Drug – bio-affecting and body treating compositions – Topical sun or radiation screening – or tanning preparations
Reexamination Certificate
2002-04-08
2004-11-09
Dodson, Shelley A. (Department: 1616)
Drug, bio-affecting and body treating compositions
Topical sun or radiation screening, or tanning preparations
C424S060000, C424S078020, C424S078080, C424S400000, C424S401000
Reexamination Certificate
active
06814959
ABSTRACT:
The invention relates to solid agents, comprising polymorphic lipid particles, with UV radiation-absorbing and/or reflecting action for application on the skin, mucous membranes, scalp and hair for protection against health-damaging UV radiation and for strengthening the natural skin barrier.
With the increase in the ozone hole and the worldwide decrease in the thickness of, the ozone layer and the resultant increasing exposure of the human skin to health-damaging UV radiation, there is an increasing need and necessity for agents which protect the skin from UV radiation, that is, which weaken or, ideally, completely block the UV radiation. The health-damaging effect of UV rays makes itself apparent in the form of skin cancer (e.g. melanoma), among other things. The increase in UV radiation load on the skin in recent years has led to a great increase in skin cancers. Whereas the incidence of some cancer types is declining, melanoma of the skin is one of the cancer types with the highest rate of increase, as a result of the increasing UV load. New cases of malignant melanoma are doubling every 5 years (E. Wolf, Angst vor der Sonne, Pharmazeutische Zeitung 144, 1839-1843). The population of countries with high and intensive exposure to the sun is affected in particular, e.g. ozone hole above South Chile, New Zealand and Australia. Thus, the incidence of malignant melanoma in Australia is five times higher than in Central Europe (E. Wolf, Angst vor der Sonne, Pharmazeutische Zeitung 144, 1839-1843).
The traditional approach to providing protection from UV radiation is the incorporation of molecules which absorb UV radiation (so-called UV blockers) in creams or lotions which are applied to the skin as protection against the sun and remain there for hours. (N. J. Lowe, Photoprotection, Seminars in Dermatology, Vol. 9, NO. 1, 1990, 78-83). Strictly speaking, the term “UV blocker” is misleading, as the UV radiation is not completely blocked, but only lessened to a greater or lesser extent, depending on the concentration and chemical nature of the substances which are used.
One of the disadvantages of the molecular UV blockers is that, analogously to drugs incorporated into cream, they diffuse into the skin. This is desired with drugs but not with UV blockers, as they cause unwelcome side-effects.
Side-effects of UV blockers are e.g. photosensitization such as photoallergy and phototoxicity, and skin irritations. With sensitive persons, a foreign substance—often a topical chemical UV filter—is activated by UV radiation and this activated form then causes this reaction (E. Wolf, Angst vor der Sonne Pharmazeutische Zeitung 144, 1839-1843). With some substance classes (salicylides), skin irritations are so marked that they cannot be applied to the skin. This has resulted in the requirement to minimize penetration into the skin (E. Mariani, C. Neuhoff, A. Bargagna, F. Bonina, M. Giacchi, G. De Guidi, A. Velardita, Synthesis, in vitro percutaneous absorption and phototoxicity of new benzylidene derivatives of 1,3,3-trimethyl-2-oxabicyclo (2,2,2) octan-6-6-one as potential UV sunscreens, Int. J. Pharm. 161, 65-73). With good solubility in the vehicle (e.g. molecular UV blockers in the oil phase of a lotion or cream), a penetration into the skin can however come about very easily. (U. Hagedorn-Leweke, B. C. Lippold, Accumulation of sunscreens and other compounds in keratinous substrates, Eur. J. Pharm. Biopharm. 46, 215-221). The skin penetration of molecular UV blockers is thus an unsolved problem. Hence the stronger call to employ physically acting light filters which do not penetrate the skin (E. Wolf, Angst vor der Sonne, Pharmazeutische Zeitung 144, 1839-1843).
