CN1938009A - Compositions comprising vitamins and/or derivatives thereof stabilised with olea europea extract and/or ionene polymers - Google Patents

Abstract

The present invention relates to compositions containing vitamins such as L-ascorbic acid and its derivatives stabilized with olean and/or ionene polymers. In particular, the present invention relates to stable compositions containing high concentrations of vitamins, such as L-ascorbic acid, which are advantageously used in the field of medicine and cosmetics, such as cosmetic and dermatological treatments of the skin, mucous and serosa.

Description

Composition comprising vitamins and/or derivatives thereof stabilized with olean extract and/or ionene polymers

The present invention relates to compositions containing vitamins and/or derivatives thereof stabilized with olean extracts and/or ionene polymers. In particular, the present invention relates to stable compositions with a high concentration of vitamins, such as ascorbic acid, preferably L-ascorbic acid, and/or derivatives thereof, which are advantageously used in the field of medicine and cosmetics, for example for the cosmetic or Dermatological treatment.

L-ascorbic acid, that is, vitamin C is widely used in the field of medicine, especially in the field of nutrition, and this substance is very important to the human body. In fact, a deficiency of this vitamin can induce a disease called "scurvy" in humans. Since vitamin C is the basis of collagen, it has attracted great interest in the field of cosmeceuticals in the last decade. In addition, the use of vitamin C as an antibacterial agent and antioxidant additive for nutraceuticals, or as a purifying and disinfecting agent for pharmaceutical preparations such as cosmetics has been well known.

However, even when ascorbic acid is completely dissolved, there is still a tendency for rapid natural breakdown in serum solutions. L-Ascorbic acid is readily soluble in water, but rapidly oxidizes in aqueous solutions, so it cannot be stabilized in sufficient concentrations in this natural solvent. On the other hand, L-ascorbic acid has very limited solubility in aqueous solutions. The instability of L-ascorbic acid in aqueous solution is attributable to its α-keto structure, interaction with water, the inevitable penetration of oxygen in solutions in which vitamins are dissolved, the effects of exposure to light, and time.

Many different methods have been proposed over the years to prepare solutions of vitamin C (L-ascorbic acid) which remain stable over a considerable period of time. In particular, International Patent Application WO98/23152 describes the preparation and action of various forms of vitamin C, both in the right-handed form (ascorbyl palmitate) and in the left-handed form (LLA), the latter of which is believed to be a cell-activating The form required for metabolism. In particular, methods for stabilizing vitamin C by dissolving the vitamin in solvents such as polyethylene glycol, ethoxydiglycol, propylene glycol, butylene glycol, propylene carbonate, glycerol, capric acid, or Glyceryl caprylate, alkyl lactate, alkyl adipate, isosorbide and mixtures thereof. However, known methods do not provide L-ascorbic acid compositions with sufficient intracellular permeability.

From the foregoing, there is a clear need for new alternative methods and compositions capable of stabilizing vitamins, especially vitamin C, which address the shortcomings of existing compositions.

The applicants of the present invention have discovered that certain compounds often used alone in pharmaceutical, dermatological and cosmetic formulations, such as olean, ionene polymers, sometimes in combination with polymeric ethers, tetraborates or thiosulfates Co-existence can stabilize L-ascorbic acid in aqueous compositions. The compounds described above allow the preparation of stable compositions with higher concentrations of L-ascorbic acid and make the compositions more potent, enhance intracellular, intranuclear, and intramitochondrial permeability and optimize bioavailability close to intracellular saturating doses. Furthermore, the combined use of L-ascorbic acid and olean and/or ionene polymer extracts creates a synergistic effect between the individual compounds of the composition, capable of enhancing the efficacy of each component.

Aqueous extracts of olean fruit have so far been rarely used in cosmetic topical treatments. The substance is a strong antioxidant and microbicide, and, moreover, in some special substances, oleouropeina exerts an important antitumor effect (Eur J. Cancer, 2000, Carcinogens. 2000). The efficacy of substances contained in the water extract of olean fruit is used in natural medicine and in the treatment of some skin and intestinal disorders (Int JAntimicrob Agents, 2002). Said substances are sometimes also used to affect the regulation of the immune system and also in the case of allergies.

Ionene polymers are currently used as carriers in molecular biology. In fact, it facilitates the passage of DNA and proteins through membrane proteins (Bioconjug Chem 2002, J Control Release. 2002). These substances are therefore used in gene therapy and, among other things, in some special forms as fungicides. It has been clearly demonstrated that ionene polymers are not cytotoxic (Macromolecules, 1972). These substances can be used as carriers and can replace the application of liposomes, nanosomes or other carriers currently used in the cosmetic or pharmaceutical field. Currently, ionene polymers have never been used in combination with olean or ascorbic acid.

Ionene polymers are a large class of compounds that also include compounds of the general formula I:

[-N(CH ₃ ) ₂ -(CH ₂ ) _x -N(CH ₃ ) ₂ -(CH ₂ ) _y -]′2Z ^- (I)

where x and y are integers and Z is a halogen. These polymers are prepared by reacting N(CH ₃ ) ₂ -(CH ₂ ) _x -N(CH ₃ ) ₂ with Z-(CH ₂ ) _y -Z (Macromolecules, 1972), for example, 1,4-dichloro Butane reacts with tetramethylethylenediamine to obtain ionene polymers.

Other ionene polymers are exemplified as follows: combining 1,4-dichlorobutane with poly(oxyethylene(dimethylimino)-ethylene(dimethylimino)vinyl dihalide), poly(2-hydroxy Ethylene-dimethylimino-2-hydroxypropene-dimethyliminomethylene) dihalide, poly[{alkyl-(3-aminopropyl)imino}propylene dihalide], Poly-[(dialkylimino) vinyl halide] or react with poly-[(hydroxyl-dialkyl-imino) vinyl halide].

