AU671645B2 - Topical application composition - 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

S4* *fo' 9- OPI DATE 24/01/94. APPLN. ID 43079/93 1111A11HIII~I~ ir I AOJDAT l4/04/94_ KCT NER PGT/DE91/00573, -Ill II111 III I 111IIIIil (21) Internationales Aktenzeichen: PCT/DE93/00573 (74) Anwilte: WALTER, Wolf-Jflrgen usw. Normannenstrage (22) Internationales Anineldedatuin: 24. Juni 1993 (24.06.93)1-,D037Bri(E) (81) Bestimmungsstaaten: AU, CA, CZ, Fl, HU, JP, NO, NZ, Prioritatsdaten: PL, RO, SK, US, europ~iisches Patent (AT, BE, CH, DE, P 4221 269.3 26. Juni 1992 (26.06.92) DE DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).

(71) Anmelder (fir alle Bestimmuntgsstaaten ausser US): LANCA- Veriiffentlicht STER GROUP AG [DE/DE]; t. 154, ED 65lf5 Mit internationalemn Recherchenbericht.

(72) Erfinder; un dvd~ v m Erfinder/Anmelder (nur ffr US) GROSS, Udo [DE/DE]; A Falkenberger Chaussee 91, D-13059 Berlin ZA- STROW, Leonhard [DE/DE]; Grabenweg 13, D-65205 6 4 Wiesbaden-Nordenstadt RODING, Joachim [DE/ DE]; Trompeterstr. 19, D-65207 Wiesbaden- Rambach STANZL, Klaus [DE/DE]; Im Eschbach 9d, D- 56323 Waldesch (DE).

(54) Title: TOPICAL APPLICATION COMPOSITION ,N 2~ (54) Bezeichnung: ZUBEREITUNG ZUR TOPISCHEN ANWENDUNG (57) 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.

(57) Zusammenfassung Die Erfindung betrifft eine Zubereitung zur topischen Anwendung mit Lichtschutzeigenschat'ten und in einer speziellen Applikationsform. Bei den bekannten Lichtschutzmitteln mit den nattirlich vorkomnmenden Wirkstoff Melanin besteht das Problem in einem unzureichenden Transport des Melanins an semnen Wirkort. ErfindungsgemiR wird dieses Problem durch eine Zubereitung zur topisc~en Anwendung gel6st, die gekennzeichnet ist durch einen Geha!t an Melanin, gel6st oder dispergiert in einem oder mehrerer. Ftuorcarbonen, die als asymmetriche lamullare Phospholipid-Aggregate in einem wiagrigen System zusammen mit einem Phospholipid vorliegen, mit einer Teilchengr6le der Aggregate im Bereich von 200 bis 3000 nm.

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!i~7I7 -r K WO 94/00097 PCT/DE93/00573 Preparation for topical use The invention relates to a cosmetic or dermatological composition having light protection properties in a special application form, in which fluorocarbon-containing asymmetric lamellar phospholipid aggregates function 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 have a damaging effect on the skin and is a significant factor for premature skin ageing. In extreme form, the action can consist in a cytogenetic change in individual skin cells and lead to the formation of skin carcinomas (melanomas). These hazards have continuously increased due to environmentally related factors (ozone hole) with an increased UV burden. In order to overcome this fact, it is customary, by means of special cosmetics and dermatological agents, to protect the exposed skin tissue by the use of special UV light protection filters. The active compound of these compositions is based on the following principles: 1. Absorption of UV light by the use of UV-active organic compounds Z. Scattering of UV light by finely dispersed titanium dioxide or other micropigments The efficacy of these systems, which can be detected simply by recording their UV absorption maxima in the wavelength range 250-400 nm or by scattering curves, is evident. The problem, however, is the biological acceptability of the substances, in particular the possible chemical substance alterations under the influf ence of energy-rich radiation.

SA further critical point is the depth of penetration of the UV filter into the skin when it is used as a constituent of a cosmetic or dermatological agent. The suitable site of action is the region between the horny layer and basal layer. In order to meet these demands, testing for one year is necessary, as has been previously I prescribed for pharmacological active compounds.