A further problem is that toxicological testing of UV blockers is in accordance with the guidelines for cosmetics, which are less strict than those for drug tests. UV blockers can decompose under the action of UV radiation. Reactive decomposition substances thus form which can be toxicologically problematical, especially where there is skin penetration. It is known of some UV blockers that they specifically bond to keratin structures of the skin and can therefore be washed off only with difficulty (U. Hagedorn-Leweke, B. C. Lippold, Accumulation of sunscreens and other compounds in keratinous substrates, Eur. J. Pharm. Biopharm. 46, 215-221). To minimize toxicity, an ideal sunscreen should be removable by washing after sunbathing.
The penetration—and therefore the side effects—can be particularly marked if the UV blockers are dissolved in the aqueous phase of oil-in-water (O/W) creams or lotions. The phase in direct contact with the skin (water phase) has a high concentration of UV blockers so that the water phase-to-skin concentration gradient is high, which, according to Fick's first law of diffusion, promotes penetration into the skin. This is an effect which is selectively exploited in pharmacy with transdermal therapeutic patches, but which is undesirable, and must be minimized, with UV blockers.
One approach to minimizing skin penetration is the use of lipophilic UV blockers with low water-solubility. These are dissolved in the oil phase of the cream or lotion. The water phase contains a much lower concentration of UV blockers. With a favourable chemical structure of the UV blocker, this can slow down penetration into the skin as a result of the concentration gradient now being smaller, but does not avoid it. UV blocker diffused out of the wtaer phase into the skin is replaced by the diffusion of further UV blocker out of the oil phase into the water phase. The redistribution into the water phase takes place according to the Nernst's distribution coefficient of a substance.
To avoid the side effect of molecular UV blockers, the approach of using particulate UV blockers has been followed. An example is the widely used inorganic titanium dioxide (B. L. Diffey, P. M. Farr, Sunscreen protection against UVB, UVA and blue light; an in vivo and in vitro comparison, British Journal of Dermatology 124, 1991, 258-263). The basic idea was that the particles, by virtue of their size, do not diffuse into the skin and thus should not cause any side-effects. After sunbathing, the particles should be washed off the skin by normal body cleaning (e.g. shower).
Particulate UV blockers such as micropigments (e.g. titanium dioxide) have an immediately, conspicuous cosmetic disadvantage in preparations with a high light-protection factor. With the necessary large amount of pigment, a whitening effect occurs (E. Wolf, Angst vor der Sonne, Pharmazeutische Zeitung 144, 1839-1843). Very small titanium dioxide particles have proven to be particularly effective (B. L. Diffey, P. M. Farr, Sunscreen protection against UVB, UVA and blue light; an in vivo and in vitro comparison, British Journal of Dermatology 124, 1991, 258-263), so that they have accordingly been used at concentrations of up to 25% in cosmetics. However, interactions and side-effects with the skin have also bee n found with titanium dioxide particles (R. G. van der Molen et al, Efficacy of micronized titanium dioxide-containing compounds in protection against UVB-induced immunosuppression in humans in vivo, Journal of Photochemistry and Photobiology 44, 2, 1998, 143-150), and it can no longer be ruled out that titanium dioxide penetrates the skin (R. G. van der Molen, Tape stripping of human stratum corneum yields cell layers that originate from various depths because of furrows in the skin, Archives of Dermatological Research, 289, 9, 1997, 514-518). Thus it has been shown for example, that titanium dioxide can photocatalyze the formation of free radicals (W. G. Wamer, Oxidative damage to nucleic acids photosensitized by titanium dioxide, Free Radical Biology and medicine, 23, 6, 1997, 851-858), which is to be viewed critically both in the skin and on the skin and also during storage.
In summary it can thus be established that, in view of the more intensive radiation load, with a simultaneous increase in use, a need exists both for more efficient and toxicologically better co
Mäder Karsten
Müller Rainer H.
Wissing Sylvia
Dodson Shelley A.
Manelli Denison & Selter PLLC
Melcher Jeffrey S.
PharmaSol GmbH
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