CN-118873492-B - Vitamin K1Injection and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparation processes, and particularly relates to a vitamin K 1 injection and a preparation method thereof. The vitamin K 1 injection provided by the invention is prepared from active ingredient vitamin K 1 , auxiliary materials and water for injection, wherein the auxiliary materials comprise solubilizer-bile acid and phospholipid, cosolvent-alkaline reagent and pH regulator, and the mass ratio of the bile acid to the phospholipid is 0.5-0.8:1. The vitamin K 1 injection does not contain surfactant, does not need to use organic solvent in the preparation process, obtains the product with quality meeting the requirements on the premise of not increasing high equipment cost input, has the clarity, color, particle size distribution, pH value, main component content, related substance content and stability consistent with those of the original developer, obviously improves the safety of clinical use, and has huge commercialized application prospect.

Inventors

• LI LAN
• OU SU
• JIANG DEGUANG
• HU MENG
• LU YUMENG
• An ye
• DUAN YULONG
• SUN LIJIE

Assignees

• 石家庄四药有限公司

Dates

Publication Date

20260512

Application Date

20240814

Claims (3)

1. 1. The vitamin K 1 injection is characterized by being prepared from active ingredients of vitamin K 1 , auxiliary materials and water for injection; The auxiliary materials comprise solubilizer, bile acid, phospholipid, cosolvent, alkaline reagent and pH regulator, wherein the mass ratio of the bile acid to the phospholipid is 0.5-0.8:1, and the phospholipid is selected from soybean lecithin, lecithin or egg yolk lecithin; the preparation method of the vitamin K 1 injection comprises the steps of adding water for injection into a liquid preparation container, sequentially adding bile acid, phospholipid and vitamin K 1 , uniformly stirring, adding the alkaline reagent, stirring until the solution is clear, adjusting pH, fixing the volume to a full amount by the water for injection, filtering, filling and sealing, and sterilizing to obtain a vitamin K 1 injection preparation; The dosage of the vitamin K 1 is 10.0g/L, the dosage of the bile acid is 44.3-54.6 g/L, the dosage of the phospholipid is 75.6-78.8 g/L, the dosage of the alkaline reagent is 4.45-6.25 g/L, the bile acid is selected from glycocholic acid, deoxycholic acid or cholic acid, the alkaline reagent is selected from sodium hydroxide or potassium hydroxide, the pH of the injection is 5.5-6.5, and the temperature of water for injection in the preparation process is 45-80 ℃.
2. 2. The vitamin K 1 injection as defined in claim 1, wherein the stirring is by means of paddle stirring, high shear stirring or high pressure homogenization.
3. 3. The vitamin K 1 injection as claimed in claim 1, wherein the sterilization condition is sterilization at 121 ℃ for 8-15 min.

Description

Vitamin K 1 injection and preparation method thereof Technical Field The invention belongs to the technical field of pharmaceutical preparation processes, and particularly relates to a vitamin K 1 injection and a preparation method thereof. Background The neonatal gastrointestinal hemorrhage is complicated in cause, and is essentially a stress ulcer, and under the influence of stress events such as shock, infection, craniocerebral injury, asphyxia and the like, the compensation mechanism of the neuroendocrine system is activated, the excitability of the sympathetic nerve is enhanced, the release amount of catecholamine is increased, the massive secretion of gastric acid is promoted, and the gastrointestinal tract is stimulated to cause hemorrhage. At present, the mechanism of coagulation dysfunction caused by digestive tract hemorrhage is not clear, and is mostly considered to be caused by inflammatory reaction, tissue injury, insufficient blood perfusion and acidosis, so that endothelial cells are damaged, protein C is activated, and thrombin secretion is inhibited. The blood coagulation factor is lost and the blood volume is reduced due to insufficient tissue perfusion after the neonatal gastrointestinal hemorrhage, and a large amount of lactic acid is produced to cause acidosis, so that the blood coagulation dysfunction is aggravated. Vitamin K 1 deficiency bleeding is a common type of neonatal digestive tract bleeding, and due to poor placenta permeability, vitamin K 1 has low storage capacity in neonatal blood and liver, but has higher participation in the process of synthesizing blood coagulation factors by the liver, if the deficiency can lead the blood coagulation factors to be unable to carboxylate and then combine with calcium to generate blood coagulation activity, the blood coagulation process cannot be participated, and thus the blood coagulation cannot be performed. Therefore, supplementing vitamin K 1 can effectively improve the concentration and activity of vitamin K 1 -dependent coagulation factors in blood plasma, and further promote coagulation. However, vitamin K 1 belongs to the class of fat-soluble vitamins, and is insoluble in water itself. In order to be suitable for newborns, vitamin K 1 is used as an injection clinically. However, the vitamin K 1 injection on the market in China has serious adverse reaction, and researchers generally consider that the adverse reaction can be related to auxiliary agents such as cosolvent Tween-80, propylene glycol and the like contained in the injection. for this reason, there is a study to avoid using the above-mentioned cosolvent, for example, patent CN 105997869A discloses a method for preparing vitamin K 1 mixed micelle, dissolving vitamin K1, phospholipid and bile salt with organic solvent, then removing the organic solvent by freeze-drying method to obtain main powder wrapped by mixed micelle, re-dissolving, filling and sterilizing to obtain vitamin K 1 injection preparation, in which organic solvent is introduced in the preparation process, and then removing the organic solvent by freeze-drying method. Patent CN 115554241A discloses a method for preparing vitamin K 1 mixed micelle, which comprises the steps of dissolving phospholipid and bile salt by using water for injection, stirring to be semi-solid viscous, drying at 60 ℃ until the water content is less than or equal to 3%, then obtaining a mixed micelle composition by a swinging granulation process, adding cosolvent 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188, adding main medicines into the mixed micelle composition, stirring for dissolving, and filling and sterilizing to obtain vitamin K 1 injection preparation, wherein the preparation process is required to be dried at 60 ℃, and a plurality of cosolvents are introduced by using the swinging granulation technology. Patent CN 110876719A discloses a method for preparing vitamin K 1 mixed micelle, which comprises the steps of dissolving vitamin K 1, phospholipid and bile salt by using ethanol, introducing inert gas into the solution, volatilizing to remove the ethanol to obtain a semisolid mixture, adding water again for dissolution, filling and sterilizing to obtain a vitamin K 1 injection preparation, wherein the preparation process uses organic solvent ethanol. Wang Yanan is equal to 2016 in 4 in the publication of "preparation and in vitro evaluation of vitamin K 1 phospholipid/bile salt mixed micelle" of impurities, namely, vitamin K 1 and phospholipid/bile salt mixed micelle are prepared by adopting a film dispersion-ultrasonic method, and chloroform is used for dissolving the medicament and phospholipid bile salt, and after the membrane is formed by distillation under reduced pressure, water is added for dissolution to form the mixed micelle. The university of Beijing Chinese medicine and pharmacy of Hongdong et al release article "application of bile salt/phospholipid mixed micelle system in pharmac