Olean and L-ascorbic acid (LAA) have important biological functions on the skin and all cellular tissues:

- They have an antioxidant effect against "oxygen free" radicals produced by the cell's metabolism, smoke, exposure to UV rays, and other pollution, and they fight cellular aging;

- anti-inflammatory due to the strengthening of the immune system;

- Enhances cellular responses to external and intracellular noxious stimuli;

- play a significant role in the regulation of the immune response;

- Intervention through important antioxidant effects in body parts where abnormal cell growth presents with changes in tumor initiation, dysplasia and/or tissue atrophy;

- Stimulating fibroblasts in human skin to synthesize collagen, especially LAA has a significant interference effect on the homeostasis of the human organ connection system. In addition, L-ascorbic acid can enhance the synthesis of protein and collagen, has anti-wrinkle function, and can chelate with ferric ions to prevent skin damage caused by excessive sun exposure (J InvestDermatol.1997, Radial Res.2003).

L-ascorbic acid, olean and ionene polymers play an important role in the treatment and prevention of cancer due to certain substances contained in olean, such as oleuropein and hydroxytyrosol, or ionene polymers The special action of the drug, when used in combination with vitamin C, makes the vitamin have direct intracellular, intramitochondrial and citoplastic effects (Cancer Immunol Immunother, 2003; Radiat Res, 2003).

Olean produces an important anti-hyperpigmentation effect due to a component of a benzene ring it contains, which inhibits tyrosinase when applied topically. In addition, an aqueous extract of olives, containing oleulin, tyrosole and hydroxytyrosol, enhances the potency of vitamin C, making it significantly resistant to degradation. In fact, the phenol group in oleuropein contained in olean fruit is a substituent, which reacts with the hydroxil group in vitamin C and dehydrates to form a bond, which has the same effect of preventing the degradation and oxidation of L-ascorbic acid (Figure 1) . The solution of vitamin C may be oxidized and reversibly reduced from L-ascorbic acid to L-ascorbic acid dehydrate, so the phenol group of oleuropein generates two hydrogen atoms to restore the L-ascorbic acid dehydrate to L-ascorbic acid. The presence of strong reducing substances can prevent oxidation, thereby preventing the degradation of vitamin C, making it highly stable.

The term "Echinacea" refers to different species of plants native to North America. The genus Echinacea comes from the Asteraceae family. According to the current classification of Echinacea, it is divided into nine types and two varieties. However, only E.purpurea, E.angustifolia and E.pallida were used for treatment.

Many pharmacological studies have demonstrated that different preparations obtained from the shoots and roots of medicinal plants of the genus Echinacea have the ability to stimulate immune system activity, enhance the function of natural killer cells and the cytotoxicity of monocytes in peripheral blood Antibody-dependent Ability. The chemical components responsible for the pharmaceutical activity are: major polysaccharides (heteroxylan and rhamno-arabinosyl-galactan), glycoproteins, cichoric acid, alkylamides, caffeic acid derivatives (Echinacea Glycosides (echinacoside, Echinacea genus), terpenes, flavonoids (from leaves), rutin, caryringene. Other pharmaceutical activities of Echinacea are antiviral, antibacterial, antifungal, anti-inflammatory, healing activities.

A particular object of the invention is therefore a composition comprising one or more vitamins and/or derivatives thereof, and an olean extract, preferably an aqueous extract, and/or one or more components thereof , such as oleaginin, tyrosol and hydroxytyrosol, and/or one or more ionene polymers, and one or more pharmaceutically and cosmetically acceptable carriers and/or excipients.

Containing ascorbic acid and/or derivatives thereof, and olean fruit extract, preferably aqueous extract, and/or one or more components thereof, such as oleuropein, tyrosol and hydroxytyrosol, and/or one or more The composition of an ionene polymer, and one or more pharmaceutically and cosmetically acceptable carriers and/or excipients is particularly advantageous.

According to the present invention, the derivatives of ascorbic acid may be esters of ascorbic acid and fatty acids, for example, ascorbyl palmitate and salts thereof.

Other vitamins, whether water-soluble or fat-soluble, vitamins that can be used in the composition according to the invention are selected from the group consisting of vitamins A, B1, B2, B3, B5, B6, B8, B9, B12, D, E, K .

The composition of the present invention may further comprise extracts of Echinea purpurea, angustifolia or pallida and/or one or more active ingredients contained therein, for example, heteroxylan and rhamno-arabinosyl-galactan, sugar Proteins, cichoric acid, alkylamides, caffeic acid derivatives eg echinacoside, Echinacea, terpenes, flavonoids eg rutin, caryringene. In fact, extracts of the Echinacea genus or their active ingredients, in addition to their pharmaceutical activity, stabilize vitamins, especially vitamin C.

In addition, the composition may comprise one or more compounds selected from polymeric ethers, such as ethylene polymers or propylene oxide, monohydric alcohols, polyhydric alcohols, such as etoxydiglycole, such as Transcutol ^(R ), also known as APV, tetraboronic acid salt or thiosulfate.

In fact, these compounds can be used as adjuvants for the stabilization of vitamins, however in the presence of olean extract and/or ionene polymers.

According to a specific embodiment of the present invention, the composition may further comprise one or more compounds selected from adenosine triphosphate, adenosine diphosphate, phosphoenolpyruvate, creatine phosphate and inorganic phosphate. These compounds represent cellular energy sources in which a proton gradient occurs.

The compositions described above may also comprise one or more substances including collagen, especially type I collagen, fibrin glue, fibrin and derivatives thereof, and dura mater. Ascorbic acid or its derivatives are especially beneficial in the treatment of wounds when used in combination with one or more of the aforementioned substances. In fact, these components are local chemoattractants for neutrophils, fibroblasts and/or endothelial cells. The above combinations can be used to treat medical devices, such as gauze, bandages, plasters, silicon bars, with the composition of the present invention, or the composition in the form of emulsion, gel, powder, paste, dispersion, solution form application. Wounds that may be treated with the compositions of the present invention include skin wounds, burns, ulcers, surgical ferrites, and chronic and acute skin and mucous injuries. All relevant components accelerate the recovery of wounds, reduce the formation of sensory-deficient scars, such as keloids, hypertrophic scars, promote the production of type I collagen, regulate the processes of regeneration of cells and extracellular matrix.