-2- According to their intended use and their individual efficacy, the UV filters are applied topically in a suitable medium in a wide concentration range between 1 and 10 Thus, DE-A-3242385 (Zabotto) describes a cosmetic composition which, in addition to other active compounds, contains 1.5 Parsol Ultra (Givaudan) for the reduction of skin ageing due to the action of light.

Melanin, which also occurs in human and animal cells, the melanocytes, is known as a natural light protection active compound in higher organisms. Melanin is a brown to black-coloured polymeric pigment of the vertebrates, which is formed, inter alia, from the amino acid tyrosine and pigments both skin, hair and iris. The melanin formed in the melanocytes of the skin migrates into the basal layer of the epidermis and there releases the pigment into the epidermal cells. Since melanin, as a polymeric substance, hardly dissolves, the previous attempts to bring this substance to its site of action by means of topical applications are to be regarded as not thoroughly successful.

The invention has set the object of making possible topical use of melanin at its site of action.

According to the invention, a preparation for topical use having light protection properties is characterised in that it contains melanin which is dissolved or dispersed in one or more lipophilic 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.

SThe naturally obtained from Sepia officinalis) or synthetically produced (oxidation of tyrosine, e.g. with H 2 0 2 melanin is present, dissolved or suspended by the fluorocarbon, encapsulated in tha core of the asymmetric lamellar phospholipid aggregates. The structural arrangement in the lamellar aggregates is Sfundamentally different from that of aqueous liposomes (vesicles). The hydrophobic nature of the fluorocarbon -3calls for a reversal in the polarity of the phospholipid molecule such that the lipophilic fatty acid radicals interact with the fluorocarbon in the core of the aggregate by dispersive forces. In this arrangement, further phospholipid bilayer films are constructed to give asymmetric lamellar globular aggregates according to specified conditions.

The novel asymmetric structure was confirmed by 31 P-NMR investigations and spectroscopic investigations.

The exceptional stability of the aggregates results from their lamellar structure and from the corresponding vurface charge.

A plurality of fluorocarbons can be employed, e.g. aliphatic straight-chain and branched fluoroalkanes, mono- or bicyclic and optionally fluoroalkyl-substituted fluorocycloalkanes, perfluorinated aliphatic or bicyclic amines, bis(perfluoroalkyl)ethenes, perfluoropolyethers and mixtures thereof. Particularly preferred fluorocarbons are those such as perfluorodecalin, F-butyltetrahydrofuran, perfluorotributylamine, perfluorooctyl bromide, bis-fluoro(butyl)ethene or bis-fluoro(hexyl)ethene or C 6

-C

9 -perfluoroalkanes. The amount of fluorocarbons here is in the range from 20 to 100 w/v, preferably in the range from 40 to 100 A particularly preferred range is that from 70 to 100 w/v.

It was possible to determine the dependence of the penetration rate and the depth of penetration on the particle size of the aggregates experimentally by separate investigations using labelled encapsulated fluorocarbons. According to these experiments, smaller particles migrate more rapidly and more deeply into the skin r tissue than larger particles. The choice of fluorocarbons or their mixtures according to their lipid solubility (represented by their critical solubility temperature CST in n-hexane) allows, as a further important criterion, i the regulation of the residence time in the tissue.

While, e.g. perfluorotributylamine (F-TBA, CST 59 0

C)

having a high CST value and poor lipid solubility has a relatively high residence time, in contrast to this 1- y I -4- 4 perfluorodecalin (PFD, CST 22°C) but also F-butyltetrahydrofuran, F-hexane and others are released correspondingly more rapidly from the tissue. With the aid of fluorocarbon mixtures, systems with desired CST values, i.e. lipid and membrane solubilities, can be prepared specifically with respect to the intended use.

