A fat-soluble vitamin injection and a preparation method thereof

Abstract

The present application relates to the technical field of pharmaceutical preparation, and discloses a fat-soluble vitamin injection and a preparation method thereof.In the present application, soybean oil, vitamin E and lecithin are mixed uniformly, and then other fat-soluble vitamins are added and mixed uniformly under the protection of inert gas; by controlling the dissolved oxygen in water for injection and the residual oxygen level in ampoule headspace, a method for preparing fat-soluble vitamin injection through one-time emulsification and conventional sterilization process is provided.The fat-soluble vitamin injection prepared by the above method has significantly improved stability, can be stored stably at 25 DEG C, and has practical significance and important social value.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, and particularly discloses a fat-soluble vitamin injection and a preparation method thereof. BACKGROUND

[0002] Fat-soluble vitamins including A, D, E and K are commonly used drugs for disease treatment. Fat-soluble vitamin injections are widely used in clinical application due to the convenience and rapidness of injection administration. However, it is well known that fat-soluble vitamins are unstable and mostly sensitive to light, moisture, heat and oxygen, and high requirements are placed on the preparation process, otherwise the product quality is difficult to guarantee.

[0003] In the prior art, in order to improve the stability of fat-soluble vitamin injections, the following means are mainly used for preparation: (1) preparation by using initial milk method: the initial milk system can effectively wrap fat-soluble vitamins in small oil droplets, so as to protect them from the influence of external environmental factors; (2) addition of metal chelating agent: the metal chelating agent can combine with trace metal ions (such as iron ions and copper ions) in the injection to form stable chelates, thereby preventing the catalytic oxidation of metal ions on fat-soluble vitamins and helping to maintain the activity and stability of vitamins; (3) sterilization at a temperature slightly lower than 121 DEG C, reduction of the storage temperature of the product. However, the product is prone to oil floating when prepared by using the initial milk method, which leads to unstable content and seriously affects the product quality; the added metal chelating agent can also complex the essential metal elements of the human body, increasing the risk of calcium or other mineral element deficiency of the human body; the reduction of the sterilization temperature does not necessarily ensure the sterile level; and the reduction of the storage temperature of the product increases the storage cost. SUMMARY

[0004] In view of the deficiencies in the prior art, the present application provides a method for preparing a fat-soluble vitamin injection by one-time emulsification and according to a conventional sterilization process, and a complex vitamin injection which can be stably stored at 25 DEG C, by adjusting the feeding sequence, controlling the dissolved oxygen in the water for injection and the residual oxygen level in the ampoule headspace.

[0005] To achieve the above-mentioned application purposes, the present application adopts the following technical solutions:

[0006] In a first aspect, the present application provides a preparation method of a fat-soluble vitamin injection, which comprises the following steps:

[0007] Step one, adding vitamin E and lecithin into soybean oil in sequence, mixing, and then adding other fat-soluble vitamins and mixing under the protection of inert gas to obtain an oil phase mixture;

[0008] Step two, mixing glycerol and water for injection and protecting under the protection of inert gas to obtain an aqueous phase mixture;

[0009] Step three, homogenizing and granulating the oil phase mixture and the water phase mixture to obtain a filling liquid;

[0010] Step four, filling and sterilizing the filling liquid to obtain a fat-soluble vitamin injection;

[0011] The dissolved oxygen in the water for injection is less than or equal to 200 ppb.

[0012] The other fat-soluble vitamins include vitamin K, vitamin D and vitamin A.

[0013] The headspace oxygen content of the ampoule is controlled to be less than or equal to 2% during the filling.

[0014] The present application provides a method for preparing a fat-soluble vitamin injection by adjusting the feeding sequence of the raw materials of soybean oil, vitamin E, lecithin and other vitamins, controlling the dissolved oxygen in the water for injection and the residual oxygen level in the headspace of the ampoule. Figure 1 The present application first dissolves tocopherol and lecithin in soybean oil, uses the oxidation difference of lecithin and different types of fat-soluble vitamins, and adjusts the feeding sequence of the raw materials to improve the stability of specific vitamins (such as vitamin A and vitamin D) during the oil phase dissolution process. Compared with the conventional preparation method of fat-soluble vitamin injection, the present application does not prepare a primary emulsion, but directly mixes the oil phase and the water phase to obtain a fine emulsion by one-off preparation, solves the problem of "oil floating", and makes the vitamin content more controllable. Since vitamin D in the oil phase is sensitive to dissolved oxygen in water, the present application controls the dissolved oxygen in the water for injection to improve the stability of vitamin D. The present application controls the residual oxygen content in the headspace of the ampoule to help maintain the stability of vitamins (especially vitamin K and vitamin A) during the sterilization process. The present application improves the existing preparation process of fat-soluble vitamin injection by adjusting the feeding sequence of the raw materials, controlling the dissolved oxygen in the water for injection and the residual oxygen level in the headspace of the ampoule. The improved method does not need to add other expensive equipment on the basis of the original equipment, and has the advantage of being suitable for popularization. In addition, the stability of the prepared fat-soluble vitamin injection product is significantly improved, and it can be stored stably at 25°C, which has practical significance and important social value.