The composition of the present invention may further comprise one or more compounds used as fillers selected from hyaluronic acid and/or derivatives thereof, such as esters, cross-linked or amidic derivatives thereof, such as gelatin Gum forms, hydroxymethylcellulose, maltodextrin, eg injectable forms. In addition, compounds of the invention may comprise one or more amino acids such as glycine, alanine, valine, leucine, isoleucine, serine, cysteine, threonine, methionine, phenylalanine , tyrosine (tyroxine), tryptophan, histidine, lysine, arginine, aspartic acid, glutamic acid, asparagine, glutamine, proline.

The compositions of the present invention have a pH in the range of 2.0 to 6.0 and are preferably in the form of slurries, gels, emulsions and creams.

As mentioned above, the compositions can also be used for the preparation of gauzes, bandages, plasters, silicon rods, for example by embedding the compositions of the invention in the aforementioned medical devices. A particular embodiment of the invention is therefore a medical device comprising the composition of the invention.

Ionene polymers that can be used conform to the following general formula (I):

[-N(CH ₃ ) ₂ -(CH ₂ ) _x -N(CH ₃ ) ₂ -(CH ₂ ) _y -]′2Z ^- (I)

wherein x and y are integers, and Z is halogen, preferably Br or Cl. For example, one such polymer can be obtained by reacting 1,4-dichlorobutane with tetramethylendiamine.

Other ionene polymers that can be used are exemplified by combining 1,4-dichlorobutane with poly(oxyethylene(dimethylimino)-ethylene(dimethylimino)vinyl dihalide), poly(2 -Hydroxyethylene-dimethylimino-2-hydroxypropene-dimethyliminomethylene) dihalide, poly[{alkyl-(3-aminopropyl)imino}propylene dihalide compounds], poly-[(dialkyl-imino)vinyl halides] or reacted with poly-[(hydroxy-dialkyl-imino)vinyl halides].

The compositions of the invention comprise ascorbic acid or its derivatives at a concentration of 0.1% to 35%, preferably 10% to 25%, more preferably 12% to 20%. The concentration of vitamin A (trans and cis tretinoin) may be 0.001% to 10%, preferably 1.5% to 3.2%. The concentration of olean extract and/or one or more components thereof, such as oleaginin, tyrosol or hydroxytyrosol, may be from 0.1% to 95%, preferably from 5% to 50%, more preferably from 15% to 30% %. The polymeric ether may be present at a concentration of 5% to 50%, the monoalcohol and/or polyol at a concentration of 5% to 50%, and the thiosulfate at a concentration of 0% to 5%, preferably 0.01% to 3%.

The concentration of Echinacea extract and/or one or more active ingredients thereof in the composition may be 0.001% to 10%, and the compounds adenosine triphosphate, adenosine diphosphate, phosphoenolpyruvate, phosphocreatine, The concentration of one or more compounds in the inorganic phosphate may range from 0.001% to 35%.

The above percentages are percentages of components relative to the weight of the composition.

In particular, the thiosulfate salts may be potassium and/or sodium and/or ammonium salts.

Thus, the composition contains a high concentration of vitamins, preferably L-ascorbic acid, in combination with other components to stabilize them, enhance their potency, intracellular, intranuclear, intramitochondrial permeability, antioxidant capacity, hydration capacity, and pleasure in use.

A specific embodiment of the present invention can be: 20% water, preferably double distilled water, 20% L-ascorbic acid, 2.66% ionene polymer of general formula (I), wherein x=3 and y=3, 0.3% Potassium thiosulfate, 15% olean fruit aqueous extract, 42% 50:50 mixture of propylene glycol and 1,2 butanediol.

Other examples are: 20% water, preferably double distilled water, 20% L-ascorbic acid, 2.66% ionene polymer according to the general formula (I), where x=3 and y=3, 0.3% potassium thiosulfate, 22% olean fruit aqueous extract, 15% polioxyethylene/polioxypropylene polymer, 20% 50:50 mixture of propylene glycol and 1,2 butanediol.

Another specific example of the composition of the present invention is: 14.2% L-ascorbic acid, 26.8% olean fruit water extract, 44% etoxyglycol, 0.06% citric acid, 14.2% purified water.

The compositions of the present invention may contain bactericidal additives, bactericides and DNA correctors with nuclear, mitochondrial and cytoplasmic effects such as oleuroside, tyrosol and hydroxytyrosol, enzymes and catalysts of intracellular biochemical agonistic reactions. Regarding the application of ionene polymers in the field of medicine, relevant data of pharmacology and clinical trials have been widely published in international journals.

Olean fruit, such as its water extract, and ionene polymer, in addition to their disinfection and bactericidal functions, also have a strong stabilizing effect on vitamins in solution, especially L-ascorbic acid. These compounds can further increase the permeability of proteins across the membrane.

A specific embodiment of the present invention relates to a composition comprising vitamins A and E, and one or more ionene polymers, and one or more pharmaceutically or cosmetically acceptable adjuvants and/or carriers . The composition is particularly suitable for the treatment of skin, mucous and serosa. It promotes collagen biosynthesis, repairs cellular damage, stabilizes and enhances the action of substances used in the pharmaceutical, dermatological and cosmetic fields, enhances the complete penetration of complexes. The composition can penetrate from the extracellular space to the inside of the cell, play its role in the cytoplasm, and act on the biosynthesis of proteins. At the same time, it acts on the nucleus to stabilize DNA, enhance the resistance to harmful stimuli, and if the DNA has been damaged, Promotes its rapid repair.

The concentration of vitamin A (trans and cis tretinoin) in the composition may range from 0.01% to 5%. Vitamin E (alpha tocopherol), for example in its acetate form, may also be present in concentrations of 0.01% to 5%. The ionene polymer concentration may range from 0.001% to 10%, preferably from 1.5% to 3.2%.

The above composition may further comprise one or more compounds selected from cogic acid, azelaic acid, phytic acid (fitic acid), glycolic acid, lactic acid, fumaric acid, tartaric acid, L-aspartic acid, L-ascorbic acid , phytic acid, arbutin. The concentration of the above compounds may be from 1.5% to 20%.

In particular, the composition may further comprise one or more emollients such as cetyl esters, glycerin, glidants such as stearyl alcohol, cheryl alcohol, emulsifiers such as cetyl alcohol, glycerin, sodium lauryl sulfate , preservatives such as methylparaben, surfactants such as Quaternium/15, fungicides such as propylparaben.

