PHARMACEUTICAL COMPOSITIONS CONTAINING FLAVANOLIGNANES AND PHOSPHOLIPIDS AS ACTIVE PRINCIPLES

Abstract: The invention relates to pharmaceutical composi­ tions containing flavanolignanes and phospholipids, suited for treatment of acute or chronic liver disease of various origin. More particularly, the flavanolignanes comprise silymarin and the phospholipids are characterized by comprising polyunsaturated acyl chains. Flavanolignanes and phospholipids show an advantageous synergism when administered together in a weight ratio of 0.5:1 to 1:5, in suitable oral formulations, with pharmaceutically ac­ ceptable excipients.

Description: The invention relates to novel pharmaceutical compositions containing a combination of two drugs, both used in the treatment of liver diseases, a) flavanoligna­ nes and b) phospholipids. More particularly, the inven­ tion relates to pharmaceutical compositions containing a combination of silymarin and phospholipids with a high content of polyunsaturated acyl chains. (It is well-known that silymarin contains three main constituents, i.e. the flavanolignanes silybin, silidianin and silicristin; this invention relates to pharmaceutical compositions contain­ ing, as a) component, both silymarin as such and one or more of the three above mentioned flavanolignanes, even though the invention will refer only to silymarin, for sake of semplicity). Silymarin is known to exert a stabilizing action on the liver-cell membrane against the poisoning effect of some injurious agents such as phalloidine, amanitine, carbon tetrachloride, galactosamine, and is widely employ­ ed in the treatment of liver diseases of various origin. Phospholipids (particularly phosphatidylcholine, which is the main constituent of all the endogenous pho­ spholipids) are essential for the normal structure and function of the liver cells, intervening in the regulation of the fluidity and permeability of the cell walls. Each liver disease, even of viral origin, involves a membrane damage resulting from an impaired synthesis of the phospholipids or a peroxidation of the same, with a consequent lysis of the walls, and necrosis of the tissue. Phospholipids, which are absorbed as such also in the gastroenteric tract, act directly on the liver-cell mem­ brane, wherein are incorporated to balance the phospholi­ pidic deficiency. It has now been found that a combination of sily­ marin (which inter alia stimulates the in vivo biosynthe­ sis of phosphatidylcholine) with exogenous phospholipids, particularly with unsaturated exogenous phospholipids from soy or liver, is more active than the single components in the prevention and treatment of liver disease. Surprising­ ly, the activity of such a combination takes place at lower doses than those usually used for the components. The weight ratio silymarin:phospholipids in the combinations according to the invention may range from 1:0.5 to 1:5; preferred combinations contain silymarin and unsaturated phospholipids in a weight ratio from 1:1 to 1:3. Particularly preferred combinations according to the invention contain a) 1 part (by weight) of silymarin con­ taining 80% of flavanolignanes, with a weight ratio sily­ bin:silidianin:silicristin = 3:1:1, and b) 2 parts(by weight) of phosphatidylcholine having a high content of polyunsaturated acyl groups. Among these combinations, particularly preferred is the one in which the b) compo­ nent is a soy phosphatidylcholine wherein the acyl groups consist of at least 60% linoleic acid groups. Likewise preferred are the combinations in which liver phospholi­ pids replace soy phosphatidylcholine, said liver phospholipids being particularly rich in linolenic acid. Non limiting examples of such a phosphatidylcholine are a soy-bean phosphatidylcholine (known as "Lipoid (R) S 100"), having a minimum content of 90% phosphatidylcholine, con­ taining on average 63% linoleic acid, 16% palmitic acid, 11% oleic acid and 3.5% stearic acid out of the total fatty acids; or a phosphatidylcholine containing 80% lino­ leic acid, 5% linolenic acid and 15% oleic acid ("EPL Nattermann"). The following pharmacological tests show the acti­ vity of the new compositions and the advantages in compa­ rison with the single components. Table 1 shows the liver protection obtained in the conventional test of liver poisoning with CCl₄, in the rat. Table 2 shows the protec­ tion obtained in the liver poisoning with praseodymium, in the rat, by the administration of silymarin, phosphatidyl­ choline and, respectively, combinations thereof. The compositions according to the invention show no toxic effects. They can be used in form of pills, capsules, packets, or as aqueous suspensions, suitably flavourised. The following examples illustrate some pharmaceutical compositions of the invention, without limiting it. EXAMPLE 1 Chewable tablets containing silymarin and phosphatidylcho­ line with a high content of polyunsaturated fatty acids (Lipoid (R) S 100) Each 3 g tablet contains: Silymarin 200 mg Lipoid (R) S 100 (phosphatidylcholine) 300 mg Ammonium glycyrrhizinate 15 mg Sodium saccharine 10 mg Talc 30 mg Magnesium stearate 20 mg Silica powder 30 mg Orange juice (dried) 350 mg Flavouring 35 mg Fructose 1495 mg Dextrose 515 mg EXAMPLE 2 Chewable tablets containing silymarin and phosphatidylcho­ line with a high content of polyunsaturated fatty acids (Lipoid (R) S 100) Each 1.5 g tablet contains: Silymarin 200 mg Lipoid (R) S 100 (phosphatidylcholine) 150 mg Ammonium glycyrrhizinate 15 mg Sodium saccharine 10 mg Silica powder 25 mg Talc 15 mg Magnesium stearate 10 mg Orange juice 250 mg Flavouring 30 mg Dextrose 255 mg Fructose 550 mg EXAMPLE 3 Granulate for suspension in water, containing silymarin and phosphatidylcholine Each 4 g packet contains: Silymarin 400 mg Lipoid (R) S 100 (phosphatidylcholine) 600 mg Lactose 2000 mg Mannitol 757.5 mg Ammonium glycyrrhizinate 10 mg Sodium saccharine 2.5 mg Orange juice 200 mg Flavouring 30 mg The pharmaceutical compositions of the invention may be administered 2-4 times a day, resulting in daily dosages of approximately 5 mg/kg body weight of silymarin and 5 mg/kg body weight of phospholipids to 25 mg/kg of silymarin and 40 mg/kg of phospholipids.

