Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-09-17
2002-07-02
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
Reexamination Certificate
active
06413950
ABSTRACT:
The invention concerns a pharmaceutical preparation in a presentation form suitable for topical application, which contains phosphoric acid esters of dithranol and its use for low irritation treatment of psoriasis.
Dithranol is one of the most proven drugs for treatment of psoriasis in dermatology. Psoriasis is still categorized among dermatoses with uncertain ethology. For this reason various preparations are employed for classical external treatment, among them ones containing dithranol, salicylic acid or urea. An important disadvantage of current pharmaceutical preparations that contain dithranol is the use of lipophilic bases due to the high lipophilicity of the active agent, from which it can penetrate into the diseased, less lipophilic regions of the skin only with great difficulty. Usually, lipophilic ointment bases are used as vehicles for dithranol. The active agent is not soluble in water and can only be partially incorporated into aqueous formulations, if larger amounts of surfactants are added, and the stability of the active agent is low here. The good therapeutic efficacy of dithranol is, however, offset by its strong staining property, which leads to low acceptance among patients and to considerable purification problems particularly with clinical treatment. Studies of the mode of action of dithranol have been concentrated on explaining the processes of radical formation in vivo. These processes are very complex in nature, but suggest that in particular the oxidation of anthrone to anthraquinone progresses via radical intermediates and thus can also be considered as proof of the efficacy of phototherapeutic treatment methods.
Based on this, i.e., on the fact that dithranol is still a very effective drug for treatment of psoriasis (for example, W. C. Marsch, DAZ, 1995, 135(38), 3498-3499) there have been numerous attempts to derivatize it (K. K. Mustakallio, Acta Derm. Venerol. (Stockh.), 1992, 172 Suppl., 7-9). The greater portion of all of the studies in this case has been concentrated on derivatives that have new substituents chiefly in position 10. It was shown that the antipsoriatic efficacy of compounds is linked to easy homolytic cleavability of the methylene proton bond in position 10 of the anthrone parent compound. In this way it becomes understandable that of the large number of new derivatives with substituents in position 10 only the monosubstituted anthrone derivatives have biological efficacy that is in some cases higher than that of dithranol itself An important disadvantage of all of the position 10 substituted derivatives is: they do not have any significant improvement of the penetration properties into the psoriatically diseased hydrophilic regions of the skin than the pure active agent dithranol.
Based on this, a task of this invention was to propose a new pharmaceutical preparation in a presentation form suitable for topical application, which contains dithranol in a form that allows clearly improved penetration into psoriatically diseased hydrophilic regions of the skin than was possible up to now.
This object preferably is achieved by the characterizing features of the present invention. Advantageous embodiments and further developments of the invention will be apparent from the description provided herein.
Thus, in accordance with the invention, a pharmaceutical preparation that contains phosphoric acid esters of dithranol as active agent is proposed. The phosphoric acid esters of dithranol that are contained in the pharmaceutical preparation in accordance with the invention are defined by the following general formulas I through IV,
Formula I: 1-Phosphoryl-8-hydroxy-9-anthrol
Formula II: 1,8-Diphosphoryl-8-hydroxy-9-anthrol
Formula III: 1-Phosphorylanthrol-8,9-cyclophosphate
Formula IV: 8-Hydroxyanthrol-1,9-cyclophosphate
in which R
1
is selected from among H, aryl groups, for example phenyl and substituted homologs, alkyl groups, for example methyl, ethyl, including higher homologs like dodecyl, and Me, especially an alkali metal or alkaline earth metal. Here it is preferred if the residue R
1
is hydrogen and potassium is present as alkali metal. In numerous studies it proved to be particularly advantageous when the active agent is defined by general formula IV where again the metal is potassium and R
1
is hydrogen.
It should be particularly emphasized in regard to the pharmaceutical preparations in accordance with the invention that the physicochemical properties of the active agents that they contain can be varied via the type of cationic components and the number of phosphate residues on the dithranol. In the form of simple metal salts with monovalent or polyvalent metal cations they are readily to moderately water soluble. In this way a targeted change is possible via the type of counterion of the phosphate residue without the phosphate structure as such having to be varied. Here the hydrophilicity of these compounds is proportional to the number of phosphate residues and thus the number of counterions. Changing the hydrophilic/lipophilic behavior is also directly possible via the phosphate structure. The highest hydration is achieved as the monoester or diphosphoric acid ester on an anthrol residue. However, cyclic anthrol phosphate structures (general formulas III and IV), which are esterified cyclically in position 9 and optionally in position 8 with another phosphoryl residue, are also possible. It should be particularly emphasized that through the great variety of structures and combinations of these phosphoric acid esters it becomes possible to make available prodrug forms in which the active agent is homogeneously distributed both in aqueous as well as in water-free preparations is present in a micellarly dissolved form or in suspended form. Preferably, the pharmaceutical preparation contains 0.1-20 wt % of the active agent, especially preferably 0.5-5 wt % of the active agent. The preparation of such a pharmaceutical preparation in which the active agent is present in homogeneously distributed or micellarly dissolved form or is suspended in an aqueous or water-free formulation is basically known from the prior art. In this regard reference is made to H. D. Dörfler, “Surface and colloid chemistry” [in German], VCH Verlags-gesellschaft, Weinheim, 1994.
With the new pharmaceutical preparation, which contains prodrugs based on phosphoric acid esters, one basically has new application forms for treatment of psoriasis. With the prodrugs in accordance with the invention the active agent can penetrate in a targeted fashion into the psoriatically diseased regions of the skin from galenically acceptable formulations, where it becomes completely released in the region of the epidermis/dermis. However, since no detectable penetration of the prodrugs from aqueous formulations into undiseased regions of the skin is detected and thus their irritation can be prevented, these drugs are excellently suitable for treatment of psoriasis. Thus, with the prodrugs in accordance with the invention a new route in the treatment of psoriasis becomes possible, by making available one of the most effective active agents in treatment by means of wash solutions, lotions or gel-like formulations. Here it is decisive that these applications very largely take place without mechanical stress on the injured and thus irritation-intolerant skin. It is possible through bathing, swabbing or other moisturization routines or general application of gels to generate an appropriate difference of concentration of prodrug from the aqueous phase to the cutis, so that penetration of active agent into the skin is triggered in the desired way. Thus it can be controlled via the choice of prodrug corresponding to the purpose, its concentration in the formula itself and also via the time of contact with these preparations. Appropriate additives like urea promote rapid keratinolysis, favor the hydration of the stratum corneum in cases of severe scaling or lesions or favor the structurization within the epidermis for an improvement of penetration into the corium.
Fries Gerhard
Huschka Christoph
Koegst Dieter
Neubert Reinhard
Schneider Jürgen
esparma GmbH
Jarvis William R. A.
Kim Vicki
Leydig , Voit & Mayer, Ltd.
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