REDUCING BLOOD CHOLESTEROL BY IN VIVO PRECIPITATION OF BILE CONSTITUENTS WITH GROUP II OR -III METAL SUBSTANCES

Abstract: The present invention concerns the use of a substance which causes the precipitation of a bile constituent in the manufacture of amedicament for reducing body cholesterol levels together with methods of manufacture of medicaments comprising same and methods of reducing body cholesterol levels using same.

Description: REDUCING BLOOD CHOLESTEROL BY IN VIVO PRECIPITAΗON OF BILE CONSTITUENTS WITH GROUP II OR -III METAL SUBSTANCES The present invention concerns the use of precipitors of bile constituents, particularly substances which provide Al 3+ ions when in aqueous solution, to cause a reduction in body cholesterol levels, together with the use of same in the manufacture of medicaments for causing a reduction in body cholesterol levels and methods of manufacture of same. High blood cholesterol levels are widely viewed as being undesirable and so it is desirable to effect a reduction in body cholesterol levels. It has previously been found (WO 95/05752) that ions of groups II and III metals may be used to effect a reduction in the absorption of fatty acids. However, it has not been previously suggested that bile constituents - i.e. cholic acid derivatives, their salt and esters - could be precipitated to effect a reduction in blood cholesterol levels. According to the present invention, there is provided the use of a substance which causes the precipitation of a bile constituent in the manufacture of a medicament for reducing body cholesterol levels. The substance may be any substance which provides ions of a group II or group III metal when in aqueous solution, particularly in the conditions prevalent in the gut. The solubility product of the substance in the form in which it is administered (to a patient) may be greater than that of the ions of the substance plus bile constituent so that the bile constituent is precipitated out. Particularly useful substances may include those which provide Al 3+ or Ca 2+ ions when in solution, for example aluminium sulphate and calcium sulphate, alums (such as potassium alum - K 2 SO 4 . Al 2 (SO 4 ),. 12 H 2 O). Mg 2+ ions may also be provided but have been found to be less effective than Ca 2+ ions and much less so than Al 3+ ions. Bile primarily comprises cholic acid derivatives, their salt and esters and so the bile constituent may be a derivative of cholic acid, or a salt or ester thereof. Bile is secreted by the liver and emulsifies fats in the duodenum prior to and as an aid to their digestion. After cleavage of fatty acids, bile salts and bile acids provide the essential component for the formation of micelles which are absorbed into the body, the bile acid and salts returning to the liver for re-circulation. Each bile acid or salt is discharged into the gut about 20 times each day, particularly after the consumption of food. The precipitation of bile constituents prevents their re-circulation and the liver replaces the lost constituents by using the circulating cholesterol (from which all bile acids, bile salt and bile esters are synthesised) and thus body cholesterol levels are decreased. The substance may be provided in a non-toxic dosage. Appropriate dosages may be readily determined using a simple dose-response assay. The substance may be provided in an active form or it may become active as a result of the chemical environment existing within the gastrointestinal system. By "active" is meant that the solubility product of the substance is greater than that of the substance and bile constituent so that the bile constituent forms a salt with, or is precipitated by, the substance. Dietary ingredients having a lower solubility product than the bile constituent salt should, of course, be avoided since they could cause displacement of the bile constituent from the ion and thus release bile constituents which may become available for absorption. Particularly useful aluminium salts are the aluminium salts of soaps such as aluminium stearate and aluminium palmitate. These are highly insoluble in aqueous solution and so will not readily release the aluminium as ions unless the aluminium is able to immediately form an even more insoluble salt, which it does with bile constituents. The substance (i.e. in the form of a medicament) may be administered immediately after consumption of a meal or, for example, within 2 hours of consumption of a meal. Also provided, according to the present invention, is a method of manufacture of a medicament for reducing body cholesterol levels comprising the use of a substance which causes the precipitation of a bile constituent. Also provided, according to the present invention, is a method of reducing body cholesterol levels comprising administering to a patient a substance which causes the precipitation of a bile constituent.

Claims: CLAIMS 1. The use of a substance which causes the precipitation of a bile constituent in the manufacture of a medicament for reducing body cholesterol levels. 2. The use of a substance according to claim 1, the substance providing ions of a group II or group III metal when in aqueous solution. 3. The use of a substance according to either one of claims 1 or 2, the solubility product of the substance in the form in which it is administered being greater than that of the ions of the substance, plus bile constituents such that the bile constituent is precipitated out. 4. The use of a substance according to any one of the preceding claims, the substance providing Al 3+ or Ca 2+ ions when in solution. 5. The use of a substance according to any one of the preceding claims, the solubility product of the substance being, as a result of the chemical environment existing within the gastrointestinal system, greater than that of the ions of the substance plus bile constituents such that the bile constituent is precipitated out. 6. The use of a substance according to any one of the preceding claims, the substance being provided in a non-toxic dose. 7. The use of a substance according to any one of the preceding claims, the medicament being taken immediately after consumption of a meal or within 2 hours of consumption of a meal. 8. A method of manufacture of a medicament for reducing body cholesterol levels comprising the use of a substance according to any one of the preceding claims. 9. A method of reducing body cholesterol levels comprising administering to a patient a substance according to any one of claims 1 - 7.

Inventors: WILLIAMS ALUN ROY, WILLIAMS, ALUN, ROY
Applicants: KAPPA PHARMACEUTICALS LTD, WILLIAMS ALUN ROY, KAPPA PHARMACEUTICALS LIMITED, WILLIAMS, ALUN, ROY
Application year: 1998
Main classification: A61K33
IPC codes: A61K31, A61K33, A61P3