREAM (A) : ⁽pip)

(I) a Seal-oil 10,0 % or Seal-oil (5,0 %) + Fish-oil (3,0 %) + όleo vegetable (2,0 %) 10.0 % b Bees Wax 03,0 % c Polyglyceryl-4-oleate 02,0 % d Silicones (ciclomethicone and dimethicone coliopol) 08,0 % e . Ssilicone (cyclomethicone) 08,0 % f Glycerylphosphorylethanolamine 01,0 % g Pigments 15,0 %

(H) a Sodium Citrate 03,0 % b Conservative agents q.s. e Demineralized Water (diluting) q.s. up to 100,0 %

Preparation :

Mix Seal-oil (or the mixture of oils indicada above), silicones, Polyglyceryl-4-oleate and

Bees Wax and conservative agents, heating up to 54 °C; Add the other elements of phase

(l), dissolving them in de-ionized water, adding Glycerylphosphorylethanolamine last, under slow stirring;

Mix phase (11) in de-ioni2;ed water ;

Mix phases (I) and (II) under slow stirring ; allow cooling;

Homogenise the resulting CREAM.

Example 6 CREAM of MAKE-UP (B) : (I) (p/p) a Seal-oil 10,0 % or Seal-oil (5,0 %) + Fish-oil (3,0 %) + όleo vegetable (2,0 %) 10.0 % b Bees Wax' 03,0 % c Polyglyceryl-4-oleate 02,0 % d Silicones (cyclomethicone and coliopol of Dimethicone) 08,0 %

Centerchem Inc. - Stamford, CT, USA e Silicone (cyclomethicone) 08,0 % f Glycerylphosphotylethanolamine 01,0 % g Pigments 15,0 %

(II) a Citrate oi^" sodium 03,0% b ConseiSvative agents q.s. e Demineralized Water (diluting) q.s. up to 100,0 %

Preparation : Mix Seal-oil (pr the mixture of oils indicated abovp), silicones, Polyglyceryl-4-oleate and Bees Wax and the conservative agents, heatmg ujp to 54 °C; Add the other elements of phase (I), disolving them in de-ionized water, adding Glycerylphosphorylethanolamine last Under slow stirring ;

Mix phase (II) in de-ionized water; Mix phases (I) and (II) under slow stirrmg ; allow cooling; Hompgenise the resulting CREAM.

Example 7 HYDRATING CREAM (I): ⁽pip)

Seal-oil 10,0 % or Seal-oil (5,0 %) + Fish-oil (3,0 %) + όleo vegetable (2,0 %) 10.0 %

+ Mineral Oil 02,0 % b Stearate of glyceryl 05,0 % c Stearate of isopropyl 04,0 % d Cethylic Alcohol 02,0 % e Steaiylic Alcohol . 02,0 % f Polysorbate 60 01,0 % g Gum of xaήtane 00,3 % h Glycerol 08,0% i Conservative Agent(s) 00,6 % j 5 % Solution of carrot extensin 05,0 % k Polipeptides of 5 % extensina hydrolisate ("Vegagpn" Centerchem⁹) 05,0 %

1 Demineralized Water (diluting) q.s. up to 100,0 %

Preparation :

Dissolve Seal-oil (or a mixture of oils indicated above) and the conservative agents in tepid, de-ionized water; Add the other elemehts, under stirring.

Example 8 MAKE-UP CREAM (C) (pip) a Seal-oil (5%) or or Seal-oil (2,5 %) + Fish-oil (1,5 %) + Vegetable Oil (1,0 %) 05,0 % b Octildodecyl-stearyl Stearate 04,0 % c Isopetyl Stearate 01,0 % d Propilene-glycol 03,0 % e Iron xyde ' 02,0 % f Titanium Dio yde 08,0 % g Tensioactive Agents¹⁰ (lecithin, polisorbate 20, sorbitane laurate) 01,0 % h Triethanolamine 01,5 % i Cohservative agents 00,6 % j Aglutinating and Thickening Agents 01,8 % k 1,5 % Solution of tomato extensine 01,0 %

I Oemineralized Water (diluting) q.s. up to 100,0 % Preparation :

Dissolve Seal-oil (or the mixture of oils indicated above) and the conservative agents in tepid de-ionized water; Add the other elements, under stirring.

Examples 9 and 10 MAKE-UP CREAMS (D) and (E) : ⁽Pip) ⁽pip) a Seal-oil 05,0 % 05,0 % or Seal-oil (2,5 %) + Fish-oil (1,5 %) + Vegetable Oils (1,0 %) 05.0 % 05,0 % b Bpiitone Gelllyfying Agente 05,0 % c "Laureth 7" 00,5 % d Propyiene-glycol 06.0 % 08,0 % e Iron Oxyde 03.1 % 02,4 %

⁹ Centerchem Inc. - Stamford, CT, USA

¹⁰ Ahiόnicos f Titanium DiOxyde 12,0 % 08,5 % g Tensioactive Agent(s) 16,0 % 20,0 % h Cyclomethicone 22,5 % 12,0 % i Dimethicone 05,0 % j Conservative agent(s) 00,5 % 00,5 % k Talcum powder 04,5 % 03,3 %

1 Sodium Chloride 02,0 % 02,0 % m 1,5 % Solution of potato extensine 00,5 % 00,5 % n Demineralized Water (diluting) q.s. up to 100,0 % 100,0 %

Preparation :

Dissolve Seal-oil (or the mixtme of oils indicated above) and thp conservative agents in tepid de- ionized water. Add the other elements, under stirring.

Example 11 MASCARA GEL : ( ip) a Seal-oil 10,0 % or Seal-oil (5,0 %) + Fish-oil (3,0 %) + Vegetable Oils (2,0 ' %) 10.0 % b 1,2-ptopanodiol 02,0 % c Glycerylphosphorylcholine (at 85 ° in Demineralized Water) 00,2 % d Carbomer 0 00,2 % e Triethanolamine 00,2 % f 95 "Ethyl Alcohol 10,0 % g PVP (polivinylpyrrolidone K 30) 01,0 % h Conservative agents q.s. i Pigments q.s. e Demineralized Water (diluting) q.s. up to 100,0 %

Preparation :

Mix Seal-oil (or the mixture of oils mdicated above), 1,2-prppanodiol, Glycerylphosphorylcholine in Demineralized Water; Add, under strong stirring, Pigments and carbomer; Neutralize with Triethanolamine in aquous solution; Add 95 ° Ethyl Alcohol and PVP (polivinylpyrrolidone K 30) under stirring.

Example 12 CAPILLARY TONIC in CREAM FOR WASHING : (p/p) a Seal-oil 05,0 % . or Seal-όii (2,5 %) + Fish-oil (1,5 %) + Vegetable Oils (1,0 %) 05.0 % b Stearalconium Cloride 02,0 % c "Ceteareth 0" 02,0 % d Citric Acid 00,3 % e Dimethicone 00,2 % f Gum o xantano 00,5 % g Cethyl Alcohol 01,0 % h Stearilic Alcohol 00,5 % i 1 % Solution of maize extensine 00,2 % j Demineralized Water (diluting) q.s. up to 100,0 %

Preparation :

Dissolve Seal-oil (or the mixture of oils indicated above) and the conservative agents in tepid de-ionised water; Add the other elements, under stirring.

9. The use (utilisation) of the compositions prepared as per the processes in accordance with Reivindication 8, characterised by the obtention of Dermatological, Cosmetic and Dermo-Cosmetic Products.