Oral antilipemic agents

#This invention relates to oral antilipemic agents for remarkably reducing lipids in blood, especially total lipid, cholesterol, triglycerides and .beta.-lipoprotein, etc.

#Despite the intensive research heretofore carried out for more than one century, the causes of arteriosclerosis have not been fully clarified yet and various mechanisms for its occurrence have been explained merely with hypotheses. In recent years, however, it is considered to be attributable to lipids' metabolism disorders, cholesterol and triglycerides which have been implicated as especially important factors. Among various drugs provided for controlling these factors, heparin, dextran sulfate and similar acidic substances are known to be effective in reducing lipids in blood, but heparin and dextran sulfate have drawbacks. They possess a very high anticoagulant activity as a side effect and cannot be administered continually for a long period of time.

#An object of this invention is to provide antilipemic agents which can be orally administered and are free of the above-mentioned drawbacks of the known drugs.

#A 100 g quantity of the methyl ester of polyglutamic acid (average molecular weight: 100,000) is dissolved in dichloroethane to a concentration of 10 wt.%. To the solution is added a mixture of 70 ml of 2 N sodium hydroxide solution, 140 ml of methanol and 140 ml of isopropanol, and the resulting mixture is stirred at room temperature for about 8 hours to effect demethylation. The product is then passed through a molecular sieve (Sephadex G-200) for the classification of molecular weight to separate a portion ranging from 80,000 to 100,000 in molecular weight (average molecular weight: 90,000). The separated portion is concentrated under reduced pressure and divided into two portions of equivalent weight. To one of the portions is added methanol and the precipitate formed is separated by filtration and dried to obtain the sodium salt of polyglutamic acid. To the other portion is added concentrated hydrochloric acid until the pH thereof reaches 4, then the solution is cooled with ice, whereby a precipitate is formed. The precipitate is separated by filtration, washed with diluted hydrochloric acid, thereafter with methanol and dried to obtain polyglutamic acid. Each powder (200 mg) of polyglutamic acid and sodium salt thereof thus obtained is mixed with 290 mg of milk sugar, 500 mg of corn starch and 10 mg of hydroxypropyl cellulose and the mixtures obtained are granulated respectively. The granules are suspended in water. Two kinds of the suspensions are orally administered to 7 rats in a dose of 50 mg/kg, respectively, to determine the reduction of lipids in blood. The rat used for test has been intravenously given a surfactant, Triton WR-1339 (trade mark, product of Ruger Chemical Corp., U.S.A.) in an amount of 200 mg/kg, previously to increase the lipids in blood. The test results are listed in Table 1.

#Table 1 ______________________________________ Rat administered with: Sodium salt Polyglu- Normal Rat given of polyglu- tamic rat surfactant tamic acid acid ______________________________________ Total lipid 220 .+-. 12 1033 .+-. 330 393 .+-. 66 373 .+-. 132 Tri- glycer- ide 44.7 .+-. 3.5 780.1 .+-. 354.5 92.0 .+-. 42.8 103.3 .+-. 67.2 Total cho- lesterol 89.9 .+-. 10.4 235.3 .+-. 41.7 121.8 .+-. 18.9 118.1 .+-. 35.3 Free cho- lesterol 25.7 .+-. 3.7 114.2 .+-. 28.8 40.0 .+-. 11.4 38.8 .+-. 11.7 .beta.- Lipo- protein 44.3 .+-. 1.3 141.7 .+-. 28.8 63.4 .+-. 16.9 61.9 .+-. 29.0 ______________________________________ Note: (Unit: mg/dl of plasma).

#Methyl ester of polyaspartic acid (average molecular weight: 35,000) is demethylated in the same manner as in Example 1, and the product is passed through a molecular sieve (Dia Filter) for the classification of molecular weight to separate a portion ranging from 10,000 to 50,000 in molecular weight (average molecular weight: 30,000). The separated portion is concentrated under reduced pressure, methanol is added to the concentrate and the resulting precipitate is separated by filtration and dried to obtain the sodium salt of polyaspartic acid. With the powder (100 mg) thus obtained are mixed 76 mg of milk sugar, 108 mg of corn starch, 58 mg of crystalline cellulose and 8 mg of talc. The mixture is encapsulated. The capsules are orally administered in a dose of 50 mg/kg to 5 dogs which have been orally given olive oil (each in 10 ml/kg) previously to increase the lipids in blood. Similar test results to those obtained in Example 1 are observed.