Synthetic cetyl esters are in no way indistinguishable in chemical composition and properties from waxes derived from natural spermaceti. These esters include mixtures of esters of fatty acids with 14 to 18 carbon atoms and alcohols, which are included in the formulation as emollients. The concentration of cetyl ester in the formulation may be from 0.1% to 10%, preferably from 5% to 9%. The concentration of stearyl alcohol can be 0.1% to 15%, preferably 5% to 12%, cheryl alcohol 5% to 12%, cetyl alcohol 0.1% to 6%, preferably 2% to 6%, glycerol 0.1% to 18%, preferably 2% to 12%, and sodium lauryl sulfate from 0.1% to 1.5%, preferably from 0.5% to 1.0%.

Cetyl esters, stearyl alcohol, cheryl alcohol and glycerin form a water-absorbing base cream that enhances the positive effect applied to the skin, and by adding 0.1% to 0.4% of methylparaben, preferably 0.05% to 0.3%, paraben Propyl parkin 0.01% to 0.1%, preferably 0.02% to 0.05%, surfactant Quaternium/150.01% to 0.15%, preferably 0.05% to 0.12%, further enhance the antiseptic effect of the composition. Deionized water or distilled water acts as an inert carrier in the formulation of the present invention for diluting and at the same time has a moisturizing effect.

According to a specific embodiment of the present invention, the composition comprises: 0.01% to 10% by weight of ionene polymer, 1% to 10% by weight of cogic acid, 1% to 30% by weight of azelaic acid, 1.5% by weight of glycolic acid and/or lactic acid % to 15% by weight, trans-cis retinoic acid 0.01% to 5% by weight, vitamin E acetate 0.5% to 5% by weight, containing at least one selected from cetyl esters, cetyl alcohol, glycerol An emollient or humectant, a preservative selected from methylparaben, propylparaben and a water-absorbing base cream of sodium lauryl sulfate as an emulsifier, finally adding water to 100% by weight.

Preferably, the above composition is in the form of a cream. Another object of the invention is the use of the composition according to the invention for cosmetic treatment, for example for the treatment of wrinkles or skin spots.

The composition of the invention can furthermore be advantageously used in the field of medicine, for the treatment of humans and in the field of veterinary medicine.

In particular, an object of the present invention is the use of the composition of the present invention in the preparation and treatment of actinic keratoses, wounds, ulcers, diabetic epidermal ulcers, oral mucosal (mucous) lesions, psoriasis, prevention and treatment of general tumors of the skin , and use in medicine for acute and chronic skin injuries.

The composition of the present invention can be used in combination with pulsed light laser technology with a wavelength of 520nm to 670nm, especially 650nm, for the human body, especially for the skin, and the proton gradient can be determined by Andrè Jagendorf's law.

Furthermore, the present invention relates to the use of ionene polymers and/or olean extracts for stabilizing compositions of vitamins or their water-soluble or fat-soluble derivatives, for example in the form of aqueous solutions or emulsions, especially comprising a A composition of one or more vitamins selected from vitamins A, B1, B2, B3, B5, B6, B8, B9, B12, D, E, K, C or derivatives thereof.

The compositions of the present invention may be prepared by techniques known to those skilled in the art.

The invention will now be described, for non-limiting purposes, on the basis of preferred embodiments, with particular reference to the accompanying drawings and examples, in which:

Figure 1 shows a schematic diagram of the interaction of L-ascorbic acid with oleuropein, olean or ionene polymer;

Fig. 2 represents the result of case 1 in embodiment 5;

Fig. 3 represents the result of case 2 in embodiment 5;

Fig. 4 represents the result of case 9 (psoriasis of the elbow) in embodiment 5;

Fig. 5 represents the result of case 9 (leg psoriasis) in embodiment 5;

Fig. 6 represents the result of case 9 (papillary psoriasis behind the ear area) in embodiment 5;

Embodiment 1: the stability research of composition of the present invention and comparative preparation

The following concentrations are % by weight:

20% L-Ascorbic Acid

20% double distilled water

2.66% ionene polymer according to general formula (I) (wherein x=3 and y=3)

0.3% potassium thiosulfate

15% SYNPERONIC P94 (polyoxyethylene/polyoxypropylene polymer)

22% olean fruit water extract

20% 50:50 mixture of propylene glycol and 1,2 butanediol.

In this preparation, the active composition capable of stabilizing L-ascorbic acid includes the following compounds: aqueous extract of olean fruit, ionene polymers, polymers and copolymers of ethylene glycol and butylene glycol, containing polyoxyethylene- Polymer formed by copolymerization of polyoxypropylene and thiosulfate.

The solution relates to the fields of pharmacy, dermatology, cosmetics, as well as medical surgery and veterinary medicine, and relates to the treatment of wounds and ulcers of biological tissues, more particularly the skin.

In the latter case, for example, equine collagen, or other types of collagen, can be impregnated in the same solution according to the invention and according to methods known in the art.

Prepare the following contrast solution (weight percent)

20% double distilled water

20% L-Ascorbic Acid

50% solution with 50% polioli.

Comparative Test

Composition of the invention

0 months later 25 months later

Slightly yellow Unchanged in color

0% decomposition 5-9.8% decomposition

Composition of the comparative preparation

0 months later 25 months later

white dark brown

0% decomposition 98% decomposition

Example 2: The stability research of composition of the present invention and contrast preparation

The following concentrations are % by weight:

20% L-Ascorbic Acid

20% double distilled water

2.66% ionene polymer according to general formula (I) (wherein x=3 and y=3)

0.3% potassium thiosulfate

15% SYNPERONIC P94 (polyoxyethylene/polyoxypropylene polymer)

42% contains a mixture of 50% propylene glycol and 1,2 butanediol

In this preparation, the active composition capable of stabilizing L-ascorbic acid includes the following compounds: ionene polymer, polymer formed by polyoxyethylene-polyoxypropylene copolymerization and thiosulfate.

The solution relates to the fields of pharmacy, dermatology, cosmetics, as well as the fields of medical surgery and veterinary medicine, and to the treatment of biological tissues, more particularly wounds and ulcers of skin disorders.

In the latter case, for example, equine collagen, or other types of collagen, can be impregnated in the same solution according to the invention and according to methods known in the art.