[0015] Preferably, the inert gas includes any one of nitrogen or a noble gas; the present application takes nitrogen as an example for illustration, and the noble gas can also achieve the same effect.

[0016] Preferably, after homogenization, a fine emulsion is obtained; the particle size of the emulsion droplets is 250 nm to 500 nm.

[0017] Preferably, the pressure of the homogenization is 400 Bar to 700 Bar.

[0018] Preferably, the sterilization temperature is 121℃ and the time is 8-12 minutes.

[0019] Preferably, the fat-soluble vitamin injection contains the following components per 1000mL: Vitamin A: 0.12-0.25g, Vitamin K: 0.10-0.3g, Vitamin D: 0.5-1.5mg, Vitamin E: 0.5-1.5g, soybean oil: 99-101g, lecithin: 8-12g, glycerol: 22-25g, sodium hydroxide: 0.01-0.02g, and the rest is water for injection.

[0020] Further preferably, the Vitamin K comprises Vitamin K1;

[0021] The Vitamin D comprises Vitamin D2;

[0022] The Vitamin E comprises alpha-tocopherol.

[0023] The lecithin in the present application comprises soybean lecithin and egg yolk lecithin for injection; the Vitamin A is added in the form of Vitamin A palmitate, and the amount is calculated by converting into Vitamin A; the Vitamin E is added in the form of racemic alpha-tocopherol; the soybean oil is injection soybean oil; and the glycerol is injection soybean oil.

[0024] In a second aspect, the present application provides a fat-soluble vitamin injection prepared by the above-mentioned preparation method of fat-soluble vitamin injection.

[0025] The fat-soluble vitamin injection provided by the present application can be stored for a long time at room temperature, reduces the storage cost under the premise of maintaining the stability of the vitamin content, improves the safety of clinical use, and has important social significance and economic value. BRIEF DESCRIPTION OF DRAWINGS

[0026] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed in the embodiments will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor.

[0027] Figure 1 The process flow chart of the preparation method of the fat-soluble vitamin injection in the present application.

[0028] Figure 2 The liquid chromatogram for determination of the content of Vitamin E in Example 1 of the present application;

[0029] Figure 3Liquid chromatogram for determination of vitamin D2 content in Example 1 of the present application. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical scheme and advantages of the present application clearer, the present application will be further described in detail below with examples. It should be understood that the specific examples described herein are only used to explain the present application and not to limit the present application.

[0031] In order to better illustrate the embodiments of the present application, further examples are provided below.

[0032] In the present application, the content determination methods of vitamin A, vitamin D2 and vitamin K1 are respectively based on the methods described in the item of content determination of vitamin A, vitamin D2 injection or vitamin K1 injection in the Chinese Pharmacopoeia 2020 edition; the content determination method of vitamin E refers to the method described in the item of fat-soluble vitamin injection (I) in the Department of Pharmaceutical Standards.

[0033] The contents of different fat-soluble vitamins measured in the present application are calculated based on the content of the corresponding vitamin in the prescription amount as 100%.

[0034] Example 1

[0035] I. The present embodiment provides a preparation method of fat-soluble vitamin injection, which is specifically as follows:

[0036] Step one, take 100g of soybean oil, 1.0g of alpha-tocopherol and 12g of egg yolk lecithin, heat to 70℃ and stir for 30min to dissolve; then add 0.1g of vitamin K1, 0.6mg of vitamin D2 and 0.2g of vitamin A, stir under nitrogen protection, dissolve uniformly at 70℃, get oil phase mixture I;

[0037] Step two, take 800mL of water for injection with dissolved oxygen of 180ppb, add 22.5g of glycerol and 0.01g of sodium hydroxide and mix uniformly, protect with nitrogen, get water phase mixture I;

[0038] Step three, introduce the oil phase mixture I and the water phase mixture I into a homogenizer, homogenize once at 70℃ and 400Bar pressure, get fine emulsion with average emulsion particle size of 486nm and milky white color, then homogenize the whole particle once, filter with 5μm and 1μm polyether sulfone, get filling liquid I;

[0039] Step four, fill the filling liquid I and control the residual oxygen in the ampoule headspace to be ≤1.8%, sterilize at 121℃ for 10min, get fat-soluble vitamin injection I.

