EP1216019A1

EP1216019A1 - No-liberating topically applicable composition as biological agent, production and utilization thereof as dermatological and/or cosmetic product

Info

Publication number: EP1216019A1
Application number: EP00958469A
Authority: EP
Inventors: Klaus-Dietrich KRÖNCKE; Annegret Kuhn; Victoria Kolb-Bachofen
Original assignee: Individual
Current assignee: Individual
Priority date: 1999-09-22
Filing date: 2000-08-18
Publication date: 2002-06-26
Also published as: DE19945484A1; AU6997200A; WO2001021148B1; WO2001021148A1

Abstract

The invention relates to a composition containing at least one NO-liberating compound for use as a topically administered agent which is biologically active at the site of application. Said composition does not contain L-arginine, salts and derivatives thereof, and also NO-polyethylenimine cellulose used in the field of pharmacy and / or cosmetics. Said invention relates to the application of a composition containing at least one pharmacologically compatible NO-liberating compound for therapy and prophylaxis of skin damage produced by electromagnetic radiation having a wavelength between 1mm to 100 nm, preferably 400 nm - 200 nm, or photodermatoses or hyperproliferative dermatoses. Said invention also relates to a method for cosmetic treatment to protect the skin from damage by ultraviolet light, whereby prior to or during irradiation an active amount of a cosmetic composition of the aforementioned type containing at least one NO-liberating compound is applied to the surface of the skin.

Description

NO-releasing topically applicable composition as a biological agent, its production and its use as dermatics and / or cosmetics

The present invention relates to topically administrable NO-releasing compositions, their preparation and their use as pharmaceuticals and / or cosmetics.

Nitric oxide (NO), which is also known in biochemistry as an endothelium-derived relaxing factor. According to Römpp Lexikon Naturstoffe 1997. p. 616, it has a number of physiological functions in vivo when it affects the human body, because it regulates blood pressure and the inhibition of platelet aggregation. wound healing, neuronal signal transmission, inactivation of bacteria, parasites and tumor cells. On the other hand, toxic concentrations of NO are held responsible for a number of diseases, e.g. septic shock, stroke, arthiritis migraine and chronic inflammation.

It is from Römpp Chemie Lexikon. 10th edition, 1998. p. 835, it is known that inorganic NO-releasing agents, for example the salt sodium nitrite in an aqueous medium, are not only sensitive to oxidation and toxic in air,

1 BES IGUNGSKQP1E but also with prolonged skin contact leads to skin irritation. According to Rompp, ibid., p. 2927, other salts, such as the inorganic sodium nitroprussiate, are used in pharmacy as a vasodilator, for example as Niprus®, but only parenterally

WO 99/13137 relates to the administration of L-arginine, its salts and derivatives on certain surfaces of the skin, wherein a substance is first applied to the skin which applies an effective amount of a substance, this amount being a biophysical external environment for the substance generated by which the substance passes from the vehicle into the skin and is absorbed by the skin. The administration of the substrate for endogenous NO formation described there serves both to stimulate blood circulation when warming cold tissue, to treat impotence, to promote hair growth, and to heal wounds superficial ulcers and finally pain relief

WO 96/13164 describes a method for accelerated healing of skin wounds by topical application of a water-insoluble NO polymer adduct, which delivers therapeutic doses of nitrogen monoxide in an aqueous environment to the surface of the wound. In addition to this wound healing effect by nitrogen monoxide, there is also prior art in this art no further statement only that the insoluble nitrogen monoxide polymer adduct is an NO-polyethyleneimine cellulose

CA 2 106 105 A1 relates to a polymer composition, a corresponding pharmaceutical preparation through which NO can be released as a cardiovascular agent

DE 44 20 523 A1 relates, according to claim 1, to the use of NO-releasing compounds for the prevention and treatment of systemic inflammations. Consequently, the oral, rectal or parenteral application site is not the site of action, but rather is only achieved after absorption. Thus, the inventive topical use of the agent locally at which the The application site is the same as the site of action, neither disclosed nor suggested for cosmetic and special medical treatment options

WO 93/020806 A1 describes the use of NO-releasing compounds for the systemic treatment of tumor diseases, US Pat. No. 5,814,666 describes the use of liposome-encapsulated NO-releasing compounds for the systemic treatment of diseases caused by microorganisms. This makes the inventive topical use of the agent locally, where the application site is the same as the site of action, for cosmetic and special medical treatment options for vulgar psonasis and diseases from the similar form of cutaneous hyperpro feration, neither disclosed nor suggested

