SK156694A3 - Compositions for local use and method of their preparation - Google Patents

Abstract

A topical application composition with light-screening properties in a special application form is disclosed. The problem with known light-screening agents containing native melanine as active substance is an insufficient melanin transport to its site of activity. The invention solves this problem with a topical application composition characterized by a content of melanin dissolved or dispersed in one or several fluorocarbons available as asymmetrical lamellar phospholipid aggregates in an aqueous system, together with a phospholipid. The particle size of the aggregates lies in the 200 to 3000 nm range.

Description

The invention relates to cosmetic and / or dermatological compositions having light-protective properties in a special application form, the asymmetric lamellar phospholipid aggregates containing fluorocarbons having the function of melanin carriers.

BACKGROUND OF THE INVENTION

It is known that short-wave UV radiation (UV / A, UV / B, UV / C, wavelength ranges from 400 to 200 nm) has a harmful effect on the skin and is an important factor in premature skin aging. In extreme form, this effect may be related to cytogenetic changes in individual skin cells and lead to the formation of skin cancers (melanomas). These risks have continuously increased due to changes in environmental factors (ozone hole), with increased UV exposure. To overcome this, it is customary to protect exposed skin tissues by using special UV protection filters found in special cosmetic and dermatological preparations. The action of the active compound in such formulations is based on the following principles:

Absorption of UV radiation using UV active organic compounds

2. UV scattering of finely dispersed titanium dioxide or other micropigments.

The efficiency of these systems, which can be measured simply by recording their UV absorption maxima in the wavelength range 250-400 nm or by measuring the scattering curves, is evident.

On the other hand, the biological acceptability of these substances and, in particular, the products of possible chemical transformations, which arise under the influence of energy - rich irradiation a.

Another critical point is the depth of penetration of the UV filter into the skin when used as a component of a cosmetic or dermatological preparation. A suitable site of action is the region

To meet these testing, such UV filters are locally between the stratum corneum and stratum basale. requirements, they need to be prescribed for pharmacological compounds over a long period of time, apply appropriately to their purpose of use and their individual efficacy over a wide range of concentrations between 1 and 10% in a suitable medium.

So eg. DE-A-3242385 (Zabotto) discloses a cosmetic composition which, among other active compounds, contains 1.5% Parsol Ultra (Givaudan) for reducing skin aging due to radiation effects.

Melanin, which also occurs in human and animal cells, in melanocytes, is known as a natural substance in higher animals that protects against radiation. Melanin is a brown-to-black colored polymeric vertebrate pigment, which is made, inter alia, of the amino acid tyrosine and pigmentes both skin and hair as well as iris. The melanin formed in the skin melts into the basal layer of the skin and transfers the pigment to the skin cells. Since melanin as a polymeric substance hardly dissolves at all, previous attempts to deliver this substance by topical application to the site of action cannot be considered to be significantly successful.

SUMMARY OF THE INVENTION It is an object of the present invention to allow the local use of melanin at its site of action.

SUMMARY OF THE INVENTION

According to the present invention, a topical formulation having protective light properties is characterized in that it contains melanin, which is dissolved or dispersed in one or more lipophilic fluorocarbons, which, as asymmetric lamellar phospholide aggregates, are present in the aqueous system together with the phospholipid, wherein the particle size of the aggregates ranges from 200 to 3000 nm.

From natural sources derived (such as from Sephia officinalis) or synthetically produced (oxidation of tyrosine with e.g. H2O2) melanin is present, dissolved or suspended in a fluorocarbon, encapsulated in the core of asymmetric lamellar aggregates of phospholides. The structural arrangement in lamellar aggregates is fundamentally different from aqueous liposomes (vesicles). Hydrophobic structures characterize the polarized fluorocarbons of phospholipid molecules so that they react lipophilically. On this globular aggregate, another ³¹ P-NMR follows the asymmetric lamellar according to the above-mentioned conditions of phospholipid bilayer films.

The new asymmetric structure has been proven by spectroscopy as well as spectral analysis. The extraordinary stability of the aggregates results from their lamellar structure and their corresponding surface charge.

