HK1002701B - Topical application composition - Google Patents

Description

The invention relates to a cosmetic or dermatological composition with photosensitive properties in a special application form, where asymmetric lamellar phospholipid aggregates containing fluorocarbons act as carriers of melanin.

It is known that short-wave UV light (UV/A, UV/B, UV/C, wavelength ranges from 400 to 200 nm) can be harmful to the skin and is a major factor in premature skin aging. In extreme cases, the effect can consist of a cellular genetic change of individual skin cells and lead to the formation of skin cancers (melanoma). These dangers have been constantly increased by environmental factors (ozone hole) with increased UV exposure. To combat this, it is common practice to use special cosmetics and dermatology to protect the exposed skin tissue by applying special UV light filters. The effectiveness of these systems, which can be demonstrated simply by capturing their UV absorption maxima in the wavelength range 250-400 nm or by scattering curves, is evident. The biological safety of these substances, in particular the possible chemical changes under the influence of high-energy radiation, is problematic.

The appropriate area of action is the area between stratum corneum and stratum basal. To meet these requirements, years of testing as prescribed for pharmacological active substances are necessary. The UV filters are applied topically in a wide concentration range between 1 and 10% in an appropriate medium, according to their purpose of application and individual efficacy.

For example, DE-A-3242385 (Zabotto) describes a cosmetic product containing, among other active substances, 1,5% Parsol Ultra (Fa. givaudan) to reduce skin aging due to light exposure.

Melanin is a brown to black polymer pigment of vertebrates, which is formed from the amino acid tyrosine and pigments both skin, hair and iris. The melanin formed in the melanocytes of the skin migrates to the basal layer of the epidermis and releases the pigment to the epidermis cells.

The purpose of the invention is to enable melanin to be applied topically to its active site.

According to the invention, a topical preparation with photosensitive properties is characterised by a content of melanin dissolved or dispersed in one or more lipophilic fluorocarbons, present as asymmetric lamellar phospholipid aggregates in an aqueous system together with a phospholipid, with a particle size of the aggregates in the range of 200 to 3000 nm.

The melanin produced naturally (e.g. from sepia officinalis) or synthetically (e.g. oxidation of tyrosine with H2O2) lies, dissolved or suspended by the fluorocarbon, encapsulated in the nucleus of the asymmetric lamellar phospholipid aggregates. The structural arrangement in the lamellar aggregates is fundamentally different from that of the aqueous liposomes (vesicles). The hydrophobic nature of the fluorocarbon requires a polarity reversal of the phospholipid molecule in such a way that the lipophilic fatty acids interact with the aggregation carbon in the nucleus of the fluorocarbon by means of dispersion forces. This arrangement is constructed according to further conditions of the lamellar-lipid complexes to form globular asymmetrical aggregates.

The novel asymmetrical structure was confirmed by 31P NMR and spectroscopic studies, and the extraordinary stability of the aggregates is due to their lamellar structure and homogeneous surface charge.

A wide variety of fluorocarbons may be used, e.g. aliphatic straight-chain and branched-chain fluoroalkanes, monocyclic or bicyclic and where appropriate fluorocyclically substituted fluoroalkanes, perfluorinated aliphatic or bicyclic amines, bis- (perfluoroalkyl) ethenes, perfluoro-polyethers or mixtures thereof.

The dependence of penetration rate and depth of penetration on the particle size of the aggregates was experimentally determined by separate studies with labeled encapsulated fluorocarbons. Afterwards, smaller particles migrate faster and deeper into the skin tissue than larger particles. The selection of fluorocarbons or their mixtures according to their lipid solubility (as shown by their critical solubility temperature CST in n-hexane) allows as another important criterion the regulation of the time spent in the tissue. While, for example, perfluorotrifluor (F-TBA, CST 59°C) with a high CST and poor lipid solubility helps to reduce the mean time to leakage, in contrast to this, lipid (DPF 22°C) is used accordingly, but also with the help of other fluorocarbons and fluorocarbons produced by the membrane.

The content of fluorocarbons in the lamellar aggregates may vary from 1 to 100% w/v depending on the purpose of use. Aliphatic straight-chain and branched-chain alkanes with 6 to 12 carbon atoms, such as perfluorohexane, perfluorooctane, perfluornonan; monocyclic or bicyclic cycloalkanes, where appropriate F-alkyl substitutions, such as perfluoromethylcyclohexane, Perfluordecalin aliphatic tertiary amines, N-containing polycyclenes such as perfluoro-tripropylamine, perfluoro-tribulamine, F-cyclohexylmethylmorpholine; Perfluorethers, such as aliphatic ether, F-alkyl furanes, bicyclic and substituted bicyclic ether with 2 or 3 oxygen atoms in the molecule, such as perfluoridehexylethers, perfluorbutyltetrahydrofurans, perfluoropolyethers; Perfluoroalkyl halogenides, such as perfluorooctyl bromide, perfluorohexyl bromide, perfluorooctyl chloride; Bis-F (alkyl) ethers, such as bis-F (butyl) ethers, bis-F (hexyl) ethers.