[0040] II. The present embodiment investigates the related indexes of the oil phase mixture I, and the specific content is as follows:

[0041] The newly prepared oil phase mixture I was sampled and analyzed for α-tocopherol, vitamin K1, vitamin D2, and vitamin A after 15 min and 45 min, respectively. The liquid chromatogram for the determination of the content of vitamin E is shown in Figure 2 The liquid chromatogram for the determination of the content of vitamin D2 is shown in Figure 3 The specific results are shown in Table 1.

[0042] Table 1

[0043]

[0044] Note: The content of vitamins is 100% based on the prescription amount.

[0045] In a third embodiment, the fat-soluble vitamin injection I was also subjected to long-term sample inspection under the condition of 25°C ± 2°C and light shielding. The content of each vitamin during the inspection period is shown in Table 2 below.

[0046] Table 2

[0047]

[0048] Note: The content of vitamins is 100% based on the prescription amount.

[0049] As can be seen from the data in Table 2, the fat-soluble vitamin injection I prepared in this embodiment is stable, with the content of the four vitamins being in the range of 98.3% to 102.1% after 24 months of inspection under the condition of 25°C ± 2°C.

[0050] Example 2

[0051] This embodiment provides a preparation method of a fat-soluble vitamin injection, which is as follows.

[0052] Step 1: 99 g of soybean oil, 1.5 g of α-tocopherol, and 10 g of egg yolk lecithin were heated to 75°C and stirred for 20 min to dissolve; then 0.2 g of vitamin K1, 1 mg of vitamin D2, and 0.12 g of vitamin A were added, and stirring was performed under nitrogen protection, and the mixture was dissolved uniformly at 75°C to obtain an oil phase mixture II;

[0053] Step 2: 800 mL of water for injection with a dissolved oxygen content of 120 ppb was obtained, 25 g of glycerol and 0.015 g of sodium hydroxide were added and uniformly mixed, and nitrogen protection was performed to obtain an aqueous phase mixture II;

[0054] Step 3: The oil phase mixture I and the aqueous phase mixture II were introduced into a homogenizer, and homogenization was performed once at 75°C and a pressure of 600 Bar to obtain a fine emulsion with an average emulsion particle size of 304 nm and a milky white color, and then homogenization was performed once to obtain a whole particle, which was filtered through 5 μm and 1 μm polyether sulfone to obtain a filling liquid II.

[0055] Step four, the filling liquid II is filled and controlled ampoule headspace residual oxygen ≤1.5%, sterilized at 121℃ for 8min, to get the fat-soluble vitamin injection II.

[0056] The example also carried out long-term sample investigation of the fat-soluble vitamin injection II under 25℃±2℃, light shielding condition, wherein the vitamin content results during the investigation are shown in Table 3 below.

[0057] Table 3

[0058]

[0059] Note: taking the vitamin content of the prescription amount as 100%.

[0060] From the data of Table 3, the fat-soluble vitamin injection II prepared in the example is stored at 25℃±2℃, after 24 months of investigation, the content of the four vitamins is in the range of 98.2%~101.1%, which is relatively stable.

[0061] Example 3

[0062] The example provides a preparation method of fat-soluble vitamin injection, which is specifically as follows:

[0063] Step one, take 101g of soybean oil, 0.5g of α-tocopherol and 8g of soybean lecithin, heat to 80℃ and stir for 10min to dissolve; then add 0.3g of vitamin K, 0.15mg of vitamin D2 and 0.25g of vitamin A, stir under nitrogen protection, dissolve uniformly at 80℃, to get oil phase mixture III;

[0064] Step two, take 800mL of water for injection with 200ppb of dissolved oxygen, add 22g of glycerol and 0.02g of sodium hydroxide and mix uniformly, protect with nitrogen, to get water phase mixture III;

[0065] Step three, introduce the oil phase mixture III and the water phase mixture III into a homogenizer, homogenize once at 80℃ and 700Bar pressure, to get fine emulsion with average emulsion particle size of 262nm, milky white, then homogenize for 2 times, filter with 5μm and 1μm polyether sulfone, to get filling liquid III;

[0066] Step four, the filling liquid III is filled and controlled ampoule headspace residual oxygen ≤1.7%, sterilized at 121℃ for 12min, to get fat-soluble vitamin injection III.