A large number of fluorocarbons can be used, for example, aliphatic linear and branched fluoroalkanes, mono- or bicyclic and optionally fluoroalkyl-substituted fluorocycloalkanes, perfluoroaliphatic or bicyclic amines, bis- (perfluoroalkyl) ethenes, perfluoropolyethers or mixtures thereof. Particularly preferred are fluorocarbons such as perfluorodecane, F-butyltetrahydrofuran, perfluorotriarylamine, perfluorooctyl bromide, bis-fluoro (butyl) ethene or bis-fluoro (hexyl) ethene or C8-C8 perfluoroalkanes. The amount of fluorocarbons ranges from 20 to 100% w / v (w / v), preferably from 40 to 100%. A range of 70 to 100% w / v is particularly preferred.

The dependence of penetration rate and penetration depth on aggregate particle size was experimentally determined by separate monitoring with labeled encapsulated fluorocarbons. According to these experiments, smaller particles migrate faster and deeper into skin tissue than larger particles. The choice of fluorocarbons, or mixtures thereof, according to their lipid solubility (represented by their critical solubility temperature of CST in n-hexane) allows, as an additional important criterion, to control the residence time in the tissue. For example, while perfluorotibutylamine (F-TBA, CST 59 ® C) with high CST and poor lipid solubility exhibits a longer residence time, perfluorodecaline (PFD, CST 22 ° C) but also F-butyltetrahydrofuran, F-hexane and others, are released reasonably faster from the tissue. With the aid of a mixture of fluorocarbons, systems having the desired CST values, i.e. solubility in lipids and membranes, can be prepared in this way, specifically with respect to the intended uses.

The fluorocarbon content of the lamellar aggregates may vary between 1 and 100% w / v depending on the intended use. Suitable fluorocarbons are: aliphatic linear and branched alkanes of 6 to 12 carbon atoms, such as perfluorohexane, perfluorooctane, perfluoronanane;

mono- or bi-cyclic cycloalkanes which are optionally substituted with F-alkyl, such as perfluoromethylcyclohexane, perfluorodecalin;

aliphatic tertiary amines, N-containing polycyclic compounds such as perfluorotripropylamine, perfluorotripylamine, F-cyclohexylmethylmorpholine;

perfluoroethers such as aliphatic ethers, F-alkylfurans, bicyclic and substituted bicyclic ethers with two or three oxygen atoms in the molecule, such as perfluorodihexyl ether, perfluorobutyltetrahydrofuran, perfluoropolyethers;

perfluoroalkyl halides such as perfluorooctyl bromide, perfluorohexyl bromide, perfluorooctyl chloride;

bis-F (alkyl) ethenes such as bis-F (butyl) ethene, bis-F (hexyl) -ethene.

The term fluorocarbons as used herein refers to perfluorinated or highly fluorinated carbon compounds or mixtures which are capable of transporting gases such as O ₂ and CO ₂ . Partially fluorinated hydrocarbon compounds within the meaning of the present invention are those in which most of the hydrogen atoms are replaced by fluorine atoms, such as bis-F (alkyl) ethenes, which are demonstrably chemically and biologically inert and thus non-toxic. This is mainly achieved when up to about 90% of the hydrogen atoms are replaced by fluorine atoms. For the purposes of the present invention, preference is given to those fluorocarbons in which at least 95% of the hydrogen atoms are replaced, more preferably 98% and in particular 100%.

Possible phospholipids are naturally occurring phospholipids, such as soy or egg lecithin, as well as lecithins (phospholipids), which can be prepared in a synthetic manner and which generally have a good effect on the skin and its treatment. Because of the advantageous effect on the stability of the asymmetric lamellar aggregates, mixtures of phospholipid with a phosphatidycholine content of from 10 to 99%, in particular 33 to 99%, in particular 60 to 90%, containing in addition other naturally occurring by-products, are mainly used. The phospholipid content of the topical formulation is between 0.5 and 20%, in particular 10 to 20%.

The particle size of the aggregates and phospholipids is selected such that their penetration into deeper layers of the skin, such as the epidermis or dermal region, does not occur according to the present invention after it has penetrated through the Stratus corneum. The particle size ranges from 200 to 3000 nm, in particular from 250 to 1000 nm.