However, the entire state of the art gives no reason to locally release NO-releasing compounds, also for the treatment and prophylaxis of skin damage and light dermatoses or hyperproliferative dermatoses such as psonasis caused by electromagnetic rays of a wavelength of 1 mm to 100 nm, preferably 400 nm to 200 nm and use seborrheic dermatoses and similar hyperproliferative dermatoses as well as a cosmetic product

The present invention is based on the object of providing an agent for topical administration which acts at the site of administration, and to provide an agent of this type for a prophylactic and therapeutic treatment of the abovementioned diseases and as a cosmetic

The present invention thus relates to a composition comprising at least one NO-releasing compound for use as a topically administrable agent which acts at the site of administration and has a biological action, L-arginine further excluding its salts and derivatives and NO-polyethyleneimine cellulose as the NO-releasing compound are

This composition contains in particular at least one pharmaceutically contractual NO-releasing compound for use as a topically administered Dispensable agent with pharmaceutical activity This pharmaceutical composition contains 1 μmol to 200 mmol, preferably 10 μmol to 100 mmol, of the NO-releasing compound, based on 100 g of the total composition

Alternatively or additionally, this composition contains at least one NO-releasing compound for use as a topically administrable agent with a cosmetic effect. In this cosmetic composition, 1 μmol to 200 mmol, preferably 5 μmol to 100 mmol, of the NO-releasing compound based on 100 g of the total composition, contain

According to a further preferred embodiment, the NO-releasing compound contained in the composition is a spontaneously NO-releasing, biochemically or physically NO-releasing compound under physiological conditions

Representatives for spontaneously NO-releasing compounds are e.g. S-nitrosothiols such as S-nitroso-thioglyzene or compounds of the class of the diazenium diolates, representative of a biochemically, for example enzymatically, NO-releasing compound is the sodium nitroprussiate, an example of compounds that are physically NO-releasing by UV rays is, for example, an alkali or alkaline earth nitrite, such as sodium nitrite

Another preferred classification possibility for the NO-releasing compound used in the compositions according to the invention can be such that it is selected from inorganic and / or organic compounds which are preferably water-soluble or dispersible, the organic compounds being selected from the class of the S-nitrosothiols and the adducts of nitrogen monoxide with a nucleophile, for example from the class of the diazenium diolates

Inorganic NO-releasing compounds are understood to mean the salts of nitrous acid, for example, the alkali and earth alkali salts in particular lithium nitrite, sodium nitrite, potassium nitrite, magnesium dinite and calcium dinitrite, furthermore also the nitro nitrate is to be classified here

Organic NO-releasing compounds are understood to be those selected from the class of S-nitrosothiols, the adducts of nitrogen monoxide with a nucleophile (diazenium diolates) and the corresponding pro-drug systems. Examples of S-nitrosothiols are S-nitrosothiols , D- (S-Nιtroso) -3-mercaptomethylpropιonyl) -L-prolιn to name where S-nitroso-thioglyzene is preferred. In the adducts of nitrogen monoxide with a nucleophile, for example, the adducts of NO with polysaccharides mentioned in US Pat. No. 5,814,666 which are linked via primary and secondary aliphatic nurse, as well as S-nitroso-N-acetyl-penicillamine, S-nitroso-penicillamine and S-nitrosogluthathione

If the aforementioned compositions are to be used as cosmetics, they can furthermore contain 0.5% by weight to 20% by weight of light stabilizers for UV-A and / or UV-B, based on the total composition, the light stabilizer preferably being selected is from the class consisting of benzylidene camphor derivatives, dibenzoylmethane derivatives, benzotriazolene derivatives, tnazine derivatives, p-aminobenzoic acid derivatives, cinnamon ester derivatives, salicylic acid derivatives, anthranilic acid derivatives, urocanic acid derivatives, benzophenone dimethyl derivatives and / or benzophenone dimethyl derivatives

With regard to the above-mentioned light protection agents, reference is made in particular to the UV filters explicitly approved according to the Cosmetics Regulation and the EU directive, as well as to the summarizing articles relating to UV adsorbers in sun cosmetics published by D H Liem and L T H Linderic in 1978 in. International Journal of Cosmetic Science 1_ pages 341 to 361 (1979) as well as on the European patent specification 193 579 and the European patent applications 0 860 165 EP-A 487404 and EP-A 904 776