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Natural phospholipids such as soybean or egg yolk, as well as synthetic lecithins (phospholipids) are considered phospholipids, which are generally known to be skin friendly and skin-care-friendly. Because of their beneficial effect on the stability of asymmetrical lamellar aggregates, phospholipid mixtures with a content of 10 to 99%, preferably 30 to 99%, especially 60 to 90% phosphatidylcholine, are preferred alongside other naturally occurring co-products.

The particle sizes of the aggregates and phospholipids are selected so that penetration into deeper layers of the skin, e.g. the epidermis or the chorionic region, is avoided and the light-protective filter according to the invention reaches its working surface after penetrating the stratum corneum.

The invention also relates to a method for the manufacture of preparations for topical application characterized by the dissolution or dispersion of melanin in one or more fluorocarbons and their conversion by homogenization with a phospholipid in an aqueous system into asymmetric lamellar phospholipid aggregates containing the fluorocarbons and melanin with particle sizes between 200 and 3000 nm.

The solubility of the polymer melanin can be increased by adding lipophilic substances to the fluorocarbon as solubility intermediates.

Homogenization can be carried out by conventional methods, e.g. by a high-pressure agitator (12000 to 15000 R/min), by ultrasound or by pressure homogenization in such a way as to ensure particle size.

The invention is explained in more detail below by means of examples. Fig.1 Graph of critical solubility temperatures (CSTs) of perfluorocarbon chemicals in n-hexane with perfluoridecaline as the starting pointFig.2 Graph of critical solubility temperatures of perfluorocarbon chemicals in n-hexane with F-octyl bromide as the starting point.

Table 1 shows some selected fluorocarbons and their O2 solubility, vapour pressure and critical solubility temperature, which allow the selection of the desired skin penetration characteristics for fluorocarbon mixtures using the composition of the invention. Other Tabelle 1

Fluorcarbon	O₂-Löslichkeit [ml O₂/100 ml FC]		CST [°C]
Perfluoroctylbromid	50	14	-24,5
Perfluordecalin	40	12,5	22
Bis-F(Butyl)ethen	50	12,6	22,5
F-cyclohexylmethylmorpholin	42	4	38,5
F-Tripropylamin	45	18,5	43
F-Dihexylether	45	2	59
F-Tributylamin	40	1	59
Perfluordecalin-F-Tributyl-amin 1/1	40	7	42
Perfluorbutyltetrahydrofuran	52	51	29
F-methylcyclohexan	57	180	8,2
F-Hexan	58	414	20

Example 1

A 10% aqueous phospholipid solution of soy lecithin and 40% phosphatidylcholine was mixed with a fluorocarbon mixture of perfluoridecalin (90%) and F-dibutylmethylamine (10%) and melanin in an ultrasonic disintegrator under cooling, and the resulting asymmetric lamellar phospholipid aggregates had a mean particle size of about 240 nm and contained melanin. The aggregates thus obtained were incorporated by conventional methods into the subsequent processing of sunscreen.

The test chemical is used to determine the concentration of the test substance.

Polyacrylsäure	0,30 %
TEA	0,30 %
p-Methylhydroxybenzoat	0,20 %
p-Propylhydroxybenzoat	0,10 %
Imidazolidinylharnstoff	0,20 %
Na-EDTA	0,06 %
Cetyl/Stearylalkohol	1,00 %
Stearinsäure	1,00 %
Isopropylmyristinat/-palmitat	3,00 %
Paraffinum subl.	4,00 %
Jojoba-Öl	2,00 %
Melanin-Phospholipid-Aggregate	10,00 %
Parfümöl	1,00 %
demineralisiertes Wasser	q.s.

The test chemical is used to determine the concentration of the test substance.

Polyacrylsäure	0,30 %
Propylenglycol	5,00 %
TEA	0,30 %
Emulgator 1	6,00 %
Emulgator 2	4,50 %
Aloe vera	2,00 %
Reisschalenöl	1,50 %
Cetyl/Stearylalkohol	1,00 %
Jojoba-Öl	1,50 %
p-Methylhydroxybenzoat	0,20 %
p-Propylhydroxybenzoat	0,10 %
Imidazolidinylharnstoff	0,20 %
Melanin-Phospholipid-Aggregate	20,00 %
Parfümöl	1,00 %
demineralisiertes Wasser	q.s.