Claims: 1. Pharmaceutical compositions with anti-hepatotoxic activity, containing as the active principle a combination of: a) one or more flavanolignanes, and b) one or more phospholipids, either alone or in association with other active princi­ ples. 2. Pharmaceutical compositions according to claim 1, containing, as a)-component, flavanolignanes selected from the group consisting of silybin, silidianin, silicristin and mixtures thereof. 3. Pharmaceutical compositions according to claims 1 and 2, containing silymarin as a)-component. 4. Pharmaceutical compositions according to claims 1-3, containing, as b)-component, phospholipids with a high content of polyunsaturated acyl groups. 5. Pharmaceutical compositions according to claim 4, containing, as b)-component, phosphatidylcholine from soy beans or from liver. 6. Pharmaceutical compositions according to claims 1-5, in which the a:b weight ratio is from 1:0.5 to 1:5. 7. Pharmaceutical compositions according to claims 1-5, in which the a:b weight ratio is from 1:1 to 1:3. 8. Pharmaceutical compositions with antihepatotoxic activity, containing as the active principle a combination of a) silymarin and b) phosphatidylcholine from soy beans in a 1:2 weight ratio. 9. Pharmaceutical compositions according to claim 8, in form of chewable tablets. 10. Pharmaceutical compositions according to claim 8, in form of hydrodispersible granulates. Claims for contracting state : AT 1. Process for the preparation of pharmaceutical com­ positions with anti-hepatotoxic activity, containing as the active principle a combination of: a) one or more flavanolignanes, and b) one or more phospholipids, either alone or in association with other active princi­ ples. 2. Process according to claim 1, wherein the flavano­ lignanes are selected from the group consisting of sily­ bin, silidianin, silicristin and mixtures thereof. 3. Process according to claim 1, wherein silymarin is used as flavanolignanes. 4. Process acording to claims 1-3, wherein the pho­ spholipids have a high content of polyunsaturated acyl groups. 5. Process according to claim 4, wherein the phospho­ lipid is phosphatidylcholine from soy beans or liver. 6. Process according to claims 1-5, in which the a:b weight ratio is from 1:0.5 to 1:5. 7. Process according to claims 1-5, in which the a:b weight ratio is from 1:1 to 1:3. 8. Process according to claims 1-7, wherein silymarin and phosphatidylcholine from soy beans are used in a 1:2 weight ratio.

Inventors: BOMBARDELLI, EZIO, MAGISTRETTI, MARIA JOSE, Magistretti, Maria José
Applicants: INVERNI DELLA BEFFA S.P.A.
Application year: 1986
Main classification: A61K31
IPC codes: A61K31, A61K38, A61P1