If desired, the above-mentioned compositions can also be artificial skin tanning agents, for example based on Dihydroxyacetone or also pigments or nanopigments with an average Pπmarkomchen size of between 5 nm and 100 nm, preferably 10 nm to 50 nm, based on metal oxides, for example based on titanium oxide, either amorphous or crystallized in the form of rutile or anatase, pigments of iron , the zinc, the zirconium or the cerium as they are usually added in sunscreens. Finally, metal oxides as described in EP-A 0 518 772 and EP-A 0 518 773 can also be used as nanopigments

In addition, the aforementioned cosmetic or pharmaceutical compositions can also contain other auxiliaries which are selected from nonionic, anionic, cationic or amphoteric emulators, thickeners, hydration agents, plasticizers, preservatives, dyes, opacifiers, agents for regulating the pH, propellants and perfumes

The compositions according to the invention are in the form of an ointment, a cream, a gel, embedded in liposomes, an oil, a milk, a solid stick or as an aerosol

According to a further preferred embodiment, the composition can be in the form of a hydrophobic ointment, a water-absorbing ointment or a hydrophilic ointment. For their use as surface ointment, paraffin hydrocarbons, such as, for example, paraffins, or also polyalkylsiloxanes, or lipid substances of vegetable or animal origin are used as the ointment base in the hydrophobic ointments such as hydrogenated oils, medium-chain Tπglyzeπde, or partial Glyzeπde, or waxes and low-viscosity esters and finally fatty alcohols and fatty acids into consideration. With the hydrophilic ointments, macrogols ie PEG or POE polymers are considered as the ointment basis. In this connection we refer to the monograph Pharmaceutical Form Theory Ms. Schoff ng-Krause, Stuttgart 1998, S 310 - 319 and S 328 - 337 and the substances and manufacturing methods described there and by Bauer, Pharmaceutical Technology Stuttgart 1986, S 312 - 323, 330 - 331 According to a further preferred embodiment, the composition can be present as a hydrophobic (= lipophilic W / O) or hydrophilic (O / W) cream. Again, we refer to the aforementioned monograph by Schoffhng-Krause, S 320 - 324 and Bauer S 323 - 328 , 331-332

In a further preferred embodiment, the composition can be in the form of a gel in the form of a hydrophobic or hydrophilic gel. Hydrophobic gels are based on liquid paraffin and polyethylene or fatty oils with additives, and hydrophilic gels are the hydrogels based on polyacrylates and acrylic acid or based von Cellulosemem We refer to the aforementioned monograph by Schoffhng-Krause S 324 - 327 and by Bauer, S 329 - 330

According to a further preferred embodiment and if the NO-releasing compound should be very sensitive to oxygen, the composition according to the invention can be in the form of a colloidally disperse system, with colloids serving as carriers for these compounds. The use of such medicinal products from liposomes for topical pharmaceutical or cosmetic use is known to the person skilled in the art. We refer here, for example, to the aforementioned monograph by Schoffhng-Krause, S 251-254 and by Bauer, S 563-570

According to a further preferred embodiment of the agent according to the invention, the composition can be in the form of an oil based on at least one fatty acid ester of a mineral or fatty oil. Such substrates are usually referred to as skin oils. We refer, for example, to the overview by G A Nowak, "The Cosmetic Preparations"

According to a further preferred embodiment, the composition can be in the form of milk, that is to say as an oil in water emulsion.We refer to the relevant chapters from Nowak on toilet milks, liquid emulsions and to the aforementioned monograph by Schoffhng-Krause S 270-286 and Bauer, S 237 - 262 According to a further preferred embodiment, the composition can be in the form of an aerosol dispersion, that is, either as a pressurized gas aerosol or as a pump aerosol. In this regard, we refer to Schoffhng-Krause, S 289 - 302, to Bauer, S 303 - 310 and to the monograph by Nowak, where the chapter on aerosols

As is known to the person skilled in the art in this field, all of the aforementioned pharmaceutical or cosmetic pharmaceutical dosage forms can be obtained in a manner known per se from the corresponding aqueous and / or fat phase by mixing and, if appropriate, homogenizing with the NO-releasing compound