Prepare the following contrast solution (weight percent)

20% double distilled water

20% L-Ascorbic Acid

50% solution with 50% polioli.

Comparative Test

Composition of the invention

0 months later 25 months later

slightly yellow slightly yellow

0% decomposition 9.5% decomposition

Comparative preparation composition

0 months later 25 months later

white dark brown

0% decomposition 98% decomposition

Example 3: Group containing 14.2% L-ascorbic acid stabilized with olean extract and ionene polymer compound

L-Ascorbic Acid 14.2% Ionene Polymer POLIBREN ^® 0.34% Olean Fruit Water Extract 26.5% Etoxydiglycol 44.0% citric acid 0.06% purified water 14.2%

The slightly yellow composition was unchanged after 25 months.

Example 4: Group containing 14.2% L-ascorbic acid stabilized with olean extract and ionene polymer compound

L-Ascorbic Acid 14.2% Olean Fruit Water Extract 26.8% Etoxydiglycol 44.0% citric acid 0.06% purified water 14.2%

The slightly yellow composition was unchanged after 25 months.

Example 5: Clinical Study of Results of Administration of Compositions of Examples 3 and/or 4

Different clinical applications of the composition according to the invention based on LAA stabilized with an aqueous extract of olean fruit and creams containing vitamins E, A and their derivatives, mixed with olea , containing cogic or azelaic acid. In fact, the clinical study was conducted on 50 patients with various skin changes such as: bedsores, diabetic ulcers, various skin tumors from dysplasia to actinic keratoses (precancerous), thermal and chemical burns , epidermal aging, surgical scars and other types of scars, various types of acne, epidermal atrophy, epidermal dehydration, psoriasis and other dermatological lesions with interesting results; Cases receiving treatment A random selection of cases.

Exemplary case n°1: Recurrence of scalp basocell carcinoma in a 74-year-old patient. The patient underwent surgery to resect the tumor and cover the area with a layer of transposition multiple flaps. In the seats where the margins reached by the tumor were not known precisely, equine collagen was implanted so the uncovered areas were exposed to the bone in a cyanide sheath. The treated parts were then treated daily with the drug in the form of a slurry of 14.2% LAA mixed with olean and/or ionene. This dosing regimen is also administered in areas including the entire scalp due to precancerous conditions such as actinic keratoses, tumor lesions, and atrophy of epidermal areas. After two weeks, it was found that significant re-epithelialization occurred at the edge of the superficial surgical wound to the collagen, no doubt acting as a bridge of cellular structures, which, from the edge, reformed the entire surface. The wound healing was complete within 3 weeks from treatment. Treatment with a composition obtained by mixing a cream based on stabilized LAA and vitamin A and its derivatives with olea results in complete restoration of surfaces with actinic keratoses and epitheliomas. The epidermis was considered normal after three months of treatment (Fig. 2).

Exemplary case n° 2: 42 year old patient with uncompensated diabetes (value 340 mg/dl) suffers from a diabetic ulcer on the first toe of the left foot and has paresthesias. Treat daily with LAA mixed with olean and/or ionene and fatty gauze. Seven days later, the epithelium was fully regenerated and sensitivity was restored (Fig. 3).

Exemplary case n°3: This case concerns the application of vitamin C (LAA) mixed with olean and/or ionene with vitamins A and E mixed with olean and/or ionene for cosmetic use in a cream. A 26-year-old patient with sun spots and "lentigo solaris" on the neck. The serum of the present invention is used together with a cream containing as active ingredients substances such as derivatives of vitamins A, C and E mixed with olea. The whitening effect is obtained mostly from serums of vitamin C and partly from creams containing cogic acid or azelaic acid stabilized with olean. After 8 weeks from the start of treatment, the patient is happy as the lentigosolaris has completely disappeared and the skin is soft, moist and consistent in color.

Exemplary case n°4: This case concerns vitamin C mixed with olean fruit and a cosmetic product containing vitamin A, C and their derivatives mixed with olean fruit, vitamin E and cogic and/or azelaic acid application of purpose. A 48-year-old patient with facial rosacea and teleangectasys due to previous treatment with tretinoin. The patient was treated with a cream comprising a slurry of the above active ingredients mixed with olean, salicylic acid and malaleuca alternifolia and vitamin C. After 4 weeks of continuous treatment, the patient underwent chemical peeling with 20% TCA, which chemically etches down to the basal layer of the epidermis, reaching some local IRD (immediate reticular dermis). Patients undergo home remedies with creams and epithelial regeneration substances based on AA, aloe vera, vitamins C, A, E mixed with olean and/or ionene. The vitamin C is dispersed over the new skin when the exfoliation phase of the new skin begins. Patients achieved complete re-epithelialization in no more than 7 days with stunning results. After peeling, the patient will be treated based on a very low dose of the cream to maintain the effect. It is worth mentioning that after exfoliation, the skin does not appear red.

Exemplary case n°5: A 20 year old patient with oily skin, hyperpigmentation and hirsutism. Treatment with creams, astringents, and vitamin C stabilized in serum is based on altering the hormone, testosterone. After two months of treatment, the skin tone is even, and oil secretion and pore size are reduced.

Exemplary Case n°6: A 72 year old patient suffers from wrinkles and marked aging. Treated with the composition of the present invention for 3 months, and carried out chemical peeling with 20% TCA in the treatment. Substances for restoring skin tone and skin tone visibly improve wrinkles and whiten.

Exemplary case n°7: A 44-year-old patient suffers from skin pigmentation, photoaging. Actinic keratoses with loss of skin elasticity. Treatment was performed twice a day with the cream of the invention. Controls were performed every two days, with doses adjusted according to the results of the patient's treatment with the creams and serums of the present invention. After 8 weeks of daily treatment, the patient's pigmentation completely disappeared, and 20% TCA chemical peeling was used to peel off to the basement membrane level.

Exemplary case n°8: A 45-year-old patient undergoing treatment for a sarcoma of the foot presented with a free margin of gran dorsale . After treatment the patient underwent radiation oncology, in which a dystrophic ulcer was induced during radiation therapy. The patient treated the irradiated part with the serum of the invention twice a day, and after 7 days not only the ulcer had been completely re-epithelialized, but a significant anti-inflammatory effect was found in the treated part.

