RU2373924C1 - Nanoform of phospholipid preparation for oral application and method for making thereof - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutics and medicine and concerns an oral medicinal form of a phospholipid preparation for prevention and treatment of hepatopathy, lipid storage disease and hepatic function recovery following intoxication, in the form of nanoparticles of diametre 30-50 nm, containing vegetable phospholipids with phosphatidyl choline content 75-98%, glycyrrhizic acid or its pharmaceutically acceptable salt and a carbohydrate with the total content of phospholipids and glycyrrhizic acid or its pharmaceutically acceptable salt 2-80 wt % and mass ratio of phospholipids to glycyrrhizic acid or its pharmaceutically acceptable salt 4:1 or less, as well as method for making thereof by mixture emulsion of vegetable phospholipids in aqueous solution of glycyrrhizic acid or its pharmaceutically acceptable salt with aqueous solution of carbohydrates at pH 6.5-7.5, then followed with homogenisation at pressure 800-1200 bar and sublimation drying.

EFFECT: there is developed oral medicinal form of the phospholipid preparation for prevention and treatment of hepatopathy, lipid storage disease and hepatic function recovery following intoxication.

3 cl, 1 ex, 3 dwg

Description

The invention relates to pharmaceuticals and medicine and relates to an oral dosage form of a phospholipid preparation for the prevention and treatment of liver diseases, lipid metabolism disorders and restoration of liver function after intoxication in the form of nanoparticles with a diameter of 30-50 nm and a method for its preparation.

Known pharmaceutical composition for the treatment and prevention of acute and chronic liver diseases, impaired lipid metabolism in atherosclerosis and related diseases, restoration of liver function after intoxication, containing phospholipids, glycyrrhizic acid or its salts and excipients (RU 2133122, A61K 31/685, 20.07. 1999). The composition is mainly used in capsule or injection form.

A known method of obtaining an injectable form of the phospholipid preparation "Phosphogliv", characterized in that the emulsion of plant phospholipids in an aqueous solution of glycyrrhizic acid or its pharmaceutically acceptable salt is mixed with an aqueous solution of a hydrocarbon, which is used lactose, maltose and / or isomaltose, at pH 6, 5-7.5 and the resulting emulsion-dispersion system is subjected to homogenization at a pressure of 800-1200 bar, followed by preliminary filtration, sterilizing filtration and freeze-drying th (RU 2304430, A61K 9/127, 20.02.2007).

A granular dosage form of a phospholipid preparation is known for the treatment and prevention of liver diseases, lipid metabolism disorders and restoration of liver function after intoxication, encapsulated in vegetable phospholipids containing 75-98% phosphatidylcholine, glycyrrhizic acid or its pharmaceutically acceptable salt and excipients, in the quality of which is used microcrystalline cellulose, calcium carbonate, calcium stearate and talc (RU 2304431, A61K 9/48 03/10/2007).

The objective of this study is to create a more effective dosage form of a phospholipid preparation for oral administration.

In recent years, special attention has been paid to phospholipid nanoparticles - colloidal drug carriers, the effectiveness of which is significantly affected by their size (less than 100 nm). Phospholipid nanoparticles (liposomes, micelles) are biodegradable, biologically inert, do not cause allergic, antigenic or pyrogenic reactions. The surface of lipid nanoparticles in comparison with other particles is easily modified to ensure directivity of delivery.

From the point of view of oral drug delivery, lipids play the role of components of various liquid oils and dispersions, which should increase the solubility and bioavailability of drug compounds.

Our studies have shown that the nanoform of a drug containing plant phospholipids, glycyrrhizic acid or its salts and carbohydrates is more effective when used orally for the treatment of liver diseases compared to the previously developed capsule form of this drug. Such a high effectiveness of the drug is due to its unique form (phospholipid nanoparticles), which has a significantly positive effect on absorption and pharmacokinetics.

Our studies have shown that in the treatment of a number of liver diseases, the intravenous administration of the drug “Phosphogliv” can be replaced by its use per os. The social significance and economic efficiency of such a replacement is not in doubt.

Firstly, studies have confirmed that the oral form, in contrast to the capsule form, consists of liposomal nanoparticles 30-50 nm in size and the content of active substances in it is much higher than in the capsule form: phospholipids by 7.69 times and glycyrate by 5.71 times.

Secondly, the use of the oral form is possible at home.

Thirdly, the cost of the product is reduced by reducing the requirements for cleanliness of premises, equipment, raw materials and water (the stage of sterilizing filtration is eliminated, the steam generator is excluded from the technological scheme, the installation for receiving water for injection, the rate of air exchange is reduced, and energy costs are reduced due to the transition from a three-stage for two-stage ventilation and the exclusion of fine filters).