The content of the fluorocarbons in the lamellar aggregates can vary between 1 and 100 w/v according to the intended use. Suitable fluorocarbons are in particular: aliphatic straight-chain and branched alkanes having 6 to 12 carbon atoms, e.g. perfluorohexane, perfluorooctane, perfluorononane; mono- or bicyclic cycloalkanes, which are optionally F-alkyl-substituted, e.g. perfluoromethylcyclohexane, perfluorodecalin; aliphatic tertiary amines, N-containing polycycles, e.g.

perfluorotripropylamine, perfluorotributylamine, F-cyclohexylmethylmorpholine; perfluoroethers, such as aliphatic ethers, F-alkylfurans, bicyclic and substituted bicyclic ethers having two or three oxygen atoms in the molecule, e.g. perfluorodihexyl ether, perfluorobutyltetrahydrofuran, perfluoropolyethers; perfluoroalkyl halides, e.g. perfluorooctyl bromide, perfluorohexyl bromide, perfluorooctyl chloride; Bis-F(alkyl)ethenes, e.g. bis-F(butyl)ethene, bis-F(hexyl)ethene.

The term "fluorocarbons" used here is understood as meaning perfluorinated or highly fluorinated carbon compounds or mixtures which are able to transport gases such as 02 and CO Partially fluorinated hydrocarbon compounds within the context of this invention are those in which most of the hydrogen atoms are replaced by fluorine atoms, e.g. the bis-F(alkyl)ethenes which, as far as can be detected, are chemically and biologically inert and thus non-toxic. This is usually achieved.when approximately up to 90 of the hydrogen atoms are "N replaced by fluorine atoms. Preferred fluorocarbons

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5 within the context of the present invention are those in which at least 95 of the hydrogen atoms are replaced, more preferably 98 and most preferably 100 Suitable phospholipids are naturally occurring pho.pholipids such as soya or egg lecithin, and also lecithins (phospholipids) which can be prepared synthetically and which overall are known as being skin-compatible and good for the skin. Because of the advantageous action on the stability of the asymmetric lamellar aggregates, phospholipid mixtures having a content from 10 to 99 preferably 30 to 99 in particular 60 to 90 of phosphatidylcholine in addition to other naturally occurring accompanying products are preferably used. The phospholipid content in the topical formulation varies between 0.5 and 20 preferably 10 to The particle sizes of the aggregates, and the phospholipids are selected such that a penetration into deeper layers of the skin, e.g. into the epidermis or the dermal region does not take place and the light protection filter according to the invention thus reaches its site of action aft it has penetrated the horny layer.

The particle sizes are in the range from 200 to 3000 nm, preferably in the range from 250 to 1000 nm.

The invention also relates to a process for the production of preparations for topical use, which is 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.

The solubility of the polymeric melanin can be increased by addition of lipophilic substances to the fluorocarbon as solubilisers. Suitable lipophilic substances are native oils, triglycerides or aliphatic alkanes, selected from the group consisting of olive oil, soya bean oil, sunflower oil, pentane, heptane, nonane, decane or mixtures thereof.

p in the r 6 The homogenisation can be effected by customary processes, e.g. using a high-speed stirrer (12,000 to 15,000 rpm), by ultrasound or by means of pressure homogenisation such that the particle size is ensured.

The invention will be illustrated in greater detail below by means of examples. In the associated drawings Fig. 1 is a diagram of the critical solubility temperatures (CST) of perfluorocarbon mixtures in n-hexane using perfluorodecalin as a starting point Fig. 2 is a diagram of the critical solubility temperatures of perfluorocarbon mixtures in n-hexane using F-octylbromide as a starting point.

Some selected fluorocarbons and their 02 solubility, their vapour pressure and their critical solubility temperature are shown in Table 1. Starting from these values, the desired characteristics for the penetration of the skin with the aid of the composition according to the invention can be selected for mixtures of fluorocarbons.