Therapy and prophylaxis of skin diseases

The composition according to the invention, which contains at least one pharmacologically contractual NO-releasing compound, can be used for the treatment and prophylaxis of dermatoses or hyperprohferative dermatoses caused by electromagnetic rays of a wavelength of 1 mm to 1 nm, preferably 400 nm - 200 nm and prophylaxis of skin diseases or the skin can be carried out both on humans and on any mammal or bird, preference is given to use in humans and in domestic and farm animals, for example dogs, horses, pigs, cattle, calves, goats, sheep, the use being on People is particularly preferred

This includes, on the one hand, the dermatoses caused by electromagnetic radiation selected from Combustio Erythema solar, light dermatoses eg Phytophotodermatm's photoallergic contact dermatitis, polymorphic light dermatosis or light urticaria and collagenoses such as cutan or systemic lupus erythematosus On the other hand, the hyperprohferative dermatoses are psonasis vulgar, seborrheic keratoses, keratoacanthomas, hyperprohferational dermatoses from the same group of forms the NO-releasing compound in such dermatoses has a differentiation-inducing effect on keratinocytes of the skin, this principle of action is to be exploited here

cosmetic

Finally, the object of the present invention is to provide a method for cosmetic treatment for protecting the skin against damage caused by ultraviolet rays and, at the same time, to cause an increase in tanning (pigmentation) during use

This relates to a method of cosmetic treatment for protecting the skin against damage caused by ultraviolet rays, which is characterized in that before or during the irradiation an effective amount of at least one NO-releasing compound-containing cosmetic composition is contacted with the skin surface

The present invention is explained below by means of manufacturing and application examples. Parts are always given as weight points. The molar NO content in the composition is measured by known methods, for example by extraction of the NO-releasing substances using suitable solvents directly using chromatographic methods such as HPLC capillary electrophoresis or other analytical methods The release of NO can be done, for example, either directly from the cream using a selective NO electrode (e.g. IsoNO World Presision Instruments, Sarasot FL USA), as well as electrochemical methods or electro- tron spin resonance or by means of chemical mescence eg after heating or UV irradiation of the cream can be detected. If the substance needs to be enzymatically converted, the activity of the guanylate cyclase can also be measured by increasing the cGMP level after appropriate aqueous extraction in the cell culture (Methods in Nitnc Oxide Research, ed. M Feelish and J Stamler, John Wiley & Sons, Chichester, 1996)

Production example 1 (basic cream DAC with S-nitroso-thiols)

In 100 g of a base cream with a fat phase of 25.5 g of white vase, 7.5 g of medium-chain glycine, 4.0 g of glycine monostearate and 6.0 g of cetylalkonol and a water phase of 7.0 g of macrogol-1000 glycerol monostearate, 10.0 9 ml of a 1 M stock solution of S-nitroso-thioglyzene (SNOTG), produced according to WR Mathews, SW Kerr J Pharmacol Exp Ther. 267 (1993), 1529-1537 with a final concentration of 80 mM at room temperature (20 ° C.) with good stirring, whereby the composition assumed a red color

Production Example 2 (hydrophobic base oil DAC with S-nitroso-thioglycene)

In 100 g of a hydrophobic base gel, obtained by reacting 5 parts of polyethylene and 95 parts of viscous paraffin, 9 ml of a 1 M stock solution of S-nitroso-thioglyzeπn (SNOTG) in a final concentration of 80 mM at room temperature (20 ° C.) with thorough stirring mixed

Production example 3 (base cream DAC with sodium nitrite)

The preparation was carried out according to preparation example 1, but 100 g of the cream, 2 ml of a 1 M stock solution of sodium nitrite (final concentration 20 mM) were added Production Example 4 (hydrophobic gel with sodium nitroprussiate)

The preparation was carried out in accordance with Preparation Example 2, but 100 g of the hydrophobic gel were added to 2 ml of a 1 M stock solution of sodium nitroprussiate (final concentration 20 mM).

Production example 5 (cream with S-nitroso-thioqlycerin as cosmetic)

Production example 1 was repeated and an additional 0.5 g of tocopherol acetate was added as a cosmetically active substance.

Example of application (in vivo study of the effects of UV radiation in healthy subjects as well as in cutaneous lupus erythematosus and in polymorphic light dermatosis):

A total of seven healthy subjects were tested (subjects 1-7). These were of different skin types (see definition below), different ages (from 20 to 53), both sexes (3m, 4w). All subjects were treated with the identical base cream according to production example 1. All people were then irradiated with 100 J / cm ² UVA (radiation source: UVASUN 3000) and / or with 150 mJ / cm ² UVB (radiation source UV 800). The irradiations were carried out in rectangular windows of about 3 cm x 6 cm on the lower back.