In accordance with the invention, an oral dosage form of a phospholipid preparation for the prevention and treatment of liver diseases, impaired lipid metabolism and restoration of liver function after intoxication in the form of nanoparticles with a diameter of 30-50 nm, containing plant phospholipids with a phosphatidylcholine content of 75-98%, glycyrrhizic acid or its pharmaceutically acceptable salt and carbohydrate, with a total content of phospholipids and glycyrrhizic acid or its pharmaceutically acceptable salt of 2-80 wt.% and mass co fosoflipidov wearing and glycyrrhizic acid or a pharmaceutically acceptable salt thereof is not greater than 4: 1. As a carbohydrate, the dosage form contains maltose, lactose and / or isomaltose. Also described is a method of obtaining an oral dosage form of a phospholipid preparation for the prevention and treatment of liver diseases, lipid metabolism disorders and restoration of liver function after intoxication in the form of nanoparticles with a diameter of 30-50 nm, containing plant phospholipids containing 75-98% phosphatidylcholine, glycyrrhizic acid or its a pharmaceutically acceptable salt and carbohydrate, with a total content of phospholipids and glycyrrhizic acid or its pharmaceutically acceptable salt, 2-80 wt.% and the mass ratio and phospholipids and glycyrrhizic acid or its pharmaceutically acceptable salt is not more than 4: 1, namely, that the emulsion of plant phospholipids in an aqueous solution of glycyrrhizic acid or its pharmaceutically acceptable salt is mixed with an aqueous solution of carbohydrate, which is used as lactose, maltose and / or isomaltose, at a pH of 6.5-7.5, and the resulting emulsion-dispersion system is subjected to 5-22 cycles of homogenization at a pressure of 800-1200 bar, followed by freeze-drying.

Example

5.12 g of ground phospholipid with a phosphatidylcholine content of at least 80% are charged into a round bottom flask under reflux; 2.6 g of glycyrate; 19.5 g of maltose and 10 ml of purified water. Intensively mixed using a highly efficient propeller stirrer in a stream of nitrogen for 10-15 minutes. The total volume of the mixture was adjusted to 200 ml and the resulting primary emulsion was passed through a high pressure homogenizer (Mini-Lab model 7.30 VH, Rannie, Denmark) under a pressure of 800 bar 5-7 times. Get a homogeneous liposomal emulsion with the following parameters:

- transparent slightly opalescent liquid;

- light transmission of the sample at 660 nm (or water transparency) of at least 60%;

- liposome diameter 30-50 nm.

The resulting liposomal emulsion is poured into a stainless steel tray with a layer thickness of 1.5-2.0 cm and frozen at a temperature of -25 ° C. The frozen sample was freeze dried (LSL SECFROID, LYOLAB F, Germany) for 48 hours.

The resulting lyophilized mass is unloaded from the tray, crushed to a state of fine crystalline granular mass and Packed 2.5 g in plastic containers or packaging type "Sachet".

The hepatoprotective properties of the injectable form of the drug “Phosphogliv” when administered orally were studied in conditions of acute experimental hepatitis caused by the introduction of carbon tetrachloride (CCI ₄ ). The results of the studies are presented in figures 1-3.

As can be seen from figures 1-3, in rats with toxic hepatitis, the administration of the oral form of Phosphogliv (FG) leads to a faster recovery of hepatic enzymes: alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), which confirms the effectiveness of the drug in a preclinical experiment.

Claims (3)

1. An oral dosage form of a phospholipid preparation for the prevention and treatment of liver diseases, lipid metabolism disorders and restoration of liver function after intoxication in the form of nanoparticles with a diameter of 30-50 nm, containing plant phospholipids with a phosphatidylcholine content of 75-98%, glycyrrhizic acid or its pharmaceutically acceptable salt and carbohydrate with a total content of phospholipids and glycyrrhizic acid or its pharmaceutically acceptable salt of 2-80 wt.% and a mass ratio of phospholipids and glycyrrhizic acid to acid or its pharmaceutically acceptable salt is not more than 4: 1. 2. The oral dosage form of the phospholipid preparation according to claim 1, containing maltose and / or isomaltose as a carbohydrate. 3. The method of obtaining an oral dosage form of a phospholipid preparation according to claim 1, characterized in that the emulsion of plant phospholipids in an aqueous solution of glycyrrhizic acid or its pharmaceutically acceptable salt is mixed with an aqueous carbohydrate solution, which is used as lactose, maltose and / or isomaltose, pH 6.5-7.5 and the resulting emulsion-dispersion system is subjected to 5-22 cycles of homogenization at a pressure of 800-1200 bar, followed by freeze-drying.

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