Exemplary case n°9: A 48-year-old patient suffered from macular psoriasis for 20 years and tried many different treatments without positive results. Cure was achieved after 3 months of treatment with the composition of the present invention, and the psoriatic lesions concentrated on the head and joint levels disappeared (Figs. 4-6).

The above cases were randomly selected from 50 cases undergoing treatment. LAA mixed with ionene polymers and/or olean, not only in the form of a serum but also in the form of a cream, containing vitamin C, vitamin A and its derivatives, vitamin E, ascorbic and azelaic acids, bearberry glycosides and phytic acid, both blended with ionene polymers and/or olean. In particular, olean and/or ionene, when mixed, have a synergistic effect and act on:

- prevention and treatment of spots (preventive effect on hyperpigmentation after exposure to sun rays, and post-inflammatory, PIH);

- Treatment and prevention of skin tumors, age spots, lentigo solaris, etc.;

- treatment of actinic keratoses;

- Treat external wounds, since the whole is involved in the healing process;

-Restore skin function and internal environment stability;

- restores and stimulates normal cellular hydration;

- restore normal skin elasticity and functions related to collagen action;

- Treat bedsores, diabetic skin ulcers, etc.;

- treatment of oral mucosal (mucous) injuries;

- the process of re-epithelialization of the epidermis and mucous;

- treatment of acne;

- treatment of burn ulcers;

-Combined treatment of surgical wounds with collagen that supports the process of epithelial regeneration stimulated by vitamin C mixed with ionene polymers.

- treatment of surgical accidents of intestinal surgery, when it is desired to prevent the development of cicatricial frenulum, since the substance is a modulator of collagen synthesis;

- treatment of skin diseases with the possible application of substances comprising vitamins C, A, E, etc. mixed with ionene polymers;

- treatment of scars and tissue infarctions as well as acute consequences of cardiac infarction, since the substance is an important mediator of healing;

- treatment of oral mucosal (mucous) lesions, including aphtas and herpes;

- Treats skin herpes.

The composition of the invention acts on the nervous system, stimulates the repair of the nerves of the epithelial tissue, in which the complex containing vitamin C plays a key role in the production of collagen.

It has been confirmed that both vitamin C and olean have the effect of preventing skin tumors, and especially protect DNA from UVB damage (Cancer Immunol Immunother.2003Nov.; 52-Eur.J.Cancer.2000Jun; 36(10): 1235/47).

In addition, it has been found that a mixture of olean, vitamin C (LAA), ionene and vitamin A and derivatives mixed with ionene and/or olean inhibits and reduces the Side effects such as neovascularization, epidermal teleangectasys do induce unaesthetism. Said protective effect on the vascular membrane is attributed to the action of the vitamin C-ionene polymer or the mixture of vitamin C and olean, which has been found clinically in patients with excellent vascularization, water Cooperative effect, and has nothing to do with the occurrence of telengactasys.

Considering the vascular protective effect of the LAA-olean and/or ionene mixture, the latter achieves its maximal efficacy in the treatment of rosacea in combination with tretinoine mixed with ionene and/or oleene, the condition Has a rich vascular component.

It is also to be noted that a mixture of LAA-olean and/or ionene polymers can accelerate the healing process of exfoliated skin after peeling.

Example 6: Composition of the invention comprising ionene, vitamin A and vitamin E The following concentrations are in % by weight:

ionene polymer 2.1 cis-retinoic acid (vitamin A) 0.08 Vitamin E Acetate 0.5 Cogic acid 4.2 cetyl ester 8.4 cetyl alcohol 4.0 glycerin 10 Methylparaben 0.2 Propylparaben 0.02 Cationic surfactant quaternium/15 0.1 Sodium dodecyl sulfate 2.5 Deionized water add up to 100%

Example 7: Composition of the invention comprising ionene, vitamin A and vitamin E The following concentrations are in % by weight:

ionene polymer 2.1 cis-retinoic acid (vitamin A) 0.05 Vitamin E Acetate 0.5 Cogic acid 4.2 Azelaic acid 20 glycolic acid 2.1 cetyl ester 8.4 glycerin 10 Methylparaben 0.2 Propylparaben 0.02 Cationic surfactant quaternium/15 0.1 Sodium dodecyl sulfate 2.5 Deionized water add up to 100%

bibliography

-WO 98/23152

-Eur J. Cancer. 2000 Jun; 36(10): 1235-47 The antioxidant/anticancer potential of phenolic compounds isolated from olive oil. Owen RW, GiacosaA, Hull WE, Haubner R, Spiegelhalder B, Bartsch H.

-Carciogenesis.2000 Nov;21(11):2085-90.Protective effect oftopically applied olive oil against photocarcinogenesis following UVBexposure of mice.Budiyanto A, Ahmed NU, Wu A, Bito T, Nikaido M O, OshisawaT, Ichia, Uedha .

-J Control Release.2002 May 17:81(1-2):201-17.Physical properties and in vitro transfection efficiency of gene delivery vectors based oncomplexes of DNA with synthetic polycations.Reschel T, Konak C, Oupickyd, Seyourich LW, K.

-Cancer Immunol Immunother.2003 Nov; 52(11)693-8.Epub 2003 Jun 24L-ascorbic acid(vitamin C) induces the apoptosis of B16 murine melanomacells via a caspase-8-independent pathway.Kang JS, et al.

-J Invest Dermatol.1997 Mar;108(3):302-6.L-ascorbic acid inhibitsUVA-induced lipid peroxidation and secretion of IL-1 alpha and IL-6 incultured human keratinocytes in vitro.Tebbe B. et al.

-Bioconjug Chem 2002 May-Jun; 13(3):548-53. Aliphatic ionenes as genedelivery agents: elucidation of structure-function relationship through modification of charge density and polymer length. Zelikin An, Putnam D, Shastri P, Langerruv R, I VA.

-Int J Antimicrob Agents2002 Oct;20(4):293-6.In vitroantimycoplasmal activity of oleuropein. Furneri PM, Marino A, Saija A, Uccella N, Bisignano G.

-Macromolecules, Vol.5 page 253. May-June 1972. lonene Polymers. Rembaum A.