The invention also relates to a process for the preparation of topical formulations, characterized in that melanin is dissolved or dispersed in one or more fluorocarbons and is converted by homogenization with a phospholipid in an aqueous system into asymmetric lamellar phospholipid aggregates containing fluorocarbons and melanin, and having a particle size between 200 and 3000 nm.

The solubility of the polymeric melanin can be increased by adding lipophilic compounds to the fluorocarbons where they act to improve solubility. Suitable lipophilic substances are natural oils, triglycerides or aliphatic alkanes selected from the group of olive oil, soybean oil, sunflower oil, pentane, heptane, nonane, decane, or mixtures thereof.

Homogenization may be accomplished by conventional methods, for example by means of a high-speed mechanical mixer (12000 to 15000 rpm), ultrasound or pressure homogenization in such a way as to ensure particle size.

The invention is further illustrated by the following examples. The attached figures show:

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Critical solubility temperature (CST) of n-hexane mixtures of perfluorocarbons using perfluorodecalin as standard.

Figure 2. Critical solubility temperature (CST) of n-hexane mixtures of perfluorocarbons using perfluorinated octyl bromide as a standard.

Some selected fluorocarbons, their oxygen solubility values, their saturated vapor pressure, and their critical solubility temperatures are listed in Table 1. Based on these data, a suitable composition of the fluorocarbon mixture can be selected according to the required skin penetration characteristics of the compositions of the invention.

Table 1 F1uórovaný solubility Saturated pressure CST hydrocarbon k acidified ka [ml 0 _2/100 ml FU] ^{Steam P} 37 ° C [mm Hg] [° C]

Perfluóroktyl-

bromi d 50 14 -24.5 Perfluórdekalí n 40 12.5 22 Bi s-F (butyl) ethene 50 12.6 22.5 F-Cyclolhexylmethyl morfolí n 42 4 38.5 F-three propyls n 45 18.5 43 F-dihexyl ether 45 2 59 F-tri-butylamines n 40 1 59 Perfluórdekali n-F- three n-butyls 1: 1 40 7 42 Perfluórbutyl- tetrahydrofuran 52 51 29 F-methylcyclohexane 57 180 8.2 F-hexane 58 414 20

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A mixture of a 10% aqueous soy lecithin phospholipid solution containing 40% phosphatidylcholine was mixed with a fluorocarbons consisting of perfluorodecalin (90%) and F-dibutylmethylamine (10%) and melanin using an ultrasonic disintegrator. The asymmetric lamellar phospholipid aggregates thus obtained had an average particle size of approximately 240 nm and contained melanin n.

The aggregates prepared in this way were mixed into the following forms of light-protective means according to conventional methods.

Example 2 - Emulsion (Body Milk)

Polyacrylic acid 0.30% TEA 0.30% Methyl p-hydroxybenzoate 0.20% Propyl p-hydroxybenzoate 0.10% Imidazolidinyl urea 0.20% Na-EDTA 0.06% Cetyl / stearyl alcohol 1.00% Stearic acid 1 .00% Isopropyl myristate / palmitate 3.00% Liquid paraffin 4.00% Jojoba oil 2.00% Melanin phospholipid aggregates 10.00% Essential oil 1.00% Demineralized water qs

Example 3 - Emulsion (cream)

Polyacrylic acid 0.30% Propylene glycol 5.00% TEA 0.30% Emulsifier 1 6.00% Emulsifier 2 4.50% Aloe vera 2.00% Rice husk oil 1.50% Cetyl / stearyl alcohol 1.00% Jojoba oil 1.50%