[0067] The example also carried out long-term sample investigation of the fat-soluble vitamin injection III under 25℃±2℃, light shielding condition, wherein the vitamin content results during the investigation are shown in Table 4 below.

[0068] Table 4

[0069]

[0070] Note: Vitamin content is 100% of the prescribed amount.

[0071] From the data in Table 4, it can be seen that the fat-soluble vitamin injection III prepared in this embodiment is stable, with the content of the four vitamins being in the range of 98.0% to 101.7% after 24 months of observation at 25°C ± 2°C.

[0072] Comparative Example 1

[0073] This comparative example provides a preparation method of a fat-soluble vitamin injection, which is basically the same as that of Example 1, except that the order of adding the raw materials in step one is different, as follows:

[0074] Step one: 100 g of soybean oil and 12 g of egg yolk lecithin were heated to 70°C and stirred for 30 min to dissolve; then 1.0 g of α-tocopherol, 0.1 g of vitamin K1, 0.6 mg of vitamin D2, and 0.2 g of vitamin A were added, and stirred under nitrogen protection, and dissolved uniformly at 70°C to obtain oil phase mixture pair I; the parameters of steps two to four were the same as those of Example 1.

[0075] The newly prepared oil phase mixture pair I was sampled and analyzed for α-tocopherol, vitamin K1, vitamin D2, and vitamin A at 15 min and 45 min, respectively, and the specific results are shown in Table 5.

[0076] Table 5

[0077]

[0078] Note: Vitamin content is 100% of the prescribed amount.

[0079] Comparative Example 2

[0080] This comparative example provides a preparation method of a fat-soluble vitamin injection, which is basically the same as that of Example 1, except that the order of adding the raw materials in step one is different, as follows:

[0081] Step one: 100 g of soybean oil was heated to 70°C and stirred for 30 min to dissolve; then 12 g of egg yolk lecithin, 1.0 g of α-tocopherol, 0.1 g of vitamin K1, 0.6 mg of vitamin D2, and 0.2 g of vitamin A were added, and stirred under nitrogen protection, and dissolved uniformly at 70°C to obtain oil phase mixture pair II; the parameters of steps two to four were the same as those of Example 1.

[0082] The content of α-tocopherol, vitamin K1, vitamin D2 and vitamin A in the freshly prepared oil phase mixture was determined after 15 min and 45 min, respectively, and the results are shown in Table 6.

[0083] Table 6

[0084]

[0085] Note: The content of vitamins is 100% based on the prescription amount.

[0086] As can be seen from the comparison of the data in Tables 1, 5 and 6, the change in the content of each vitamin in the intermediate obtained in Example 1 is significantly better than that in Comparative Examples 1 and 2, which may be due to the synergistic antioxidant effect of soybean oil, tocopherol and lecithin, which consumes the oxygen that may exist in the oil and protects the stability of vitamins, thereby ensuring the stability of the material.

[0087] Comparative Example 3

[0088] This comparative example provides a preparation method of a fat-soluble vitamin injection, which is basically the same as that of Example 1, except that the dissolved oxygen in the water for injection is controlled at 400 ppb in step two, and the remaining steps and parameters are the same as those of Example 1. The fat-soluble vitamin injection prepared is denoted as fat-soluble vitamin injection Comparative Example III. It is determined that the content of vitamin D2 in the obtained fat-soluble vitamin injection Comparative Example III is 92.4% (wherein the content of vitamin D2 is 100% based on the prescription amount).

[0089] Comparative Example 4

[0090] This comparative example provides a preparation method of a fat-soluble vitamin injection, which is basically the same as that of Example 1, except that the dissolved oxygen in the water for injection is controlled at 500 ppb in step two, and the remaining steps and parameters are the same as those of Example 1. The fat-soluble vitamin injection prepared is denoted as fat-soluble vitamin injection Comparative Example IV. It is determined that the content of vitamin D2 in the obtained fat-soluble vitamin injection Comparative Example IV is 91.6% (wherein the content of vitamin D2 is 100% based on the prescription amount).