-Radiat Res.2003 Mar;159(3):371-80.Evaluation of the effect of ascorbic acid treatmentmeng on wound healing in mice exposed to different doses offfractionated gamma radiation.Jagetia GC, Rajanikant GK, Rao SK.

Claims (82)

1, compositions comprises one or more vitamin and/or its derivant, and olive extract, preferred its water extract, and/or one or more its components, for example oleuropeine, butyl alcohol and hydroxytyrosol, and/or ionene polymer, and acceptable auxiliary and/or carrier on one or more pharmacy or the cosmetic conduct and learning.

2, compositions as claimed in claim 1, wherein said vitamin and/or its derivant are ascorbic acid and/or its derivant.

3, compositions as claimed in claim 2, wherein said ascorbic acid are the L-ascorbic acid.

4, compositions as claimed in claim 2, wherein the derivant of ascorbic acid is the ester of ascorbic acid and fatty acid or its salt formation.

5, compositions as claimed in claim 4, wherein the ester of ascorbic acid and fatty acid formation is an ascorbyl palmitate.

6, compositions as claimed in claim 1, wherein vitamin is selected from vitamin A, E, D, K, B1, B2, B3, B5, B6, B8, B9, B12.

7, the described compositions of aforementioned each claim, wherein the olive extract is a water extract.

8, compositions as claimed in claim 1 further comprises one or more active component that contain among Echinea purpurea extract, angustifolia or pallida and/or Echinea purpurea extract, angustifolia or the pallida.

9, compositions as claimed in claim 8, one or more active component that contain among wherein said Echinea purpurea extract, angustifolia or the pallida are selected from different xylan (heteroxylanes), Fructus rhamni (Rhamnus davurica Pall.)-Arabic glycosyl-galactan, glycoprotein, chicoric acid, alkylamide, caffeic acid derivant, flavonoids, Flos Caryophylli alkene.

10, compositions as claimed in claim 9, wherein the caffeic acid derivant is echinacoside or Echinacea Species.

11, compositions as claimed in claim 9, wherein flavonoids is a rutin.

12, the described compositions of aforementioned each claim further comprises one or more chemical compounds, and it is selected from polymeric ether, monohydric alcohol, polyhydric alcohol, tetraborate or sulfate.

13, compositions as claimed in claim 12, wherein polymeric ether is ethene polymers or expoxy propane.

14, compositions as claimed in claim 12, wherein polyhydric alcohol is etoxydiglycol.

15, the described compositions of aforementioned each claim further comprises one or more chemical compounds, and it is selected from adenosine triphosphate, adenosine diphosphate (ADP), phosphoenolpyruvate, phosphagen, inorganic phosphate.

16, the described compositions of aforementioned each claim further comprises one or more materials, and it is selected from collagen, Fibrin Glue, fibrin and its derivant, cerebral dura mater.

17, compositions as claimed in claim 15, wherein collagen is type i collagen.

18, the described compositions of aforementioned each claim further comprises one or more chemical compounds, and it is selected from hyaluronic acid or derivatives thereof, hydroxy methocel, maltodextrin, aminoacid.

19, the described compositions of aforementioned each claim, its form is serosity, gel, Emulsion, emulsifiable paste, medical instruments.

20, compositions as claimed in claim 19, wherein medical instruments are gauze, binder, Gypsum Fibrosum, silicon rod.

21, compositions as claimed in claim 1, wherein ionene polymer has general formula (I):

[-N(CH ₃) ₂-(CH ₂) _x-N(CH ₃) ₂-(CH ₂) _y-] ^.2Z ^- (I)

Wherein x and y are integer, and Z is a halogen.

22, compositions as claimed in claim 21, wherein Z is Br or Cl.

23, compositions as claimed in claim 21, wherein ionene polymer is by 1, and 4-dichloroetane and the reaction of four methylene diamidogen (tetra-methylen-diamine) obtain.

24, compositions as claimed in claim 1, wherein ionene polymer is selected from by 1,4-dichloroetane and poly-(oxygen ethylene (dimethylimino)-ethylene (dimethylimino) ethylene dihalide), poly-(2-hydroxyalkyl vinyl-dimethylimino 2-hydroxy propylene-dimethylimino methylene) dihalide, poly-[{ alkyl-(3-aminopropyl) imino group } cyclopropane dihalide], poly--[(dialkyl group-imino group) ethylene halogenide] or obtain those with poly--[(hydroxyl-dialkyl group-imino group) ethylene halogenide] reaction.

25, the described compositions of aforementioned each claim, wherein the concentration of ascorbic acid or derivatives thereof is 0.1% to 35%.

26, compositions as claimed in claim 25, wherein the concentration of ascorbic acid or derivatives thereof is 10% to 25%.

27, compositions as claimed in claim 25, wherein the concentration of ascorbic acid or derivatives thereof is 12% to 20%.

28, the described compositions of aforementioned each claim, wherein the concentration of vitamin A is 0.01% to 5%.

29, the described compositions of aforementioned each claim, wherein the concentration of vitamin E is 0.01% to 5%.

30, the described compositions of aforementioned each claim, wherein the concentration of ionene polymer is 0.001% to 10%.

31, compositions as claimed in claim 30, the concentration of its ionene polymer are 1.5% to 3.2%.

32, the described compositions of aforementioned each claim, wherein the concentration of olive extract is 0.1% to 95%.

33, the described compositions of aforementioned each claim, wherein the concentration of olive extract is 5% to 50%.

34, the described compositions of aforementioned each claim, wherein the concentration of olive extract is 15% to 30%.

35, the described compositions of aforementioned each claim, wherein the concentration of polymeric ether is 5% to 50%.

36, the described compositions of aforementioned each claim, wherein the concentration of monohydric alcohol and/or polyhydric alcohol is 5% to 50%.

37, the described compositions of aforementioned each claim, wherein the concentration of thiosulfate is 0% to 5%, preferred 0.01% to 3%.

38, the described compositions of aforementioned each claim, wherein Echinacea purpurea and/or its concentration a kind of or the various active composition are 0.001% to 10%.

39, the described compositions of aforementioned each claim, wherein, one or more compound concentrations that are selected from adenosine triphosphate, adenosine diphosphate (ADP), phosphoenolpyruvate, phosphagen, inorganic phosphate are 0.001% to 35%.