Example 4 Lotion

Emulgatorensystem	34,00 %
bestehend aus Wasser, Stabilisatoren, Polyglycerinester,Polyoxyethylenester, Isopropylpalmitat
Glycerin	5,00 %
MgSO₄.7H₂O	0,50 %
Melanin-Phospholipid-Aggregate	6,00 %
p-Methylhydroxybenzoat	0,20 %
p-Propylhydroxybenzoat	0,10 %
Imidazolidinylharnstoff	0,30 %
Parfümöl	1,00 %
demineralisiertes Wasser	qs

Example 5 Lash powder pressed with light protection factor

Talkum	40,00 %
Mg-Carbonat	1,50 %
Mg-Stearat	2,50 %
Kaolin	2,20 %
Farben	15,80 %
Perglanzpigmente	21,50 %
Parfümöl	1,50 %
Seidenprotein	5,00 %
Emulsion als Prozeßvermittler
Emulgator	4,50 %
Siliconöl, flüchtig	2,50 %
Melanin-Phospholipid-Aggregate	4,50 %
Konservierung	0,30 %
demineralisiertes Wasser	qs.

Claims (14)

1. Preparation for topical use, characterised in that it contains melanin, dissolved or dispersed in one or more fluorocarbons, which are present as asymmetric lamellar phospholipid aggregates in an aqueous system together with a phospholipid, with a particle size of the aggregates in the range from 200 to 3000 nm.
2. Preparation according to Claim 1, characterised in that the amount of fluorocarbons is in the range from 1 to 100 % w/v.
3. Preparation according to Claim 1 or 2, characterised in that the fluorocarbons are selected from the group which consists of aliphatic straight-chain and branched fluoroalkanes, mono- or bicyclic, optionally fluoroalkyl-substituted, fluorocycloalkanes, perfluorinated aliphatic or bicyclic amines, bis-(perfluoroalkyl)ethenes, perfluoropolyethers and mixtures thereof.
4. Preparation according to Claim 3, characterised in that the fluorocarbons are selected from the group which consists of perfluorodecalin, F-butyltetrahydrofuran, perfluorotributylamine, perfluorooctyl bromide, bis-fluoro(butyl)ethene and C₆-C₉-perfluoroalkanes.
5. Preparation according to one of Claims 1 to 4, characterised in that the amount of fluorocarbons is in the range from 20 to 100 % weight/volume, preferably in the range from 40 to 100 %, in particular in the range from 70 to 100 %.
6. Preparation according to one of Claims 1 to 5, characterised by one or more fluorocarbons having a critical solubility temperature below 50°C, preferably below 30°C.
7. Preparation according to one of Claims 1 to 6, characterised in that the phospholipids are selected from the group consisting of natural phospholipids such as soya lecithin and egg lecithin, synthetic phospholipids and hydrogenated lecithins and/or partially hydrogenated phospholipids.
8. Preparation according to one of Claims 1 to 7, characterised in that phosphatidylcholine is present in an amount from 10 to 99 % by weight, preferably 30 to 99 %, in particular 70 to 90 %.
9. Preparation according to one of Claims 1 to 8, characterised in that, in addition to phosphatidylcholine, lysolecithins are present in the concentration range from 1 to 10 % by weight.
10. Preparation according to Claim 1, characterised in that, in addition to melanin and fluorocarbon, a solubiliser, selected from the group consisting of the native oils such as olive oil, soya bean oil, sunflower oil, the triglycerides or the aliphatic alkanes such as pentane, heptane, nonane or decane, and mixtures within or between the groups, is present.
11. Process for the production of preparations for topical use, characterised in that melanin is dissolved or dispersed in one or more fluorocarbons and this dispersion is converted by homogenisation with a phospholipid in an aqueous system into asymmetric lamellar phospholipid aggregates containing the fluorocarbons and melanin, having particle sizes between 200 and 3000 nm.
12. Process according to Claim 11, characterised in that a solubiliser, selected from the group consisting of the native oils such as olive oil, soya bean oil, sunflower oil, the triglycerides or the aliphatic alkanes such as pentane, heptane, nonane or decane, and mixtures within or between the groups, is added to melanin and the fluorocarbons.
13. Use of asymmetric lamellar phospholipid aggregates for the production of agents for introducing melanin into the skin region above the epidermis, the asymmetric lamellar phospholipid aggregates consisting of a phospholipid and one or more fluorocarbons containing melanin dissolved or dispersed therein, the particle size of the aggregates being in the range from 200 to 3000 nm.
14. Use according to Claim 13, characterised by a phosphatidylcholine content of the phospholipids from 10 to 99 % by weight, preferably 30 to 99 %, in particular 70 to 90 %.