[0091] Comparative Example 5

[0092] This comparative example provides a preparation method of a fat-soluble vitamin injection, which is as follows:

[0093] (1) The vitamin A, vitamin D2, vitamin E, vitamin K1, soybean oil for injection, egg yolk lecithin and glycerol for injection were weighed according to the prescription provided in Example 1 of the present application and prepared for use;

[0094] (2) Preparation of the water phase: about 80% of the total amount of water for injection was added into a stainless steel tank, and the prescribed amount of glycerin for injection was added while stirring;

[0095] (3) Preparation of the oil phase: the prescribed amount of soybean oil for injection was added into another stainless steel tank, and a nitrogen stream was introduced, and the prescribed amount of vitamin A, vitamin D2, vitamin E, vitamin K1 and egg yolk lecithin was added, and stirring was performed until the egg yolk lecithin was dissolved;

[0096] (4) Preparation of the initial emulsion: a nitrogen stream was introduced, and the oil phase was slowly added into the high-speed stirred water phase, and high-speed stirring was continued for at least 5 minutes, and then the pH value of the solution was adjusted to be within the range of 8.0±0.2 using a 1M sodium hydroxide solution, and then the initial emulsion was diluted to the theoretical amount, and stirring was performed until uniformity was achieved;

[0097] (5) A nitrogen stream was introduced, and the initial emulsion was subjected to low-pressure homogenization 4 times at 5MPa, and then was subjected to high-pressure homogenization once at 30MPa, and then was cooled, and then was filtered using a filter membrane with a pore size of 10μm, and then a filtrate was obtained.

[0098] (6) The filtrate was filled into 10ml transparent glass ampoules, and then was sealed after being filled with nitrogen, and then was subjected to moist heat sterilization at 118℃ for 25min, and then was subjected to lamp inspection, and then the fat-soluble vitamin injection No. V was obtained.

[0099] In the preparation process of the fat-soluble vitamin injection No. V, it was found that the initial emulsion prepared in step (4) was unstable, and when the homogenization time was 30min, a small amount of oil stars were found on the milky white liquid surface, and the particle size was 1-3μm; when the homogenization time was 60min, a small amount of oil droplets were found on the milky white liquid surface, and the particle size was 5-10μm. According to the method recorded in the comparative document, oiling was extremely easy to occur during the production process, and the oil contained vitamins, and meanwhile, the oil could not enter the human body, otherwise, great safety hazards would be caused. According to the preparation method provided in Example 1 of the present application, the obtained emulsion droplets had a nanoscale particle size, and the distribution range was narrow, and the emulsion was more stable, and the product quality could be more controlled.

[0100] The above merely describes preferred embodiments of the present application, and is not intended to limit the present application, and any modification, equivalent replacement or improvement made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing a fat-soluble vitamin injection, characterized by, The preparation method comprises the following steps: Step one, adding vitamin E and lecithin into soybean oil in sequence, mixing, then adding other fat-soluble vitamins, mixing under the protection of inert gas, and obtaining oil phase mixture; Step two, mixing glycerol and water for injection under the protection of inert gas, and obtaining water phase mixture; Step three, homogenizing and granulating the oil phase mixture and the water phase mixture, and obtaining filling liquid; Step four, filling and sterilizing the filling liquid, and obtaining fat-soluble vitamin injection; The dissolved oxygen in the water for injection is less than or equal to 200 ppb; The other fat-soluble vitamins comprise vitamin K, vitamin D and vitamin A; The vitamin K is vitamin K1, the vitamin D is vitamin D2, and the vitamin E is α-tocopherol; The headspace oxygen content of the ampoule is controlled to be less than or equal to 2% during filling; The fat-soluble vitamin injection comprises the following components in an amount of 1000 mL: vitamin A 0.12 g-0.25 g, vitamin K 0.10 g-0.3 g, vitamin D 0.5 g-1.5 mg, vitamin E 0.5 g-1.5 g, soybean oil 99 g-101 g, lecithin 8 g-12 g, glycerol 22 g-25 g, sodium hydroxide 0.01 g-0.02 g, and the rest is water for injection.

2. The method for preparing a fat-soluble vitamin injection solution according to claim 1, characterized by, The inert gas comprises any one of nitrogen or rare gas.

3. The method for preparing the fat-soluble vitamin injection solution as described in claim 1, characterized in that, The particle size of the emulsion droplet after homogenization is 250 nm-500 nm.

4. The method for preparing the fat-soluble vitamin injection solution as described in claim 1, characterized in that, The pressure of homogenization is 400 Bar-700 Bar.

5. The method for preparing the fat-soluble vitamin injection solution as described in claim 1, characterized in that, The sterilization temperature is 121 ℃, and the sterilization time is 8 min-12 min.

6. A fat-soluble vitamin injection solution characterized in that, The fat-soluble vitamin injection is prepared by the preparation method of any one of claims 1-5.

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