a g -6 r jll i r- _i 7 Table 1 Fluorocarbon 02 solubility Vapour CST [ml of 02/100 ml Pressure of Fc] P 7 .C [mm Hg] Perfluorooctyl bromide 50 14 -24.5 Perfluorodecalin 40 12.5 22 bis-F(butyl)ethene 50 12.6 22.5 F-cyclohexylmethylmorpholine 42 4 38.5 F-tripropylamine 45 18.5 43 F-dihexyl ether 45 2 59 F-tributylamine 40 1 59 Perfluorodecalin-Ftributylamine 1:1 40 7 42 Perfluorobutyltetrahydrofuran 52 51 29 F-methylcyclohexane 57 180 8.2 F-hexane 58 414 Example 1 A 10 strength aqueous phospholipid solution of soya lecithin and containing 40 phosphatidylcholine was mixed with cooling in an ultrasonic disintegrator with a fluorocarbon mixture composed of perfluorodecalin (90 and F-dibutylmethylamine (10 and melanin. The asymmetric lamellar phospholipid aggregates obtained in this process had a mean particle size of approximately 240 nm and contained the melanin.

The aggregates prepared in this manner were incorporated into the following processing forms of light protection agents according to customary processes.

Example 2 Emulsion (body lotion) Polyacrylic acid 0.30 TEA 0.30 p-Methylhydroxybenzoate 0.20 p-Propylhydroxybenzoate 0.10 -8- Imidazolidinylurea 0.20 Na EDTA 0.6 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 Perfume oil 1.00 Demineralised water g.s.

Examp~le 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 p-Methylhydroxybenzoate 0.20 p-Propylhydroxybenzoate 0.10 Imidazolidinylurea 0.20 Melanin/phospholipid aggregates 20.00 Perfume oil 1.00 Demineralised water q. s.

Example 4 Lotion Emulsifier system consisting of water, 34.00 stabilisers, polyglycerol esters, polyoxyethylene esters, isopropyl palmitate Glycerol 5.00 IMgSO 4 7H 2 0 0.50 Melanin.1phospholipid aggregates N p-Methylhydroxybenzoate 0.20 p-Propylhydroxybenzoate 0.10 9 Imidazolidinylurea 0.30 Perfume oil 1.00 Demineralised water q.s.

Example 5 Eveshadow, compressed with light protection factor Talc 40.00 Mg carbonate 1.50 Mg stearate 2.50 Kaolirn 2.20 Colorants 15.80 Pearl lustre pigments 21.50 Perfume oil 1.50 Silk protein 5.00 Emulsion as processing means Emulsifier 4.50 Silicone oil, volatile 2.50 Melanin/phospholipid aggregates 4.50 Preservative 0.30 Demineralised water q.s.

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Claims (13)

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 zange 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 fluorcalkanes, mono- or bicyclic, optionally fluoroalkyl-substituted, fluorocycloalkanes, per- fluorinated aliphatic or bicyclic amines, bis- (perfluoroalkyl) ethenes, perf luoropolyethers and mixtures thereof.

4. Preparation according to Claim 3, characterised in that the fluorocarbons are selected from the group which consists of perfluorodecalin, F-butyltetrahydro- furan, perfluorotributylamine, perfluorooctyl bromide, bis-fluoro(butyl)ethene and C 6 -C,-perfluoroalkanes. Preparation according to one of Claims 1 to 4, characterised in that the amount of fluorocarbons is in the range f-om 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 characterised by one or more fluorocarbons having a critical solubility temperature below 50C, preferably below 300C.

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 a4 and hydrogenated lecithins ar/or partially hydrogenated 1' phospholipids. /V T LU I '^Ar o' ban RMON-

8. Preparation accorhing 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 phosphatidyl- choline, lysolecithins are present in the concentration range from 1 to 10 by weight. 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 20 phospholipid in an aqueous system into asymmetric lamellar phospholipid aggregates containing the fluoro- carbons 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, sun- flower oil, the triglycerides or the aliphatic alkanes such as pentane, heptane, nonane or decane, or the mixtures within or between the groups, is, added to melanin and the fluorocarbons.

13. Use of asymmetric lamellar phospholipid aggre- gates 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 S phosphatidylcholine content of the phospholipids from fe"" ''i -12- to 99% by weight, preferably 30 to 99 %F I.n particular 70 to 90 A preparation for 'topical use substantially a~s herein des,cribed in the examples'.

16., A process for the production-of preparations for topical use substantially as herein described in the examples. V a, L..