40, the described compositions of aforementioned each claim, wherein thiosulfate provides with the form of potassium salt and/or sodium salt and/or ammonium salt.

41, the described compositions of aforementioned each claim, comprise 20% water, preferred DDW, the 20%L-ascorbic acid, the ionene polymer of 2.66% formula (I), wherein x=3 and y=3,0.3% Potassium hyposulfite., 15% olive water extract, 50: 50 mixture of 42% propylene glycol and 1,2 butanediol.

42, the described compositions of aforementioned each claim, comprise 20% water, preferred DDW, 20%L-ascorbic acid, the ionene polymer of 2.66% formula (I), wherein x=3 and y=3,0.3% Potassium hyposulfite., 22% olive water extract, 15% polyoxyethylene/polyoxypropylene polymer, 50: 50 mixture of 20% propylene glycol and 1,2 butanediol.

43, the described compositions of aforementioned each claim comprises the 14.2%L-ascorbic acid, 26.8% olive water extract, 44%etoxyglycol, 0.06% citric acid, 14.2% purified water.

44, the described compositions of aforementioned each claim, its pH value is 2.0 to 6.0.

45, the medical instruments that comprise the thin compound that defines as claim 1-44.

46, compositions as claimed in claim 1 comprises vitamin A and E, and one or more ionene polymers, and one or more acceptable carrier and/or adjuvants pharmaceutically or on the cosmetic conduct and learning.

47, compositions as claimed in claim 46, wherein the concentration of vitamin A is 0.01% to 5%.

48, compositions as claimed in claim 46, wherein the concentration of vitamin E is 0.01% to 5%.

49, compositions as claimed in claim 46, wherein the concentration of ionene polymer is 0.001% to 10%.

50, compositions as claimed in claim 49, wherein the concentration of ionene polymer is 1.5% to 3.2%.

51, as each described compositions among the claim 46-50, further comprise one or more chemical compounds, it is selected from cogic acid, Azelaic Acid, phytic acid, glycolic, lactic acid, fumaric acid, tartaric acid, L-aspartic acid, L-ascorbic acid, phytic acid, arbutin.

52, compositions as claimed in claim 51, wherein said one or more component concentrations are 1.5% to 10%.

53, as each described compositions among the claim 46-52, further comprise one or more softening agents, flowable, emulsifying agent, antiseptic, surfactant, antifungal.

54, compositions as claimed in claim 53, wherein softening agent is that concentration is 0.1% to 10% cetyl ester.

55, compositions as claimed in claim 54, wherein the concentration of cetyl ester is 5% to 9%.

56, compositions as claimed in claim 53, wherein to be selected from concentration be that 0.1% to 15% stearyl alcohol, concentration are 5% to 12% cheryl alcohol to flowable.

57, compositions as claimed in claim 56, wherein the concentration of stearyl alcohol is 5% to 12%.

58, compositions as claimed in claim 53, wherein to be selected from concentration be that 0.1% to 6% hexadecanol, concentration are that 0.1% to 18% glycerol, concentration are 0.1% to 1.5% sodium lauryl sulphate to emulsifying agent.

59, compositions as claimed in claim 58, wherein the concentration of hexadecanol is 2% to 5%.

60, compositions as claimed in claim 58, wherein the concentration of glycerol is 2% to 12%.

61, compositions as claimed in claim 58, wherein the concentration of sodium lauryl sulphate is 0.5% to 1.0%.

62, compositions as claimed in claim 53, wherein antiseptic is that concentration is 0.1% to 0.4% methyl hydroxybenzoate.

63, compositions as claimed in claim 62, wherein the concentration of methyl hydroxybenzoate is 0.05% to 0.3%.

64, compositions as claimed in claim 53, wherein surfactant concentrations is 0.01% to 0.15%.

65, as the described compositions of claim 64, wherein surfactant concentrations is 0.05% to 0.12%.

66, compositions as claimed in claim 53, wherein antifungal is that concentration is 0.01% to 0.1% propylparaben.

67, as the described compositions of claim 66, wherein the concentration of propylparaben is 0.02% to 0.05%.

68, as each described compositions among the claim 46-67, comprise ionene polymer 0.01% to 10% weight, cogic acid 1% to 10% weight, Azelaic Acid 1% to 30% weight, glycolic and/or lactic acid 1.5% to 15% weight, trans-cis-retinoic acid 0.01% to 5% weight, Vitamin E acetate 0.5% to 5% weight, contain at least a cetyl ester that is selected from, hexadecanol, the softening agent of glycerol or wetting agent, be selected from methyl hydroxybenzoate, the antiseptic of propylparaben and as the absorbent substrate emulsifiable paste of the sodium lauryl sulphate of emulsifying agent adds water to 100% weight at last.

69, as being used in the compositions in the field of medicaments among the claim 1-68 as described in each.

70, as the purposes of each described compositions among the claim 1-68 in the cosmetics treatment.

71, as the described purposes of claim 70, be used for the treatment of wrinkle.

72, as the described purposes of claim 70, be used for the treatment of skin speckle.

73, as the purposes of the described compositions of claim 1-68 in the medicine of preparation treatment actinic keratosis.

74, as the purposes of the described compositions of claim 1-68 in the medicine of preparation treatment wound.

75, as the purposes of the described compositions of claim 1-68 in the medicine of preparation treatment ulcer.

76, treat diabetes epidermis ulcer as the described compositions of claim 1-68 in preparation, and the purposes in the medicine of acute and chronic skin injury.

77, as the purposes of the described compositions of claim 1-68 in the medicine of preparation treatment oral mucosa (mucous) damage.

78, as the purposes of the described compositions of claim 1-68 in the medicine of preparation prevention and treatment cutaneous tumor.

79, as the purposes of the described compositions of claim 1-68 in the psoriatic medicine of preparation treatment.

80, ionene polymer and/or olive are used for the stable purposes that contains the compositions of vitamin.

81, as the described purposes of claim 80, wherein compositions is aqueous solution or Emulsion.

82, as the described purposes of claim 80, wherein vitamin is selected from the group of vitamin A, B1, B2, B3, B5, B6, B8, B9, B12, C, D, E, K composition.

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