Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1985-02-26
1987-09-15
Daus, Donald G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544243, 544262, 544302, A61K 31505, C07D48704
Patent
active
046940065
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel transient prodrug forms of allopurinol useful in the prevention and treatment of hyperuricemia, to methods for preparing the prodrug forms, to pharmaceutical compositions containing such prodrug forms, and to methods for using the prodrug forms.
As employed in this application, the term "prodrug" denotes a derivative of allopurinol which derivative, when administered to warm-blooded animals, e.g. humans, is converted into the proven drug, i.e. allopurinol.
The term "transient" indicates that the conversion of the prodrug forms proceeds in such a manner that the proven drug form (parent allopurinol) is released, and the remaining moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.
These novel prodrug forms of allopurinol are certain derivatives of allopurinol which possess a desirable high lipophilicity and/or improved aqueous solubility in comparison to the parent compound, allopurinol.
2. Description of the Prior Art
Allopurinol is a widely used agent for the treatment and prevention of hyperuricemic states such as gout. Allopurinol and its main metabolite oxipurinol lower the level of uric acid in plasma and urine by inhibiting xanthine oxidase, the enzyme catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid (cf. e.g. Spector, 1977; Elion, 1978). In addition to its use as prophylaxis against and treatment of gout and other chronic hyperuricemic states allopurinol is commonly used to prevent the development of hyperuricosuria that often results from the rapid lysis of cells in patients with malignancies who are undergoing treatment with cytotoxic drugs or radiation (cf. e.g. Elion, 1978).
Allopurinol is conventionally administered orally in the form of tablets. However, the development of nausea and vomiting among patients undergoing cancer chemotherapy frequently precludes the use of oral preparations in these patients. Consequently, a pharmaceutical and medical need exists for allopurinol preparations useful for the control of hyperurecemia in patients with neoplastic disease as well as in other individuals who are unable to take or retain oral medications.
Alternative means of administering allopurinol may be provided by the use of injectable and rectal preparations.
However, since allopurinol is only slightly soluble in water (about 0.5 mg/ml at 25.degree. C.) acceptable injection preparations such as for intramuscular injection, are not available. Presently, it is only possible to deliver sufficient amounts of allopurinol parenterally by infusion. The infusion fluids used contain the sodium salt of allopurinol at a concentration of 0.5-1% and are strongly alkaline (pH about 10.5-11.5); consequently, their administration may cause thrombophlebitis or perivascular inflammation.
With respect to the rectal route of administering allopurinol recent studies have demonstrated that this approach using allopurinol per se is not a suitable and reliable mode of therapy (Chang et al., 1981; Appelbaum et al., 1980, 1982). It was shown in these studies that virtually no allopurinol or only very minute amounts (<5%) is absorbed from various suppository preparations administered rectally to man. This very poor ability of allopurinol to be absorbed rectally can be attributed to the low lipophilicity of the drug combined with its poor water solubility.
Although oral administration of allopurinol provides the attainment of effective serum concentrations the absorption of the compound is not complete. Thus, it has been reported that the absolute systemic bioavailability of oral allopurinol tablets in man are about 70% (Appelbaum et al., 1982) while another study (Elion et al., 1966) reported that about 20-25% of an oral dose is excreted in the stool unchanged. The incomplete and variable absorption behaviour of allopurinol can, like noted above for the rectal absorption, be attributed to the low water and lipid solubility of the drug.
Thus, it is q
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Bundgaard Hans
Falch Erik
A/S GEA
Daus Donald G.
Noel M.
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