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Novel fat-soluble vitamin mixed micelle injection and preparation method thereof

A fat-soluble vitamin, mixed micelle technology, applied in the directions of drug combination, pharmaceutical formulation, emulsion delivery, etc., can solve the problems of reduced zeta potential, high process requirements, oil-water separation, etc., achieving less use, safety, and uniform distribution. , the effect of good stability

Pending Publication Date: 2021-06-01
江苏华阳制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, it has been reported that the phospholipids used in mixed micelles are almost natural phospholipids, but the unsaturated fatty acids in natural phospholipids can lead to the formation of peroxides, so the chemical stability is not high, for example, it will cause more impurities and affect the micelles. The stability of the system is manifested in the appearance of turbidity and unclearness, the decrease of zeta potential, etc.
[0005] Problems in the current preparation technology of cholic acid+phospholipid mixed micelles: ①Almost all organic solvents appear in the preparation process, such as CN110876719A, CN102525917B, etc., use ethanol to dissolve each component, industrial scale-up production needs explosion protection, and the solvent residue of drugs needs to be strictly controlled; ② The existing preparation methods include freeze-drying and reconstitution. However, fat-soluble drugs after water removal are prone to oil droplets (cholic acid or phospholipids are liquefied), and oil-water separation may occur after reconstitution with water, making it difficult to restore to the state before lyophilization. ③ there is another film hydration method, such as CN104288110B, but vacuum distillation is required, and the equipment and process requirements for industrialized scale-up production are relatively high

Method used

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  • Novel fat-soluble vitamin mixed micelle injection and preparation method thereof
  • Novel fat-soluble vitamin mixed micelle injection and preparation method thereof
  • Novel fat-soluble vitamin mixed micelle injection and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Preparation specification is the vitamin K1 mixed micelle injection of 1ml:10mg, and the prescription of 1000 batches is as shown in table 1:

[0051] Table 1

[0052] Element Dosage Vitamin K1 10g Glycocholic acid 30g Hydrogenated Soy Lecithin 45g sodium hydroxide 4.5g Hydrochloric acid (37%w / w) 0 Water for Injection up to 1000ml

[0053] preparation steps

[0054] (1) Take by weighing prescription quantity 10% (w / w) water for injection, prepare the NaOH aqueous solution of concentration 4% (w / w);

[0055] (2) Weigh 30g of glycocholic acid and dissolve it in the solution in step (1), and separately prepare a concentration of 1% (w / w) NaOH aqueous solution and 1M aqueous hydrochloric acid solution with water for injection to adjust the pH value of the solution in step (2) to 6±0.5;

[0056] (3) Weigh 45 g of hydrogenated soybean lecithin and slowly add it to the solution in step (2), and disperse it by high-pressur...

Embodiment 2

[0062] The quality of the vitamin K1 mixed micelle injection prepared in Example 1 was compared with the commercially available imported product Konakion MM (batch number F3318F01).

[0063] The commercially available imported product Konakion MM (CHEPLAPHARMArzneimittel GmbH / Roche Pharma AG) vitamin K1 injection prescription is shown in Table 2.

[0064] Table 2 Prescription of commercially available imported product Konakion MM

[0065] Element Dosage Vitamin K1 10g Glycocholic acid 54.6g Soy lecithin 75.6g sodium hydroxide 4.6g hydrochloric acid Appropriate amount Water for Injection up to 1000ml

[0066] By comparing Table 1 and Table 2, it can be seen that the surfactant used in Example 1 of the present invention is less (Example 1: Glycocholic Acid 30g+Hydrogenated Soy Lecithin 45g, commercially available product: Glycocholic Acid 54.6g+Soy Lecithin 75.6g ), thus reducing the potential for vascular irritation of surf...

Embodiment 3

[0087] Study on the Effect of Different Stirring Processes on the Properties of Mixed Micellar Solutions

[0088] The stirring process directly affects the dispersion state of the micellar solution and thus affects the properties of the micelles. The vitamin K1 mixed micelle solution was prepared with reference to the prescription and process of Example 1. The fixed mixed micelle type was glycocholic acid+hydrogenated soybean lecithin and the ratio was 1:1.5. Different mixing processes were investigated:

[0089] ① Low-speed mixing process, the instrument is an electric mixer (Yuhua instrument), the stirring speed is 100rpm, and the constant temperature is 60°C;

[0090] ②High-speed stirring process, the instrument is SF-158 series laboratory disperser (Deli Motor), the stirring speed is 3500rpm, and the constant temperature is 60°C;

[0091]③ Microjet homogeneous shearing, the instrument is M-110EH-30 microfluidics homogenizer (Microfluidics International corporation), worki...

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Abstract

The invention relates to the field of preparation of injection preparations, in particular to a novel fat-soluble vitamin mixed micelle injection and a preparation method thereof.The novel fat-soluble vitamin mixed micelle injection is prepared from fat-soluble vitamins, cholic acid, hydrogenated phospholipid, a pH regulator and water for injection, the pH regulator is selected from one or two of sodium hydroxide or hydrochloric acid. The novel mixed micelle of the cholic acid and the hydrogenated phospholipid is prepared by adopting a microjet homogenization technology, the clinical adverse reaction is reduced by using fewer surfactants in the prescription, the safe and simple mixed micelle preparation process which only uses the water for injection as a solvent in the technology is realized, the feasibility of industrial amplification production is increased, and the production cost is reduced. A novel fat-soluble vitamin injection preparation with high safety and good stability is expected to be industrially produced.

Description

technical field [0001] The invention relates to the field of preparation of injection preparations, in particular to a novel fat-soluble vitamin mixed micelles injection and a preparation method thereof. Background technique [0002] Fat-soluble vitamins refer to vitamins that are insoluble in water but soluble in organic solvents and vegetable oils. They are substances necessary for the body to maintain normal metabolism and functions, including vitamin A (retinol), vitamin D (D2 and D3), vitamin E, Vitamin K (K1 and K2). Among them, vitamin A is a yellow flaky crystal, insoluble in glycerin and water, easily soluble in chloroform, ethanol, ether and other organic solvents and vegetable oils, prone to light and oxygen degradation, and the oxidation speed is accelerated under thermal conditions; vitamin D2 is white needle-shaped Crystal or crystalline powder, vitamin D3 is white columnar crystal or crystalline powder, insoluble in water, easily soluble in chloroform, ethano...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K47/24A61K47/28A61K45/00A61P3/02
CPCA61K9/0019A61K9/1075A61K45/00A61K47/24A61K47/28A61P3/02
Inventor 汤怀松刘世成邢臻真
Owner 江苏华阳制药有限公司