As can be seen in detail from the table below, all subjects benefited from the anti-inflammatory effect of the NO-releasing compound on long-term observation, and most benefited from tanning enhancement (pigmentation) in UVA.

In subject 7, the results 24 hours after testing are not yet evident, unfortunately the observation on day 4 has not been recorded here, but there are notes that also show positive effects. This subject is too interesting because it is an atopic with asthma and many allergic complaints.

Subject 8 is a patient with cutaneous lupus erythematosus who also benefited significantly.

Subject 9 is a patient with polymorphic light dermatosis who benefited very impressively from the NO application (papules).

Legend to the table below:

0 not tested

A streaked

E + erythema just visible

E ++ severe erythema

E +++ erythema with infiltrate

P + pigmentation just visible

P ++ strong pigmentation

P +++ very strong pigmentation

A distinction is usually made between skin types I to VI, the examination takes into account skin types II to V (cf. W. Umbach, Kosmetik Stuttgart 1988,

P. 121):

Skin type I always erythema, no tanning

Skin type II always erythema, sometimes tanning

Skin type III sometimes erythema, always tanning

Skin type IV no erythema, always tan

Skin type V dark-skinned breeds

Skin type VI black

Claims

claims

1. Composition containing at least one NO-releasing compound as a topically administrable agent at the site of application with a biological effect, L-arginine, its salts and derivatives, and NO-polyethyleneimine cellulose being excluded as the NO-releasing compound.

2. Composition, in particular according to claim 1, containing at least one NO-releasing compound for use as a topically administrable agent with a cosmetic effect.

3. Composition according to claim 1, comprising at least one pharmacologically acceptable NO-releasing compound for use as a topically administrable agent with pharmaceutical activity.

4. Composition according to claim 2, characterized in that it

Contains 1 μmol to 200 mmol, preferably 5 μmol to 100 mmol, of the NO-releasing compound based on 100 g of the total composition

5. Composition according to claim 3, characterized in that it

Contains 1 μmol to 200 mmol, preferably 10 μmol to 100 mmol, of the NO-releasing compound, based on 100 g of the total composition.

6. Composition according to the preceding claims, characterized in that the NO-releasing compound is an under physiological conditions spontaneously NO-releasing, biochemically or physically NO-releasing compound

Composition according to the preceding claims, characterized in that the NO-releasing compound is selected from inorganic and / or organic compounds, the organic compounds being selected from the class of S-nitrosothiols and the adducts of nitrogen monoxide with a nucleophile (eg diazenium diolates)

Composition according to Claim 2 or 5-7, characterized in that they further contain 0.5% by weight to 20% by weight of light stabilizers for UV-A and or UV-B, based on the total composition, the light stabilizer preferably being selected from the class consisting of Benzyhdencampferdeπvaten, Dibenzoyimethandeπvaten, Benzotπazoldeπvaten, Tπazindeπvaten, p-Aminobenzoesauredeπvaten, Cinnamic acid derivatives, Anthranilsauredenvaten, Urocaninsauredenbenvatenates or

Composition according to the preceding claims, characterized in that it further contains a carrier which has at least one fatty phase based on mineral, vegetable or animal oils or waxes fatty acids, fatty alcohols having 6 to 22 carbon atoms

Composition according to the preceding claims, characterized in that it is in the form of an ointment, a cream, a gel embedded in liposomes, an oil, a milk of a solid stick or as an aerosol

Use of a composition containing at least one pharmacologically acceptable NO-releasing compound for the treatment and prophylaxis of electromagnetic waves of a wavelength of 1 mm to 1 nm, preferably 400 nm - 200 nm, caused skin damage and light dermatoses or hyperproliferative dermatoses, such as, for example, psoriasis vulgar or seborrheic keratoses.

12. Use according to claim 11, characterized in that the dermatoses caused by electromagnetic radiation are selected from combustio, erythema solar, light dermatoses or collagenoses such as e.g. cutaneous or systemic lupus erythematosus.

13. Use of a composition containing at least one NO-releasing compound as a cosmetic product.

14. A method of cosmetic treatment for protecting the skin against damage caused by ultraviolet rays, characterized in that an effective amount of at least one NO-releasing compound-containing cosmetic composition according to claim 2 or 5-10 is contacted with the skin surface before or during the irradiation ,