Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Patent
1987-10-02
1989-06-06
Dixon, Jr., William R.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
514 77, 424400, A61K 910, A61K 31685, C07F 909
Patent
active
048370231
DESCRIPTION:
BRIEF SUMMARY
Hexadecylphosphocholine is a known substance. In Pharmazie 37, 1982, pages 706-707, a lysing and fusogenic action is stated herefor. It has now been found that this compound also possesses an excellent anti-tumour action and, in comparison with homologous compounds, which are described in European Application 108 565, is characterized by the following surprising properties: whereas similar compounds with a shorter alkyl radical, such as for example tetradecylphosphocholine, show practically no anti-tumour action (for example, in vitro in the L1210 colony experiment or in vivo on the autochthanous methylnitrosourea-induced mammary carcinoma of the rat), those with a longer alkyl radical, such as for example octadecylphosphocholine, are admittedly anti-tumour effective but, at the same time, far too toxic and, therefore, not usable as medicaments. Thus, for example, in the case of a determination of the subacute toxicity during a treatment of 5 weeks at an anti-tumour effective daily dose of 77 .mu.mole/kg. rat orally, there was obtained an extremely high mortality which was 80% of all animals. Therefore, in spite of an anti-tumour action, the median survival time in comparison with the control was shortened by 72% in the case of octadecylphosphocholine-treated animals. In comparison thereto, in the case of hexadecylphosphocholine-treated animals, the mortality was lower by a half and, as a result of the absence of a chronic toxicity, it resulted in a highly significant increase of the median survival time of 26% in comparison with the controls.
Thus, within the homologous alkyl compounds, hexadecylphosphocholine occupies a surprising special position in that only heaxadecylphosphocholine possesses a practically useful good anti-tumour action. Homologues with shorter alkyl radicals possess no or a much too low anti-tumour action. Homologues with longer alkyl radicals are admittedly effective against tumours but, at the same time, are much too toxic. Therefore, only hexadecylphosphocholine displays a sufficient anti-tumour action in non-toxic doses.
The invention concerns medicaments which contain hexadecylphosphocholine as active material and are especially suitable for the treatment of tumours.
Such medicaments possess an outstanding cytotoxic effectiveness which was demonstrated not only in vivo on chemically-induced mammary carcinoma of the rat but also in vitro on leukaemia cells in the cell culture. Furthermore, in a clinical pilot study in the case of female patients with mammary carcinomas, skin metastases were completely healed in the case of topical use.
It is known that hitherto no medicament for the treatment of tumours, especially of malignant tumours, was available which was satisfactory in all respects. Thus, for example, for the topical treatment of skin metastases in patients with metastasing tumours, at present only 5-fluorouracil is available. Further developments of other cytostatics have hitherto not progressed to clinical maturity for this manner of administration. On the other hand, from a clinical point of view, such a concept of palliative therapeutic use is especially desirable since alternative concepts of treatment, such as surgical measures, radiation therapy and systemic chemotherapy, constitute comparatively aggressive therapy modalities. Furthermore, a considerable number of patients are available as potential treatment candidates for such a topical treatment. Thus, e.g. the proportion of mammary carcinoma patients who display a skin attack amount to about 25 to 35%.
The prerequisite for topical treatment on the part of the active material to be used are compatibility to the skin, cytotoxic effectiveness against tumour cells and sufficiently deep penetration.
Therefore, the object of the invention is, in the first place, to provide a medicament which is suitable for the topical treatment of tumours. A further object of the invention is, in addition, also to provide, in general, a medicament usable in other forms of administration which combines a good effectiveness against tumo
REFERENCES:
Unger, et al., Klin. Wochenstr. 63: 565-571 (1985).
Ando, et al., Cancer. Res. 32: 125-129 (1972).
Eibl, et al., Canc. Res. Clin. Oncol. 111 (suppl) 1986.
Eibl, et al., J. Clin. Res. Clin. Oncol 111(suppl) 1986, abstracts Ncy 21 and Ncy 22.
Bekemer, et al., Agents & Actions 11(6/7): 565-564 (1981).
Zeller, et al., "Dialog Abstract".
Croft et al, The activity of alkyl phosphoryl cholines and related derivatives against leishmania donovani. CA107 (19): 168296c.
Brunsman David M.
Dixon Jr. William R.
Max-Planck-Gesellschaft Zur Foederung der Wissenschaften
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