Methyl p-hydroxybenzoate Propyl p-hydroxybenzoate Inrididolidinyl urea Melani's new phospholipid aggregates Essential oil Demineralized water 0.20 0.10 0.20 20.00 1.00 q. with. % % % % % Example 4 - Milk Emulsification system consisting of 34.00 % water, stabilizers, esters polyglycerols, polyoxyethylene esters, isopropyl palmitate Glyceri n 5.00 % MgSO ₄ .7H ₂ O 0.50 % Melani's new phospholipid aggregates 6.00 % Methyl p-hydroxybenzoate 0.20 % Propyl p-hydroxybenzoate 0.10 % Imidazolidinyl urea 0.30 % Essential oil 1.00 % Demineralized water q. with. Example 5 Eye shadow with light protection factor talc 40.00 % Magnesium carbonate 1.50 % Magnesium stearate 2.50 % Kaolí n 2.20 % Farbi vá 15.80 % Pigment of pearl chandelier 21.50 % Essential oil 1.50 % Silk protein 5.00 % Emulsion as processing agent Emulsifying agent 4.50 % Si 1 icon oil, volatile 2.50 % Melani's new phospholipid aggregates 4.50 % Preservative 0.30 % Demineralized water qs

Claims (14)

A topical formulation comprising melanin dissolved or dispersed in one or more fluorocarbons which, as asymmetric lamellar aggregates of phospholipids, are present in an aqueous system together with phospholipids, wherein the particle size of the aggregates is in the range of 200 to 3000 nm. The composition of claim 1, wherein the amount of fluorocarbons is in the range of 1 to 100% w / v. Composition according to one of claims 1 or 2, characterized in that the fluorocarbons are selected from the group consisting of aliphatic linear and branched fluorocarbons, mono- or bicyclic or fluoroalkyl-substituted fluorocycloalkanes, perfluorinated aliphatic or bicyclic amines with (perfluoroalkyl) ethenes, perfluoro polyethers and mixtures thereof. The composition of claim 3, wherein the fluorocarbons are selected from the group consisting of perfluorodaline, F-butyltetrahydrofuran, perfluorotibutylamine, perfluorooctyl bromide, bis-fluoro (butyl) ethene, and C 8 -C 8 perfluoroalkanes. Composition according to one of Claims 1 to 4, characterized in that the amount of fluorocarbons is in the range from 20 to 100% w / v, preferably in the range from 40 to 100%, and in particular in the range from 70 to 100%. %. Composition according to one of Claims 1 to 5, characterized in that it contains one or more fluorocarbons having a critical solubility temperature below 50 ° C, preferably below 30 ° C. Composition according to one of Claims 1 to 6, characterized in that the phospholipids are selected from the group consisting of natural phospholipids such as soy lecithin and egg lecithin, also synthetic phospholipids, hydrogenated lecithins and / or partially hydrogenated phospholipids. Composition according to one of Claims 1 to 7, characterized in that the phosphatidylcholine is in the range from 10 to 99% by weight, in particular from 30 to 99%, in particular from 70 to 90% by weight. %. Composition according to one of Claims 1 to 8, characterized in that in addition to phosphatidylcholine, lysolecithins are present in a concentration range of 1 to 10% by weight. A composition according to claim 1, characterized in that in addition to melanin and a fluorocarbon there is also a solvent selected from the group of natural oils such as olive oil, soybean oil, sunflower oil, triglycerides or aliphatic alkanes such as pentane , heptane, nonane, decane or mixtures thereof within one group or from different groups. 11. A process for the preparation of topical formulations which comprises dissolving or dispersing melanin in one or more fluorocarbons and converting the dispersion by homogenization in an aqueous phospholipid system to asymmetric lamellar phospholipid aggregates containing fluorocarbons; and melanin, and having a particle size between 200 and 3000 nm. A process according to claim 11, characterized in that a solvent selected from the group of natural oils, such as olive oil, soybean oil, sunflower oil, triglycerides or aliphatic alkanes, such as pentane, heptane, is added to the melanin and fluorocarbons. nonane, decane or mixtures thereof within one group or from different groups. A method of using asymmetric lamellar phospholipid aggregates for delivering melanin to the epidermal skin area, wherein the asymmetric lamellar phospholipid aggregates consist of phospholipid and one or more fluorocarbons in which melanin is dissolved or dispersed and the particle size of the aggregates is in the range of 200 to 200 3000 nm. The method of use according to claim 13, characterized in that the phosphatidylcholine content of the phospholides is in the range from 10 to 99% by weight, in particular from 30 to 99%, and in particular from 70 to 90% by weight. %.