SK279823B6 - PREPARATIONS FOR LOCAL USE, THEIR PREPARATION - Google Patents

Abstract

A topical application composition characterised 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 ranges between 200 to 3000 nm. Said composition is prepared by dissolving melanine in flourocarbons. A dispersion thereby obtained is converted by means of homogenisation in the aqueous system, together with a phospholipid to symmetrical lamellar phospholipid aggregates, which are used as a melanine transporter onto the skin area above the epiderm.

Description

Technical field

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

BACKGROUND OF THE INVENTION

It is known that shortwave 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 that arise under the influence of energy-rich radiation is problematic.

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 area between stratum comeum and stratum basale. To meet these requirements, long-term testing is required, as prescribed for pharmacological compounds. The UV filters are applied locally appropriately for the purpose of their use and their individual efficacy over a wide concentration range of 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) to reduce skin aging due to radiation effects.

Melanin, which also occurs in human and animal cells, in melanocytes, is known to be 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 melanocytes of the skin travels to 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 invention, the 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 phospholipid aggregates, are present in an aqueous system together with a phospholipid, the particle size being aggregates range from 200 to 3000 nm.

From natural sources obtained (such as Sephia officinalis) or synthetically produced (oxidation of tyrosine with e.g. H ₂ O ₂ ) melanin is present, dissolved or suspended in a fluorocarbon, encapsulated in the core of asymmetric lamellar phospholipid aggregates. The structural arrangement in lamellar aggregates is fundamentally different from the structure of aqueous liposomes (vesicles). The hydrophobic nature of the fluorocarbon requires the polarity of the phospholipid molecules to be reversed so that the lipophilic fatty acid radicals with the fluorocarbon found in the core of the aggregate interact with each other by dispersing forces. For this arrangement, additional phospholipid bilayer films are provided in addition to the asymmetric lamella globular aggregates according to the above conditions.

The new asymmetric structure was demonstrated by both ³ P-NMR spectroscopy and spectral analysis. The extraordinary stability of the aggregates is the result of their Iamellam structure and their corresponding surface charge.

A large number of fluorocarbons may be used, for example aliphatic linear and branched fluoroalkanes, mono- or bicyclic and optionally fluoroalkyl-substituted fluoro cycloalkanes, perfluorinated aliphatic or bicyclic amines, bis- (perfluoroalkyl) ethenes, perfluoropolyethers or mixtures thereof. Particularly preferred are fluorinated hydrocarbons such as perfluorodecalin, F-butyltetrahydrofuran, perfluorotibutylamine, perfluorooctyl bromide, bisfluoro (butyl) ethene or bis-fluoro (hexyl) ethene or C ₆ -C ₉ perfluoroalkanes. The amount of fluorocarbons ranges from 20 to 100% w / v, preferably from 40 to 100%. Particularly preferred is a range from 70 to 100% w / v.

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 another important criterion, to control the residence time in the tissue. For example, while perfluorotripylamine (F-TBA, CST 59 ° C) with high CST and poor lipid solubility has a longer residence time, perfluorodecalin (PFD, CST 22 ° C) as well as F-butyltetrahydrofuran, F-hexane and others , they are released reasonably faster from the tissue. With mixtures of fluorocarbons, systems with the desired CST values, i.e. lipid and membrane solubility, can be prepared in this way, specifically with respect to the intended use.

The fluorocarbon content of the lamellar aggregates may vary between 1 and 100% w / v, depending on the application. Suitable fluorocarbons are, in particular: aliphatic linear and branched alkanes of 6 to 12 carbon atoms, such as perfluorohexane, perfluorooctane, perfluoromonane; mono- or bicyclic 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 having two or three oxygen atoms in the molecule, such as perfluorohexyl ether, perfluorobutyltetrahydrofuran, perfluoropolyethers; perfluoroalkyl halides such as perfluorooctyl bromide, perfluorohexyl bromide, perfluorooctyl chloride; bis-F (alkyl) ethenes such as bis-F (butyl) ethene, bisF (hexyl) -ethene.

As used herein, the term "fluorocarbons" refers to perfluorinated or highly fluorinated carbon compounds or mixtures that 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. Due to 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%, which in addition contain 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, for example the epidermis or the dermal region, does not reach the site of action according to the invention after penetrating through Stratus comeum. 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 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), by ultrasound, or by pressure homogenization in such a way as to ensure particle size.

