Preparation method for polyene phosphatidyl choline for injection

Abstract

The invention discloses a preparation method for polyene phosphatidyl choline for injection. The preparation method comprises the following steps: dissolving with a proper solvent by taking soyabean lecithin as a raw material, performing elution twice with a ternary mixed solvent consisting of multi-halogenated hydrocarbon, low carbon alcohol and water through column chromatography, and drying to obtain a product polyene phosphatidyl choline. The product obtained by the preparation method disclosed by the invention is high in phosphatidylcholine content (98.0%-99.9%, HPLC (high performance liquid chromatography) process), low in impurity content (less than 1.0% of lysophosphatidyl choline, less than 0.5% of phosphatidyl inositol, less than 0.5% of phosphatidyl ethanolamine, less than 0.2% of free fatty acid and less than 0.2% of triglyceride), and low in oxidative index (an acid value lower than 0.5, a peroxide value lower than 1.0 and methoxy phenylamine value lower than 5.0), so that the product quality reaches the quality standards of polyene phosphatidyl choline for injection.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical engineering, and in particular relates to a preparation method of polyene phosphatidylcholine for injection. Background technique [0002] Polyene phosphatidylcholine is a mixture extracted from soybeans with phosphatidylcholine (PC) as the main component. It is mainly used for adjuvant treatment of liver and gallbladder diseases in clinical practice. It is a hepatoprotective drug with a positive effect. Various types of liver diseases, such as hepatitis, chronic hepatitis, hepatic necrosis, cirrhosis, hepatic coma (including prodromal coma); fatty liver (also seen in diabetics); bile obstruction, poisoning, prevention of recurrence of gallstones; treatment before and after surgery , especially hepatobiliary surgery; pregnancy poisoning, including vomiting; psoriasis; neurodermatitis, radiation syndrome. The preparation technology of polyene phosphatidylcholine is relatively complicated. D...

AI Technical Summary

Problems solved by technology

The molecular weight of phosphatidylcholine and other phospholipids is relatively close, and it is still difficult to obtain a single phosphatidylcholine by membrane separation method, and its product content is too low to meet the requirements of injection excipients

The solvent extraction method achieves the purpose of enrichment and purification through the difference in the solubility of phosphatidylcholine in two-phase solvents, and has poor selectivity to various phospholipid impurities with very similar physical and chemical properties.

[0005] Adsorption method is a more commonly used purification method. By choosing adsorbents with different physical and chemical properties to stir and adsorb the raw material solution to be adsorbed, the effect of purification is achieved. Common adsorbents include: aluminum oxide, silica gel, etc. This method is only for Phosphatidylethanolamine (PE), acid value and other indicators have a certain adsorption effect, and it is difficult to ensure that key indicators such as content and lysophosphatidylcholine (LPC) meet the standards for injection

[0006] Silica gel column chromatography is another commonly used separation and purification method. The ratio of the stationary phase to the substance to be separated, the type and ratio of the elution solvent have a huge impact on the separation effect and impurity removal ability of column chromatography. Column chromatography The solvent and ratio selection of the method are related to the properties of the product itself and the properties of impurities. Although this method is common, there is no report on the method that can make the product quality meet the quality standards for injections and meet the requirements of commercial mass production at the same time.

[0007] There are many patents using column chromatography to purify phosphatidylcholine, among which Japanese patents JP52083912A and JP52057212A disclose silica gel column chromatography with chloroform-ethanol or chloroform-methanol as eluent to obtain the content of phosphatidylcholine 80% and 89% of the products respectively, the contents of the above two patented products are both lower than 98%, which cannot meet the requirements for injection

[0008] Chinese patent CN103073572A discloses a product with a peroxide value of 0.84, an acid value of 9.06, and a phosphatidylcholine content of 88.6%-92.1% through steps such as heating at 180°C, acetone deoiling, centrifugation, and silica gel adsorption and filtration. The high-temperature treatment of phospholipids in this patented technology will lead to the production of aldehydes and ketones (methoxyaniline value), and the purity, acid value, fatty acid and other indicators of the obtained product cannot meet the requirements of injection standards.

[0009] Chinese patent CN100500676C discloses that soybean powder phospholipid is used as raw material to extract, perform one alumina chromatography and one silica gel chromatography, and elute with low-carbon alcohol-water to obtain a product with an acid value of 8.7 and a phosphatidylcholine content of 93.4%. The phosphatidylcholine content of the obtained product is low, the acid value is high, and the indicators such as triglyceride, fatty acid, and methoxyaniline value cannot be effectively controlled

[0010] Chinese patent CN102633832A discloses a method of using silica gel column chromatography and eluting with alcohol-water to obtain products containing phosphatidylcholine with a content of 90%-97.5%, but this patent method cannot be controlled while purifying the content Triglycerides, free fatty acids and oxidation indicators meet the requirements of raw materials for injection

[0011] As reported above, the patented technical method of phosphatidylcholine column chromatography cannot control key indicators such as product impurity limit, triglyceride, fatty acid, peroxide value, and methoxyaniline value. It is difficult to apply the above technical method to injection Raw material field

At present, in the technical field of developing phosphatidylcholine for injection, there is no method for controlling physical and chemical indicators such as peroxide value and methoxyaniline value. Phosphatidylcholine itself is highly unstable, and the development of such products requires excessive reliance on Due to the freshness of starting materials and technical constraints, domestic polyene phosphatidylcholine for injection mainly relies on imports, resulting in high prices for polyene phosphatidylcholine and long delivery cycles. Polyene phosphatidylcholine preparations are not used in Development and popularization in the market

Images