The invention is further illustrated by the following examples.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure t. 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 standard.

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

Table 1

Fluorinated Solubility Saturated CST Vapor Pressure HydrocarbonP ₃₇ ° C [th 07100 ml FU] [mmHg] [° q

Perfluóroktyl-

bromide 50 14 -24.5 perfluorodecalin 40 12.5 22 Bis-F (butyl) ethene 50 12.6 22.5 F-Cyclolhexylmethyl morpholino 42 4 38.5 F-tripropylamine 45 18.5 43 F-dihexyl 45 2 59 F-tributylamine 40 1 59 Perfluorodecalin-F- tributylamine 1: 1 40 7 42 Perfluórbutyl- tetrahydrofuran 52 51 29 F-methylcyclohexane 57 180 8.2 F-hexane 58 414 20

preparations

DETAILED DESCRIPTION OF THE INVENTION

Example 1

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

The aggregates prepared in this way were mixed into the following light-protective means in a customary manner.

Example 2

Emulsion (Body Milk) Polyacrylic acid TEA

Methyl p-hydroxybenzoate Propyl p-hydroxybenzoate Imidazolidinyl urea Na-EDTA

Cetyl / stearyl alcohol Stearic acid Isopropyl myristate / palmitate Liquid paraffin Jojoba oil Melanin phospholipid aggregates

0,30%

0,30%

0.20%

0.10%

0.20%

0,06%

1,00%

1,00%

3,00%

4,00%

2,00%

10,00%

Essential Oil 1.00%

Demineralized water q. with.

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 0.20%

Propyl p-hydroxybenzoate 0,10%

Imidazolidinyl urea 0.20%

Melanin phospholipid aggregates 20.00%

Essential Oil 1.00%

Demineralized water q. with.

Example 4

Milk

Emulsifying system consisting of 34.00% water, stabilizers, polyglycerol esters, polyoxyethylene esters, isopropyl palmitate

Glycerin 5.00%

MgSO ₄ .7H ₂ O 0.50%

Melanin 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%

Kaolin 2,20%

Dyes 15,80%

Pearl Chandelier Pigment 21,50%

Essential Oil 1.50%

Silk Protein 5.00%

Emulsion as a Processing Agent Emulsifying Agent 4.50%

Silicone oil, volatile 2,50%

Melanin phospholipid aggregates 4.50%

Preservative 0.30%

Demineralized water q. with.

Claims (14)

Topical formulations 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 a phospholipid, wherein the particle size of the aggregates ranges from 200-3000 nm. Formulations according to claim 1, characterized in that the amount of fluorocarbons lies in the range from 1 to 100% w / v. Compositions according to either of Claims 1 and 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, bis ( perfluoroalkyl) ethenes, perfluoropolyethers and mixtures thereof. Compositions according to claim 3, characterized in that the fluorocarbons are selected from the group consisting of perfluorodecalin, F-butyltetrahydrofuran, perfluorotributylamine, perfluorooctyl bromide, bis-fluoro (butyl) ethene and C ₆ -C ₉ perfluoroalkanes. Formulations 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%. Formulations according to one of claims 1 to 5, characterized in that they contain one or more fluorocarbons having a critical solubility temperature below 50 ° C, preferably below 30 ° C. Formulations 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. Formulations 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. Formulations according to one of Claims 1 to 8, characterized in that lysolecithins are present in addition to phosphatidylcholine in a concentration range of 1 to 10%. weight Formulations according to claim 1, characterized in that in addition to melanin and a fluorocarbon, a solvent is 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. Process for the preparation of topical preparations according to claims 1 to 10, characterized in that melanin is dissolved or dispersed in one or more fluorocarbons and this dispersion is converted by homogenization in an aqueous phospholipid system into asymmetric lamellar phospholipid aggregates containing fluorinated hydrocarbons and melanin, and having a particle size between 200 and 3000 nm. A method 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, nonane is added to melanin and fluorocarbons. , decane or mixtures thereof within a single group or from different groups. Use of 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 3000 nm. Use according to claim 13, characterized in that the phosphatidylcholine content of the phospholipids SK 279823 od6 ranges from 10 to 99% by weight, especially from 30 to 30% by weight 99% by weight, and in particular from 70 to 90% by weight.